Ovarian Cancer Risk-Reduction and Screening in BRCA1/2 Mutation Carriers

Abstract

Objective:

To determine the utilization of risk-reducing strategies and screening protocols for ovarian cancer in female BRCA1/2 carriers.

Methods:

This study was a sub-analysis of female participants from a larger multicenter, cross-sectional survey of BRCA1/2 mutation carriers unaffected by cancer. The questionnaire was administered electronically via email at four institutions located in the northeast United States. Data were analyzed with Fisher’s exact test.

Results:

The survey was completed by 104 female BRCA mutation carriers. BRCA subtypes included 54.3% BRCA2, 41.0% BRCA1, and 2.9% both. The age at which patients underwent genetic testing varied 21.2% were 18–24 years, 25.0% were 25–34 years, 29.8% were 35–44 years, and 24.0% were 45 years or older. Nearly, all respondents (97.1%) reported that a provider had discussed risk-reducing surgeries. Of the 79 females who underwent genetic testing before 45 years of age, 53.2% reported that a health care provider recommended taking combined oral contraceptive pills (COCs) to reduce their risk of ovarian cancer, and, of these women, 88.1% chose to use them. COCs were offered at higher rates among women who were younger at the age of genetic testing (18–24: 86%, 25–34: 62%, 35–44: 23%; p < 0.0001). Approximately half (55.8%) of the respondents reported having been offered increased screening for possible early detection of ovarian cancer, of which 81.0% chose to undergo screening. The majority utilized a combination of transvaginal ultrasound and serum CA125 measurements. There were no differences observed in screening utilization based on BRCA mutation type.

Conclusion:

In our cohort of female BRCA mutation carriers, risk-reducing surgery was offered to almost all women, whereas only half were offered risk-reducing medication and/or increased screening. Further investigation is needed to identify barriers to the utilization of risk-reducing strategies among this high-risk population.

Introduction

BRCA1/2 mutation carriers have an increased average lifetime risk for ovarian cancer of 39% (18%–54%) for BRCA1 and 11% (2.4%–19%) for BRCA2 carriers.¹ Published guidelines recommend a variety of interventions to reduce this increased risk through surgical and medical prophylaxis.

Risk-reducing surgery with bilateral salpingo-oophorectomy (BSO) is recommended between 35 and 40 years for BRCA1 carriers and 40 and 45 years for BRCA2 carriers, and upon completion of childbearing.² A risk-reducing BSO is sometimes delayed because of a patient’s fear of entering into menopause or a continued desire for fertility.³ Prior to surgery, female BRCA mutation carriers have the option to use combined oral hormonal contraceptive pills (COCs) as risk-reducing medication. COCs have been shown to significantly reduce the lifetime risk of ovarian cancer for both high- and low-risk females. With one year of use, COCs can reduce the risk of ovarian cancer by 33%–80% for BRCA1 carriers.^4
–6 A similar study within the BRCA2 carrier population was limited by sample size but demonstrated similar trends.⁵ The effect of risk reduction for ovarian cancer is positively correlated with the duration of COC use, and its impact is long-lasting.⁵ In addition to decreasing ovarian cancer risk, COC use has not been shown to increase the risk of breast cancer in high-risk BRCA mutation carriers.^6
–8

Screening for ovarian cancer, even in high-risk females, has limited supporting data, as no studies have shown improved survival rates.^9,10 Serial serum CA125 measurements and transvaginal ultrasound were as screening in a UK-based prospective cohort of high-risk females (16.9% with BRCA1/2 mutations).¹¹ Although they found that screening led to an earlier stage of cancer diagnosis, survival analysis was not performed owing to a low number of events. The authors concluded that screening could be offered to patients who deferred or declined risk-reducing surgery. The American College of Obstetricians and Gynecologists clinical guidelines recommend considering short-term screening in high-risk women starting at the age of 30–35 years until undergoing risk-reducing surgery.⁶

Few studies have assessed the utilization of these risk-reducing or screening methods in females at high risk for ovarian cancer. The objective of this study was to determine the utilization of risk-reducing strategies and screening protocols for ovarian cancer in female BRCA1/2 carriers.

Methods

We performed a sub-analysis of female participants from a larger multicenter, cross-sectional survey of BRCA1/2 mutation carriers unaffected by cancer.¹² Participants who received care between 1996 and 2019 were recruited from hospital databases at four institutions (Women and Infants Hospital, Yale University, Maine Medical, and Hartford Healthcare) located in the northeast United States. The electronic questionnaire was distributed via email and included 2–23 fixed-response questions on ovarian cancer risk-reducing and screening strategies. Study inclusion criteria comprised the following: (1) English-speaking, (2) received a positive BRCA1 or BRCA2 genetic test result, (3) at least 18 years of age, and (4) unaffected by ovarian, fallopian tube, peritoneal, or breast cancer. For this sub-analysis, we narrowed the inclusion criteria to only female participants.

As previously described, a survey methodologist was to develop the questionnaire, and the instrument was piloted with five BRCA mutation carrier participants.¹² The questionnaire was distributed and stored on REDCap where the data remained anonymous. Data collection occurred from March 26, 2018, through June 26, 2019. Institutional Review Board approval was obtained at each institution (Care New England Women & Infants, Yale University, MaineHealth, and Hartford Healthcare).

In this study, we performed a sub-analysis of the female respondents to assess utilization of ovarian cancer risk-reducing strategies and screening protocols. Missing data were labeled as “Prefer not to answer” in the analysis, and denominators were listed in the tables. Questionnaire response options to questions on the age of genetic testing and age of BSO were provided in the order of five-year age ranges. Categorical variables were compared by Fisher’s exact tests. Two-tailed p-values <0.05 were considered statistically significant. No adjustments for multiple comparisons were performed. Statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC). In accordance with the journal’s guidelines, we will provide our data for independent analysis by a selected team by the Editorial Team for the purposes of additional data analysis or for the reproducibility of this study in other centers if such is requested.

Results

The larger multicenter study had 142 completed surveys with a response rate of 34% (422 eligible individuals). Of these, 126 surveys were completed by BRCA mutation carriers unaffected by cancer. In total, 83% (n = 104) of the participants identified as female and were included in our sub-analysis.

Of the 104 female BRCA mutation carriers, the majority were White (95.2%), non-Hispanic (97.1%), and well-educated (79.8% with at least a bachelor’s degree) (Table 1). Half (51%) reported an annual household income of at least $100,000. BRCA subtypes included 53.8% BRCA2, 41.3% BRCA1, and 2.9% with both. The age at which patients underwent genetic testing varied: 21.2% were 18–24 years, 25.0% were 25–34 years, 29.8% were 35-44 years, and 24.0% were 45 years or older. The majority of ordering providers were genetic counselors (56.7%), with fewer tests ordered by OBGYNs (18.3%), primary care providers (4.8%), gynecologic oncologists (4.8%), and breast surgeons (3.8%).

Table 1.

Demographics of a Cohort of Female BRCA1/2 Mutation Carriers Unaffected by Cancer (n = 104)

Demographics	n	%
Hispanic or Latina
Yes	3	2.9
No	101	97.1
Race
American Indian or Alaska Native	1	1.0
Black or African American	2	1.9
Native Hawaiian or other Pacific Islander	1	1.0
White	99	95.2
Puerto Rican	1	1.0
Other/Prefer not to answer	2	1.9
Annual household Income
Less than $50,000	10	9.6
At least $50,000 but less than $75,000	11	10.6
At least $75,000 but less than $100,000	16	15.4
At least $100,000	53	51.0
Prefer not to answer	14	13.5
Highest level of education
Some college/technical school or less	19	18.3
Bachelor’s degree	48	46.2
Graduate degree	35	33.7
Prefer not to answer	2	1.9
Age at completion of survey (years)
18–24	10	9.6
25–34	21	20.2
35–44	23	22.1
45–54	31	29.8
55–64	14	13.5
65 and above	5	4.8
Age at BRCA genetic testing (years)
18–24	22	21.2
25–34	26	25.0
35–44	31	29.8
45–54	18	17.3
55 and above	7	6.7
BRCA mutation type
BRCA1	43	41.3
BRCA2	56	53.8
Both	3	2.9
Don’t know/Prefer not to answer	2	1.9

Nearly all respondents (97.1%) reported that a provider had discussed risk-reducing surgeries. Sixty women underwent a risk-reducing BSO which was recommended by gynecologic oncologists (58.3%), OBGYNs (48.3%), and genetic counselors (46.7%).

Of the 79 females who underwent genetic testing before 45 years of age, approximately half (53.2%) reported that a provider recommended COCs for ovarian cancer risk-reduction and 37 (88.1%) reported taking them (Table 2). COCs were offered at higher rates among women who were younger at the age of genetic testing (18–24: 86%, 25–34: 62%, 35–44: 23%; p < 0.0001) (Table 3). A higher proportion of women with BRCA1 (60.0%) reported being offered COCs than women with BRCA2 (42.5%), although this difference was not statistically significant (p = 0.1) (Table 3). Twenty-four (30.4%) women underwent BSO within the same five-year range, as their genetic testing, and therefore the specific timeframe between genetic testing and undergoing the BSO was unable to be determined. Of the remaining 55 women who reported not having completed a BSO or had completed a BSO at an older age than their genetic testing, 37 (67.3%) were offered COCs and 34 (61.8%) reported using COCs for risk reduction.

Table 2.

Utilization of Ovarian Cancer Risk-Reducing Medication and Screening Methods among Female BRCA1/2 Mutation Carriers Unaffected by Cancer

Ovarian cancer risk-reducing medication	n	%
Has a provider ever recommended you take birth control pills to reduce your risk of ovarian cancer?
Yes—All responders (n = 104)	45	43.3
Yes—Responders who underwent genetic testing before 45 years of age (n = 79)	42	53.2
Have you ever taken birth control pills to reduce your risk of ovarian cancer?
Yes—All responders (n = 104)	39	37.5
Yes—Responders who underwent genetic testing before 45 years of age (n = 79)	37	46.8

Ovarian cancer screening	n	%
Has a provider ever offered you screening methods for ovarian for the possible detection of ovarian cancer?
Yes—All responders (n = 104)	58	55.8
Yes—Responders who underwent genetic testing before 45 years of age (n = 79)	44	55.7
Have you ever undergone ovarian cancer-screening methods?
Yes—All responders (n = 104)	47	45.2
Yes—Responders who underwent genetic testing before 45 years of age (n = 79)	33	41.8
For women who tested <45 years, what methods of ovarian cancer screening have you ever used?
Both transvaginal ultrasound and CA125	21	63.6
Transvaginal ultrasound only	7	21.2
CA125 only	4	12.1
Don’t know/Prefer not to answer	1	3.0

Table 3.

Healthcare Provider Recommendations for Ovarian Cancer Risk-Reducing Medication and Utilization of Ovarian Cancer-Screening Methods Stratified by Age at Genetic Testing and BRCA Mutation Type in Female BRCA Mutation Carriers Who Underwent Genetic Testing before 45 Years (n = 79)

Has a provider ever recommended you take birth controlpills to reduce your risk of ovarian cancer?	Yes (n)	%	p
Age at genetic testing (years)			<0.0001
18–24	19	86.4
25–34	16	61.5
35–44	7	22.6
BRCA subtype			0.10
BRCA1	21	60.0
BRCA2	17	42.5
Both	2	100
Don’t know/Prefer not to answer	2	100

Have you ever undergone ovarian cancer-screening methods?	Yes (n)	%	p
Age at genetic testing (years)			0.22
18–24	6	27.3
25–34	11	42.3
35–44	16	51.6
BRCA subtype			0.32
BRCA1	14	40.0
BRCA2	17	42.5
Both	0	100
Don’t know/Prefer not to answer	2	100

Approximately, half (55.8%) of all female respondents reported having been offered increased screening for possible early detection of ovarian cancer, and 81% of these women underwent screening (n = 47/58) (Table 2). Of the women who had their genetic testing before 45 years, 41.8% (n = 33) underwent increased ovarian cancer screening. The screening tests utilized were both transvaginal ultrasound and serum CA125 (63.6%), transvaginal ultrasound alone (21.2%), or CA125 alone (12.1%) (Table 2). There were no differences observed in screening utilization based on BRCA mutation type (BRCA1 40.0% vs. BRCA2 42.5%; p = 0.32) or age of genetic testing (p = 0.22) (Table 3). Screening was utilized by 50% (n = 31/62) of women who underwent BSO, 38.5% (n = 15/39) of women who had used COCs, and 53.8% (n = 7/13) of women who had neither undergone BSO or had used COCs.

Discussion

Summary of main results

While the vast majority of BRCA mutation carriers were offered risk-reducing surgeries, only half (53%) of women were recommended to take risk-reducing COCs, identifying an important area for targeted educational efforts. Women were more likely to be offered COCs if they were younger at the time of their genetic testing.

Despite the limited evidence supporting screening in this population, approximately half (56%) of participants were offered ovarian cancer screening. When offered, screening was utilized by the majority (81%) of patients. The most commonly utilized screening method was a combination of transvaginal ultrasound and serum CA125 measurements, although data were not collected on the frequency of obtaining these tests.

Results in the context of published literature

Data on COCs within the BRCA population have largely focused on their association with ovarian and breast cancer, and to the best of our knowledge, no literature has been published on whether providers are offering these options to their patients. Several systematic reviews and meta-analyses have been published demonstrating risk reduction with COC use in ovarian cancer largely comparing COC ever-use to never-use in case–control and retrospective reviews with cohorts from the 1980–1990s. These studies have reported varying rates of COC use (9%–72%).^7,13
–15 One European-based retrospective cohort reported rates of ever-use of COCs at 89% in BRCA1 and 81% in BRCA2 carriers unaffected by cancer, with an average duration of use of 8–9 years.⁵ Our data provide a more modern snapshot of COC use within BRCA1 and BRCA2 carriers within the United States, with a specific focus on what providers are offering patients as risk-reducing options.

Similarly, research on ovarian cancer screening has largely focused on its efficacy rather than its current utilization. A 2008 survey study of patients with BRCA (who received care between 1996 and 2008) queried participants on their utilization of risk-reducing surgery and ovarian cancer-screening tests.¹⁶ They found that 40% of women had undergone at least one screening test (transvaginal ultrasound or serum CA125). A quarter (26%) underwent screening tests at least three or more times during the three years preceding the survey.¹⁶ These rates are comparable, although slightly lower, than the rates of utilization of ovarian cancer screening that we identified.

Strengths and weaknesses

Our data contribute to the limited research on utilization of ovarian cancer risk-reducing strategies and screening techniques in a BRCA-mutated population. This survey study was developed under the guidance of a survey methodologist and was piloted prior to implementation. The survey was administered at four institutions across the northeast United States region, and despite the regional variation, the demographics of the cohort were predominately educated, non-Hispanic, White women. We did have a similar representation of BRCA1 and BRCA2 mutation carriers in the cohort.

Limitations include the inherent lack of power with a sub-analysis of a larger study. The homogenous racial demographic of the cohort limits its applicability to more diverse patient populations. There is inherent recall bias with the use of a survey, and although the survey was administered between 2018 and 2019, participants received their care between 1996 and 2019. Historical variations in practice patterns, particularly in regard to hormonal contraception use and screening methods, may contribute to the low rates of use. Furthermore, patient’s recollection of their provider counseling and recommendations may be limited. Cross-referencing patient-reported experiences with clinical documentation or prescriptions would strengthen future research.

Implications for practice and future research

COCs have the potential to reduce a BRCA mutation carrier’s risk of ovarian cancer and can be initiated at early ages, prior to the recommended age for prophylactic surgery. However, our data suggest that many candidates are still not being offered these medications by their healthcare providers. This identifies an area for improvement and a need for further investigation into the barriers to utilization of ovarian cancer risk-reducing medications.

Despite the limited evidence supporting ovarian cancer screening, 45% of BRCA carriers in our sample were utilizing ovarian cancer-screening methods. Future research is needed to evaluate the impact of this screening as well as guide stronger recommendations on screening in patients at elevated risk for ovarian cancer.

Conclusions

Our study identified that although almost all of the female BRCA1/2 mutation carriers were offered risk-reducing surgery, only half were offered risk-reducing medications with COCs. Ovarian cancer screening was also offered to half of the women and was opted to be utilized by the majority, most commonly among those having undergone both transvaginal ultrasound and serum CA125 measurements. Further investigation is needed to identify barriers to utilization of risk-reducing medications.

Footnotes

Authors’ Contributions

J.B.D.: Formal analysis, Writing. J.H.: Conceptualization, Methodology, Investigation. K.R.: Conceptualization, Methodology, Supervision, Writing. L.B.: Conceptualization, Methodology. J.L.: Conceptualization, Methodology. J.S.-W.: Conceptualization, Methodology. C.R.: Methodology, Formal analysis, Writing. M.C.: Methodology, Writing. E.L.: Methodology, Investigation. E.H.: Supervision, Investigation. D.D.: Investigation. A.B.: Supervision, Investigation. L.B.: Supervision, Investigation. M.T.: Investigation. A.S.: Conceptualization, Methodology, Supervision, Writing.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study did not receive any financial support.

The findings were presented as a virtual poster at the Society for Gynecologic Oncology 52nd Annual Meeting in Phoenix, AZ, on March 18–21, 2022, and as a presentation at the New England Association of Gynecologic Oncologists Annual Meeting in Newport, RI, on June 10–12, 2022.

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