Amicus Curiae Brief — Zubik v. Burwell, 136 S. Ct. 444 (2015) (No. 14-1418)

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8, 14-1453, 14-1505,

15-35, 15-105, 15-119 & 15-191

| SESE ——————

IN THE

Supreme Court of the United States

DAVID A. ZUBIK, ET AL.,

Petitioners,

Vv.

SYLVIA BURWELL, ET AL.,

Respondents.

[CAPTIONS CONTINUED ON INSIDE COVER]

On Writs of Certiorari to the

United States Courts of Appeals for the

Third, Fifth, Tenth, and D.C. Circuits

BRIEF OF THE OVARIAN CANCER RESEARCH

FUND ALLIANCE, ITS PARTNER MEMBERS AND

SCIENTIFIC ADVISORS AS AMICI CURIAE IN

SUPPORT OF RESPONDENTS

JESSICA L. ELLSWORTH*

Counsel of Record

JESSICA B. LIVINGSTON MICHELLE A. KISLOFF

HOGAN LOVELLS US LLP ANDREWS. FURLOW

1200 Seventeenth Street LOWELL M. ZETA

Buite 1500 HOGAN LOVELLS US LLP

Denver, CO 80202 555 Thirteenth Street, N.W.

Washington, D C. 20004

(202) 637-5886

jessica.ellsworth@hoganlovells.com

Counsel for Amici Curiae

M¥usonw-Eres Prinnnc Co., Inc. — (202) 789-0096 — WaASHINGTON.D C 20002

PRIESTS FOR LIFE, ET AL., Petitioners,

DEPARTMENT OF HEALTH & HUMAN SERVICES, ET

AL., Respondents.

ROMAN CATHOLIC ARCHBISHOP OF WASHINGTON, ET

AL., Petitioners,

Vv.

SYLVIA BURWELL, ET AL., Respondents.

EAST TEXAS BAPTIST UNIVERSITY, ET AL., Petition-

ers,

SYLVIA BURWELL, ET AL., Respondents.

LITTLE SISTERS OF THE POOR HOME FOR THE AGED,

DENVER , COLORADO, ET AL., Petitioners,

SYLVIA BURWELL, ET AL., Respondents.

SOUTHERN NAZARENE UNIVERSITY, ET AL., Petition-

ers,

SYLVIA BURWELL, ET AL., Respondents.

GENEVA COLLEGE, Petitioner,

Vv.

SYLVIA BURWELL, ET AL., Respondents.

TABLE OF CONTENTS

Page

ee Ce ictesccsccctscnsscncsssesccnsnenesenies ix

STATEMENT OF INTEREST .................ccccccssssseeseees 1

SUMMARY OF ARGUMENT.....................cccceeseeeeeeeees 3

IE tacncetaiiateinitiannpnnciidcnntetnciiiaiemeasiatinmmncmentiis 5

I. PETITIONERS’ RELIGIOUS BELIEFS ARE

NOT SUBSTANTIALLY BURDENED BY

THE ACCOMMODATION REGULATIONS .....5

Il. THE ACCOMMODATION REGULATIONS

FURTHER A COMPELLING PUBLIC

HEALTH INTEREST BY ENSURING

ACCESS TO CANCER PREVENTIVE

A. Contraceptives provide significant medi-

cal benefits separate from prevention of

TID isccsisicintchiuntiteendtenteseititinnduiiatiaaaiiianienniaiiienn 9

B. The cancer-prevention benefits of contra-

ceptives played a key role in the govern-

ment’s decision to include the contracep-

tive coverage provision in the ACA.............. 17

C. Ensuring access to cancer-prevention

health benefits is a compelling govern-

ESTATES RE Sart nee 19

IE vserenccenscncsnmnentinetinssnansnimnimmetanmeccmnnses 26

LIST OF AMICI PARTNER MEMBERS

AND SCIENTIFIC ADVISORS OF THE

(i)

TABLE OF CONTENTS—Continued

OVARIAN CANCER RESEARCH FUND

APPENDIX A— C. La Vecchia & S. Frances-

chi, Oral Contraceptives and Ovarian

Cancer,

8 Eur. J. Cancer Prevention 297 (1999)................. la

APPENDIX B— Aminah Jatoi et. al., Prior

Oral Contraceptive Use in Ovarian Cancer

Patients: Assessing Associations with Over-

all and Progression-Free Survival,

15 BMC Cancer 711 (2015) ..............cccscceeseeseeeeees 19a

APPENDIX C— M. T. Faber et al., Oral Con-

traceptive Use and Impact of Cumulative

Intake of Estrogen and Progestin on Risk of

Ovarian Cancer,

24 Cancer Causes Control 2197 (2019)................ 33a

APPENDIX D— Laura J. Havrilesky et al.,

Oral Contraceptive Pills as Primary Preven-

tion for Ovarian Cancer,

122 Obstetrics & Gynecology 139 (2013)............. 55a

APPENDIX E— V. Beral et al., Ovarian

Cancer and Oral Contraceptives: Collabora-

tive Reanalysis of Data from 45 Epidemiolog-

ical Studies Including 23,257 Women with

TABLE OF CONTENTS—Continued

Ovarian Cancer and 87,303 Controls,

BE Titer BI GI cnceececcccccncccccccccccccccccccscscenses T4a

APPENDIX F— Julia B. Greer et al., Andro-

genic Progestins in Oral Contraceptives and

the Risk of Epithelial Ovarian Cancer,

105 Obstetrics & Gynecology 731 (2005)........... 100a

APPENDIX G— Roberta B. Ness et al., Risk of

Ovarian Cancer in Relation to Estrogen and

Progestin Dose and Use Characteristics of

Oral Contraceptives,

152 Am. J. Epidemiology 233 (2000).................. 120a

APPENDIX H— Harvey A. Risch et al., Parity,

Contraception, Infertility, and the Risk of

Epithelial Ovarian Cancer,

140 Am. J. Epidemiology 585 (1994).................. 139a

APPENDIX I— Susan E. Hankinson et al., A

Quantitative Assessment of Oral Contracep-

tive Use and Risk of Ovarian Cancer,

80 Am. J. Obstetrics & Gynecology 708

APPENDIX J— Alice S. Whittemore et al.,

Characteristics Relating to Ovarian Cancer

Risk: Collaborative Analysis of 12 US Case-

Control Studies — II. Invasive Epithelial

TABLE OF CONTENTS—Continued

Ovarian Cancers in White Women,

136 Am. J. Epidemiology 1184 (1992)................ 174a

APPENDIX K— The Cancer and Steroid

Hormone Study of the Ctrs. for Disease Con-

trol and the Nat’! Inst. of Child Health and

Human Dev., The Reduction in Risk of Ovar-

ian Cancer Associated with Oral-

Contraceptive Use,

316 New Eng. J. Med. 650 (1987) ...............000000- 200a

APPENDIX L— Xiao Ou Shu et al., Popula-

tion-Based Case-Control Study of Ovarian

Cancer in Shanghai,

49 Cancer Res. 3670 (1989) ...........ccccccccsescesseeeeee 217a

APPENDIX M— A. Antoniou et al., Average

Risks of Breast and Ovarian Cancer Associ-

ated with BRCA 1 or BRCA 2 Mutations

Detected in Case Series Unselected for Fami-

ly History: A Combined Analysis of 22 Stud-

1es,

72 Am. J. Hum. Genetics 1117 (2003) ............... 235a

APPENDIX N— S. lodice et al., Oral Contra-

ceptive Use and Breast or Ovarian Cancer

Risk in BRCA1/2 Carriers: A Meta-Analysis,

46 Eur. J. Cancer 2275 (2010)..............ccccecceeeeee 267a

TABLE OF CONTENTS—Continued

Page

APPENDIX O— J. Brian Szender and

Shashikant B. Lele, Fallopian Tube Ligation

or Salpingectomy as Means for Reducing

Risk of Ovarian Cancer,

17 Am. Med. Ass’n J. Ethics 843 (2015) ............ 288a

APPENDIX P— Victoria Sopik et al., Why

Have Ovarian Cancer Mortality Rates De-

clined? Part I. Incidence,

138 Gynecologic Oncology 741 (2015)................ 298a

APPENDIX Q— Collaborative Group on

Epidemiological Studies on Endometrial

Cancer, Endometrial Cancer and Oral Con-

traceptives: An Individual Participant Meta-

analysis of 27,276 Women with Endometrial

Cancer from 36 Epidemiological Studies,

16 Lancet Oncology 1061 (2015) ..............0.00000e. 324a

APPENDIX R— Robin M. Beining et al., Meta-

Analysis of Intrauterine Device Use and Risk

of Endometrial Cancer,

18 Annals Epidemiology 492 (2008)................... 349a

APPENDIX S— D. Hubacher, Noncontracep-

tive Health Benefits of Intrauterine Devices:

A Systematic Review,

57 Obstetrics & Gynecology Surv. 120 (2002) ...364a

TABLE OF CONTENTS—Continued

APPENDIX T— Abraham Benshushan et al.,

IUD Use and the Risk of Endometrial Can-

cer,

105 Eur. J. Obstetrics & Gynecology & Re-

prod. Biology 166 (2002) ...............:csscesseeeeseees

APPENDIX U— Deirdre A. Hill et al., Endo-

metrial Cancer in Relation to Intra-Uterine

Device Use,

70 Int'l] J. Cancer 278 (1997) ..............cccccceeeeeeee

APPENDIX V— Susan Sturgeon et al., Intrau-

terine Device Use and Endometrial Cancer

Risk,

26 Int'l J. Epidemiology 496 (1997) .................

APPENDIX W— F. Parazzini et al., Jntrauter-

ine Device Use and Risk of Endometrial

Cancer,

70 Brit. J. Cancer 672 (1994) .............cccccceeeee.

APPENDIX X— Xavier Castellsagué et al.,

Intra-uterine Contraception and the Risk of

Endometrial Cancer,

54 Int'l J. Cancer 911 (1993) .............cccccceeeeeeee

APPENDIX Y— Roberta B. Ness et al., Con-

traception Methods, Beyond Oral Contracep-

tives and Tubal Ligation, and Risk of Ovari-

Page

vii

TABLE OF CONTENTS—Continued

an Cancer,

21 Annals Epidemiology 188 (2011)................... 442a

APPENDIX Z— Daniel W. Cramer et al.,

Conditions Associated With Antibodies

Against the Tumor-Associated Antigen

MUC1 and Their Relationship to Risk for

Ovarian Cancer,

14 Cancer Epidemiology, Biomarkers & Pre-

REE a ee 459a

APPENDIX AA— Xavier Castellisagué et al.,

Intrauterine Device Use, Cervical Infection

with Human Papillomavirus, and Risk of

Cervical Cancer: A Pooled Analysis of 26

Epidemiological Studies,

12 Lancet Oncology 1023 (2011) ...................000. 480a

APPENDIX BB— Adam Sonfield et al., Impact

of the Federal Contraceptive Coverage

Guarantee on Out-of-Pocket Payments for

Contraceptives: 2014 Update,

91 Contraception 44 (2015) ................ccccccceeeeeees 501la

APPENDIX CC— Jonathan M. Bearak et al.,

Changes in Out-of-Pocket Costs for Hormo-

nal IUDs After Implementation of the Af-

fordable Care Act: An Analysis of Insurance

TABLE OF CONTENTS—Continued

Benefit Inquiries,

93 Contraception 139 (2016) .................c.00eee0e0- 512a

APPENDIX DD— Nora V. Becker & Daniel

Polsky, Women Saw Large Decrease in Out-

of-Pocket Spending for Contraceptives After

ACA Mandate Removed Cost Sharing,

34 Health Aff. 1204 (2015) .................ccccceeceeeseees 528a

TABLE OF AUTHORITIES

Page

CASES:

Burwell v. Hobby Lobby Stores, Inc.,

134 S. Ct. 2751 (2014)..............-.0..2.. 2, 9, 20, 21, 22

E. Tex. Baptist Univ. v. Burwell,

793 F.3d 449 (Sth Cir. 2015)...................scccsseeeseees 5

Eden Foods, Inc. v. Sebelius,

733 F.3d 626 (6th Cir. 2013)...0.000000.e cece eee 2

Geneva Coll. v. Sec’y U.S. Dep’t of

Health and Human Servs.,

TTB P.Bb GBB GIG Glo. BORD ..n-<cocccnceececeeceeccccceseccese 5

Gilardi v. Dep’t of Health & Human

Servs.,

733 F.3d 1208 (D.C. Cir. 2013) ...........000....000 2, 22

Little Sisters of the Poor Home for the

Aged v. Burwell,

794 F.3d 1151 (10th Cir. 2015) 0.0.0.0... cece 5

Priests for Life v. U.S. Dep’t of Health

& Human Servs.,

772 F.3d 229 (D.C. Cir. 2014).............. 5, 19, 20, 22

Real Alternatives, Inc. v. Burwell,

__ F.3d __, No. 1:15-cv-0105,

2015 WL 8481987 (M.D. Pa.

I a 20

Univ. of Notre Dame v. Burwell,

786 F.3d 606 (7th Cir. 2015)......0000000. cee 21

STATUTES:

es i i crccseevicnctccsveneeceresassovions 18

TABLE OF AUTHORITIES—Continued

Page

eg EE 5

REGULATIONS:

Interim Final Rules Relating to Coverage

of Preventive Services Under the

Affordable Care Act,

75 Fed. Reg. 41,726 (July 19, 2010) .................... 18

Coverage of Certain Preventive Services

Under the Affordable Care Act,

78 Fed. Reg. 39,870 (July 2, 2013) .................. 7, 20

OTHER AUTHORITIES:

American Cancer Soc’y, Cancer Facts &

Figures 2015, http://www.cancer.org/acs/

groups/content/@editorial/documents/docu

ment/acspce-044552.pdf (last visited Feb.

ETN AE ee ee 10

Guttmacher Institute, State Policies in Brief

(as of February 1, 2016): Insurance Cover-

age of Contraceptives, http://www.gutt

macher.org/statecenter/spibs/spib_ICC.pdf

(last visited Feb. 17, 2016)...............cccccceeceeeseeeees 23

HRSA, HHS, Women’s Preventive Services

Guidelines, http://www.hrsa.gov/womens

guidelines/ (last visited Feb. 17, 2016).................. x

TABLE OF AUTHORITIES—Continued

IOM, Clinical Preventive Services for Wom-

en: Closing the Gaps (2011), https://

iom.nationalacademies.org/Reports/20 1 1/C

linical-Preventive-Services-for-Women-

Closing-the-Gaps.aspx (last visited Feb.

Se eee iceuninepcinniscnsennisinennienttnianiipsinnpsanensenteticin

Rachel K. Jones, Guttmacher Institute,

Beyond Birth Control: The Overlooked

Benefits of Oral Contraceptive Pills (2011),

http://www.guttmacher.org/pubs/Beyond-

Birth-Control.pdf (last visited Feb. 17,

St iesetaheedstiniiiebinidendieintiniingssapinnibaiebnniediiieneees

NCI, A Snapshot of Ovarian Cancer,

http://www.cancer.gov/research/progress/s

napshots/ovarian (last visited Feb. 17,

aril isenietenaideinsccninebesuibnieianeaninnnatinibinibiantispetinnnnd

NCI, Endometrial Cancer Prevention — For

Health Professionals (PDQ®), http://www.

cancer.gov/types/uterine/hp/endometrial-

prevention-pdq (last visited Feb. 17, 2016)....

NCI, Ovarian, Fallopian Tube, and Primary

Peritoneal Cancer Prevention (PDQ®),

http://www.cancer.gov/types/ovarian/

patient/ovarian-prevention-pdq#section/all

(last visited Feb. 17, 2016).....................00000-+-

Page

xii

TABLE OF AUTHORITIES—Continued

Page

NCI, The Genetics of Cancer,

http://www.cancer.gov/about-cancer/caus-

es-prevention/genetics (last visited Feb.

ne Maan asdineinsncuebiitnlshdaiceansaidapiinabtaaiibiininnibddesindsnn

NCI, Surveillance, Epidemiology, and End

Results Program, Stat Fact Sheets: Endo-

metrial Cancer, http://seer.cancer.gov/stat-

facts/html/corp.html (last visited Feb. 17,

Soa edctndchinitciensiniabesieintentinetiinnadumbuattinnebetis 13, 14, 15

IN THE

Supreme Court of the United States

Nos. 14-1418, 14-1453, 14-1505,

15-35, 15-105, 15-119 &15-191

DAVID A. ZUBIK, ET AL., Petitioners,

SYLVIA BURWELL, ET AL., Respondents.

On Writs of Certiorari to the

United States Courts of Appeals for the

Third, Fifth, Tenth, and D.C. Circuits

BRIEF OF THE OVARIAN CANCER RESEARCH

FUND ALLIANCE, ITS PARTNER MEMBERS AND

SCIENTIFIC ADVISORS AS AMICI CURIAE IN

SUPPORT OF RESPONDENTS

STATEMENT OF INTEREST!

The Ovarian Cancer Research Fund Alliance, along

with the partner members and scientific advisors

listed on the last page of this brief (collectively, the

“Alliance”) respectfully submit this brief as amici

curiae. The Alliance is a non-profit organization and

the foremost advocate for women with ovarian cancer

in the United States. To that end, the Alliance

advocates for increased research funding for the

1 No party or counsel for a party authored or paid for this brief

in whole or in part, or made a monetary contribution to fund

the briefs preparation or submission. No one other than amici

or their members or counsel made a monetary contribution to

the brief. All parties have consented to the filing of this brief in

letters lodged with the Clerk.

development of an early detection test, improved

healthcare practices, and life-saving treatment

protocols. The Alliance also advocates for increased

access to medicines and treatments that can help

lower the risk of ovarian and other gynecologic

cancers.

The Alliance, under its predecessor entity's title as

the Ovarian Cancer National Alliance, has filed

amicus briefs in other cases involving the Affordable

Care Act’s contraceptive coverage regulations in this

Court and the courts of appeals. See Burwell v.

Hobby Lobby Stores, Inc., 134 S. Ct. 2751 (2014);

Eden Foods, Inc. v. Sebelius, 733 F.3d 626 (6th Cir.

2013); Gilardi v. Dep’t of Health & Human Servs.,

733 F.3d 1208 (D.C. Cir. 2013). It is participating

here because the questions presented here are of

tremendous importance to amicfs members. The

Alliance believes that its expertise in the cancer-

preventive benefits of oral and other contraceptives

may aid this Court in addressing the far-reaching

implications of the questions presented. Ovarian

and endometrial cancers kill thousands of American

women each year. And because there is currently no

way to reliably detect ovarian cancer at an early

stage, prevention remains the primary weapon

against this devastating disease. An extraordinary

amount of medical research shows that for many

women at higher risk of developing ovarian cancer,

oral contraceptive use can be the difference between

developing this deadly cancer and not developing it.?

2 For the convenience of the Court, the medical research

discussed in this brief is included in the attached appendices.

The regulations and accommodation at issue take

an important step toward increasing access to this

critical preventive treatment in the battle against

ovarian and other deadly gynecologic cancers. Peti-

tioners’ interpretation of the Religious Freedom

Restoration Act (RFRA) would jeopardize that pro-

gress and needlessly prevent access to preventive

care for thousands of women whose employers object

to contraceptive use, even where the employer can

opt out of the requirements to which they object

simply by filling out a form stating their religious

objections. That outcome is neither sound as a

matter of health policy nor compelled by RFRA.

SUMMARY OF ARGUMENT

1. To succeed on their RFRA claims, Petitioners

must prove that their exercise of religion is “substan-

tially burdenled]” by the regulatory accommodation

at issue. For the reasons persuasively stated by each

of the courts of appeals in these cases and in the

Government's brief, Petitioners’ substantial burden

claim is unfounded. In addition, with respect to

coverage for women who use contraceptives solely to

secure the many preventive health benefits of these

drugs that are unrelated to procreation, the govern-

ment’s accommodation imposes no burden at all on

Petitioners’ religious exercise.

2. Even if the accommodation regulations did

impose a substantial burden on Petitioners’ religious

exercise, there is ample evidence that application of

any such burden to Petitioners is in furtherance of a

number of compelling governmental interests, in-

cluding significant preventive health benefits of

contraceptives that are entirely unrelated to procrea-

tion. Oral contraceptives and intrauterine devices

([UDs) are widely recognized preventive therapies

for reducing the risk of ovarian, endometrial, and

other gynecologic cancers.

These cancers are particularly deadly. Ovarian

cancer kills thousands of American women each

year. More than one-half of the women diagnosed

with the disease will die within five years. With no

effective way to detect ovarian cancer at an early

stage, prevention remains the most effective tool to

combat the disease. Endometrial cancer—which

forms in the tissue lining of the uterus—likewise

kills thousands of American women each year. For

these women, contraceptives are a potentially life-

saving cancer-preventive treatment.

The medical practice of prescribing contraceptives

to reduce a woman’s risk of developing these cancers

played a key role in the government’s decision-

making when it implemented the women’s preven-

tive-screening provision of the Affordable Care Act

(ACA). The contraceptive coverage requirement, and

the accommodation developed for employers that

object on religious grounds, are thus based, in part,

on the government’s compelling interest in ensuring

that women can reduce their risk of developing

ovarian and other forms of cancer through having

cost-free access to oral contraceptives. Assuring that

all women have affordable access to such treat-

ment—whether through employer-sponsored insur-

ance or via the accommodation regulations—is

critical to meeting this compelling interest. Petition-

ers RFRA theory wrongly jeopardizes access to

potentially life-saving preventive health benefits and

should be rejected.

ARGUMENT

I. PETITIONERS’ RELIGIOUS BELIEFS ARE

NOT SUBSTANTIALLY BURDENED BY THE

ACCOMMODATION REGULATIONS.

To succeed with a RFRA claim, Petitioners must

first demonstrate that their religious exercise is

“substantially burdenled]” by the challenged regula-

tions. 42 U.S.C. § 2000bb-1(a). The opinions of the

courts of appeals in these cases, as well as the Gov-

ernment’s brief, convincingly refute Petitioners’

argument that the accommodation allowing them to

opt out of the contraceptive coverage requirement

substantially burdens their religious exercise. See,

e.g., Geneva Coll. v. Sec’y U.S. Dep’t of Health and

Human S«rvs., 778 F.3d 422, 442 (3d Cir. 2015);

Little Sisters of the Poor Home for the Aged v. Bur-

well, 794 F.3d 1151, 1180 (10th Cir. 2015); E. Tex.

Baptist Univ. v. Burwell, 793 F.3d 449, 459 (5th Cir.

2015); Priests for Life v. U.S. Dep’t of Health &

Human Servs., 772 F.3d 229, 237 (D.C. Cir. 2014);

Br. for Resp’ts at 52-53.

The cancer prevention benefits of contraceptives,

which this brief presents in detail,’ offer yet another

reason why the challenged regulation does not

impose a substantial burden on Petitioners’ religious

exercise. Contraceptives provide significant medical

benefits that do not fall within the scope of Petition-

ers’ religious objections to their use, including pre-

vention of many serious and deadly cancers. Many

women, such as women who are not fertile or who

are beyond child-bearing age, use contraceptives

solely to obtain these substantial preventive benefits.

8 See infra Section II.

Although the most common reason women use oral

contraceptives is to prevent pregnancy, 14 percent of

users—1.5 million women—rely on them exclusively

for non-contraceptive purposes.4 A 2011 study

analyzed, among other things, data from women who

have never had sexual intercourse, totaling approxi-

mately 762,000 women, and confirmed that almost

all of them reported using oral contraceptives for

non-contraceptive reasons.®

When contraceptives are prescribed and taken for

non-contraceptive purposes, the challenged regula-

tions do not conflict with Petitioners’ stated religious

belief, which is based solely on the contraceptive

effect of these products. For this reason, as well as

those explained in the opinions below and in the

Government's brief, the challenged accommodation

imposes no substantial burden on Petitioners.

Il. THE ACCOMMODATION REGULATIONS

FURTHER A COMPELLING PUBLIC HEALTH

INTEREST BY ENSURING ACCESS TO

CANCER PREVENTIVE TREATMENTS.

Petitioners’ RFRA claims also fail because of the

abundant evidence that any “burden” to Petitioners

furthers numerous compelling governmental inter-

ests, including significant preventive health benefits

of contraceptives that are unrelated to procreation.

It is well established based on decades of clinical

research that oral contraceptives and IUDs can

4 Rachel K. Jones, Guttmacher Institute, Beyond Birth Control:

The Overlooked Benefits of Oral Contraceptive Pills 3 (2011),

http://www.guttmacher.org/pubs/Beyond-Birth-Control.pdf (last

visited Feb. 17, 2016).

5 Id. at 4.

reduce a woman’s risk of developing ovarian and

endometrial cancer and other forms of gynecologic

malignancies by as much as 50 percent. The signifi-

cant preventive association of the use of oral contra-

ceptives with a lower risk of ovarian and endometrial

cancer is a great discovery for women’s health and

public health. Contraceptives are potentially life-

saving preventative treatments that are particularly

vital for women with a higher risk of developing the

disease because of a family history of ovarian cancer

or because they inherited the BRCA1 or BRCA2 gene

mutations. Women need access to what currently is

the only weapon available to fight ovarian and

endometrial cancer that also allows them to preserve

their ability to conceive. To be sure, contraceptives

enable women to avoid unintended pregnancies and

to safeguard their health when a pregnancy is haz-

ardous or life threatening. But the scope of contra-

ceptives’ health services and benefits reaches well

beyond the prevention of unwanted pregnancy.

The Health Resources and Services Administration

(HRSA), an agency of the U.S. Department of Health

and Human Services (HHS), specifically considered

benefits to women’s health other than their contra-

ceptive uses when the agency issued the final regula-

tions relating to coverage of women’s preventive

health services under the ACA. See Coverage of

Certain Preventive Services Under the Affordable

Care Act, 78 Fed. Reg. 39,870, 39,872 (July 2, 2013)

(“[Tlhere are demonstrated preventive health bene-

fits from contraceptives relating to conditions other

than pregnancy (for example, prevention of certain

cancers)”).

In determining the scope of recommended coverage

for preventive services for women as envisioned by

the ACA, HRSA relied in part on a report by the

Institute of Medicine (IOM) analyzing the effective-

ness of various preventive services for women.* The

purpose of the IOM report was to “identify preven-

tive services necessary for women’s health and well-

being and to identify specific services that could

supplement the current list of recommended preven-

tive services for women.”’ The IOM report recog-

nized that contraceptive methods frequently have

benefits that are separate from their use in pregnan-

cy-prevention and, in particular, that “[l]ong-term

use of oral contraceptives has been shown to reduce a

woman’s risk of endometrial cancer.” HRSA adopt-

ed the IOM’s recommendation that preventive ser-

vices for women include “[a]ll Food and Drug Admin-

istration approved contraceptive methods, steriliza-

tion procedures, and patient education and counsel-

ing for all women with reproductive capacity.”®

The IOM recommendations make clear that the

government has a compelling interest in ensuring

that women have access to contraceptives as an

essential preventive treatment to protect their

health and well-being. A wealth of scientific evi-

dence collected over decades consistently confirms

the significant preventive association of oral contra-

ceptives and IUDs with a lower risk of users develop-

6 See IOM, Clinical Preventive Services for Women: Closing the

Gaps 1 (2011), https://iom.nationalacademies.org/Reports

/2011/Clinical-Preventive-Services-for-Women-Closing-the-

Gaps.aspx (last visited Feb. 17, 2016).

? Id. at 3.

8 Id. at 107.

® HRSA, HHS, Women’s Preventive Services Guidelines,

http://www.hrsa.gov/womensguidelines/ (last visited Feb. 17,

2016).

ing certain deadly gynecologic cancers. The ACA

contraceptive coverage regulations, including the

religious objection accommodation, promotes wom-

en’s health by ensuring that all women, regardless of

employer, can access preventive treatments that

significantly reduce the risk of some of the most

prevalent and deadly cancers. Women are entitled to

this access as a matter of federal law; the accommo-

dation in the regulations allows Petitioners to avoid

any obligation to provide it themselves.

A. Contraceptives provide significant medical

benefits separate from prevention of pregnan-

cies.

1. There is conclusive evidence that oral contra-

ceptives provide access to potentially life-saving

health benefits for women by reducing the risk of

ovarian cancer. Hobby Lobby, 134 S. Ct. at 2799

(Ginsburg, J., dissenting) (“[T]he Government has

shown that the contraceptive coverage for which the

ACA j-ovides furthers compelling interests in public

health and women’s well being . . . [and] secures

benefits wholly unrelated to pregnancy, [such as]

preventing certain cancers, menstrual disorders, and

pelvic pain.”). Ovarian cancer is the deadliest gyne-

cologic cancer and the fifth leading cause of cancer

deaths for women.!® In 2015, the American Cancer

Society (ACS) estimated that approximately 14,180

American women died from ovarian cancer—more

than died from any other gynecologic cancer.'!! ACS

10 NCI, A Snapshot of Ovarian Cancer, http://www.cancer.gov/

research/progress/snapshots/ovarian (last visited Feb. 17, 2016).

1 American Cancer Soc’y, Cancer Facts & Figures 2015, at 4,

http://www.cancer.org/acs/groups/content/@editorial/documents/

document/acspc-044552.pdf (last visited Feb. 17, 2016).

also estimates that approximately 21,290 women in

the United States were diagnosed with the disease

for the first time in 2015.!2 The high mortality rate

reflects the lack of reliable early detection mecha-

nisms and effective screening tests to detect ovarian

cancer at an early stage. Most women receive the

diagnosis at an advanced stage when it is often too

late for any treatment to have a high probability of

success.'3 Consequently, prevention is currently the

most effective weapon to combat this deadly disease.

The landscape of preventive treatments is very

limited. Treatment options include the removal of

fallopian tubes and ovaries (known as prophylactic or

salpingo-oophorectomy) and the closure of the fallo-

pian tubes (tubal ligation), both of which require

invasive surgeries and come with drastic conse-

quences that irreversibly prevent a woman from ever

conceiving a child.'4 A significantly less invasive

method is the use of oral contraceptives. It is well

established, through multiple clinical investigations

over decades, that the use of oral contraceptives

lowers risk of developing ovarian cancer. Indeed, as

early as 1999, the scientific consensus was that “[t]he

protection offered by oral contraceptives against

ovarian cancer risk is one of the most consistent

2 Id. at 4.

'3 NCI, A Snapshot of Ovarian Cancer, http://www.cancer.gov

/research/progress/anapshote/ovarian (last visited Feb. 17,

2016).

14 NCI, Ovarian, Fallopian Tube, and Primary Peritoneal

Cancer Prevention (PDQ®), http://www .cancer.gov/types/ovari-

an/patient/ovarian’prevention-pdq#eection/all (last visited

Feb. 17, 2016).

epidemiological findings.” The significant protec-

tive association between oral contraceptive use and

the risk of ovarian cancer has been identified in

retrospective “case-control” studies (which compare

women diagnosed with ovarian cancer to women who

did not develop the disease) and prospective “cohort”

studies (which follow a sample group of women over

time and later evaluate whether they develop ovari-

an cancer).!6

1% C. La Vecchia & S. Franceschi, Oral Contraceptives and

Ovarian Cancer, 8 Eur. J. Cancer Prevention 297, 297 (1999).

16 See, e.g., Aminah Jatoi et. al., Prior Oral Contraceptive Use

in Ovarian Cancer Patients: Assessing Associations with

Overall and Progression-Free Survival, 15 BMC Cancer 711

(2015); M. T. Faber et al., Oral Contraceptive Use and Impact of

Cumulative Intake of Estrogen and Progestin on Risk of

Ovarian Cancer, 24 Cancer Causes Control 2197 (2013); Laura

J. Havrilesky et al, Oral Contraceptive Pills as Primary

Prevention or Ovarian Cancer, 122 Obstetrics & Gynecology

139 (2013); V. Beral et al., Ovarian Cancer and Oral Contracep-

tives: Collaborative Reanalysis of Data from 45 Epidemiological

Studies Including 23,257 Women with Ovarian Cancer and

87,303 Controls, 371 Lancet 303, 307-312 (2008); Julia B. Greer

et al., Androgenic Progestins in Oral Contraceptives and the

Risk of Epithelial Ovarian Cancer, 105 Obstetrics & Gynecology

731, 735 (2005); Roberta B. Ness et al., Risk of Ovarian Cancer

in Relation to Estrogen and Progestin Dose and Use Character-

istics of Oral Contraceptives, 152 Am. J. Epidemiology 233, 239

(2000); Harvey A. Risch et al., Parity, Contraception, Infertility,

and the Risk of Epithelial Ovarian Cancer, 140 Am. J. Epide-

miology 585, 589 (1994); Susan E. Hankinson et al., A Quanti-

tative Assessment of Oral Contraceptive Use and Risk of

Ovarian Cancer, 80 Am. J. Obstetrics & Gynecology 708, 712-

714 (1992); Alice S. Whittemore et al., Characteristics Relating

to Ovarian Cancer Risk: Collaborative Analysis of 12 US Case-

Control Studies — II. Invasive Epithelial Ovarian Cancers in

White Women, 136 Am. J. Epidemiology 1184, 1192 (1992); The

Cancer and Steroid Hormone Study of the Ctrs. for Disease

A greater than 20 percent relative risk reduction

occurs for every five years a woman takes oral con-

traceptives.'7 A 2008 study analyzed the public

health effects of oral contraceptive use and concluded

that oral contraceptives prevented approximately

200,000 cases of ovarian cancer worldwide since the

drugs were first approved in 1960 and saved approx-

imately 100,000 women who otherwise would have

died from the disease.'*® That number is “likely to

increase substantially in the future, with the further

ageing of past users of oral contraceptives and the

increasing numbers of new users.”!9

The need for preventive therapies such as contra-

ceptives is even stronger for women who are at a

higher risk of developing ovarian cancer and women

with endometriosis. In particular, women with a

family history of ovarian cancer, who have inherited

mutations in the BRCA1 and BRCA2 genes, or who

have hereditary nonpolyposis colorectal cancer

(Lynch Syndrome), face an elevated risk of heredi-

tary ovarian cancer.” The BRCA1 and BRCA2 genes

collectively account for approximately 15 percent of

Control and the Nat'l Inst. of Child Health and Human Dev.,

The Reduction in Risk of Ovarian Cancer Associated with Oral-

Contraceptive Use, 316 New Eng. J. Med. 650, 654 (1987). But

see Xiao Ou Shu et al., Population-Based Case-Control Study of

Ovarian Cancer in Shanghai, 49 Cancer Res. 3670, 3673 (1989)

(finding a slight increase in ovarian cancer risk associated with

oral contraceptive use, although increase was not significant).

17 Beral et al., supra, at 303-314.

18 Id. at 307, 312.

19 Jd. at 312.

20 NCI, The Genetics of Cancer, http://www.cancer.gov/about-

cancer/causes-prevention/genetics (last visited Feb. 17, 2016).

ovarian cancers.”?! Roughly 1.3 percent of women in

the general population will develop ovarian cancer

during their lives.22, However, according to recent

estimates, approximately 39 to 46 percent of women

who inherit a BRCAI1 mutation and 10 to 27 percent

of women who inherit a BRCA2 mutation will devel-

op ovarian cancer during their lifetimes. There is a

24 percent lifetime risk of developing ovarian cancer

for women with Lynch Syndrome.”

The benefits of contraceptives also appear to extend

to women who have been diagnosed with ovarian

cancer. A 2015 study evaluated the connection

between oral contraceptive use and patients who

ultimately develop the disease. The study concluded

that oral contraceptive use prior to a diagnosis of

ovarian cancer is associated with improved progres-

sion-free survival in patients, or the length of time

patients lived with the disease without it worsening

and improved survival. Another 2015 study deter-

mined that ovarian cancer mortality rates decreased

21 A. Antoniou et al., Average Risks of Breast and Ovarian

Cancer Associated with BRCA 1 or BRCA 2 Mutations Detected

in Case Series Unselected for Family History: A Combined

Analysis of 22 Studies, 72 Am. J. Hum. Genetics 1117, 1117-

1130 (2003) (discussing strong evidence supporting association

between BRCA 1 and BRCA 2 mutations and an increased risk

for ovarian cancer); S. Iodice et al., Oral Contraceptive Use and

Breast or Ovarian Cancer Risk in BRCA1/2 Carriers: A Meta-

Analysis, 46 Eur. J. Cancer 2275, 2276 (2010) (same).

2 NCI, Surveillance, Epidemiology, and End Results Program,

Stat Fact Sheets: Endometrial Cancer, http://seer.cancer.gov

/statfacte/htmV/corp.html. (last visited Feb. 17, 2016).

23 J. Brian Szender and Shashikant B. Lele, Fallopian Tube

Ligation or Salpingectomy as Means for Reducing Risk of

Ovarian Cancer, 17 Am. Med. Ass’n J. Ethics 843, 844 (2015).

*% Jatoi et al., supra, at 5.

by 23 percent from 1973 to 2011, due in part to the

availability of oral contraceptives.25 However, the

investigators estimated that from 2010 to 2030, the

annual number of cases of ovarian cancer in the

United States will increase by 37 percent due to the

aging baby-boomer generation and population

growth.”6

Oral contraceptives are the only viable preventive

treatment to reduce the risk of ovarian cancer while

preserving a woman’s ability to conceive. But the

number of annual diagnoses and mortality rates will

only increase if employers can cut off access for

women who need these preventive treatments.

2. Women who use oral contraceptives during

their reproductive years also benefit from long-term

protection against endometrial cancer. Endometrial

cancer is the most common invasive gynecologic

cancer among women in the United States. In 2015,

the National Cancer Institute (NCI) estimated that

there were approximately 54,870 new cases of endo-

metrial cancer, and approximately 10,170 women

diagnosed with endometrial cancer died during the

year.27 Cancer of the endometrium, which is the

lining of the uterus, typically strikes women around

age 60, after the end of their reproductive years; for

that reason, the preventive benefits of contraceptive

use are especially pronounced for these women. Ifa

woman is diagnosed after the cancer has spread of

25 Victoria Sopik et al., Why Have Ovarian Cancer Mortality

Rates Declined? Part I. Incidence, 138 Gynecologic Oncology

741, 746 (2015).

26 Id. at 748.

27 NCI, supra note 22.

metastasized, NCI estimates that her five-year

survival rate is between 17 and 68 percent.”8

According to a 2015 study, the protective effect of

oral contraceptives on endometrial cancer lasts for

over thirty years.29 This large study examined more

than 140,000 women from around the world, and the

results confirmed that every five years of oral contra-

ceptive use was associated with a 24 percent reduc-

tion in the risk of endometrial cancer. The risk

reduction of oral contraceptive use was even strong-

er, with a 31 percent lower lifetime risk of developing

endometrial carcinoma as compared to 17 percent

lower risk for less common sarcomas.*! The study

concluded that over the past fifty years, up to

400,000 cases (out of 3.4 million total cases) of endo-

metrial cancers have been prevented by women’s use

of oral contraceptives, including approximately

200,000 cases in the past decade.22 Women with

hereditary nonpolyposis colorectal cancer syndrome

have a markedly increased risk of endometrial

cancer compared with women in the general popula-

tion. Women with a family history of endometrial

cancer in a first-degree relative are also at increased

% Id.

28 Collaborative Group on Epidemiological Studies on Endome-

trial Cancer, Endometrial Cancer and Oral Contraceptives: An

Individual Participant Meta-analysis of 27,276 Women with

Endometrial Cancer from 36 Epidemiological Studies, 16

Lancet Oncology 1061, 1061 (2015).

% Id. at 1065.

31 Jd. at 1067.

82 Id. at 1068.

risk.*3 Access to contraceptives as a preventive

treatment is critical for these women.

3. Studies also confirm that IUDs decrease the

risk for endometrial cancer and that IUD use (at

least short term) also decreases the risk of ovarian

cancer.*4 These studies have demonstrated that

women who have used an IUD at some point experi-

enced a significant protective effect, reducing their

risk of developing endometrial cancer by one-third to

one-half compared to women who never used an IUD

83 NCI, Endometrial Cancer Prevention — For Health Profes-

sionals (PDQ®), http://www.cancer.gov/types/uterine/hp/endo

metrial-prevention-pdq (last visited Feb. 17, 2016).

3% Robin M. Beining et al., Meta-Analysis of Intrauterine

Device Use and Risk of Endometrial Cancer, 18 Annals Epide-

miology 492, 492-499 (2008) (discussing decreased risk of

endometrial cancer); D.Hubacher, Noncontraceptive Health

Benefits of Intrauterine Devices: A Systematic Review, 57

Obstetrics & Gynecology Surv. 120, 120-128 (2002) (same);

Abraham Benshushan et al., JUD Use and the Risk of Endome-

trial Cancer, 105 Eur. J. Obstetrics & Gynecology & Reprod.

Biology 166, 167 (2002) (same); Deirdre A. Hill et al., Endome-

trial Cancer in Relation to Intra-Uterine Device Use, 70 Int'l J.

Cancer 278, 279 (1997) (same); Susan Sturgeon et al., Jntrau-

terine Device Use and Endometrial Cancer Risk, 26 Int'l J.

Epidemiology 496, 498 (1997) (same); F. Parazzini et al.,

Intrauterine Device Use and Risk of Endometrial Cancer, 70

Brit. J. Cancer 672, 673 (1994) (same); Xavier Castellaagué et

al., Intrauterine Contraception and the Risk of Endometrial

Cancer, 54 Int'l J. Cancer 911, 915 (1993) (same); Roberta B.

Ness et al., Contraception Methods, Beyond Oral Contracep-

tives and Tubal Ligation, and Risk of Ovarian Cancer, 21

Annals Epidemiology 188, 188-196 (2011) (discussing decreased

risk of ovarian cancer); Daniel W. Cramer et al., Conditions

Associated With Antibodies Against the Tumor-Associated

Antigen MUCI1 and Their Relationship to Risk for Ovarian

Cancer, 14 Cancer Epidemiology, Biomarkers & Prevention

1125, 1126-1131 (2005) (same).

(after controlling for factors such as age, child-

bearing, and family history).°5 In addition, IUDs

may significantly reduce the risk of cervical cancer.

According to a 2011 study analyzing multiple inter-

national studies, women who used an IUD for at

least one year reduced their risk of developing cervi-

cal cancer by 50 percent, compared to women who

had never used an IUD.

All of these data make clear that FDA-approved

contraceptives are an important preventive tool to

protect women’s health. The coverage regulations

ensure that women will have the opportunity to

access these potentially life-saving preventive thera-

pies, regardless of their employers’ religious views.

B. The cancer-prevention benefits of contracep-

tives played a key role in the government's de-

cision to include the contraceptive coverage

provision in the ACA.

The reduced risk of ovarian cancer and other dead-

ly cancers is a significant preventive health benefit of

long-term contraceptive use. These preventive

benefits, which are unrelated to the prevention of

unintended pregnancies, were central to the govern-

ment’s interest in requiring coverage of contracep-

tion under the ACA.

Section 2713 of the Public Health Service Act, the

statute on which the contraceptive coverage re-

85 Benshushan et al., supra, at 167; Castellsagué et al., supra,

at 912.

% Xavier Castellsagué et al., Intrauterine Device Use, Cervical

Infection with Human Papillomavirus, and Risk of Cervical

Cancer: A Pooled Analysis of 26 Epidemiological Studies, 12

Lancet Oncology 1023, 1029 (2011).

quirement is based, does not itself require coverage

of contraceptives. Rather, the statute requires group

health plans and health insurance issuers offering

group or individual health insurance coverage to

cover and impose no cost-sharing on four specified

categories of preventive medical treatment. The last

of these categories is, “with respect to women, such

additional preventive care and screenings not [oth-

erwise recommended by the U.S. Preventive Services

Task Force] as provided for in comprehensive guide-

lines supported by the Health Resources and Ser-

vices Administration for purposes of this paragraph.”

42 U.S.C. § 300gg-13(a)(4). Section 2713 makes clear

that Congress’s chief intent was to ensure that

women have access to any medical treatment that

effectively prevents illness and disease—which long-

term use of contraceptives does by reducing women’s

risk of ovarian cancer and other deadly cancers.

This focus on promoting access to significant pre-

ventive benefits was carried through each step of

Section 2713’s implementation. When HHS issued

rules to implement the statute, the agency explained

that the law was needed because health plans lack

the incentive to cover preventive services and indi-

vidual patients lack the immediate incentive or

ability to obtain them, resulting in avoidable illness

and costly treatment down the road. Interim Final

Rules Relating to Coverage of Preventive Services

Under the Affordable Care Act, 75 Fed. Reg. 41,726,

41,731 (July 19, 2010). Likewise, when HHS en-

gaged IOM to analyze what preventive services

should be included in the guidelines envisioned by

Section 2713, the agency’s charge to [OM focused on

identifying preventive services and screenings that

“have been shown to be effective for women” and “are

needed to fill gaps in recommended preventive

services for women.”3’

Under any of these standards, the cancer preven-

tion benefits of contraceptives merit their inclusion

among the preventive treatments for which coverage

is required under Section 2713. Indeed, in identify-

ing FDA-approved contraceptives as a preventive

treatment that should be included in the HHS guide-

lines (and ultimately in the set of services for which

coverage is required under Section 2713), IOM’s

report expressly cited preventive health benefits of

contraception that are unrelated to pregnancy,

including reduced risk of endometrial cancer and

other serious diseases.** Long-term use of contracep-

tives offer women an opportunity to significantly

reduce the risk that they will die of ovarian or endo-

metrial cancer or suffer from other gynecologic

diseases, and the government rightly recognized

those benefits by including contraceptives in the

preventive-services coverage regulations.

C. Ensuring access to cancer-prevention health

benefits is a compelling government interest.

The government has “overlapping and mutually

reinforcing compelling interests” in safeguarding

public health, ensuring that women have equal

access to health care, and assuring access to seam-

less, affordable contraceptive coverage. Priests for

Life, 772 F.3d at 257, 263-264. These interests are

furthered by the ACA contraceptive regulations and

the accommodation process. See Coverage of Certain

31 See IOM, supra, at 2.

38 See id. at 107.

Preventive Services Under the Affordable Care Act,

78 Fed. Reg. at 39,872, 39,887.

1. There is no dispute that the promotion of pub-

lic health is a compelling government interest. See,

e.g., Hobby Lobby, 134 S. Ct at 2780; Priests for Life,

772 F.3d at 259-262; Real Alts., Inc.v. Burwell, __

F.3d __, No. 1:15-cv-0105, 2015 WL 8481987, at *27

(M.D. Pa. Dec. 10, 2015) (“comprehensive access to

health care serves a compelling government interest”

in promoting public health). The government also

has a compelling interest in eliminating the gender

discrimination that results from the fact that

healthcare costs fall disproportionately on women.

Priests for Life, 772 F.3d at 262-264 (recognizing

government’s compelling interest in gender equality);

Real Alts., Inc., __ F.3d __, 2015 WL 8481987, at *26

(certain “health obstacles” are “unique to women,”

and “eliminating the past practice of discrimination

against women in the provision of health care cover-

age is sufficiently compelling to justify” the contra-

ceptive coverage requirement).

2. The government furthers these compelling

interests by requiring coverage for contraceptives as

preventive health services necessary to protect the

health and well-being of female employees. Priests

for Life, 772 F.3d at 258 (“The government’s asserted

compelling interest here, writ large, is in a sustaina-

ble system of taxes and subsidies under the ACA to

advance public health.”). Five members of the Court

determined as much in Hobby Lobby. 134 S. Ct. at

2785-2786 (Kennedy, J., concurring) (the contracep-

tive coverage requirement “serves the Government’s

compelling interest in providing insurance coverage

that is necessary to protect the health of female

employees”); id. at 2799 (Ginsburg, J., dissenting)

(“[Tlhe Government has shown that the contracep-

tive coverage for which the ACA provides furthers

compelling interests in public health and women’s

well being . . . [and] secures benefits wholly unrelat-

ed to pregnancy, [such as] preventing certain can-

cers, menstrual disorders, and pelvic pain.”). The

remaining members all presumed that “the interest

in guaranteeing cost-free access to the four chal-

lenged contraceptive methods is compelling within

the meaning of RFRA.” Id. at 2780.

Petitioners argue that the government has no com-

pelling interest in providing access to contraceptives

because the ACA only requires access to “preventive

care.” Br. for Pet’rs in Nos. 14-1418, 14-1453 & 14-

1505 at 62 Wan. 4, 2016). But Hobby Lobby “shows

that the government has a strong argument” that the

ACA’s contraceptive coverage regulations and asso-

ciated accommodation further compelling govern:

ment interests. Univ. of Notre Dame v. Burwell, 786

F.3d 606, 624 (7th Cir. 2015). And although some

Petitioners object to only certain methods of contra-

ception, a decision by the Court in Petitioners’ favor

would allow them to claim entitlement to exemption

from the ACA’s contraceptive coverage regulations

and associated accommodation as to all FDA-

approved contraceptives. That some Petitioners

object to only certain contraceptive methods “does

not lessen [the government’s] compelling interests.”

Hobby Lobby, 134 S. Ct. at 2799-2800 (Ginsburg, J.,

dissenting).

3. Fundamental to amicrs interests, the cancer-

preventive-health effects of contraceptives are criti-

cal to furthering the government’s compelling inter-

ests in promoting public health and ensuring that

women have equal access to health care. The signifi-

cant protective benefits of oral contraceptives and

IUDs are supported by an extensive body of research

demonstrating that contraceptives are one of the few

evidence-based methods for the prevention of ovarian

cancer and other deadly gynecologic cancers. See

supra pp. 9-17. Contrary to Petitioners’ argument

that the government's compelling interests are

“highly abstract” and too “broadly” framed, this

empirical evidence supports a specific, concrete, and

identifiable government interest in reducing women’s

risk of lethal gynecologic cancers. Hobby Lobby, 134

S. Ct at 2799 (Ginsburg, J., dissenting) (the contra-

ceptive coverage “secures benefits wholly unrelated

to pregnancy, [such as] preventing certain cancers,

menstrual disorders, and pelvic pain.”); Priests for

Life, 772 F.3d at 262 (under the ACA’s contraceptive

provision, “[t]he government further relied on the

ways that contraceptive use can promote and im-

prove women’s health apart from their procreative

health needs”); Gilardi, 733 F.3d at 1240 (Edwards,

J., concurring in part and dissenting in part) (recog-

nizing that contraceptives are prescribed to “reduce

the risk of ovarian, endometrial, and gynecologic

cancers,” to prevent disease, and “preserve the

health” of women with certain health conditions).

Given the high case-fatality rate associated with

ovarian cancer and the lack of effective early detec-

tion techniques, prevention represents a critical

opportunity to reduce morbidity and mortality rates

of the disease. The government thus has a compel:

ling interest in promoting public health by ensuring

39 Br. for Pet’rs in Nos. 14-1418, 14-1453 & 14-1505 at 66 Wan.

4, 2016); Br. for Pet’rs in Nos. 15-35, 15-105, 15-119, & 15-191

at 57 (Jan. 4, 2016).

that women have access to contraceptives, without

cost sharing, as preventive therapies.

4. To achieve this compelling interest, the gov-

ernment must be able to provide women access to

affordable contraceptives. Indeed, the gravity of

interests at stake, and the life and death nature of

the cancers at issue, confirms that it is critical that

contraceptives are both accessible and affordable. At

the time the ACA became effective, twenty-eight

states already had requirements that private insur-

ance plans cover a full range of FDA-approved pre-

scription contraceptive methods, and the ACA aug-

mented those requirements by prohibiting cost

sharing.“” The prohibition on cost sharing is essen-

tial because women—particularly those at a high

risk for ovarian cancer—must have access to afford-

able contraceptives over a long period of time so they

can take full advantage of the preventive benefits

detailed above, in consultation with their physicians.

Fortunately and as expected, the ACA’s contracep-

tive coverage regulations have dramatically reduced

the financial barriers to affordable contraceptives.

Implementation of the regulations has already

increased affordable access to contraceptive services

for millions of women. According to a 2014 study,

the percentage of women who did not pay any out-of-

pocket expense for oral contraceptives increased from

“ Guttmacher Institute, State Policies in Brief (as of February

1, 2016): Insurance Coverage of Contraceptives, http://www.

guttmacher.org/statecenter/spibs/spib_ICC.pdf (last visited Feb.

17, 2016).

15 to 67 percent between fall 2012 and spring 2014.*!

During that same time, the average out-of-pocket

cost for oral contraceptives dropped from $14.35 to

$6.48.42 Studies showed similarly dramatic results

for access to affordable IUDs: in March 2014, only

13 percent of women faced out-of-pocket costs for an

IUD, compared to 58 percent in January 2012.8 The

average out-of-pocket costs for IUD insertion fell

from $293.28 in June 2012 to $145.24 just one year

later.

The financial benefit to all women of the contracep-

tive coverage regulations cannot be overstated.

Estimates show that women will save an average of

$254.91 on the oral contraceptive pill and $248.30 on

IUD insertions annually.“ In 2013 alone, the re-

ported savings in out-of-pocket costs on oral contra-

ceptive pills was $483 million.“ One study argues

that the more accurate estimate, based on the 6.88

million privately insured women who use oral con-

41 Adam Sonfield et al., Impact of the Federal Contraceptive

Coverage Guarantee on Out-of-Pocket Payments for Contracep-

tives: 2014 Update, 91 Contraception 44, 45, 47 (2015).

42 Id. at 47. The median out-of-pocket cost dropped from $10.00

to $0.00 in that same time-period. Id.

43 Jd. See also Jonathan M. Bearak et al., Changes in Out-of-

Pocket Costs for Hormonal [IUDs After Implementation of the

Affordable Care Act: An Analysis of Insurance Benefit Inquir-

ies, 93 Contraception 139, 141 (2016).

“ Nora V. Becker & Daniel Polsky, Women Saw Large De-

crease in Out-of-Pocket Spending for Contraceptives After ACA

Mandate Removed Cost Sharing, 34 Health Aff. 1204, 1207

(2015).

4 Id. at 1208.

4 Id. at 1209.

traceptive pills, is an astonishing $1.4 billion per

year.*?

All women deserve access to affordable contracep-

tives. Indeed, data suggested that a “nontrivial

portion of women with interest in an IUD but with-

out any coverage”’—between 8.8 and 37.9 percent—

“worked for a religious employer that denies contra-

ceptive coverage.”** The cost savings that flow from

the ACA’s contraceptive coverage regulations are

critical to furthering the government’s compelling

interest in promoting public health by providing

access to affordable healthcare treatments. These

massive cost savings should be available to all wom-

en, including those who work for religious nonprofits

that need only complete self-certification forms to

opt-out of providing contraceptive coverage them-

selves.

“7 Id.

# Bearak et al., supra, at 142.

7 . .

The accommodation mechanism that Petitioners

challenge here ensures access to critical preventive

therapies—therapies that should be affordable and

available to all women, regardless of the religious

beliefs of their employers. The regulations at issue

promote a compelling interest while providing a non-

burdensome mechanism to accommodate religious

objections. This Court should reject the Petitioners’

challenge to that accommodation and allow all

women access to this potentially life-saving preven-

tive care.

CONCLUSION

For the foregoing reasons, as well as those in Re-

spondents’ brief, the judgments of the Third, Fifth,

Tenth, and D.C. Circuits should be affirmed.

Respectfully submitted,

JESSICA L. ELLSWORTH*

Counsel of Record

JESSICA B. LIVINGSTON MICHELLE A. KISLOFF

HOGAN LOVELLS US LLP ANDREW S. FURLOW

1200 Seventeenth Street LOWELL M. ZETA

Suite 1500 HOGAN LOVELLS US LLP

Denver, CO 80202 555 Thirteenth Street, N.W.

Washington, D.C. 20004

(202) 637-5886

FEBRUARY 2016 jessica_ellsworth@hoganlovells.com

Counsel for Amici Curiae

LIST OF AMICI PARTNER MEMBERS AND

SCIENTIFIC ADVISORS OF THE OVARIAN

CANCER RESEARCH FUND ALLIANCE

Partner Members

The Bluegrass Ovarian Cancer Support

Bright Pink

FORCE: Facing Our Risk of Cancer Empowered

Help Keep a Sister Alive

HERA Women’s Cancer Foundation

Minnesota Ovarian Cancer Alliance

Ovarian Cancer 101

Ovarian Cancer Alliance of Arizona

Ovarian Cancer Coalition of Greater California

Ovarian Cancer Alliance of Oregon & SW

Washington

Ovarian Cancer Education & Research Network, Inc.

Sandy Rollman Ovarian Cancer Foundation

Sherie Hildreth Ovarian Cancer (SHOC) Foundation

Susan Poorman Blackie Ovarian Cancer Foundation

Utah Ovarian Cancer Alliance

WNY Ovarian Cancer Project, Inc.

You'll Never Walk Alone

University School of Medicine

Molly A. Brewer, D.V.M., M.D., M.S., University of

Connecticut Health Center

Doug Levine, M.D., Memorial Sloan Kettering

APPENDIX

APPENDIX A

EUROPEAN JOURNAL OF CANCER PREVENTION 1999, 8, 297-

304

ORAL CONTRACEPTIVES AND

OVARIAN CANCER

C La Vecchia',’ S. Franceschi’

(Received 23 March 1999; accepted 11 May 1999)

_ The protection conveyed by oral contraceptives against

ovarian cancer risk is one of the best established and most

important features of epithelial ovarian cancer on a public

health scale. Ovarian cancer incidence and mortality rates

have been declining in most developed countries for women

born after 1920, and the decline was greater in countries

where oral contraceptive use has been more widespread.

Thus, data from descriptive epidemiology are consistent with

‘a favourable effect of oral contraceptives on ovarian cancer

‘isks. The overall estimated protection from cohort and

tase—control studies is approximately 40% in ever oral

tontraceptive users, and increases with duration of use to

mote than 50% for users of 5 years or longer. The

tavourable effect of oral contraceptives against ovarian

cancer risk persists for at least 10-15 years after use has

and it is not confined to any particular type of oral

Contraceptive formulation. However, available data do not

provide definite evidence for more recent low-dose

" Istituto di Ricerche Farmacologiche ‘Mario Negri’ Milan, Italy.

? Istituto Satistica Medica ¢ Biometria, Universita degli Studi di

Milano, Milan, Italy.

5 Servizio di Epidemiologia, Centro di Riferimento Onccologico,

Aviano, Italy. Correspondence to: C La Vecchia, Istituto di Ricerche

“Mario Negri’, Via Eritrea 62, 20157 Milan, Italy. Fax:

Farmacologiche

(+39) 2 3320 0231.

formulations and for longer periods of latency or recency of

use. The protection is also observed on _ borderline

malignancy ovarian neoplasms, and probably on benign

epithelial cysts as well. There is suggestive evidence of

some protection for sex-cord-stromal cancers, but not for

germ cell neoplasms. In terms of biological mechanisms,

oral contraceptives are thought to act on ovarian cancer risk

by affecting the lifetime number of ovulations. The

protection attributable to oral contraceptives on ovarian

cancer risk is one of the major issues on any individual

risk/benefit assessment and public health evaluation of this

type of contraceptive use.

Key words: oral contraceptives, ovarian cancer,

epidemiology, risk.

Introduction

The protection offered by oral contraceptives against

ovarian cancer risk is one of the most consistent

epidemiological findings, and one of the important examples

— on a public health scale — of large-scale chemopreventive

interventions.

In several developed countries young women showed

substantial declines in ovarian cancer incidence and

mortality, partly or largely attributable to the protection

afforded by oral contraceptives (Para-zzini et al., 1991a; La

Vecchia et al., 1992, 1998).

Cohort analyses based on data from Switzerland (Levi et

al., 1987), Britain (Villard-Mackintosh ef a/., 1989), Sweden

(Adami ef al., 1990), England and Wales (dos Santos Silva

and Swerdlow, 1995) and the Netherlands (Koper ef ai.

1996), as well as a systematic analysis of mortality trends in

16 major European countries (La Vecchia ef al., 1992, 1998),

showed that women born after 1920, i.e. from the generations

who had used oral contraceptives — had consistently reduced

ovarian cancer rates. The downward trends were greatest in

countries where oral contraceptives have been more widely

utilized (La Vecchia ef al., 1998).

Thus, descriptive data on ovarian cancer incidence and

mortality are consistent with the hypothesis of a favourable

impact of oral contraceptive use on subsequent ovarian

cancer rates.

There are still a few open issues, including a clearer

understanding of the biological mechan-ism(s), the

potentially different role of various types of oral

contraceptive formulations, and the very longterm

implications of oral contraceptives, including potential

interactions with hormone replacement therapy (HRT) and

other exogenous hormones in the assessment of a woman’s

global exposure to exogenous hormones. These issues will

be considered in the present paper, which will review the

main results from cohort and case-control studies.

Cohort studies

The main results of cohort studies on oral contraceptive and

Ovarian cancer are summarized in Table 1.

Three cohort studies on oral contraceptives conucted in the

US and Britain provided data on a total of about 100 cases of

epithelial ovarian cancer. These included the US Walnut

Creek Study (Ramcharan ef al., 1981), whose recruitment

was made in 1968-72, including 10,638 women aged 18-54

years. Up to 1977 a total of 16 cases of ovarian cancer were

reported, corresponding to an age-adjusted RR for ever oral

contraceptive use of 0.4.

The Royal College of General Practitioners’ study was

based on 47,000 women recruited in 1968 in 1400 British

general practices (Beral ef a/., 1988); 30 cases of ovarian

cancers were observed up to 1987, corresponding to

multivariate RRs of 0.6 [95%, confidence interval (CI) 0.3-

1.4] for ever pill users and of 0.3 for >10 years’ use.

Allowance in the analysis was made for age, parity, smoking,

and social class.

The Oxford Family Planning Association study was based

on 17,032 women enrolled between 1968 and 1976 from

various family planning clinics in the UK (Vessey and

Painter, 1995). Up to October 1993, 42 cases of ovarian

cancer were registered, corresponding to RRs of 0.4 (95% CI

0.2-0.8) for ever oral contraceptive use and of 0.3 (95% Cl

0.1-0.7) for >8 years of use. Adjustment was made for age

and parity.

The results of these cohort studies on contraceptives are

thus compatible with RRs of ovarian cancer around 0.5 for

ever use and 0.3 for long-term use.

Furthermore, in the nurses’ health study, based on 121,700

registered nurses aged 30-55 years in 1976, 260 cases of

ovarian cancer were prospectively observed between 1976

and 1988 (Hankinson ef al., 1995). The multivariate RR for

ever use, which essentially reflected former use, was 1.1

(95% CI 0.83-1.43), but declined to 0.6 (95% CI 0.32-1.07)

for use >5 years. Adjustment was made for age, tuba!

ligation, age at menarche, age at menopause, smoking end

body mass index.

Thus, the overall RR from cohort studies is around 0.8 for

ever use and 0.5 for long-term use, on the basis of

approximately 350 cases of ovarian cancer.

Although the total amount of data available from cohort

studies on oral contraceptive and ovarian cancer is limited,

and the possibilities of allowance for confounding are

restricted, the consistency of available findings supports the

existence of a real protective effect of oral contraceptive on

ovarian carcinogenesis.

Case-control studies

Epidemiological evidence from case-control studies on oral

contraceptive and ovarian cancer is well defined and

consistent: at least 20 out of 21 studies published between

1980 and 1997 found relative risks below unity, the sole

apparent outlier being a study conducted in China (Shu et al.,

1989). Table 2 gives the main results of case-control studies

of ovarian cancer published between 1980 and 1997.

Willett et al. (1981), in a case-control study of 47 cases of

ovarian cancer and 470 controls nested in the Nurses’ Health

Study cohort (based on 121,694 registered nurses aged 30-55

years in 1986 and residing in 11 larger US states) found an

age-adjusted RR of 0.8 (95% Cl 0.4-1.5) for ever oral

contraceptive use, and of 0.2 (95% CI 0.1-1.0) for women

aged 35 years or younger, who were more likely current or

recent users.

Table 1.

Selected cohort studies on combined oral contraceptives

(COC) and ovarian cancer, 1980-97

Hildreth ef al. (1981) considered 62 cases of epithelial

ovarian cancer and 1068 hospital controls aged 45-74 years

from Connecticut, diagnosed between 1977 and 1978. The

response rate was 71% for both cases and controls. The

multivariate RR for ever pill use, after allowance for age and

parity, was 0.5 (95% CI 0.2-1.5).

Weiss ef al. (1981), in a population-based case—control

study of 112 cases diagnosed between 1975 and 1979 from

Washington and Utah, found an RR (adjusted for

demographic factors and parity) of 0.6 for ever use and of 0.4

(95% CI 0.15-1.28) for longest use, of borderline statistical

significance (P = 0.04). Response rate was 66% for cases

and 92% for controls.

Franceschi ef al. (1982) considered data on 161 cases of

epithelial ovarian cancers and 561 hospital controls

interviewed in Milan, Italy in 1979-80. The age-adjusted RR

for ever pill use was 0.7 (95% CI 0.4-1.1).

Cramer ef al. (1982) in a population-based case—control

study of 144 cases and 139 population controls conducted

during the period 1978-81 the greater Boston area found an

RR, adjusted for age and parity, of 0.4 (95% CI 0.2-1.0) for

ever pill use, in the absence of a consistent duration risk

relationship (RR = 0.6 for >5 years). However, this could be

due to chance becasue of the small number of cases. The

response rate was around 50% for both cases and controls.

Rosenberg ef al. (1982), in a hospital-based case-control

study of 136 cases and 539 controls collected between 1976

and 1980 from various areas of the USA and Canada, found

an age-adjusted RR of 0.6 (95% CI 0.4-0.9) for ever pill use

and of 0.3 for use of >5 years. The response rate was 94%

for both cases and controls, and the results were not

materially modified by multivariate analysis.

Risch et al. (1983) provided data from a case-control study

of 184 cases and 705 controls from Washington and Utah

diagnosed between 1975 and 1979, giving a significant

multivariate RR estimate of 0.89 per year of oral

contraceptive use. Response rate was 68% for both cases and

95% for controls.

In a case-control study conducted in 1980-89 on 150 cases

and 250 hospital control from Athens, Greece, Tzonou ef al.

(1984) found a multivariate RR (adjusted for age, age at

menopause and use of HRT) of 0.4 (95% CI 0.1-1.1). The

lack of significance is explained through the low frequency

of oral contraceptive use in that population.

The Cancer and Steroid Hormone (CASH) study (1987)

was a population-based investigation conducted between

December 1980 and December 1982 in eight areas of the

USA on 546 women aged 20-54 years with ovarian cancer

(492 epithelial) and 4227 controls. The response rate was

71% for cases and 83% for controls. The multivariate RR,

adjusted for age and parity, for ever pill use was 0.6 (95% Cl

0.50.2), and decreased to 0.2 (95% CI 0.1-0.4) for use >10

years. The results were consistent when specific

formulations of oral contraceptives were considered

separately. However, no meaningful protection was evident

for very short-term use, i.e. 3-6 years (Gross ef al., 1992).

Harlow ef ail. (1988) provided information on oral

contraceptive use on 92 cases of borderline malignancy

epithelial ovarian cancers and 124 controls diagnosed

between 1980 and 1985. The RR for ever use, adjusted for

age and parity, was 0.4, in the absence, however, of a

consistent duration—trisk relationship.

Wu ef al. (1988), in a hospital-based case-control study of

299 cases and 752 controls diagnosed in 1983-85 from the

San Francisco Bay area found an RR, adjusted for parity, of

0.7 (95% CI 0.5-1.1) for ever OC use and of 0.4 (95% Cl

0.3-0.7) for >3 years of use. The overall RR per year of use

was 0.88 (95% CI 0.83-0.94). The response rate was about

70% for both cases and controls.

‘Shu et al. (1989) in a case-control study conducted in

1984-86 in Shanghai, China, on 229 ovarian cancer cases

(172 epithelial) and an equal number of controls found an RR

(adjusted for education, parity, ovarian cysts and age at

menarche) of 1.8 (95% CI 0.8-4.1) for ever oral contraceptive

tise. However, only 21 cases and 12 controls had only ever

tised oral contraceptive. The response rate was 89% for

tases and 100% for controls.

The World Health Organization (WHO) Collaborative

Study of Neoplasia and Steroid Contraceptives (1989)

imcluded data on 365 cases of histologically confirmed

epithelial ovarian cancer and 2397 hospital controls

interviewed between 1979 and 1986 in seven (mainly

developing) countries of the world. The response rate was

73% for cases and 94% for controls. The multivariate RR

{adjusted for age, centre, year of interview and parity) for

ever oral contraceptive use was 0.75 (95% CI 0.56-1.01), and

decreased to 0.54 (95% CI 0.33-0.58) for 10 years’ use or

longer. The protection was of similar magnitude in

developed and developing countries (Thomas, 1991).

In a case-control study conducted in 1978-81 in the

Washington, DC area, on 296 patients with epithelial ovarian

cancer and 343 hospital controls, Hartge ef al. (1989) found

RRs (adjusted for age and race) of 1.0 (95% CI 0.7-1.7) for

ever oral contraceptive use, and of 0.8 (95% CI 0.4-1.5) for

>5 years’ use. The response rate was 74% for cases and 78%

for controls.

Booth et al. (1989) in a hospital-based case-control study

of 213 cases and 451 controls interviewed between 1978 and

1983 in London and Oxford, England, found multivariate

RRs of approximately 0.5 for ever use, and of 0.1 (95% Cl

0.01-1.0) for >10 years’ use, with a significant inverse trend

in risk with duration of use. Allowance was made for age,

social class, gravidity and duration of unprotected

intercourse.

Parazzini ef al. (1991b) provided data on 505 cases of

epithelial ovarian cancer under 60 years of age and 1375

hospital controls interviewed between 1983 and 1989 in

northern Italy. § The multivariate RR (adjusted for

sociodemographic factors, parity, age at menarche, lifelong

menstrual pattern, menopausal status and age at menopause)

for ever oral contraceptive use was 0.7 (95% CI 0.5-1.0),

which decreased to 0.5 (95% CI 0.3-0.9) for >2 years’ use,

with a significant inverse trend in risk with duration.

Response rate was 98% for both cases and controls.

Parazzini ef al. (1991c) also considered 91 cases of

borderline malignancy epithelial ovarian cancer and 237

hospital controls interviewed between 1983 and 1990 in

northern Italy. The multivariate RR (adjusted for age,

education, parity and age at menopause) for ever pill use was

0.3 (95% CI 0.2-0.6), and that for >2 years’ use was 0.2

(95% CI 0.08-0.6). The response rate was 98% for both

cases and controls.

In a case-control study of 189 cases and 200 controls

conducted in 1989-91 in greater Athens, Greece

(Polychronopoulou ef al., 1993), only three cases and seven

controls reported ever pill use, corresponding to a

multivariate RR of 0.80 (95% CI 0.11-3.67). The response

rate for cases was about 90%.

Rosenberg ef al. (1994) updated their 1982 report,

iding data collected between 1977 and 1998 on 441

cases of epithelial ovarian cancer and 2065 hospital controls

from various US areas. The response rate was 94% for both

cases and controls. The multivariate RR for ever use was 0.7

(95% CI 0.6-1.0). No appreciable protection was observed

up to 3 years’ use, but the RR declined to 0.5 (95% CI 0.2-

0.9) for >10 years’ The risk estimates were similar for

various types of oral contraceptive formulations.

Risch ef al. (1994, 1996) provided data on 450 cases of

epithelial ovarian cancer aged 35-79 years and 564 controls

diagnosed between 1989 and 1992 in Ontario, Canada. The

response rate was 71% forcases and 65% for controls. The

overall multivariate RR per each year of pill use, adjusted for

age, parity, lactation, HRT use, tubal ligation, hysterectomy

andfamily history of breast cancer was 0.90 (95% CI 0.86-

0.94), and the protection was stronger for serous and

eridometrioid than for mucinous neoplasms.

Purdie et al. (1995) in a population-based study of 824

cases and 860 controls diagnosed between 1990 and 1993 in

three Australian states found an RR around 0.6 for ever use,

which declined to 0.26 (95% CI 0.18-0.38) for >10 years of

use. Response rate was 90% for cases and 73% for controls.

cage enh alg pen ged grange tyne

factors, family history of cancer, talc use, smoking, and

teproductive and hormonal factors.

The findings of two meta-analyses of case-control studies

bi the issue are also included in Table 2.

These were conducted on 971 cases and 2258 controls from

three European countries (Franceschi ef al., 1991) and on

2197 cases and 8893 controls in white women from 12 US

studies (Whittemore ef al., 1992) (i.e. a total of over 3100

tases, and 11 000 controls).

‘In the European meta-analysis (Franceschi et a/., 1991) the

fiultivariate RR was 0.6 (95% CI 0.4-0.8) for ever use, and

10a

0.4 (95% CI 0.2-0.7) for longest use. Allowance was made

for age and other sociodemo-graphic factors, menopausal

status and parity.

In the US meta-analysis (Whittemore ef al, 1992)

corresponding values were 0.7 (95% CI 0.5-0.6) for ever use

and 0.3 (95% CI 0.2-0.4) for use >6 years. Adjustment was

made for age, study and parity. The results were similar

when hospital- or population-based studies were considered

separately. The RRs were 0.7 for both types of studies for

ever oral contraceptive use, 0.6 for hospital-based and 0.3 for

population-based for longest use (>6 years), 0.95 and 0.90

(significant) per added year of use. An inverse association

was also observed in a further analysis of 110 black cases

and 251 black controls (RR = 0.7 for ever use and 0.6 for >6

years’ use; John ef al., 1993). The US meta-analysis also

included data on 327 borderline malignancy epithelial

ovarian neoplasms in white women. The RRs were 0.8 (95%

CI 0.6-1.1) for ever oral contraceptive use, and 0.6 (95% CI

0.40.9) for >S years’ use (Harris ef al., 1992).

Discussion

The most convincing aspect of the inverse relationship of

oral contraceptive on ovarian cancer risk is given by the

consistency of the results, independently from type of study

(hospital- or population-based), geographic area (North

America, Europe, Australia or developing areas of the world)

and type of analysis, including allowance for covariates,

which differed from study to study, but tended to include

larger numbers of variables in most recent ones. Likewise,

the inverse relationship between oral contraceptive and

ovarian cancer was observed for most types of formulations

considered, including low dose ones (CASH, 1987;

Rosenblatt et al., 1992; Rosenberg ef al., 1994).

The overall estimate of protection for ever use is

approximately 40%, and a steady inverse relationship exists

with duration of use. The protection was over 50%, and

probably around 60%, for long-term use (i.e. >5 years).

lla

Parity is a well-recognized protective factor for ovarian

cancer (Parazzini ef al., 1991a), and is a correlate of oral

contraceptive use, i.e. a potentially relevant confounder. The

inverse relationship between oral contraceptive and ovarian

cancer, however, also was observed after adequate allowance

for parity in most studies, and was consistently reproduced in

several studies across separate strata of parity, as well as of

age and of other potential covariates, including marital status,

education, menopausal status, other types of contraceptive

use, and other selected menstrual and reproductive factors.

Other potential confounding or indication bias, including

selective exclusion of oral contraceptive use by smokers and

by women at risk of liver and thromboembolic diseases

(Fioretti et al., 1997) were also unlikely to materially modify

the inverse association observed between oral contraceptive

use and ovarian cancer risk.

At least two studies (Harlow ef al., 1988; Parazzini ef ai.,

1991), and the meta-analysis of 12 US studies (Harris et ai.,

1992), also considered borderline epithelial ovarian tumours.

An inverse relationship was evident for these neoplasms too,

suggesting that oral contraceptives exert a protection to the

whole spectrum of epithelia] ovarian carcinogenesis.

Limited information is available on different histological

types of epithelial ovarian cancer. In a Canadian study

(Risch et al., 1996), the protection was apparently stronger

for non-mucinous (OR = 0.89 per year of use) than for

mucinous (OR = 0.98 per year of use) tumours. This

observation, however, requires confirmation in other data-

sets.

With reference to nonepithelial ovarian cancers, 38 germ

cell neoplasms and 45 sex-cord-stromal neoplasms were

considered from the collaborative analysis of 12 US case-

controls studies (Horn-Ross ef al., 1992). The multivariate

RRs among ever oral contraceptive users were 2.0 (95% Cl

0.8-5.1) for germ cell cancers and 0.4 (95% CI 0.2-0.8) for

sex-cord-stromal neoplasms. The data were inadequate for

12a

evaluating duration of use, or any other time-risk

relationship.

Likewise, the few available data indicate a consistent

protection of oral contraceptive on benign epithelial tumours

(ovarian cysts) (Parazzini ef al., 1989; Booth ef al., 1992),

but not on benign ovarian teratomas (Westhoff ef a/., 1988;

Parazzini et al., 1995).

The favourable effect of oral contraceptive on epithelial

ovarian cancer seems to persist for at least 10-15 years after

oral contraceptive use has ceased (Franceschi ef al., 1991;

Whittemore ef al., 1992; CASH, 1987; Rosenberg ef ai.,

1994), and is not confined to any particular type of oral

contraceptive formulation (Rosenblatt ef al, 1992;

Rosenberg ef al., 1994). There is some suggestion that low-

dose formulations may be slightly less protective: in the

WHO Collaborative Study on Neoplasia and Steroid

Contraceptives (Rosenblatt ef a/., 1992), the RR of ovarian

cancer for ever oral contraceptive use was 0.68 and 0.81 for

high- and low-dose preparations, respectively.

Very little information is available on progestin-only oral

contraceptives. In a hospital-based case-control study of 441

cases and 2065 controls recruited between 1977 and 1991

from various US states (Rosenberg et al., 1994), 1% of cases

versus 3% of controls had only ever used progestin-only oral

contraceptives. The unadjusted OR was 0.3.

From a biological viewpoint, the beneficial effect of oral

contraceptives on ovarian cancer risk has been interpreted

chiefly within the framework of the incessant ovulation

theory, i.e. a multistage theory of ovarian carcinogenesis

(Casagrande ef al., 1979). Ovariostasis, induced by oral

contraceptives as well as by pregnancy and menopause,

avoids the exposure of ovarian epithelium to recurrent trauma

and contact with follicular fluid (Parazzini et al., 1991a).

Oral contraceptive use may also protect against ovarian

cancer by reducing exposure to pituitary gonadotropins,

13a

which stimulate the growth of cell lines derived from human

ovarian carcinoma (Simon ef al., 1983). The lack of apparent

protection by menopause replacement therapy (Parazzini ef

al., 1991a; Whittemore ef al., 1992), however, does noi

support the existence of a favourable role of gonadotropin

stimulation on ovarian carcinogenesis.

Since the incidence of ovarian cancer is already appreciable

in middle age, and survival from the disease is unsatisfactory,

the protection attributable to oral contraceptive use

corresponds to a far from negligible number of deaths, and it

is therefore one of the major issues in any risk/benefit and

public health evaluation on the pill (Gross and Schlesselman,

1994; La Vecchia ef al., 1996). In such a sense, oral

contraceptives represent one of the most important available

chemopreventive agents.

Acknowledgements-This work was conducted with the

contribution of the Italian Association for Cancer Research.

The authors thank Mrs M.P. Bonifacino for editorial

assistance.

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17a

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18a

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19a

APPENDIX B

RESEARCH ARTICLE

OPEN ACCESS

PRIOR ORAL CONTRACEPTIVE USE IN OVARIAN

CANCER PATIENTS: ASSESSING ASSOCIATIONS

WITH OVERALL AND PROGRESSION-FREE

SURVIVAL

Aminah Jatoi ', Nathan R. Foster’, Kimberly R. Kalli’,

Robert A. Vierkant”, Zhiying Zhang’, Melissa C. Larson’,

Brooke Fridley‘ and Ellen L. Goode’

Abstract

Background: Prior studies have described a reduced risk

of developing ovarian cancer with the use of oral

contraceptives. In this context, we decided to examine if oral

contraceptive use prior to a diagnosis of ovarian cancer is

associated with better overall and progression-free survival.

Methods: This retrospective cohort study included ovarian

cancer patients who were seen at the Mayo Clinic in

Rochester, Minnesota from 2000 through 2013. Patients

completed a risk factor questionnaire about previous oral

contraceptive use, and clinical data were extracted from the

electronic medical record.

- Results: A total of 1398 ovarian cancer patients responded

to questions on oral contraceptive use; 571 reported no prior

‘use with all others having responded affirmatively to oral

contraceptive use. Univariate analyses found that oral

‘tontraceptive use (for example, ever versus never) was

* Correspondence: jatoi.aminah@mayo.edu

' Department of Oncology, Mayo Clinic, 200 First Street SW,

Rochester, MN 55905, USA

Full list of author information is available at the end of the article

20a

associated with better overall survival (hazard ratio (HR)

0.73 (95 % confidence interval (0): 0.62, 0.86); p = 0.0002)

and better progression-free survival (HR 0.71 (95 % CI: 0.61,

0.83); p < 0.0001). In multivariate analyses, contraceptive

use continued to yield a favorable, statistically significant

association with progression-free survival, but such was not

the case with overall survival.

Conclusions: This study suggests that previous oral

contraceptive use is associated with improved progression

free survival in patients diagnosed with ovarian cancer.

Keywords: Ovarian cancer, Survival, Oral contraceptives

Decades of data show that oral contraceptive use reduces

the risk of ovarian cancer. A greater than 20% relative risk

reduction appears to occur for every 5 years a woman reports

taking oral contraceptives [1]. This risk reduction is

particularly salient among women who have used oral

contraceptives for 10 years or longer at any point in their

lives, and it also occurs in high-risk women, such as those

with BRCAl and BRCA2 germline mutations [2].

Continuous ovulation is thought to predispose to ovarian

epithelial cell DNA damage, which in turn gives rise to

carcinogenesis, thus providing mechanistic plausibility to

how cessation of ovulation from oral contraceptives might

lead to lower cancer risk [3].

Although large pooled analyses suggest that oral

contraceptives could prevent 200,000 cases of ovarian cancer

and 100,000 deaths from this malignancy over 20 years, such

deductions have not spawned large-scale prevention trials [4,

5]. The many decades of follow up required to capture a

small number of cancer cases, the enormous funding

necessary to conduct prevention trials of sizable complexity,

and the fact that oral contraceptives can also confer negative

effects, such as an increased risk of thrombophlebitis and

breast cancer, all lessen enthusiasm for the conduct of such

prevention trials. Moreover, to date, the above robust

2la

observation has not yet dramatically changed clinical

practice.

In contrast to these data on ovarian cancer prevention, few

studies have specifically sought to assess whether oral

contraceptives prior to an ovarian cancer diagnosis is

associated with better outcomes after contracting this

malignancy. This possibility builds on previous data on the

purported role of oral contraceptives in preventing ovarian

cancer. Moreover, in contrast to primary prevention,

establishing this observation could lead to prospective

research aimed at improving outcomes in ovarian cancer

patients. Thus, to further examine the effects of previous oral

contraceptives on outcomes in ovarian cancer patients, we

studied patients at the Mayo Clinic in Rochester, Minnesota.

Our main aim was to determine whether oral contraceptive

use prior to a diagnosis of ovarian cancer is associated with

better overall and progression-free survival within the

context of in depth multivariate analyses undertaken within a

consecutively-recruited and monitored cohort of ovarian

cancer patients.

Methods

Overview

This study focused on women with invasive primary

epithelial ovarian, fallopian tube, or peritoneal cancer seen at

the Mayo Clinic in Rochester, Minnesota. The study of all

these hynors in aggregate has substantial precedent because

these malignancies behave and are treated similarly. The

Mayo Clinic Institutional Review Board (IRB) approved this

study. As described previously, patients were consecutively

recruited from 2000 through 2013 from the Mayo Clinic in

Rochester, Minnesota [6]. All patients had to be 20 years of

age or older and had to have provided written informed

consent. Patients then completed a paper risk factor

questionnaire (see below) that included queries on previous

oral contraceptive use. Trained medical personnel extracted

details on tumor histology, type of surgery, and

22a

administration of chemotherapy from the electronic medical

record.

Study endpoints

Outcome data were acquired through April 2014. Data on

cancer recurrence were updated via the Mayo Clinic

electronic medical record and included a mailed ques-

tionnaire to patients and medical record review. Vital status

was gleaned from the Mayo Clinic electronic medical record,

the Mayo Clinic Cancer Registry, and registration records.

Death certificates were requested from the appropriate

government bodies with the appropriate permissions to

confirm dates of death.

This study analyzed overall survival, as defined as the

interval from a histologic-or cytologic-confirmed cancer

diagnosis to date of death. If vital status was unknown for a

specific patient, that patient was censored on the date of last

contact or at five years, whichever occurred first. The

rationale for this approach rests in the fact that the majority

of ovarian cancer-related deaths occur in the first five years

after diagnosis. Progression-free survival was also assessed

and was defined as the date from cancer diagnosis to the date

of initiation of second-line cancer treatment or death.

Although vital status was assessed in all patients,

progression-free survival had been assessed in only a subset.

Definition of covariates

Oral contraceptive use was the main variable of interest,

and it was assessed by means of a self-administered

questionnaire. Patients were asked, “Have you ever used oral

contraceptive pills (“the pill”)?” and were asked to mark the

appropriate response of “yes” or “no.” If they answered

“yes,” they were then asked to estimate duration of use in

years, as summarized in this report as both a categorical

variable (1-48 months and > 48 months) and a continuous

variable. Other hormone-related variables were also

assessed; these included age at menarche and menopause

23a

status. Patients were also assessed for number of live births,

coded as nulliparous versus one or two versus three or more.

This grouping of parity was done because of efforts to

maintain statistical power and because it appeared clinically

reasonable.

A variety of clinical covariates, many of which have

prognostic associations, were also considered. These

consisted of 1) cancer stage; 2) cancer histology: high grade

serous, low grade serous, endometrioid versus clear cell,

mucinous, mixed epithelial, borderline invasive mixed

epithelial, and other; 3) tumor grade; 4) outcome of initial

Surgery: no residual disease versus </= 1 cm of residual

disease versus > 1 cm residual disease; 5) platinum-based

‘chemotherapy administered within the first three months of

‘surgery: yes versus no [7]; 6) patient age at cancer diagnosis;

7) smoking history: never versus former versus current; and

8) first degree family history of breast or ovarian cancer: yes

“Versus no.

Analyses

Chi-square or Wilcoxon rank-sum tests were used, as

appropriate, to compare all the covariates between never- and

éver- oral contraceptive users. Univariate analyses were

undertaken for al] the variables described above. Oral

contraceptive use was examined in two separate analyses: 1)

based on a “ever” and “never” patient response and 2) based

on duration of oral contraceptive use: never versus 1-48

tnonths versus > 48 months or patient-reported years of use

aS a continuous variable. All variables were examined to

assess their individual associations with overall survival and

progression-free survival. Kaplan Meier curves were

constructed to visualize unadjusted associations. Cox

proportional hazards modeling accounting for left truncation

was used for univariate and multivariate analyses with

estimation of HRs and 95 % Cls. Left truncation is a

Standard method undertaken to limit sampling bias when one

24a

is unable to consistently observe the time when an event

might have occurred.

Table 1

Demograpics

Multivariate analyses were then conducted to identify the

independent prognostic association of each of these variabies

and to estimate the effects of these variables on overall and

progression-free survival endpoints. Three models were

constructed with inclusion of 1) all variables except those

with high rates of missing data; 2) variables that, in

univariate analyses, had yielded a statistically significant

association (p < 0.01) with overall and disease-free survival;

and 3) variables that, in univariate analyses, had yielded a

statistically significant association with overall survival and

disease-free survival (p < 0.01) except those with notable

missing data. These models were constructed in this manner

to avoid biases that might arise from missing data. All

statistical tests were two-tailed, and a p-value of < 0.05 is

considered statistically significant. All statistical analyses

were performed using Statistical Analysis Software version

9.3 (SAS Institute, Cary, North Carolina).

Results

Demographics

This study focused on 1398 ovarian cancer patients who

had completed a questionnaire on oral contraceptive use at

study entry. Within this cohort, 571 reported no prior oral

contraceptive use. Among oral contraceptive users, the

patient-reported median duration was 60 months (range: | to

444 months).

Baseline characteristics appear in Table 1. Patients who

had used oral contraceptives were more likely to have had no

residual disease from surgery but were less likely to have

started platinum-based chemotherapy after surgery. Patients

25a

who had used oral contraceptives were also diagnosed at an

earlier age and had fewer live births.

Overall survival and progression-free

At the time of this report, 562 patients had died, and 656

had developed recurrent cancer or had died after accounting

for left truncation. Univariate analyses, which do not take

into account confounding factors, suggested that oral

contraceptive use (ever versus never) was associated with

better overall survival (HR 0.73 (95 % CI: 0.62, 0.86); p =

0.0002) (Fig. 1). Similarly, univariate analyses also suggest

oral contraceptives (ever versus never) was associated with

more favorable progression-free survival (hazard ratio (HR)

0.71 (95 % confidence interval (CI): 0.61, 0.83); p < 0.9001)

(Fig. 2). These survival advantages were also observed when

oral contraceptive use was further characterized based on

duration of use. Compared to never users, patients who

reported using oral contraceptive for one to 48 months

manifested a more favorable overall survival and

progression-free survival, as did patients who reported using

them for more than 48 months (data not shown).

In the three constructed multivariate models, oral

contraceptive use did not yield a statistically significant

improvement in overall survival, but it did yield such an

association with improved progression-free survival (Table

2).

Of note, the multivariate models pointed to patient age as a

major confounder, as younger age was strongly associated

with oral contraceptive use. For example, in the first model,

with no adjustment for age, oral contraceptive use was, in

fact, associated with better overall survival (HR = 0.70; p <

0.001) as well as with better progression—free survival.

However, after adjusting for age, this association with overall

‘survival lost its statistical significance, although the

association with improved progression-free survival was

maintained. Furthermore, we performed separate analyses on

associations with oral contraceptive use and overall survival

26a

and progression-free survival based on whether patients had

residual disease postoperatively and found these prognostic

associations with oral contraceptive use were sustained.

*¢+*s

Fig. 1

***

Fig. 2

Discussion

This study examined whether oral contraceptive use prior

to a diagnosis of ovarian cancer was associated with

improved overall survival and progression-free survival. We

observed this protective association in univariate analyses,

but multivariate analyses yielded less consistent findings. In

the latter, prior oral contraceptive use was associated with

improved progression-free survival but not with overall

survival. Younger patients reported greater use of oral

contraceptives as well as longer survival. This study

provides corroborative evidence that previous oral

contraceptive use is associated with better clinical outcomes

in patients diagnosed with ovarian cancer, at least with

respect to progression-free survival.

Indeed, our findings are particularly noteworthy because of

the detailed nature of our multivariate analyses. The fact that

we were able to adjust for highly relevant clinical covariates

such as the extent of the primary debulking surgery and the

fact that we had detailed follow up information on

consecutively-treated patients strengthen this report. Our

study provides an important contribution to an emerging

body of literature that indicates oral contraceptive use prior

to a diagnosis of ovarian cancer is associated with better

outcomes. Only a few studies have examined whether oral

contraceptives appear to change outcomes in patients who

develop ovarian cancer at a later date. First, using the

Nurses’ Health Study, the New England Case-control Study,

the Australian Ovarian Cancer Study, and the NIH-AARP

27a

Diet and Health Study, Poole and others examined numerous

lifestyle factors and their effect on clinical outcomes in

ovarian cancer patients [5]. Among 4,342 patients with

Ovarian cancer, previous oral contraceptive use was

associated with a lower risk of death (five-year increase in

relative risk 0.69 (95 % confidence interval (CI): 0.58, 0.82)).

These investigators noted that their study design might not

have captured patients with rapidly fatal malignancies and

that limited clinical data were available to accommodate

some of their analyses. Nonetheless, this observation appears

plausible, particularly given the earlier-referenced studies

that have focused on cancer prevention. Second, several

investigators, including Vessey and others from the Oxford

Family Planning Association Contraceptive Study,

Hannaford and others from the Royal College of General

Practitioners’ Oral Contraceptive study, and those from the

Collaborative Group on Epidemiological Studies of Ovarian

Cancer have also reported decreased overall mortality among

Ovarian cancer patients who had used oral contraceptives

prior to their cancer diagnosis [1, 8, 9]. The above two

studies used a cohort design of oral contraceptive users and

non-users and reported on death from ovarian cancer. These

studies confirm the observation from Poole and others,

although their primary goal was to understand cancer risk.

Table 2

Multivariate analyses for overall survival and

progression-free survival

***

However, not all studies of oral contraceptive use and

outcome have been consistent. For example, Nagle and

others reported on 676 women diagnosed with ovarian

cancer, and, although 310 women had used oral contra-

beptives, the latter did not demonstrate a protective

association with respect to ovarian cancer mortality (adjusted

hazard ratio (HR) 0.88 (95 % CI: 0.70, 1.11) [10]. This study

examined a cohort of women with ovarian cancer and looked

28a

at survival of cancer patients who were users of oral

contraceptives and cancer patients who were not users of oral

contraceptives. These authors concluded that “reproductive

and hormonal exposures prior to diagnosis do not influence

survival from invasive ovarian cancer, in contrast to their

substantial effects on the etiology of this disease,” and others

have drawn similar conclusions [11]. Taken together, these

studies provide justification for generating the study reported

here.

Is this favorable association between prior oral

contraceptive use and survival mechanistically plausible? It

appears to be. First, as alluded to earlier, previous studies

that have shown oral contraceptives protect against the

development of primary ovarian cancer suggest that cessation

of ovulation halts the repeated monthly trauma that occurs on

the surface of the ovary, thereby limiting the possibility of

epithelial cell mutation and subsequent carcinogenesis [3].

Similar mechanisms might be invoked to explain the

favorable prognostic associations observed here. In an

analogous fashion, epithelial ovarian cancer cells that

undergo repeated, monthly trauma from ovulation are

perhaps more likely to develop DNA mutations. The more

frequent the trauma, the more apt these cells are to develop

aberrant DNA mutations; the more numerous the DNA

mutations, the more aggressive the cancer [12]. Although

this line of thinking may contradict the hypothesis that

ovarian cancer originates from fallopian tube fimbria, it

nonetheless merits consideration, particularly because the

fimbria are also exposed to hormones in the follicular fluid

[13]. Second, in a preclinical model, Romero and others

observed that contraceptive hormone exposure decreased

matrix metalloproteinase-2 activity, invoking this

observation to explain the effects of oral contraceptives on

carcinogen-esis and perhaps also on the improved clinical

outcomes observed by us and others [14]. One might

speculate that the role of matrix metalloproteinase-2 proteins

29a

in modifying the extracellular matrix confers long-term

consequences that attenuate the malignant potential of

ovarian cancers and provide greater susceptibility to cancer

treatment. In view of a growing literature that underscores

an inverse association between oral contraceptive use and

poor outcomes from ovarian cancer, it appears important to

probe into and delineate the mechanisms that underlie these

observations, such as those posited above.

Our study has at least three limitations. First, the

questionnaire we used did not capture detailed information

on oral contraceptive product formulation, which may be

informative, as oral contraceptives with high progesterone

content appear to carry a more protective effect [15].

Second, the exact cause of death for many patients is still

being curated and thus cause-specific mortality was not

analyzed here, although our use of censoring data at date of

last contact and limiting follow up to 5 years post-diagnosis

are attempts to mitigate this limitation. Nonetheless, it

remains possible that deceased older patients had died more

frequently of non-cancer causes, a plausible scenario that

inight explain why our study did not reveal an improvement

‘in overall survival with oral contraceptive use in multivariate

analyses, despite having captured an improvement in

progression-free survival. Finally, this study provides

limited data on how recently oral contraceptives had been

used, and such timing issues would likely have an important

fiipact on the strength of this association. Despite such

tithitations, our study - coupled with several that preceded it

points to a need to investigate mechanisms that explain how

and why prior oral contraceptive use appears to improve

tical outcomes in ovarian cancer patients. Understanding

such mechanisms might lead to more effective therapeutic

‘ifitetventions in patients diagnosed with this malignancy.

Competing interests

The authors declare that they have no competing interests.

30a

Authors’ contributions

AJ, NF, KK, RV, ZZ, ML BF, and EG contributed to the

conception, design, analysis, and interpretation of data. AJ,

NF, KK, RV, ZZ, ML BF, and EG were all involved in

drafting the manuscript or revising it critically for important

intellectual content. All authors have given final approval of

the version to be published. All agree to be accountable for

all aspects of this work.

Acknowledgement

The authors acknowledge Karin Goodman, APRN, CNP

for her work in abstracting the data from the clinical records

for this study. This work was supported in part by

P50CA136393, P30CA15083, and ROICA122443 from the

United States’ National Cancer Institute.

Author details

‘Department of Oncology, Mayo Clinic, 200 First Street

SW, Rochester, MN 55905, USA. *Department of Health

Sciences Research, Mayo Clinic, Rochester, MN, USA.

‘Department of Kinesiology and Community Health,

University of Illinois at Urbana-Champaign, Champaign, IL

USA. “Department of Biostatistics, University of Kansas

Medical Center, Kansas City, KS, USA.

Received: 26 February 2015 Accepted: 10 October 2015

Published online: 15 October 2015

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L, Lee Al. Cancer risk among users of oral

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33a

APPENDIX C

ORIGINAL PAPER

ORAL CONTRACEPTIVE USE AND IMPACT OF

CUMULATIVE INTAKE OF ESTROGEN AND

PROGESTIN ON RISK OF OVARIAN CANCER

M. T. Faber, A. Jensen, K. Frederiksen, E. Glud, E.

Hegdall, C. Hegdall, J. Blaaker, S. K. Kjzr

Abstract

Purpose Oral contraceptive use decreases the risk of

Ovarian cancer, but no previous studies have assessed the

impact of cumulative intake of estrogen and progestin on

Ovarian cancer risk.

Methods We used data from a population-based case-

control study conducted in Denmark in 1995-1999 among

women aged 35—79 years; 554 women with epithelial ovarian

cancer and 1,564 age-matched controls were included in the

analyses. Data were analyzed in multiple logistic regression

models.

Results The use of combined oral contraceptives only and

the mixed use of combined and progestin-only pills

decreased the risk of ovarian cancer, while no association

was found with exclusive use of progestin-only pills. No

major differences in risk were found for users of combined

oral contraceptives with high- and low-potency estrogen and

progestin. There was no effect of cumulative progestin

intake, but decreased risks of ovarian cancer with increasing

cumulative intake of estrogen (OR = 0.82; 95 % CI 0.67-

0.99, per 100 mg estrogen) and increasing duration of oral

contraceptive use (OR = 0.95; 95 % CI 0.92-0.98, per year of

\ise) were found. No effect of cumulative estrogen intake

was found, however, after adjustment for duration of oral

contraceptive use.

34a

Conclusions The protective effect of oral contraceptives

against ovarian cancer may be sufficiently explained by

duration of anovulation. This suggests that if the estrogen

and progestin doses are sufficient to cause anovulation, a

higher intake of estrogen or progestin confers no extra

protection against ovarian cancer.

Keywords Ovarian cancer - Oral contraceptives - Estrogen

- Progestin - Potency - Duration - Case—control study

M. T. Faber, A. Jensen, K. Frederiksen, E. Hogdall, S. K. Kjer

Virus, Lifestyle and Genes, Danish Cancer Society Research

Center, Strandboulevarden 49, 2100 Copenhagen, Denmark

e-mail: susanne@cancer.dk

E. Glud

Department of Gynecology and Obstetrics, Nordsjzllands

Hospital, Hillerad, Denmark

E. Hogdall

Department of Pathology, Herlev University Hospital,

Copenhagen, Denmark

C. Hogdall, S. K. Kjer

Department of Gynecology, Rigshospitalet, University of

Copenhagen, Copenhagen, Denmark

J. Blaakzr

Department of Obstetrics and Gynecology, Aarhus University

Hospital, Skejby, Denmark

Introduction

It is well known that oral contraceptive use decreases the

risk of ovarian cancer [1, 2]. The protective effect is

concordant with the “incessant ovulation” hypothesis, which

propo: *s that repeated, uninterrupted ovulations during the

reproductive years cause micro-trauma to the ovarian surface

epithelium, leading to malignant transformation [3]. The

decreased risk of ovarian cancer associated with oral

contraceptive use may not be due to anovulation alone,

however, as oral contraceptives are known to suppress

secretion of gonadotropic hormones from the pituitary gland,

35a

including follicle-stimulating hormone and __ luteinizing

hormone, which are suggested to increase ovarian cancer risk

by increased cell growth and inhibition of apoptosis [4].

Furthermore, oral contraceptives may reduce ovarian cancer

risk by increasing progestin stimulation [5]. In experimental

studies, progestin inhibited the growth of ovarian epithelial

cells [6], and the synthetic progestin levonorgestrel induced

apoptosis in ovarian surface epithelium [7].

Most oral contraceptive pills contain a combination of

estrogen (ethinylestradiol or mestranol) and progestin, but

progestin-only preparations exist as well. Since they became

available, considerable changes have been made in the

estrogen and progestin content of combined oral contraceptives

with regard to generic substance, dose, and potency (i.e., the

amount required to produce an effect of given intensity) [8].

The first oral contraceptives introduced contained 50 j.tg

ethinylestradiol (or an equivalent 100 j.tg mestranol) and are

‘referred to as “high-dose” oral contraceptives, whereas so-

Called “low-dose” oral contraceptives, which were introduced

in the late 1970s, contained 20-40 j.tg ethinylestradiol [8].

At the same time as the reduction in estrogen dose, new types

of progestins were developed [8]. Concern has been raised

that the newer types of oral contraceptives do not protect

‘against ovarian cancer to the same degree as the older high-

Yose formulations [9]; however, relatively few observational

Studies have addressed whether the specific hormone content

bf oral contraceptives affects the degree of protection against

“ovarian cancer, and the findings are equivocal [9—16].

Furthermore, to our knowledge, no studies have been

published that assessed the possibility of an independent

effect of cumulative intake of estrogen and progestin from

bral contraceptives (i.e., lifetime doses of estrogen and

progestin from oral contraceptives) on ovarian cancer risk

nd thus whether the protective effect may be explained by

mechanisms other than anovulation.

36a

Using data from a large Danish population-based case-

control study on ovarian cancer, the MALignant OVArian

cancer study (MALOVA), we examined the association

between oral contraceptive use and risk of ovarian cancer.

We collected comprehensive information on the estrogen and

thus able to examine the impact of cumulative intake of

estrogen and progestin on ovarian cancer risk.

Materials and methods

The study is based on the data from the MALOVA study,

which has been described in detail elsewhere [17].

Between January 1995 and May 1999, women aged 35-79

years who were scheduled for an explorative laparotomy or

laparoscopy because of a suspicion of an ovarian tumor were

asked to participate in the study. The women were recruited

from 16 gynecological departments in Denmark. Women

with ovarian tumors were interviewed personally as soon as

possible after the diagnosis by trained nurses and were asked

to give blood and tissue samples. A total of 959 women with

histologically verified ovarian cancer were identified. Of

these, 53 were considered too ill to participate, and 45 died

before contact was made, leaving 861 eligible cases. Of

these, 180 women did not wish to participate, leaving 681

women (79.1 %) who were included in the MALOVA study;

579 gave a personal interview and blood and tissue samples,

and 102 gave only a blood sample. For the present study,

women who gave only a blood sample and women with non-

epithelial ovarian cancer (nm = 25) were excluded, leaving 554

women with ovarian cancer for the final analyses: 343 with

serous, 50 with mucinous, 75 with endometrioid, 44 with

clear cell, and 42 with other histological types of ovarian

cancer (including undifferentiated and papillary

adenocarcinomas).

Using the unique Danish personal identification number as

the key identifier, we drew a random sample of women aged

35—79 years from the general female population in the study

37a

area. The controls were included simultaneously with cases

and frequency matched in five-year intervals using the age

distribution of women with ovarian cancer registered in the

Danish Cancer Registry in 1987—1992. In all, 3,839 women

were invited as controls with a personal interview and a

blood sample. Contact could not be achieved with 301

women, 269 women were excluded because they had

undergone bilateral oophorectomy, six women had moved

out of the study area, and 126 women were too ill to

participate, leaving 3,137 women as eligible controls. Of

these, 1,021 women refused to participate in the study. There

were therefore 2,116 (67.5 %) controls; 1,564 were

interviewed personally and 552 by telephone. We included

only the 1,564 women with a personal interview as controls,

as the telephone interview did not include detailed

information about oral contraceptive use.

~ During the interviews, the women were asked whether they

had ever used combined oral contraceptives or progestin-only

pills for at least one month. A life-event calendar and lists and

color photographs of all brands on the market in Denmark

between January 1, 1966, and December 31, 1994, were used

to obtain detailed information about oral contraceptive use.

Each woman was asked in which period and for how long

she had used a specific brand. To help the woman recall the

Specific brand name, she was shown photographs of oral

tontraceptive brands marketed in the relevant period. If she

€ould not recognize the brand from the photographs, her

tisage was recorded as “unspecified oral contraceptive use.”

‘As mestranol (100 j.tg) is approximately equipotent to

'tthiny-lestradiol (50 j.tg) [18], formulations containing more

‘fian 100 j.tg mestranol or 50 j.tg ethinylestradiol were

‘tategorized as “high-estrogen,” whereas formulations

‘containing <100 j.tg mestranol or 50 j.tg ethinylestradiol

‘Were categorized as “low-estrogen” formulations. There are

‘ho universally recognized standards for categorizing

‘progestin potency; however, as in previous studies [14, 16], we

38a

categorized formulations with a dose equivalent to 0.30 mg

norgestrel or more as “high-progestin” and formulations with

<0.30 mg norgestrel or its equivalent as “low-progestin”

according to Grant’s glycogen deposition assay as described

by Dickey and Stone [19]. Characterization of progestins not

described in the paper by Dickey and Stone was performed

using information from other sources [15, 16, 20]. Table |

shows the different types of progestins that were contained in

the formulations used and their categorization as either high

or low dose.

Table 1

Characterization of progestins

Statistical analysis

Associations between various measures of oral contraceptive

use and risk of ovarian cancer were estimated in multiple

logistic regression models and expressed as odds ratios

(ORs) with corresponding 95 % confidence intervals (CIs).

All analyses were adjusted for age in five-year categories

corresponding to the sampling of controls. Furthermore, all

analyses were adjusted for pregnancy (ever/never pregnant

and number of pregnancies), family history of breast and/or

ovarian cancer (yes/no), and hormone replacement therapy

use (ever/never). These potential confounders were selected

on the basis of a priori knowledge of their possible role in the

development of ovarian cancer. We also considered other

potential confounders (menopausal status, breast-feeding,

maternal age at first and last pregnancy, tubal ligation,

hysterectomy, body mass index, smoking status, and

education) and included them in the final model if they

altered the estimate for the association between ever/never

use of any oral contraceptives and ovarian cancer risk by 10

% or more. However, this was not the case for any of the

additional confounders, and therefore, none of them were

included in the final logistic regression model.

39a

Three analytical approaches were used. First, the associations

with (a) the use of combined oral contraceptives only, (b) the

use of progestin-only pills only, and (c) the mixed use of

combined and progestin-only pills, respectively, and risk of

Ovarian cancer were investigated. Secondly, the association

between the use of combined oral contraceptives according to

hormone potency and ovarian cancer risk was examined.

Finally, the associations between cumulative lifetime dose of

estrogen and progestin and duration of oral contraceptive use,

respectively, and ovarian cancer risk among women with a

specified use of combined oral contraceptives and progestin-

only pills were assessed. For the latter analysis, two models

were fitted. Model 1 included adjustment for the selected

potential confounders, while model 2 also included mutual

adjustment between cumulative intake of estrogen,

cumulative intake of progestin, and duration of oral

contraceptive use.

Women with mixed use (i.e., women who used different

kinds of combined oral contraceptives), women who did not

remember the brand they had used, and women who used

only progestin-only pills were excluded from the analyses

concerning hormone potency. Among women with a

specified use of oral contraceptives, the cumulative intake of

estrogen and progestin from combined oral contraceptives and

progestin-only pills was calculated by summarizing the

intake (i.e., the specific dose multiplied by duration of use)

for each period the woman had used oral contraceptives.

‘Women who could not remember the name of the brand they

had used were excluded from the analyses on cumulative

intake of estrogen and progestin.

The linearity of the association with each of the quantitative

variables (number of pregnancies, cumulative intake of

estrogen and progestin, and duration of oral contraceptive

tise) was tested by comparison with a linear spline model

with knots placed at the quartiles among cases by means of a

likelihood ratio test. No significant deviation from linearity

40a

was found for any of these variables (p (0.05), except for

cumulative intake of progestin (p = 0.02). In model 2,

however, with mutual adjustment between cumulative

progestin intake, cumulative estrogen intake, and duration of

oral contraceptive use, no significant deviation from linearity

was observed for cumulative progestin intake (p = 0.53).

Associations between cumulative estrogen and progestin intake

and duration of oral contraceptive use, respectively, and

ovarian cancer risk were illustrated graphically by fitting a

linear spline with knots placed at the quintiles.

As the generic content of each contraceptive preparation

varied, we tested whether the effect of different types of

estrogens and progestins varied. The effect of the two

artificial estrogens, ethinylestradiol and mestranol, in oral

contraceptives was not statistically significantly different (p

= 0.88). Progestins were divided into four major groups on

the basis of their chemical derivation: estranes (nor-

ethisterone, lynestrenol, and ethynodiol), old gonanes

(levonorgestrel and norgestrel), pregnanes (megestrol acetate,

cyproterone acetate, and medroxyprogesterone acetate), and

new gonanes (gestodene, norgestimate, and desogestrel)

(Table 1). No statistically significantly difference was found in

the association between the use of these four groups of

progestins and ovarian cancer risk (p = 0.12). Because of a

limited number of cases, we were unable to test differences

in the effect of the progestins within the four groups.

All p values were two-sided, and a significance level of 5

% was used. All analyses were performed using the SAS

software package (version 9.2; SAS Institute, Cary, NC,

USA).

Results

Table 2 shows age-adjusted ORs for the associations

between potential confounders and ovarian cancer risk. Ever

being pregnant (OR = 0.38; 95 % CI 0.28-0.52) and ever

breast feeding (OR = 0.52; 95 % Cl 0.41-0.66) both

decreased the risk of ovarian cancer. In contrast, an

4la

increased risk of ovarian cancer was observed among women

who had ever used hormone replacement therapy (OR =

1.26; 95 % CI 1.02—1.55), women with a family history of

breast and/or ovarian cancer (OR = 1.44; 95 % CI 1.10—

1.90), and women who had been hysterectomized (OR =

1.55; 95 % CI 1.15~-2.08). The associations between

menopausal status, tubal ligation, education, body mass

index, smoking status, and risk of ovarian cancer were not

statistically significant.

Table 2

Age-adjusted odds ratios (OR) and 95% confidence inervals

(CI) for the association between various potential confounders

and risk of ovarian cancer

Table 3 shows the characteristics of oral contraceptive use.

Any use of oral contraceptives was reported by 46 % of cases

and 57 % of controls. Combined oral contraceptive use only

was reported by 40 % of cases (88 % of ever users) and 48 %

of controls (84 % of ever users). Exclusive use of progestin-

only pills was reported by 1.8 % of both cases and controls (4

% of ever users among cases and 3 % of ever users among

controls), while the mixed use of combined and progestin-

only pills was reported by 3.8 % of cases (8 % of ever users)

and 7.5 % of controls (13 % of ever users). Among both

cases and controls, most women had started using oral

‘contraceptives when they were first introduced onto the

Danish market, i.e., in 1966 or 1967. This was reflected in

the time since first and last use of oral contraceptives, as

most women in both the case and the control group had first

used the products 25 years or more before diagnosis or

interview and had last used them 20 years or more before

diagnosis or interview. Most of the case women had used

oral contraceptives for fewer than five years, whereas almost

equal numbers of control women had _ used oral

contraceptives for fewer than five years and for five years or

more. The cumulative intake of estrogen varied from 0.63 to

42a

732.6 mg (data not shown), and 35 women with ovarian

cancer (25.4 % of specified oral contraceptive users) and 195

control women (32.0 % of specified oral contraceptive users)

had a cumulative estrogen intake of 130 mg or more.

Cumulative intake of the progestin component ranged from

3.15 to 46,879 mg (data not shown), and 37 cases (25.5 % of

specified oral contraceptive users) and 156 controls (24.7 %

of specified oral contraceptive users) had a cumulative

progestin intake of 3,500 mg or more. In all, 145 case

women (57.5 % of ever users) and 632 control women (71.0

% of ever users) provided information about estrogen and

progestin dose.

Table 3

Characteristics of oral contraceptive use among ovarian

cancer cases and controls

se?

Exclusive use of combined oral contraceptives was

associated with a statistically significantly decreased risk for

ovarian cancer (OR = 0.68; 95 % CI 0.53-0.88), while no

association was observed for the solitary use of progestin-

only pills (OR = 0.97; 95 % CI 0.45—2.14). The mixed use of

combined and progestin-only pills also decreased the risk

(OR = 0.50; 95 % CI 0.28—0.87) (Table 4).

Table 4

Adjusted odds ratios (ORs) and 95% confidence intervals (CIs)

for the association between different measures of oral

contraceptive use and risk of ovarian cancer

The risk of ovarian cancer associated with oral

contraceptive use according to hormone potency was assessed

in 395 case women and 1,039 control women with a

specified use of combined oral contraceptives (Table 5).

These women used the same brand of combined oral

contraceptives in all the periods of oral contraceptive use.

The risk decreased with the use of both high- and low-

potency progestins compared with never use of combined

43a

oral contraceptives, although the association was statistically

significant only among users of high-potency progestins (OR

= 0.59; 95 % CI: 0.42-0.83). Likewise, the associations

between the use of both high- and low-potency estrogen

formulations and ovarian cancer risk revealed a protective

effect of estrogen, although the effect was statistically

significant only for users of high-potency estrogens (OR =

0.60; 95 % CI: 0.44—0.83). In analyses for users of combined

oral contraceptives only, no statistically significant difference

in ovarian cancer risk was found between the use of high-

potency progestin and the use of low-potency progestin or

between the use of high-potency estrogen and the use of low-

potency estrogen. When combined oral contraceptives were

categorized into four groups based on different combinations

of high- or low-petency estrogen and progestin, a statistically

Significantly lower risk uf ovarian cancer was found for users

of high-estrogen/high-progestin formulations than for never

‘users (OR = 0.57; 95 % CI 0.41-0.80). For the other

‘vombinations of high- and low-potency estrogen and

progestin, for which there were a limited number of cases

and controls, no convincing associations with risk of ovarian

‘cancer were seen. Furthermore, when users of high-

estrogen/high-progestin formulations served as the reference

proup, no major differences were found among the four

| Table 5

‘Adjusted odds ratios (ORs) and 95% confidence intervals (CIs)

of ovarian cancer among women with a specified use of

combined oral contraceptives, according to hormone potency

ses

Table 6 shows the associations between cumulative intake

Of estrogen and progestin and duration of oral contraceptive

lise, respectively, and ovarian cancer risk among 446 cases

and 1,305 controls with a specified use of oral

contraceptives. Cumulative estrogen intake was associated

with a statistically significantly decreased risk of ovarian

44a

cancer (OR = 0.82; 95 % CI 0.67-0.99, per 100 mg

estrogen), while cumulative progestin intake did not

influence the risk. Furthermore, increasing duration of oral

contraceptive use decreased the risk (OR = 0.95; 95 % CI

0.92-0.98, per year of use). When the three variables were

mutually adjusted, each extra year of oral contraceptive use

decreased the risk of ovarian cancer by 6 % (94 % CI 0.89-

0.98, per year of use), but the protective effect of cumulative

estrogen intake was no longer present.

The last result is presented in more detail in Fig. 1, which

depicts the risk of ovarian cancer (OR) as a function of (a)

cumulative estrogen intake, (b) cumulative progestin intake,

and (c) duration of oral contraceptive use among women with

a specified use of oral contraceptives. The curves for

cumulative estrogen and progestin intake show no apparent

association with ovarian cancer risk, while the curve for

duration of oral contraceptive use shows that the risk

decreased with duration of use independently of the

cumulative intake of estrogen and progestin.

As shown in Table 7, associations between cumulative

estrogen and progestin intake and duration of oral

contraceptive use, respectively, and risk of histological types

of ovarian cancer were generally similar to those observed

for overall ovarian cancer. Because of smaller numbers of

cases, however, the risk estimates for the different

histological types (mucinous, clear cell, and other ovarian

cancers in particular) were less precise than those for overall

ovarian cancer. The association with duration of use was

strongest for ovarian cancer of serous and endometrioid

origin, but absent for mucinous ovarian cancer.

Table 6

Adjusted odds ratios (ORs) and 95% confidence intervals (CIs)

of ovarian cancer according to cumulative estrogen and

progestin intake and duration of oral contraceptive use among

women with a specified use of oral contraceptives

45a

Fig 1

*s +s

Discussion

In this population-based case-control study, we find that

the use of combined oral contraceptives and the mixed use of

combined and progestin-only pills decrease the risk of

ovarian cancer; no association is found with exclusive use of

progestin-only pills. In relation to the effect of hormone

potency, no major differences in risk of ovarian cancer is

found between the use of combined oral contraceptives with

high- and low-potency estrogen and progestin. We find no

effect of cumulative progestin intake but do observe a

decreased risk of ovarian cancer with increasing cumulative

estrogen intake and increasing duration of oral contraceptive

use. When cumulative progestin intake, cumulative estrogen

intake, and duration of oral contraceptive use are mutually

adjusted, however, the effect of cumulative estrogen is no

longer present, while the decreased risk associated with

duration of oral contraceptive use persists. Thus, our results

indicate that the protective effect of oral contraceptives

against ovarian cancer is independent of the estrogen and

progestin dose and may be sufficiently explained by duration

of anovulation.

’ The decreased risk of ovarian cancer associated with the

use of combined oral contraceptives observed in this study

confirms previous findings [15, 16, 21]. Our observation that

tach extra year of oral contraceptive use decreased the risk of

Ovarian cancer by 6 % is in agreement with other studies,

Which showed risk reductions of 5-8 % per year of use [12,

14, 21, 22}.

Few studies have examined the effect of high- and low-

potency contraceptives on ovarian cancer risk, and the

findings were ambiguous. In line with our results, some

Studies found that the protective effect was independent of

the potency of estrogen [9, 11, 13]. In contrast, one case~

46a

control study [10] found less protection against ovarian

cancer with low-estrogen formulations than with high-

estrogen formulations, while another case-control study [12]

showed greater protection from low- than from high-estrogen

pills. However, in none of these studies were the differences

statistically significant. In a recent review, Cibula et al. [23]

concluded that the protective effect of oral contraceptives

against ovarian cancer risk did not differ between users of

high- and low-estrogen formulations.

With regard to the progestin component of oral

contraceptives, we found no difference in the protective effect

of those with high- and low-potency progestins. Other

studies have found associations between progestin potency

and ovarian cancer risk. In an experimental study, Rodriguez

et al. [7] found that progestin induced apoptosis in the

ovarian epithelium of macaques, leading to the hypothesis

that the progestin component may be the major factor in the

protective effect of combined oral contraceptives. In line

with this hypothesis, supported in a review by Risch [5], two

case-control studies showed that oral contraceptives containing

high-dose progestin conferred greater protection against

ovarian cancer than those with low-dose progestin [14, 15].

Conversely, another case-control study found that the use of

low-progestin formulations reduced the risk more

substantially than the use of high-progestin formulations

[16].

Table 7

Adjusted odds ratios (ORs) and 95% confidence intervals (CIs)

of histological types of ovarian cancer according to cumulative

estrogen and progestin intake and duration of oral

contraceptive use among women with a specified use of oral

contraceptives

The primary mechanism of action of combined oral

contraceptives is prevention of ovulation [23] by inhibiting

the production and secretion of follicle-stimulating and

47a

luteinizing hormones by steroid feedback on the pituitary

gland. The estrogen component inhibits the release of

follicle-stimulating hormone and thus suppresses the

development of the dominant ovarian follicle, while the

progestin component inhibits the release of luteinizing

hormone thereby preventing ovulation. Progestin-only pills

partly suppress ovulation, but the anovulatory effect varies.

However, the progestins also thicken the cervical mucus and

decrease tubal motility, thereby creating a difficult passage

for sperm. Furthermore, progestins thin the endometrium,

resulting in tissue less receptive for implantation [24—26].

We are the first to report on the association between

cumulative lifetime dose of estrogen and progestin and risk

of ovarian cancer. The risk of ovarian cancer decreased with

increasing duration of oral contraceptive use but not with

cumulative estrogen and progestin intake, supporting the

“incessant ovulation” theory, according to which chronic

ovulation contributes to ovarian cancer by causing repeated

trauma of the ovarian surface epithelium {3}. This suggests

that, as long as the dose of estrogen and progestin is

sufficient to cause anovulation, a higher intake of estrogen or

progestin will not further protect against ovarian cancer.

Therefore, the protective effect of oral contraceptive use on

ovarian cancer risk is likely to be sufficiently explained by

duration of anovulation. This conclusion is also supported by

our finding that the risk was not decreased by exclusive use

of progestin-only pills, although based on small numbers.

Furthermore, Fig. 1 demonstrated that increasing duration of

oral contraceptive use decreased the risk of ovarian cancer

independently of the cumulative intake of estrogen and

progestin. Thus, our results do not support the concern raised

by Ness et al. [9] that oral contraceptives with low doses of

estrogen and progestin might be less protective against

ovarian cancer than high-dose formulations.

A potential role of gonadotropins in the pathogenesis of

ovarian cancer has also been suggested. Gonadotropins are

48a

synthesized in the anterior pituitary gland and may be

involved in the transformation and progression of normal

ovarian surface epithelium to neoplastic ovarian surface

epithelium [4]. As oral contraceptive use results in reduced

exposure to gonadotropins due to the steroid feedback on the

pituitary gland, oral contraceptives may also protect against

ovarian cancer by suppressing gonadotropin levels.

Previous studies have not examined the association

between the hormone content of oral contraceptives and

different histological types of ovarian cancer but only

assessed the effect of ever/never use and duration of oral

contraceptive use. In our study, separate analyses for the

major histological types of ovarian cancer showed that

duration of oral contraceptive use was associated with

decreased risks of mainly serous and endometrioid ovarian

cancer, with no reduction in risk of mucinous ovarian cancer.

Compatible with our findings, four studies [27~30] found

that ever use of oral contraceptives decreased the risk of non-

mucinous Ovarian cancers only. In contrast, three other

studies [3 1—33] found no difference in the protective effect of

oral contraceptive use against the major histological types.

Our study has several strengths, including the population-

based design, the size of the study population, the higher

response rates than in most other case-control studies, and

the ability to control for known risk factors for ovarian

cancer. In addition, we were able to assess for the first time

the impact of cumulative intake of estrogen and progestin on

ovarian cancer risk. The study also has some limitations. An

important one is the retrospective nature of the study and the

possible introduction of recall bias. Our information on oral

contraceptive use was, however, based on _ personal

interviews that included explicit questions, rather than self-

completed questionnaires, and this may have reduced recall

bias. Furthermore, the use of a life-event calendar and

photographs increased the reliability of the information.

Nevertheless, a large proportion of oral contraceptive users

49a

were excluded from the analyses because they did not

the brand they had used, which may have

introduced some degree of differential misclassification,

especially in the analyses concerning the risk of ovarian

cancer associated with oral contraceptive use according to

hormone potency, and these results should therefore be

interpreted with caution. Although we had reasonably high

participation rates, we cannot rule out the possibility that the

exposure to oral contraceptives of the women who did not

participate differed from that of the women who participated.

Thus, some degree of selection bias cannot be excluded.

Furthermore, as most of the formulations used by the women

in our study contained both progestin and estrogen, we were

unable to separate the effects of the two hormones on ovarian

cancer risk completely. Some of the results in the present

study were limited by imprecise risk estimates due to a low

number of study subjects, e.g., the results concerning the use

of progestin-only pills, the results concerning low-

estrogen/high-progestin use and the results on low-

estrogen/low-progestin use. Lastly, as the MALOVA study

was conducted in the 1990s among women who had primarily

used older-generation pills with high doses of estrogen and

progestin, we were unable to evaluate the effect of more recent

formulations. Nevertheless, as we found that the protective

effect of oral contraceptives may be independent of the doses

of progestin and estrogen, this is not likely to have affected

the generalizability of our results.

In conclusion, we found no independent effect of

cumulative intake of estrogen and progestin on ovarian

cancer risk after taking into account duration of use; thus, the

protective effect of oral contraceptives appears to be due

mainly to inhibition of ovulation. This suggests that, as long

as the doses of estrogen and progestin are sufficient to cause

anovulation, a higher intake of estrogen or progestin will not

add greater protection, although further studies are needed to

confirm this finding. Lastly, the benefits of oral

50a

contraceptive use should be balanced against possible side

effects, such as venous thromboembolism [34] and potentially

increased risks of cancers of the cervix and the central

nervous system [35].

Acknowledgments The study received financial support

from The Danish Cancer Society and The National Cancer

Institute (Grant RO1 CA61107).

Conflict of interest The authors declare that they have no

conflict of interest.

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APPENDIX D

REVIEW

ORAL CONTRACEPTIVE PILLS AS PRIMARY

PREVENTION FOR OVARIAN CANCER

A SYSEMATIC REVIEW AND META-ANALYSIS

Laura J. Havrilesky, MD, MHSc, Patricia G. Moorman, PhD,

William J. Lowery, MD, Jennifer M. Gierisch, PhD, MPH, Remy

R. Coeytaux, MD, PhD, Rachel Peragallo Urrutia, MD, Michaela

Dinan, PhD, Amanda J. McBroom, PhD, Vic Hasselblad, PhD,

Gillian D. Sanders, PhD, and Evan R. Myers, MD, MPH

OBJECTIVE: To estimate the overall reduction in ovarian

cancer risk associated with the use of oral contraceptive pills

(OCPs) and whether reduction in risk is affected by specifics of

OCP use, such as formulation or duration of use.

DATA SOURCES: We searched PubMed, Embase, the

Cochrane Database of Systematic Reviews, and Clinical-Trials.gov

for studies published from January 1990 to June 2012, with

primary analysis of studies published since January 2000.

METHODS OF STUDY SELECTION: We reviewed 6,476

citations. We included English-language controlled studies with

human participants reporting a quantitative association between

exposure to OCPs (in which the explicit or implicit indication for

OCP use was prevention of pregnancy or ovarian cancer)

compared with no use of OCPs. Two investigators independently

reviewed the title and abstract and full-text of articles for inclusion

or exclusion decision; discordant decisions were resolved by team

TABULATION, INTEGRATION, AND RESULTS: Fifty-

five studies met inclusion criteria. A random-effects meta-analysis

of 24 case-control and cohort studies showed significant reduction

in ovarian cancer incidence in ever-users compared with never-

users (odds ratio 0.73, 95% confidence interval 0.66—0.81). There

was a significant duration-response relationship, with reduction in

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incidence of more than 50% among women using OCPs for 10 or

more years. The lifetime reduction in ovarian cancer attributable

to the use of OCPs is approximately 0.54% for a number-needed-

to-treat of approximately 185 for a use period of 5 years.

CONCLUSION: Significant duration-dependent reductions in

ovarian cancer incidence in the general population are associated

with OCP use.

From the Departments of Obstetrics and Gynecology,

Community and Family Medicine, Medicine, and Biostatistics and

Bioinformatics, Duke University School of Medicine, the Duke

Cancer Institute, Duke University Health System, the Duke

Evidence-based Practice Center, Duke Clinical Research Institute,

the Center for Health Services Research in Primary Care, Durham

Veterans Affairs Medical Center, and the Duke Clinical Research

Institute, Durham, North Carolina; and the Department of

Obstetrics and Gynecology, University of North Carolina at

Chapel Hill School of Medicine, Chapel Hill, North Carolina.

Funded under contract no. 290-2007-10066-Ifrom the Agency

for Healthcare Research and Quality (AHRQ) and the Centers for

Disease Control and Prevention (CDC), United States Department

of Health and Human Services. The authors of this report are

responsible for its content. Statements in the report should not be

construed as endorsement by AHRQ, CDC, or the United States

Department of Health and Human Services.

The authors thank Liz Wing, MA, for editorial assistance,

Kathryn Roth Lallinger, MSLS, and Michael Musty, BA, for

project coordination, and Megan von Isenburg, MSLS, for help

with the literature search and retrieval.

Corresponding author: Laura J. Havrilesky, MD, Duke

University School of Medicine, Box 3079 DUMC, Durham, NC

27710; e-mail: laura. havrilesky@dm.duke.edu.

Financial Disclosure

The authors did not report any potential conflicts of interest.

Ovarian cancer is the eighth most common cancer in women

(annual age-adjusted incidence 12.3/ 100,000) but is the fifth

leading cause of cancer death (8.2/100,000).' Despite advances in

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primary treatment, the mortality rate for ovarian cancer remains

the highest among the gynecologic malignancies. Because ovarian

cancer typically presents at a later stage (with concomitant higher

mortality) than other common cancers,’ there has been intense

interest in developing effective screening strategies.

Unfortunately, screening studies to date have not demonstrated

reductions in mortality and false-positive rates have been high,’*

leading the U.S. Preventive Services Task Force to recommend

against screening the general population for ovarian cancer (a “D”

recommendation).’

Oral contraceptive pills (OCPs) represent a potentially promising

primary prevention strategy for ovarian cancer. Several large

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