Majke Van Bommel

Table 4. Overview of current guidelines regarding contraception in BRCA1/2-PV carriers.

1 Slovakia, SAGO, Guidelines for complex genetic analysis of hereditary breast ovarian cancer syndrome in Slovak population, 2015. Recommendations/Conclusion: Hormonal contraception is not necessarily contraindicated in carriers of a mutation; however, the benefits need to be considered. Status: Not contraindicated.

2 The Netherlands, NVOG, Erfelijk en familiair ovariumcarcinoom (in English: Hereditary and familial ovarian carcinoma), 2015. Recommendations/Conclusion: No reason to advise against OCP in healthy women with a BRCA1/2 mutation aged 25 years or below. Data regarding LR-IUD and the risk of breast cancer in healthy BRCA1/2 mutation carriers is lacking, therefore no statement can be made on the safety of these IUDs in this specific group. There is some data showing that the use of LR-IUD after breast cancer does not increase the risk of recurrence of breast cancer. Status: Not contraindicated.

3 United States, ACOG, US Medical Eligibility Criteria for Contraceptive Use, 2016. Recommendations/Conclusion: Evidence does not suggest that the increased risk for breast cancer among women with either a family history of breast cancer or breast cancer susceptibility genes is modified by the use of combined oral contraceptives. Status: Not contraindicated.

4 Spain, SEGO, Clinical guidelines in hereditary breast and ovarian cancer, 2016. Recommendations/Conclusion: Oral contraceptives in BRCA1/2 mutation carriers can reduce the risk of ovarian cancer by 50%, with the benefit being greater with longer duration of treatment. Their use is not contraindicated, although there is a possibility of an increased risk of breast cancer. Status: Not contraindicated.

5 Canada, SOGC, Canadian Contraception Consensus, 2017. Recommendations/Conclusion: The use of combined oral contraception in BRCA1/2 carriers is controversial but appears to be associated with a decreased risk of ovarian cancer and no increase in the risk of breast cancer. Women with a history of breast cancer >5 years ago: benefit for expert consultation prior to advising against contraceptive use. In general: adequate counseling prior to OCP initiation to ensure an informed choice and improve adherence and continuation. Status: Ambivalent, counsel.

6 United Kingdom, NICE, Surveillance proposal for BRCA, 2017. Recommendations/Conclusion: Women <35 years with a family history of breast cancer: in keeping with general health advice on the use of the OCP. Women >35 years with a family history of breast cancer: inform on an increased breast cancer risk associated with taking the OCP, and that their absolute risk increases with age. BRCA1 carriers: conflicting effects of a potential increased risk of breast cancer under the age of 40 years and the lifetime protection against ovarian cancer risk from taking the OCP should be discussed. The OCP should not be prescribed purely for prevention of cancer. Status: Ambivalent, counsel.

7 United States, ACOG, Clinical management guidelines for Obstetrician-Gynecologists: Hereditary Breast and Ovarian Cancer Syndrome, 2017. Recommendations/Conclusion: Given the magnitude of the potential benefits (e.g., ovarian and endometrial cancer risk reduction, pregnancy prevention, cycle regulation), it is appropriate for women with mutations in BRCA1 or BRCA2 to use oral contraceptives if indicated, and use for cancer prophylaxis is reasonable. Although there have been conflicting reports in the literature on the effect of oral contraceptives on breast cancer risk. In high-risk women who are undergoing tubal sterilization for contraception, bilateral salpingectomy followed by future oophorectomy may be a reasonable option to offer, but ovarian cancer risk reduction remains under evaluation. Status: Not contraindicated.

8 Canada, SOGC, Gynaecologic management of hereditary breast and ovarian cancer, 2018. Recommendations/Conclusion: Combined hormonal contraceptive use is an effective method of chemoprevention for ovarian/tubal/peritoneal cancer in the general population and women with BRCA1/2. The use of OCP in young BRCA1 variant carriers should be individualized, taking into account the risks and benefits. Status: Ambivalent, individualize.

9 United Kingdom, FSRH, Guideline-combined-hormonal-contraception, 2019. Recommendations/Conclusion: Amongst BRCA carriers, use of OCPs is associated with reduced risk of ovarian cancer with use, proportional to the duration of use. The evidence is stronger for BRCA1 carriers but exists for both BRCA1 and BRCA2. This advantage would need to be weighed against the potential increased risk of breast cancer. Women with a BRCA mutation should be advised that current use of combined hormonal contraception is associated with a small increased risk of breast cancer which reduces with time after stopping combined hormonal contraception. Status: Ambivalent, counsel.

10 United Kingdom, FSRH, UK Medical Eligibility Criteria (UKMEC) for contraceptive use, 2019. Recommendations/Conclusion: Carriers of a known gene mutations associated with breast cancer (e.g. BRCA1/BRCA2): Copper IUD: no restriction for use. LR-IUD, progestogen-only-implant, medroxyprogesterone acetate, progestogen-only-pill, combined hormonal contraception: the advantages generally outweigh the theoretical or proven risks. Status: Not contraindicated.

11 United States, NCCN, Genetic/familial high-risk assessment: Breast and ovarian cancer, 2019. Recommendations/Conclusion: The use of oral contraceptives significantly reduced the risk of ovarian cancer by approximately 50% for both the BRCA1 and BRCA2 mutation carriers. Studies on the effects of oral contraceptive use on breast cancer risk among BRCA1/2 mutation carriers have reported conflicting data. Status: No advice reported.

12 The Netherlands, NHG, Anticonceptie (in English: Contraception), 2020. Recommendations/Conclusion: BRCA ≥35 years: absolute contra-indication for hormonal contraceptives. BRCA 25-35 years: relative contra-indication for hormonal contraceptives. BRCA <25 years: no contra-indication for hormonal contraceptives. Status: Contra-indicated, depending on age. 13 WHO, Medical eligibility criteria for contraceptive use, 2015. Recommendations/Conclusion: Women with a family history of cancer or with breast cancer susceptibility genes (such as BRCA1 and BRCA2): Combined oral contraceptive, combined contraceptive patch, vaginal ring or injectable contraceptive: no restriction for use. Status: Not contraindicated. 14 ESMO, Prevention and screening in BRCA mutation carriers, 2016. Recommendations/Conclusion: The use of the OCP may be considered as a risk-reducing measure for ovarian cancer. It should however be noted that there are conflicting data whether OCP increases breast cancer risk among BRCA1/2 carriers. Status: Not contraindicated. Table 4 presents the recommendations of each guideline. As shown, most guidelines recommend (individualized) counselling about cancer risks when discussing contraception with BRCA1/2-PV carriers. One guideline stands out as it describes an absolute contraindication for hormonal contraception in BRCA1/2-PV carriers aged 35 years or older, and a relative contraindication for carriers aged 25 to 35 years. 41 Discussion Main findings In this systematic review using meta-analyses, we investigated the impact of contraceptive use on breast and ovarian cancer risk among BRCA1/2-PV carriers. Regarding breast cancer risk, the data were limited to the OCP, and the results were heterogenous between the reported outcome measures: breast cancer risk was either increased (HR 1.55, 95% CI 1.36; 1.76) or unaffected (OR 1.06, 95% CI 0.90; 1.25) by use of the OCP. This increased breast cancer risk was even found 10 years after the last OCP use; however, no clear association was identified between breast cancer risk and duration of OCP use. By contrast, OCP use reduced ovarian cancer risk, with a HR of 0.62 (95% CI 0.52; 0.74) and an OR of 0.49 (95% CI 0.38; 0.63), and longer usage of OCP might lower ovarian cancer risk. These beneficial effects seem to vanish over time following the cessation of OCP use, however. TL was found to decrease ovarian cancer risk as well, with a HR of 0.44 (95% CI 0.26; 0.74) and an OR of 0.74 (0.53; 1.03). The impacts of these contraceptives on cancer risks were similar for BRCA1-PV and BRCA2-PV carriers. No data were available regarding other types of contraception and their effects on cancer risks in BRCA1/2-PV carriers. Interpretation The impact of contraceptives on cancer risks has been investigated for some time, and previous systematic reviews and meta-analyses have been published about their effects on the BRCA1/2-PV population. 42-48 Our study is the most up to date, however, and is based on the largest sample sizes thus far. We also summarized the evidence using meta-analyses, in contrast to some others. 44, 47, 49 Furthermore, unlike previous meta-analyses, we specifically searched for contraceptive methods in our systematic search, instead of factors influencing cancer risks in general. We did not restrict our search strategy to either OCP or TL, as others have done. 42, 44-46, 48 Despite these differences, the results of the previous reviews and meta-analyses are highly comparable to ours. Moreover, the preventive effect of OCP on ovarian cancer risk was consistently found in the previous meta-analyses, 42, 43, 48, 49 and the results from meta-analyses regarding TL and the reduced ovarian cancer risk were consistent with ours. 43, 45, 46 Regarding breast cancer risk, the results of earlier meta-analyses are less consistent. Some studies revealed differing results between outcome measures and across study designs, similar to our findings. 42, 43 Others found no statistically significant effect of OCP on breast cancer risk, 48, 49 which might be explained by the variation in the included study populations. The negative impact of OCP on breast cancer risk and the beneficial effect on ovarian cancer risk identified here in BRCA1/2-PV carriers are similar to previous findings in the general population; 5, 50 however, the impact on cancer risks may be more clinically relevant for people who already have a high risk of cancer, such as BRCA1/2-PV carriers, although this is personal. One patient might want to avoid every additional risk, while another one might question the relevance of additional increased risk when the baseline risk of breast cancer is already as high as approximately 70%. Importantly, as we investigated risk ratios, the increase in absolute percent points will be higher in case of a high baseline risk than in case of a low baseline risk. Regarding ovarian cancer, reliable screening is unavailable, and mortality rates are high as it is generally diagnosed at an advanced stage. 51, 52 This might favor the usage of OCP among high-risk women, but the advice to undergo a risk-reducing salpingo-oophorectomy around the age of 40 (and its high uptake) may reduce the relevance of the beneficial effect of OCP use. 53, 54 Further, BRCA1/2-PV carriers can choose to undergo a risk-reducing mastectomy, the uptake of which varies greatly across cultures. After mastectomy, which greatly reduces breast cancer risk by at least 90–95%, 55, 56 the influence of OCP on breast cancer risk may be negligible. Previous risk-reducing surgeries should therefore be taken into account in the contraceptive advice for BRCA1/2-PV carriers. In other cases, the use of contraceptives might influence breast cancer management strategies; for example, OCP might increase breast density, as was previously described for hormone replacement therapy, although the data are inconsistent. 57-59 Higher breast density negatively affects the evaluability of imaging techniques. Further, magnetic resonance imaging (MRI) is aimed to be performed between day 5 and 15 of the menstrual cycle of premenopausal women to optimize evaluability; thus, the optimal timing of an MRI can be challenging in non-menstruating women, for example when using an LR-IUD. Other factors to be included in counselling are age, reversibility of contraception, and whether contraceptives have been used already (e.g., is stopping/switching indicated?). Moreover, the benefit of adequate contraception could be considered to outweigh the very low risk of developing a certain type of cancer at a young age (<25 years). Because of the protective effect of TL on ovarian cancer risk, this might be the optimal approach to combine contraception with ovarian cancer prevention; however, TL is not suitable for young women who have (latent) child wish because it is irreversible. For women who have already been using contraceptives, it is important to include the effect of prolonging contraceptive use on cancer risks in counselling, which was also concluded in a recent investigation in which absolute cancer risks as influenced by OCP were estimated in a hypothetical cohort of BRCA1/2-PV carriers. 60 We found that, with increasing time since last OCP use, the preventive effect on ovarian cancer disappears, whereas the increased breast cancer risk remains for more than 10 years after last use. We should take into account that women who stopped OCP more than 10 years ago are potentially older than those who have never used these contraceptives, and that the formulation of OCPs has changed over time (lower hormonal dosages, different steroid types). An earlier meta-analysis suggested that breast cancer risk is lower in users of newer OCP formulations (after 1975) than those who used OCPs formulated before 1975. Regarding ovarian cancer risk, Schrijver et al. reported a reduced ovarian cancer risk for BRCA1-PV carriers using OCP formulations initiated before 1975 and no significant effect for formulations initiated after 1975, compared with the risk of women who had never used these OCPs. For BRCA2-PV carriers, a pre-1975 initiation did not significantly reduce ovarian cancer risk, whereas a post-1975 initiation did, compared with those who never used these OCPs. 18, 48 We also evaluated the effect of modernity of OCP on cancer risks in the present study. As OCP formulations were poorly described in the individual studies, we performed analyses with studies published more than 10 years ago versus those published in the last 10 years, in which we found consistent results as those obtained in the analyses of all studies combined. The lack of clear data regarding age at first or last use and formulation of OCP may be one explanation for the remaining increased breast cancer risk after the cessation of OCP use. Additional research regarding the potential impact of changing formulations over time is therefore needed. Both OCP and TL reduce ovarian cancer risk, but the underlying etiology remains unclear. One hypothesis is that ovarian cancer risk increases with increasing numbers of ovulations, which is counteracted by the prevention of ovulation by OCPs. 61, 62 The hypothesis that (serous) ovarian cancer originates in the fallopian tubes is increasingly accepted. 63, 64 Potentially, the traumatized ovarian surface epithelium (as during ovulation) is more prone to the attachment of premalignant cells from the fallopian tube, which may then undergo further malignant transformation on the ovary. The preventive effect of TL might support the hypothesis of a central role for the fallopian tube in the origin of ovarian cancer as well; for example, TL may act as a mechanical barrier against malignant or premalignant cells moving from the tubes towards the ovaries. 45, 46 One study investigated the impact of contraceptives on premalignant lesions of ovarian cancer and found no significant association between either OCP or TL on either p53 signatures or on tubal intraepithelial carcinogenic lesions. 65 Further hypotheses regarding TL preventing ovarian cancer include the inhibition of retrograde menstruation; 45, 46 a decreased blood flow towards the ovaries, which could alter the levels of growth factors and hormones; 46, 66, 67 the inhibition of the spread of infections from the external genitalia upwards; 45, 46 and that TL surgery can enable the removal of suspicious ovarian tissue. These theories may apply to salpingectomy as well. Nowadays, most gynecologists perform salpingectomy instead of TL as a surgical sterilization method. Of the four studies included in the meta-analysis of TL, one stated that it focused on the tying of the fallopian tubes, while the others did not specify whether the sterilization included salpingectomy. 34, 36, 37, 39 In the general population, salpingectomy was found to be more effective than sterilization (TL) in reducing ovarian cancer risk. 9 Based on the findings of Falconer et al. and the pathogenesis of (serous) ovarian cancer in which the fimbriated ends seem crucial, it is possible that, among BRCA1/2-PV carriers, salpingectomy might be more effective than TL in reducing ovarian cancer risk. 64 Currently, salpingectomy is being investigated as a method to reduce ovarian cancer risk in BRCA1/2-PV carriers in ongoing trials (NCT04294927, ISRCTN 25173360, NCT04251052). Data were unavailable regarding the impact of other contraceptive methods (e.g., copper IUD, LR-IUD, transdermal contraceptive patch, vaginal ring, contraceptive injection, progestogen-only contraceptive pill, and contraceptive implant) on cancer risks among women at high inherited risk for breast and ovarian cancer at the time we performed our systematic search. Nevertheless, in early 2022, the first study that investigated progestin only contraceptives including the implant, the injection, and the IUD among BRCA1/2-PV carriers was published, revealing a preventive effect of the implant on ovarian cancer risk but no significant effects on ovarian cancer risk were found for the injection, the hormonal IUD, and the non-hormonal IUD. 68 As we found comparable results in the general population and the BRCA1/2-PV population regarding OCP and TL, one could imagine that other contraceptives may similarly impact cancer risks as well. 5, 10 For the general population, data regarding breast cancer risk and other contraceptives are available: an increased relative risk of breast cancer was found for the LR-IUD and the levonorgestrel-only pill, whereas no significant influence was found for the contraceptive patch, vaginal ring, contraceptive injection, and contraceptive implant. Regarding ovarian cancer risk, the use of an IUD (both copper-bearing and levonorgestrel-releasing) or a contraceptive implant was found to be protective. 5, 6, 7, 69-72 To fully counsel BRCA1/2-PV carriers about the contraceptive options, data regarding the impact of contraceptive methods other than OCP and TL on cancer risks in the BRCA1/2-PV population are needed. For clinical practice, it would be interesting to translate our outcomes into absolute risks. However, we should be aware that for both the HR and the OR this is difficult. The HR corresponds to different relative risks at different time points and the odds ratio represents the ratio of cumulative risks (expressed as odds) at a certain timepoint and those timepoints as well as the ages of the participating women vary across studies. Also, data regarding the risk of breast and ovarian cancer in women without contraceptives are unclear as earlier studies that calculated cumulative lifetime risks of breast and ovarian cancer among BRCA1/2-PV carriers do not provide information about whether those women did or did not use contraceptives. 1, 73 It is highly likely that the populations included in those studies consist of a mixture of users and non-users. Taking into account those limitations, our results suggest that compared to a breast cancer risk of 70% in BRCA1/2-PV carriers in general, the breast cancer risk in those that used OCP lies between 68 and 75% based on our OR, and between 76 and 80% based on our HR. Regarding ovarian cancer, overall, BRCA1-PV carriers have a risk of 44%, based on our OR this risk would be between 23 and 33% for OCP-users and based on our HR between 29 and 37%. Compared to the risk of 17% in BRCA2-PV carriers in general, for OCP-users a risk between 7 and 11% (based on OR) or between 10 and 13% (based on HR) would be suggested. For tubal ligation and ovarian cancer risk, compared to the overall risk of 44% for BRCA1-PV carriers, TL would result in a risk between 29 and 45% based on our OR, or between 17 and 37% based on our HR. Compared to the risk of 17% for BRCA2-PV carriers, our OR suggest that TL leads to a risk between 10 and 17% and our HR suggest a risk between 5 and 13%. Strengths and limitations The main strengths of our study include the large number of more than 38,000 BRCA1/2-PV carriers and the performance of meta-analyses, which heighten the level of evidence. We also broadly investigated cancer risks and current recommendations across nations by providing an overview of all relevant international guidelines. In contrast to most previous studies, we did not limit our research to certain types of contraceptives, and we investigated both breast and ovarian cancer risk. Unfortunately, data regarding the formulations of OCPs were unavailable in most of the included studies. The wide variety in age of the included women, and therefore probably the variety of OCP formulations used, may have influenced our results, as OCPs prescribed between the 1960s and 1990s were significantly different from the OCPs used today. We tried to increase the generalizability to modern OCP formulations by conducting additional analyses with studies published >10 years ago versus <10 years ago. Due to the retrospective design of the majority of the included studies, recall and survival bias may influence our results. Further, the analysis of the association between duration of use and cancer risks was limited due to the availability of aggregate data only, as well as the heterogeneity in the way duration of use was categorized across studies. For the same reasons, we were also unable to provide age- or dosage-related effects. Conclusion In conclusion, among BRCA1/2-PV carriers, breast cancer risk was found to be increased by OCP usage compared with those who had never used these contraceptives, with the risk remaining increased for more than 10 years after cessation of use. Ovarian cancer risk was lower among OCP users, but this effect vanishes after cessation of use. TL protects against ovarian cancer. No data are available for other kinds of contraceptives. We should be aware that OCP formulations have changed with time, and we will not know the safety profile of newer OCP formulations for a few years yet. Counselling BRCA1/2-PV carriers regarding contraceptives should be personalized, balancing both genetic and non-genetic individual risk factors (such as prior risk-reducing surgeries, prior breast cancer, and age), as well as taking into account patients’ preferences (such as reversibility, ease of use, reliability, and effect on the menstrual cycle). To optimize counselling and provide clear recommendations for women at high risk for breast and ovarian cancer, future (prospective) research should focus on other (commonly used) contraceptive methods and cancer risks in this specific population.