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EPI-13-0298R Oral Contraceptive Use and Risk of Cancer

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Oral Contraceptive Use and Risk of Breast, Cervical, Colorectal, and Endometrial

Cancers: A Systematic Review

Jennifer M. Gierisch1,2,3, Remy R. Coeytaux2,4, Rachel Peragallo Urrutia5, Laura J. Havrilesky6,7,

Patricia G. Moorman4, William J. Lowery6, Michaela Dinan8, Amanda J. McBroom2, Vic

Hasselblad9, Gillian D. Sanders2,3, Evan R. Myers6

1 Center for Health Services Research in Primary Care, Durham Veterans Affairs Medical

Center, Durham, NC

2 Duke Evidence-based Practice Center, Duke Clinical Research Institute, Durham, NC

3 Department of Medicine, Duke University School of Medicine, Durham, NC

4 Department of Community and Family Medicine, Duke University School of Medicine,

Durham, NC

5 Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill School

of Medicine, Chapel Hill, NC

6 Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC

7 Duke Cancer Institute, Duke University Health System, Durham, NC

8 Duke Clinical Research Institute, Durham, NC

9 Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham,

NC

Running Title: Oral Contraceptives and Breast, Cervical, Colorectal, and Endometrial Cancers

Keywords: Breast, Cervical, Endometrial, Colorectal, Oral Contraceptives

on July 12, 2020. © 2013 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 6, 2013; DOI: 10.1158/1055-9965.EPI-13-0298

http://cebp.aacrjournals.org/


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Financial Support: All authors received support and this project was funded under Contract No.

290-2007-10066-I from the Agency for Healthcare Research and Quality (AHRQ) and the

Centers for Disease Control and Prevention (CDC), U.S. Department of Health and Human

Services.

Corresponding Author: Jennifer M. Gierisch, Department of Medicine, Duke University

Medical Center, Campus Box 104427 DUMC, Durham, NC, 27701; phone, 919-688-5519; fax,

919-688-1300; [email protected]

Disclosure of Potential Conflicts of Interest: None of the authors have any relationships they

believe could be construed as resulting in an actual, potential, or perceived conflict of interest

with regard to the manuscript submitted for review.

Acknowledgments: 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.

Disclaimer: The authors of this report are responsible for its content. Statements in the report

should not be construed as endorsement by AHRQ, CDC, the U.S. Department of Health and

Human Services, or the U.S. Department of Veterans Affairs.

Word Count: 5652 (body text only); Tables: 4 (Supplementary Data); Figures: 5





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ABSTRACT

Oral contraceptives (OC) may influence the risk of certain cancers. As part of the AHRQ

Evidence Report, Oral Contraceptive Use for the Primary Prevention of Ovarian Cancer, we

conducted a systematic review to estimate associations between OC use and breast, cervical,

colorectal, and endometrial cancer incidence. We searched PubMed®, Embase®, and Cochrane

Database of Systematic Reviews. Study inclusion criteria were women taking OCs for

contraception or ovarian cancer prevention; includes comparison group with no OC use; study

reports quantitative associations between OC exposure and relevant cancers; controlled study or

pooled patient-level meta-analyses; sample size for nonrandomized studies >100; peer-reviewed,

English-language; published from January 1, 2000 forward. Random-effects meta-analyses were

performed by estimating pooled odds ratios with 95% confidence intervals.

We included 44 breast, 12 cervical, 11 colorectal, and 9 endometrial cancers studies.

Breast cancer incidence was slightly but significantly increased in users (OR=1.08, CI 1.00–

1.17); results show a higher risk associated with more recent use of OCs. Risk of cervical cancer

was increased with duration of OC use in women with human papillomavirus infection;

heterogeneity prevented meta-analysis. Colorectal cancer (OR=0.86, CI 0.79–0.95) and

endometrial cancer incidences (OR=0.57, CI 0.43–0.77) were significantly reduced by OC use.

Compared with never use, ever use of OCs is significantly associated with decreases in

colorectal and endometrial cancers and increases in breast cancers. Although elevated breast

cancer risk was small, relatively high incidence of breast cancers means that OCs may contribute

to a substantial number of cases.





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INTRODUCTION

Oral contraceptives (OCs), the most common form of effective and reversible contraception

in the United States (1), significantly decrease the personal and societal burdens associated with

unintended or unwanted pregnancy (2,3). OCs also have significant noncontraceptive health

benefits, such as improving acne and regulating dysmenorrhea (4-7). However, OC use is not

without risks. Many studies demonstrate serious adverse events associated with OC use,

including venous thromboembolic disease, myocardial infarction, and stroke (8-10).

In addition to the risk of acute harms, the use of OCs may influence the risk of certain

cancers (11). OC use may promote or initiate tumors of the breast or cervix (12-14). For breast

cancer, these risks may be even greater for women at elevated risk due to family history of

cancer or genetic mutation carrier status (e.g., BRCA1/2); however, results from studies are

inconclusive (15,16). OC use has also been associated with a greater risk of certain clinically

challenging types of breast tumors (17). Conversely, OC use is associated with significant

reductions in colorectal, endometrial, and ovarian cancers (11,18-20). A recent systematic review

and meta-analysis supports a significant risk reduction for ovarian cancer incidence and mortality

associated with the use of OCs (20).

Assessing the risk of cancer associated with OC use is fraught with difficulties. For example,

cancer is a disease with a long latency period, and the time between exposure to OCs and

diagnosis of cancer may span decades. Also, temporal variations in OC formulations available on

the market and used over a woman’s lifetime may influence associations between cancer risk and

OC use. Further, patterns of OC use over a lifetime may be influenced by factors that also affect

cancer risks (e.g., gravidity, parity, breastfeeding). Duration of OC use or length of time since

ceasing use (i.e., recency) may also modify the risk of cancers associated with OCs (13,21).





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We performed a systematic review and meta-analysis, sponsored by the Agency for

Healthcare Research and Quality (AHRQ) and the Centers for Disease Control and Prevention

(CDC), to inform the use of OCs to reduce the risk of ovarian cancer (20). In addition to the

primary question regarding ovarian cancer, we also addressed other harms and benefits of OC

use. In this paper, we examine the evidence for associations between OC use and the risks of

developing four cancers: breast, cervical, colorectal, and endometrial. When possible, we

conducted meta-analyses of the literature to assess the risk of developing these cancers following

OC use; we also examined risk by duration of OC use and time since last OC use (20).

MATERIALS AND METHODS

We followed the methodology recommended in AHRQ’s “Methods Guide for Effectiveness

and Comparative Effectiveness Reviews” (22). Methods are summarized here, with complete

details provided in the full AHRQ report (20).

Search strategy

In collaboration with an experienced librarian, we conducted searches of PubMed, EMBASE,

the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov to identify relevant

published literature. Our searches were date-limited to articles published from January 1, 1990,

to June 29, 2012. For the outcomes presented in this paper, we restricted the results to 2000

forward for the following reason. Formulations of OCs have been changed and updated almost

continuously since their introduction to the U.S. market in 1957; such changes have not occurred

at discrete time points. Also, year-by-year market share, duration of use, and patterns of use are

not readily available and would vary based on the country in which a given study was conducted.

Realizing the inaccuracy of any discrete cutoff date with regard to current OC formulations, we





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limited the publication years of included studies to those published from 2000 forward to try to

maximize the proportion of subjects who used OC formulations similar to those currently on the

market. We supplemented electronic searches with a manual search of citations from key review

articles. Exact search strings are provided in Appendix A of the full AHRQ report (20).

Selection criteria

Inclusion criteria for studies relevant to this paper were (1) study includes women taking OCs

for contraception or primary prevention of ovarian cancer; (2) study includes comparison group

with no use of combination or progestin-only OCs (either no contraceptive method at all or

contraceptive methods other than combination or progestin-only OCs); (3) study reports

quantitative associations between exposure to OCs and breast, cervical, colorectal, or

endometrial cancer incidence; (4) controlled study (randomized trials, cohort studies, case-

control studies) or pooled patient-level meta-analyses; (5) sample size for nonrandomized studies

>100 subjects; (6) study is peer-reviewed and English-language; and (7) published on or after

January 1, 2000. Exclusion criteria were (1) study reports outcomes related to the use of OCs

only for contraception, or in specialized populations such as women immediately post-

termination of pregnancy, or women receiving assisted reproductive technologies; (2) study does

not provide a description of the OC formulation(s) or length of OC use; or (3) publication type is

editorial, review, or letter to the editor.

Reviewer pairs used prespecified criteria to assess titles and abstracts. Full-text articles

included by either reviewer underwent further evaluation. Eligibility decisions and

disagreements were reconciled through discussion or by a third reviewer. For included studies,

we abstracted data on study populations, interventions, outcomes, quality, and applicability. We

used criteria developed by AHRQ to assess study quality, summarized as good, fair, or poor (22).





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Quality ratings for individual articles within study groupings could differ based on articles’

reporting quality, evaluated outcomes, and statistical and analytical methods used. We screened

and abstracted data using DistillerSR software (Evidence Partners Inc, Manotick, ON, Canada).

Data synthesis

When at least three studies were available with comparable study designs and outcomes, we

performed random-effects meta-analyses grouped by study design (case-control or cohort study)

and estimated pooled ORs with 95% confidence intervals (CIs). As there were no significant

differences by design, we used a random-effects model to combine subgroups and estimate the

overall effect. When studies reported multiple models, we used the most adjusted model. We

evaluated heterogeneity visually and with the Cochran Q statistic using a threshold P value of

less than 0.10. We included pooled analyses in our meta-analyses if all these conditions were met

by the pooled analysis: none of the individual papers were already included in the meta-analysis,

at least half of the studies were published on or after January 1, 2000, and data were presented

such that their inclusion in meta-analysis was feasible.

Not all studies meeting criteria for inclusion in the review were included in meta-analyses.

The reasons for exclusion from meta-analysis were (1) study populations that represented

specialized subgroups (e.g., BRCA mutation, family history, age at diagnosis ≤45 years, cancer

subtype); (2) studies that reported a subset of results from the same study as another article

already included in the analysis; and (3) studies that did not report an OR for ever OC use versus

never OC use. When studies gave results only by subgroup (premenopausal, postmenopausal),

we combined subgroups to generate an estimate only when the combined group represented a

broad population. When possible, we conducted sensitivity analyses by including only U.S.-





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based studies. These analyses were performed using Comprehensive Meta-Analysis Version 2

(Biostat; Englewood, NJ; 2005) (23).

We estimated the increase or decrease in absolute risk of cancer from estimates of the

lifetime incidence of malignant cases for women beginning at age 45 years generated using the

National Cancer Institute’s DevCan software (24), estimated lifetime ever use of OCs from the

National Survey of Family Growth (25), and the ORs (with 95% CIs) produced in our meta-

analyses. We then calculated the number needed to treat (NNT) or number needed to harm

(NNH) by taking the inverse of the absolute risk. Because we were unable to perform meta-

analysis of the association of OC use and cervical cancer among populations that were selected

for HPV-positive status, we were unable to generate estimates of change in absolute risk.

When we had sufficient studies to assess the effect of duration of OC use, we used a random-

effects model to compute ORs. We required that the ORs were given relative to no OC use and

that the population studied was not restricted to a particular subpopulation. The challenge of

performing a meta-analysis on duration of OC use is that individual studies reported ORs for

different duration intervals. We assumed that the logarithm of each OR could be described by a

linear model. The model included a random-effects term, σ2, as well as terms for time point

intervals. We then used independent variables to create the time period desired. The model was

fitted using SAS PROC NLMIXED (SAS Institute Inc.; Cary, NC; 2009) with “subject” set to

the particular study.

We evaluated strength of evidence using the approach described in AHRQ’s “Methods

Guide” (22,26).





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RESULTS

Of the 6,476 unique citations screened, we identified 44 studies relevant to breast, 12 to

cervical, 11 to colorectal, and 9 to endometrial cancers (Figure 1). Several included studies were

relevant to more than one outcome of interest. All studies were observational; we did not identify

any eligible randomized controlled trials. We did not identify any qualitative difference between

breast, cervical, colorectal or endometrial cancers and OC use based on probable dates of

exposure when examined by study recruitment date versus publication date.

Breast cancer incidence

Forty-four studies (19 good quality, 25 fair, and 3 poor) evaluated the association between

OC use and breast cancer incidence (16,17,27-78). Of these, 29 were case-control studies, 14

were cohort studies, and 1 was a pooled analysis (Supplementary Table 1). Fifteen case-control

studies (38,682 women) (16,27-30,33,37,48,49,51,54,56,73,74,78) and 8 cohort studies (317,341

women across 5 studies and 3,981,072 person-years across 3 studies) (59-61,63,65,67-69) met

criteria for meta-analysis examining ever versus never OC use. Figure 2 shows the results

suggesting that a history of OC use slightly but significantly increases breast cancer incidence

compared with never OC use (OR=1.08; 95% CI, 1.00 to 1.17), with a Q value of 73.35 for 21

degrees of freedom (DF); P < 0.001. In a sensitivity analysis of only U.S.-based studies, effect

sizes were smaller and no longer statistically significant (OR 1.03; CI, 0.93 to 1.14). Based on

the point estimates of the meta-analyses, the approximate increase in estimated lifetime absolute

risk of breast cancer from ever use of OCs is 0.89% (NNH 113).

Fourteen studies (16,27,30,36,37,44,48,49,54,59-61,63,69,78) met criteria for the meta-

analysis examining duration of OC use. We found no time-dependent relationship as a function

of duration of use: 1–12 months (OR = 0.95; CI, 0.83 to 1.09); 13–60 months (OR = 1.03; CI,





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0.92 to 1.15); 61–120 months (OR = 1.01; CI, 0.90 to 1.13); and >120 months (OR = 1.04; CI,

0.93 to 1.17). Heterogeneity was significant (t = 5.84, 19 DF, P < 0.0001).

Eleven studies (16,27,30,33,37,38,46,49,51,53,59,61) met criteria for the meta-analysis

examining time since last OC use. Results show a time-dependent relationship as a function of

time since last OC use, with higher risk associated with more recent use of OCs and ORs that

approach 1 (no effect) by ≥20 years of use: 0–5 years (OR = 1.21; CI, 1.04 to 1.41); 5–10 years

(OR = 1.17; CI, 0.98 to 1.38); 10–20 years (OR = 1.13; CI, 0.97 to 1.31); >20 years (OR = 1.02;

CI, 0.88 to 1.18). Heterogeneity was significant (σ = 0.12; t value = 4.95 for 11 DF, P = 0.0004).

The strength of evidence for the effect of ever OC use on breast cancer incidence was

moderate. Most studies were of good or fair quality, exhibited consistent findings, and

confidence interval for summary estimate were precise. However, all included studies were

observational; thus there may be some risk of bias due to limitations of the study designs. The

strength of evidence was low for both duration of use and time since last use for risk of breast

cancer incidence; results were inconsistent with a high level of heterogeneity across studies.

Cervical cancer incidence

Twelve studies (five good, four fair, four poor quality) evaluated the association between OC

use and cervical cancer incidence (63,65,66,69,70,73,79-87), including two articles from an

International Agency for Research on Cancer (IARC) study representing distinct populations

(86,87). Of these, nine were case-control studies, three were cohort studies, and one was a pooled

analysis. Only two studies were conducted with U.S.-based populations (Supplementary Table

2).

Persistent infection with one or more oncogenic HPV types is required for cervical

carcinogenesis; thus, women who are HPV-positive represent the most relevant population to





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assess the risks for cervical cancer associated with OC use. Only three studies (80,83,86)

assessed the association between OC use and cervical cancer among women who are HPV-

positive. Limited studies across comparisons precluded quantitative synthesis; we summarize

each study below.

One fair-quality study (86) pooled data from eight case-control studies of HPV-positive

patients with cervical cancer. Ever use of OCs was associated with a statistically nonsignificant

increase in invasive cervical cancer (OR = 1.29; CI, 0.88 to 1.91) and cervical cancer in situ (OR

= 2.54; CI, 0.95 to 6.78). However, duration of use was significantly associated with cancer

incidence such that HPV-positive women who used OCs for 5–9 years (OR = 2.82; CI, 1.46 to

5.42) and ≥10 years (OR = 4.03; CI, 2.09 to 8.02) experienced a significant increase in the risk of

cervical cancers compared with never users. This estimate did not vary by time since first or last

use; the trend was not observed for women who used OCs for <5 years.

Two case-control studies (80,83), both rated poor quality, also assessed the risk of cervical

cancer associated with OC use among HPV-positive women. One study (80) recruited hospital-

based HPV-positive cases and controls in Lima, Peru. Results of this study were included in the

pooled analysis above and, thus, could not be combined again. Compared with HPV-positive

controls, HPV-positive women who had ever used OCs were at elevated risk of cervical cancer

compared with women who had never used OCs (OR = 2.7; CI, 0.90 to 8.4), but the contrast was

not significant. This study did not compute any analysis by duration of use.

The other case-control study (83) assessed the association between OC use and cervical

cancer among hospital-based HPV-positive cases and HPV-positive community controls in the

United States. This study assessed duration of OC use; ever use versus never use was not

calculated. Increasing the duration of OC use—categorized as <5 years, 5–10 years, and >10





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years—was associated with a decrease in cervical cancers. This trend was significant only in

women with <5 years of use compared with never users (OR = 0.6; CI, 0.4 to 0.9).

In populations that were not selected for HPV-positive status, 6 case-control studies

representing 5,436 women (73,79,81,82,84,85) and 3 cohort studies (63,65,69) representing

3,981,072 person-years met criteria for the meta-analysis examining ever versus never OC use.

Figure 3 shows results indicating increased odds of cervical cancer for women who had ever

used OCs compared with women who never used OCs (OR = 1.21; CI, 0.91 to 1.61), but the

comparison was not significant. There was a large amount of heterogeneity (Q = 25.52, 7 DF, P

< 0.001), possibly due to differences in HPV status among studies, which made the estimates

unstable. We could not conduct sensitivity analysis by U.S.-based studies because only one study

was conducted within the U.S. Results from this case-control study (79) show a statistically

significant increase in risk with ever use of OCs (OR = 2.7; CI, 1.2 to 5.8).

Six studies (63,79,81,82,85,87) met criteria for the meta-analysis examining duration of OC

use. Results show no time-dependent relationship as a function of duration: 1–60 months (OR =

0.99; CI, 0.58 to 1.70) and >60 months (OR = 1.47; CI, 0.91 to 2.38). Heterogeneity was

significant (t = 4.72; 5 DF, P = 0.0033).

The strength of evidence for the effect of ever OC use on cervical cancer incidence among

HPV-positive women was insufficient. Only three studies assessed risk in HPV-positive women,

and most were of poor quality. Results were inconsistent, sensitivity analysis yielded

qualitatively different estimates of effects, and confidence intervals were wide. Studies did not

control for factors that may influence risk such as age at first use by duration or age at sexual

debut, which is likely highly correlated with age at first use. Future studies could influence

magnitude and, possibly, direction of effect.





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Colorectal cancer incidence

Eleven studies (4 good, 6 fair, 1 poor quality) evaluated the association between OC use and

colorectal cancer incidence (63,65,66,68,88-95). Of these, 3 were case-control studies, 7 were

cohort studies, and 1 was a pooled analysis. Nine studies were conducted in Western countries

and two in China (Supplementary Table 3).

Three case-control studies (88-90), one pooled analysis (94), and seven cohort studies

(63,65,68,91-93,95) representing 503,816 women across 8 studies and 2,969,189 person-years

across 3 studies met criteria for the meta-analysis examining ever versus never OC use. Figure 4

shows the results demonstrating a decrease in the risk of colorectal cancers among women who

ever used OCs compared with women who never used OCs (OR = 0.86; CI, 0.79 to 0.95; Q =

17.17, P < 0.046). We conducted sensitivity analyses of studies that included only patients from

the U.S; results were similar to analyses containing all studies, but the confidence interval

eclipsed 1 (OR = 0.83; CI, 0.69 to 1.01). Based on the point estimates of the meta-analyses, the

approximate decrease in absolute risk of colorectal cancer is 0.76% (NNT 132).

Ten studies (63,65,68,88-92,94,95) met criteria for the meta-analysis examining duration of

OC use. We categorized duration of use into 2 intervals and found no time-dependent

relationship as a function of duration: 1–60 months (OR = 0.88; CI, 0.77 to 1.01) and >60

months (OR = 0.88; CI, 0.76 to 1.01). There was no significant heterogeneity (t = 1.52; 9 DF, P

= 0.164).

The strength of evidence for the effect of OC use on colorectal cancer incidence was

moderate. Results were consistent across studies, and the summary estimate demonstrated high

precision with a tight confidence interval. Future studies will not likely have an impact on the

direction of effect but may slightly influence the magnitude of the effect. The strength of





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evidence for duration was insufficient; the test was underpowered and we found significant

heterogeneity.

Endometrial cancer incidence

Nine studies (six good, two fair, one poor quality) evaluated the association between OC use

and endometrial cancer incidence (63,65,66,69,70,73,96-100). Of these, four were case-control

studies and five were cohort studies. Only two studies were conducted in the U.S.

(Supplementary Table 4).

Three case-control studies (73,97,100) and 4 cohort studies (63,65,69,98) representing

308,198 women (within 4 studies) and an additional 3,981,072 person-years (within the other 3

studies) were included in this meta-analysis examining ever versus never OC use. Figure 5

shows results indicating a protective effect for endometrial cancer associated with ever OC use

(OR = 0.57; CI, 0.43 to 0.77). Heterogeneity was significant (Q = 26.11, 6 DF, P < 0.001). We

also explored how our findings changed when including only U.S.-based studies. Only one study

was conducted with patients from the U.S. and reported a somewhat greater protective effect

than summary estimates for all studies (OR = 0.34; CI, 0.25 to 0.47). Based on the point

estimates of the meta-analyses, the approximate decrease in absolute risk of endometrial cancer

is 1.77% (NNT 60).

DISCUSSION

Our results are confirmatory of initial analyses and reviews, including those which included

studies published prior to 2000.. This evidence synthesis highlights some of the tradeoffs about

nonreproductive outcomes that patients and providers need to consider with the use of OCs:

increased risk for some cancers (breast and cervical) but decreased risk for others (colorectal and





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endometrial). Other considerations include decreased risk of ovarian cancer (101) and increased

risk for thromboembolic events (102). Estimating the overall balance of benefit and harm is

difficult from a technical sense and because the timing of the outcomes affected by OC use is

variable—some risks and benefits are seen only during use, while others occur 20 to 30 years in

the future. Moreover, different patients may well have different values for those outcomes.

We found that the risk of breast cancer was slightly—but significantly—elevated for women

who have ever used OCs compared with women who have never used OCs. Although the

relative increase in risk was small (OR = 1.08), the relatively high incidence of breast cancer

diagnosis means that OC use may contribute to a substantial number of cases. We found no time-

dependent relationship as a function of duration of OC use. Duration results should be

interpreted with caution; there was significant heterogeneity, and the test was underpowered—

which is not surprising, given that breast cancer is relatively uncommon during the ages when

women are most likely to be using OCs. We also found that women with more recent use had an

elevated risk of breast cancer, with decreasing risk over time, so that by 10 years since last use,

the risk among users was equivalent to never users.

Our results are consistent with results of other meta-analyses and pooled analyses that

identified a small increase in the relative risk of breast cancer associated with having ever used

OCs—a risk that diminishes over time since last use (12,103). The Collaborative Group on

Hormonal Factors in Breast Cancer, a collaborative reanalysis of individual data in 153,536

women, found a small but significant increase in the relative risk of breast cancer (OR = 1.07 ±

0.02) (12). Similar to our results, the Collaborative Group did not identify an increase in risk

with increasing duration of use or after discontinuation of use for ≥10 years. Another recent

meta-analysis of premenopausal breast cancer across 37 studies found a somewhat larger





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increase in the risk (OR = 1.19; CI, 1.09 to 1.29), with the greatest risk associated with OC use

prior to first full-term pregnancy (OR = 1.44; CI, 1.28 to 1.62) (104). These results support our

finding that recent use (≤5 years) is associated with an increased risk of breast cancer. Women

who delay first full-term pregnancies may also be more likely to be recent users of OCs relative

to a breast cancer diagnosis. These results cannot be directly compared with ours, as this meta-

analysis was restricted to premenopausal women or women <50 years who may be at elevated

risk due to other factors (e.g., genetic mutations), or represent cancer subtypes that differentially

affect younger women. An alternative explanation of an association between OC use and

increased incidence may be more surveillance in women who use OCs. Women who use OCs

must come in contact with the health care system on a regular basis, thus increasing their chances

of receiving referrals for preventive screenings such as mammography.

We found no significant increase in the risk of cervical cancer among ever OC users

compared with never users across nine pooled studies. We also found no time-dependent

relationship as a function of duration of OC use. It is important to note that this contrast was

underpowered with only five included studies. However, women having long-term use of OCs

(≥5 years) were at an elevated but not statistically significant risk of cervical cancer compared

with never users.

Three studies (2,592 women) assessed OC use and cervical cancer incidence among HPV-

positive women. Results were similar to those of women not selected for HPV status. Many

studies did not control for factors that may influence risk, such as age at first OC use by duration

or age at sexual debut, which is likely highly correlated with age at first use. Future research is

needed to assess the additional cervical cancer risk associated with OC use among HPV-positive





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women. However, both studies reported statistically significant increased risk of death with ≥8

years of OC use compared with never use.

Our cervical cancer results differ in some ways from other evidence syntheses published over

the last 10 years. Smith and colleagues (13) pooled study-level data across 28 studies and found

an overall significant increase in the risk of cervical cancer when comparing ever versus never

users of hormonal contraceptives (RR = 1.2; CI, 1.1 to 1.3). We found a similar increase in the

risk of cervical cancers, but our summary estimate was not significant. Both our review and the

Smith study found the risk of cervical cancer increased with prolonged exposure. This effect

weakened but remained significant when stratifying duration by time since use. For our review,

this effect was significant only for women who used OCs for ≥5 years compared with never

users; we did not have sufficient studies to stratify by time since last use. The International

Collaborative of Epidemiological Studies of Cervical Cancer undertook a collaborative patient-

level reanalysis of 24 observational studies (105). Results expand the duration by recency effect.

The analysis found that excess risk of cervical cancers increases with duration of use, but this

effect declined after discontinuing OCs and was equivalent to the risk of nonusers after 10 years

of nonuse.

Key methodological differences between our study and the two recent syntheses preclude

drawing exact comparisons. First, we included only studies of invasive cervical cancers; other

studies also included carcinoma in situ and cervical intraepithelial neoplasia grade 3. It is likely

that effects differ between invasive cancers and cancer-precursor lesions. In fact, a case-case

comparison in the collaborative reanalysis showed significant differences in the risks for in situ

and invasive cervical cancers for nearly every category of time since last use by duration of use.

Second, we included studies that assessed only the effects of oral contraceptives; the two other





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recent syntheses included all forms of hormonal contraceptives. It is possible that formulation

differences contribute to some of the differences between our results and their findings.

However, the collaborative reanalysis reported separate findings for progestin-only injectable

contraceptives and found a similar pattern to those reported for OCs. Third, we did not include

the three studies conducted with women selected for HPV infection status. The effects of this

decision appear to be negligible; both prior reviews noted similar patterns of findings when

controlling for HPV status as a covariate (13) compared with HPV uncontrolled studies or

among the subset of women with a confirmed HPV infection compared with populations not

selected for HPV status (105). Last, we date-limited our search from 2000 forward in order to

minimize the effect of older formulations; other studies had no such date restrictions. Despite

these differences, we found similar patterns of increased risk by duration of use. There is no

direct evidence to suggest that cervical cancer screening recommendations should be different

based on duration of OC use.

We found that the risk of colorectal cancer was significantly decreased for women who have

ever used OCs compared with women who have never used OCs. However, we found no

evidence of a time-dependent relationship as a function of duration. Duration results should be

interpreted with caution; the test was underpowered.

Our results are similar to two other evidence syntheses that also assessed the risk of

colorectal cancers associated with OC use (11,106). These meta-analyses both found a pooled

relative risk of approximately 0.82, which is comparable to our pooled findings. These reviews

also found no increase in the protective effect by duration of use. The similarity between our

findings and those of the other two reviews is noteworthy. We limited our studies from January

2000 forward so that we had a greater probability of capturing a set of studies with newer OC





19

formulations that may confer differential effects. Thus, we shared no studies in common with the

study by Fernandez and colleagues (106), and we excluded 12 older or non-English studies and

included five newer studies (63,68,90,93,95) compared with the systematic review by Bosetti

and colleagues (11). Similarity in our findings with these earlier evidence syntheses suggests that

OCs confer a significant protective effect for colorectal cancer, and future research could

investigate OCs potential as a beneficial therapy for chemoprevention.

We identified nine studies that evaluated the association between OC use and the incidence

of endometrial cancers; seven were included in our meta-analysis to assess ever versus never OC

use. We found a significant protective effect with ever OC use and a time-dependent relationship

as a function of duration categorized as <60 months and ≥60 months of total use.

Our study is one of the few systematic reviews and meta-analyses to summarize the evidence

on the effects of OCs on endometrial cancers. Grimes and colleagues (107) conducted a

systematic review and qualitative synthesis of studies up to 1993. They identified 13 case-control

studies with protective ORs ranging from 0.1 to 0.6, with most effects clustering around 0.5.

Two of the three cohort studies identified also found protective effects of OC use. Schlesselman

and colleagues (108) conducted a meta-analysis of 11 case-control studies. A significant duration

trend was reported such that longer durations of use conferred greater protection (RR = 0.44 for

4 years of use; RR = 0.33 for 8 years of use; RR = 0.28 for 12 years of use; P < 0.0001). We

found a similar trend but used a different analytic approach; direct comparisons are difficult to

draw. This meta-analysis also reported on time since last use and found that the protective effect

of OCs is diminished after they are discontinued but still persists even 20 years after cessation.

We did not have sufficient studies to assess the effect of time since last use. Protective effects of

OCs may vary with formulation. However, our results are similar to other studies conducted in





20

the 1990s that may have included different formulations based on market availability.

Unfortunately, there is limited data on the formulations used in the majority of the studies

reviewed, and it is likely that the distribution of formulations in the studies included in this

review are different compared to contemporary OC formulation distribution. If the association

between OC use and cancer varies based on formulation, particularly estrogen dosage and type

of progestin, then estimates of reduction or increases in future cancer risk among current pill

users are subject to considerable additional uncertainty. Our results—in combination with other

evidence reviews—confirm that OCs confer a significant protective effect on the risk of

endometrial cancers.

Limitations

While we performed a comprehensive systematic review and evidence synthesis of the

current research on OC use and the incidence of breast, cervical, colorectal, and endometrial

cancers, there are limitations to our approach and findings. As expected, we identified no

randomized trials; such studies are not likely feasible. Thus, we included only observational

studies in our meta-analyses. Even the highest quality observational studies are susceptible to

multiple forms of bias (e.g., confounding). Most included studies adjusted for multiple likely

sources of cofounding; when possible, we used the most adjusted point estimates in our meta-

analyses. Recall bias is also a common source of diminished quality in observational studies. Our

findings were remarkably similar across case-control studies and cohort studies, which suggests

a lack of evidence for recall bias of OC use across study types. Also, we found significant

heterogeneity across many of our comparisons. We included a diverse group of studies

conducted across the world; differences in study populations and geographic variability in other

risk factors not routinely assessed (e.g., access to health care) likely contributed to this





21

heterogeneity. This may be particularly true for cancers such as breast, cervical, and colorectal,

where screening can affect both incidence and mortality and where there may be associations

between OC use and screening behaviors. Sensitivity analyses using only U.S.-based studies (or

with patients from the U.S.) showed similar patterns to unrestricted analyses. Also, studies varied

considerably in the type and specification of covariates, which may be a likely source of

heterogeneity. To try to maximize the proportion of subjects who used OC formulations similar

to those currently on the market, we included only studies published in 2000 and later However,

study publication date is a gross estimate of OC formulation exposure because observational

studies published since 2000 still represents some cohorts exposed to earlier formulations. It may

have been preferable to limit studies by year of diagnosis instead of publication date. Yet, many

of our findings are consistent with other meta-analyses without date restrictions, which suggests

that current OC formulations may have similar carcinogenic or protective effects compared with

older formulations. Still, given the long latent period between exposure and tumor development,

it is likely that recent publications may not fully assess the effect of formulations introduced in

the past 20 years.

Conclusion

This systematic review of the literature identified several gaps in the evidence that warrant

future investigation. Several subgroups deserve further attention; there are limited data on the

effects of OCs on cancer risk in women at elevated risk of malignancy due to behavioral risk

factors such as smoking, heavy alcohol consumption, obesity, or physical inactivity. These

factors are known to be associated with cancer development, and so behavioral risk factors may

modify the association between OCs and cancers. We found that duration of use conferred a

different pattern of risk, but we found limited support of a time-dependent relationship. Because





22

the benefits and risks associated with OC use differ by pattern of use, more research is needed on

the interaction of different patterns of use (e.g., duration by time since last use, age at initiation

by duration) on the risk of breast, cervical, colorectal, and endometrial cancers in order to

optimize the risks and benefits of OC use.

Quantifying the potential impact of changes in OC formulations is difficult. Although our

analyses were based on more recently published data, and we did not identify an obvious

association based on probable dates of exposure within these studies, the long lag time between

"typical" exposure to OCs and incident cancers means that the distribution of formulations

among subjects in even the most recent literature is likely to be different than the distribution

among current OC users. This uncertainty affects both estimated harms (increased risk of breast

cancer) and benefits (decreased risk of endometrial and colorectal cancer).





23

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FIGURE LEGENDS

Figure 1. Literature flow diagram

*Note that a given study may address more than one outcome group.

MI, myocardial infarction; OC, oral contraceptive; RCT, randomized controlled trial; VTE,

venous thromboembolism

Figure 2. Forest plot of ever versus never oral contraceptive use and breast cancer

incidence

CI, confidence interval; OC, oral contraceptive

Figure 3. Forest plot of ever versus never oral contraceptive use and cervical cancer

incidence


Figure 4. Forest plot of ever versus never oral contraceptive use and colorectal cancer

incidence


Figure 5. Forest plot of ever versus never oral contraceptive use and endometrial cancer

incidence





Published OnlineFirst September 6, 2013.Cancer Epidemiol Biomarkers Prev Jennifer M. Gierisch, Remy R. Coeytaux, Rachel Peragallo Urrutia, et al. and Endometrial Cancers: A Systematic ReviewOral Contraceptive Use and Risk of Breast, Cervical, Colorectal,

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