Abstract
Background:
Germline genetic testing enables primary cancer prevention, including through prophylactic surgery. We examined risk-reducing surgeries in unaffected individuals tested for hereditary cancer susceptibly between 2010 and 2018 in the Kaiser Permanente Northwest health system.
Methods:
We used an internal genetic testing database to create a cohort of individuals who received tests including one or more high-penetrance hereditary cancer susceptibility gene. We then identified post-testing bilateral mastectomy, bilateral salpingo-oophorectomy (BSO), and total hysterectomy procedures in electronic health record and claims data through 2019. We describe surgery utilization by genetic test results and National Comprehensive Cancer Network (NCCN) guidelines.
Results:
The cohort included 1,020 individuals, 16% with pathogenic/likely pathogenic (P/LP) variants in one or more of the following genes: BRCA1, BRCA2, CHEK2, APC, MUTYH, ATM, MSH2, PALB2, BRIP1, MLH1, MSH6, EPCAM, FLCN, RAD51C, RAD51D, TP53. Among individuals with P/LP variants making them candidates for mastectomy, BSO, or hysterectomy per NCCN guidelines, 34% (33/97), 24% (23/94), and 8% (1/12), respectively, underwent surgery during follow-up. Fifty three percent (18/37) of hysterectomies were among APC, BRCA1, and BRCA2 P/LP variant heterozygotes, typically concurrent with BSO. Three individuals with variants of uncertain significance (only) and 22 with negative results had prophylactic surgery after genetic testing.
Conclusion:
Uptake of risk-reducing surgery following usual care genetic testing appears to be lower than in studies that actively recruit high risk patients and provide testing and follow-up care in specialized settings. Factors in addition to genetic test results and NCCN guidelines motivate prophylactic surgery use and deserve further study.
Keywords: hereditary cancer, genetic testing, prophylactic surgery, risk management, primary prevention
Precis:
Germline genetic testing enables primary cancer prevention, such as prophylactic surgery. Uptake of risk-reducing surgery following usual care genetic testing appears to be lower than documented in prior studies, which often recruited high risk patients and provided testing and follow-up care in specialized settings.
INTRODUCTION
Family history screening followed by germline genetic testing is an important clinical pathway for identifying inherited cancer susceptibility. The United States Preventive Services Task Force (USPSTF) recommends family history screening for all adult women to determine their likelihood of carrying a disease-associated BRCA1 or BRCA2 genetic variant and eligibility for in-depth consultation with a genetics provider.1 National Comprehensive Cancer Network (NCCN) guidelines specify family history criteria, including instances of breast, colorectal, endometrial, ovarian, pancreatic, and prostate cancer, that indicate a need for genetic evaluation, irrespective of personal cancer history.2,3 Identifying inherited susceptibility prior to a cancer diagnosis (i.e., in unaffected individuals) offers the opportunity to prevent cancer morbidity and mortality, including through prophylactic surgery.
Unaffected individuals with genetic risk factors conferring increased lifetime breast, ovarian, and/or endometrial cancer risk can consider bilateral mastectomy, bilateral salpingo-oophorectomy (BSO), and total hysterectomy as risk-management options.2,3 Except for chemoprevention and colonoscopy, these prophylactic surgeries are the only risk-management approaches that reduce personal cancer risk.4–6 Prophylactic surgery has been shown to be clinically- and cost-effective for many high-risk groups, but come with mental, emotional and physical health risks.7–12 Prior studies have consistently identified under- and delayed- prophylactic surgery utilization as impediments to genomic medicine’s population impact on cancer outcomes.13–15 Underuse of BSO and total hysterectomy are of specific concern, as effective ovarian and endometrial cancer surveillance methods do not exist and these cancers are often diagnosed at a stage where treatment options are limited.9,16 More recently, there has been an interest in “overuse” of prophylactic surgeries as a potential harm of expanded multigene panel testing, particularly among individuals who learn they harbor variants of uncertain significance (VUS) or pathogenic and likely pathogenic (P/LP) variants that do not have clear risk-management implications.14,17
Most previous research on the uptake and timing of risk-reducing surgeries has been conducted in individuals with disease-associated variants in BRCA1 or BRCA2.13,14,18 Unaffected high-risk individuals were typically identified through research protocols at specialty cancer centers that offered free access to genetic testing or risk-management supports that are rare within usual care. There is a need for contemporary studies of prophylactic surgery utilization outside of selected populations, particularly as hereditary cancer genetic testing is increasing in community settings and expanding beyond the BRCA1 and BRCA2 genes. This study examined risk-reducing surgeries in unaffected individuals tested for hereditary cancer susceptibly between 2010 and 2018 within a large integrated health care system in the Pacific Northwest. We identified all health plan members who received any genetic test that included one or more of the following high-penetrance cancer susceptibility genes: BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, or EPCAM. Genetic tests ranged from single gene tests to multigene panels that included over fifty genes. We describe surgery uptake by genetic test results and, for those with disease-causing variants, alignment between surgical uptake and current NCCN guidelines.
MATERIALS AND METHODS
Study Population
We conducted a retrospective cohort study in Kaiser Permanente Northwest (KPNW), an integrated health care delivery system serving approximately twenty-five percent of its catchment area in Oregon and Southwest Washington State. KPNW’s members are demographically representative of the coverage area and are 69% non-Hispanic White, 8% Hispanic, 5% Asian, and 3% Black. The remainder of the membership identify as American Indian or Alaskan Native, Pacific Islander, two or more races or their racial identity is unknown. About 2% of members are below 200% of the federal poverty level. Genetic counseling services at KPNW are referral-based, including self-referral, and triaged according to perceived clinical urgency. Individuals receive pre- and post-test counseling from a genetic counselor and/or a medical geneticist. Appointment types during the study period include in-person and virtual (phone or telemedicine/video).
Eligible individuals for this study were aged 18 years or older at the time of genetic testing and had at least one genetic test performed between January 1, 2010 and December 31, 2018 that included one or more high penetrance hereditary cancer susceptibility gene (BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM). We excluded health plan members who had actively opted out of research participation, generally, or genetic research, specifically (N=436). We used the KPNW tumor registry to exclude individuals with prior diagnoses of breast cancer, ovarian cancer (including tubal and peritoneal), and endometrial cancer (N=1,333). We also excluded members with male, other, or unknown sex (N=180) as recorded in the electronic health record (EHR) and those who never received their genetic test results (N=33) (Figure 1). The study was approved by the KPNW Institutional Review Board with a waiver of written informed consent.
Figure 1.
Cohort construction.
Data Resources
KPNW maintains comprehensive administrative and clinical databases that are available for research. Data from the EHR, administrative systems, and claims are incorporated into a research data warehouse using a unique health record number for each health plan member.19,20
Surgery Data
We searched the research data warehouse, including EHR and outside claims systems, for evidence of surgery (bilateral mastectomy; BSO; and total hysterectomy) using procedure codes compiled from the Healthcare Effectiveness Data and Information Set performance measures and manual EHR review of a random sample of members not included in our cohort, but known to be eligible for prophylactic surgery (Supplemental Table 2). We captured surgeries performed during study follow-up, defined as the time between the index genetic test and either the end of the study period (December 31, 2019) or one of the following censoring events: an incident breast, ovarian, or endometrial cancer diagnosis, disenrollment from the health plan, or death.
Additional Member Data
Age, race/ethnicity, and insurance type were extracted from the research data warehouse at the index test order date as were death dates. Incident cancer diagnoses were determined using the tumor registry data.
Genetic Testing Data
Information about genetic test orders and results was obtained from a clinical database maintained outside the data warehouse that tracks data at the order, gene, and variant level. The database captured orders and results for genetic tests sent to commercial laboratories performing most of the health care system’s cancer genetic testing during the study period. We collapsed order data at the member level and used the earliest order as the index order except when subsequent order results had implications for clinical management (Supplemental Table 1). For index orders, we used information contained in the order itself to determine test type as divided into the following predetermined categories: single site; gene rearrangement; panel ≤ 50 genes; panel > 50 genes. Per database design, genetic test results were categorized into the following predetermined categories: P/LP variant(s) identified; negative; or only VUS identified. Negative results included benign and likely benign variants identified.
Statistical Analysis
We summarized cohort characteristics including years of health plan enrollment before genetic testing and years of study follow-up (time elapsed between genetic testing and either the end of the study period or a censoring event). We described bilateral mastectomy, BSO and total hysterectomy uptake by index test results in individuals with intact organs (both breasts, both ovaries, and uterus, respectively). For members with P/LP variants, we further stratified by NCCN’s surgery-related guidelines for that specific gene (surgery recommended, surgery recommended for consideration, no specific surgery recommendations).2,3 We calculated the mean time to surgery following the index test (in days) and the mean age at which surgery was performed (in years) for individuals who had surgery during the follow-up period. We also characterized members who did not pursue surgery but were candidates per current NCCN guidelines given their genetic test results.
To determine patient-level factors independently associated with bilateral mastectomy and BSO uptake, we used multivariable logistic regression models to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). All models included the following variables: age at testing, years of follow-up data, year member received testing (i.e., secular trend), and years of prior health plan enrollment. We dichotomized age at testing (<35 or ≥35 years) in BSO models because NCCN guidelines recommend BSO starting at age 35 years or upon completion of childbearing. Otherwise age was treated as a continuous variable. Mastectomy models also included index test results (P/LP variant in BRCA1 or BRCA2 vs P/LP variant in PALB2 or TP53). We could not construct a regression model for hysterectomy due to the small number of individuals who were candidates for this surgery based on NCCN guidelines and genetic test results.
In exploratory analyses, we examined use of alternate breast cancer risk-management approaches (surveillance breast magnetic resonance imaging (MRI) and chemoprevention with tamoxifen or raloxifene) in women who were candidates for bilateral mastectomy but who did not complete surgery during study follow-up. We also identified concurrent BSO and total hysterectomy procedures that occurred during study follow-up.
RESULTS
Tested Individuals
The cohort included 1,020 individuals with a mean follow-up time of 3 years (range <1–10 years) (Table 1). Cohort members were mostly non-Hispanic White (87%) commercially insured (83%) long-term health system members (9 years mean prior health plan enrollment, range <1–50 years). Genetic testing volume increased over time, with more than half of index tests occurring between 2016 and 2018. For 70% of the sample the index test was a small panel (between two and 50 genes analyzed). As expected, most test results were negative; 16% identified at least one P/LP variant (i.e., test positive). Test positive individuals had P/LP variants in 16 genes: BRCA1, BRCA2, CHEK2, APC, MUTYH, ATM, MSH2, PALB2, BRIP1, MLH1, MSH6, EPCAM, FLCN, RAD51C, RAD51D, TP53. Over half of P/LP variants identified (57%) were in BRCA1 or BRCA2 (Table 2). A total of 22 patients had an incident breast, ovarian, or endometrial cancer diagnosed during study follow-up, which were considered censoring events (Table 1).
Table 1.
Cohort characteristics.
| Characteristics | N = 1,020 |
|---|---|
| Age at index test (years) | |
| Mean (Range) | 48 (18–90) |
| Follow-up data (years) | |
| Mean (Range) | 3 (<1–10) |
| Race/ethnicity, N (%) | |
| Non-Hispanic White | 886 (87) |
| Hispanic | 42 (4) |
| Black | 13 (1) |
| Asian | 30 (3) |
| All other race/ethnicities* | 18 (2) |
| Race/ethnicity unknown | 31 (3) |
| Insurance type, N (%) | |
| Commercial or private | 845 (83) |
| Medicare | 162 (16) |
| Medicaid | 10 (1) |
| Other | 3 (0.3) |
| Prior health plan enrollment (years) | |
| Mean (Range) | 9 (<1–50) |
| Index test year, N (%) | |
| 2010 | 55 (5) |
| 2011 | 70 (7) |
| 2012 | 70 (7) |
| 2013 | 86 (8) |
| 2014 | 87 (9) |
| 2015 | 116 (11) |
| 2016 | 179 (18) |
| 2017 | 180 (18) |
| 2018 | 177 (17) |
| Index test classification, N (%) | |
| Single gene test | 229 (22) |
| Gene rearrangement (BART) | 34 (3) |
| Small panel (≤ 50 genes) | 719 (70) |
| Large panel (> 50 genes) | 38 (4) |
| Index test result, N (%) | |
| Negative | 706 (69) |
| VUS only | 146 (14) |
| P/LP variant(s)† | 170 (16) |
| Incident cancer diagnosis, N (%) | |
| Breast | 18 (2) |
| Ovarian | 2 (<1) |
| Endometrial | 2 (<1) |
Abbreviations: BART: BRACAnalysis Rearrangement Test; VUS: variant of uncertain significance; P/LP: pathogenic or likely pathogenic.
Includes individuals identified in medical record as Native American, Native Hawaiian or Pacific Islander, more than one race/ethnicity, or other (no further description given).
Two patients had two P/LP variants.
Table 2.
Pathogenic or likely pathogenic (P/LP) index test results.
| Gene with P/LP variant | N (%) |
|---|---|
| Total* | 170 (100) |
| BRCA1 | 50 (29) |
| BRCA2 | 47 (28) |
| CHEK2 | 19 (11) |
| APC | 8 (<5) |
| MUTYH | 7 (<5) |
| ATM | 4 (<5) |
| MSH2 | 4 (<5) |
| PALB2 | 4 (<5) |
| BRIP1 | 3 (<5) |
| MLH1 | 3 (<5) |
| MSH6 | 3 (<5) |
| EPCAM | 2 (<5) |
| FLCN | 2 (<5) |
| RAD51C | 2 (<5) |
| RAD51D | 2 (<5) |
| TP53 | 2 (<5) |
Genes with n=1: BARD1, PMS2, RET, FANCC, NF1, SMAD4, SMARCA4, TSC1. One individual had P/LP variants in MSH2 and EPCAM; one individual had P/LP variants in MUTYH and BRCA1.
Risk-Reducing Surgery
Bilateral mastectomy
Five percent (45/997) of individuals with intact breasts underwent bilateral mastectomy during study follow-up (Table 3). Mastectomy uptake was highest among those with P/LP variants in BRCA1, BRCA2, PALB2, or TP53, for whom NCCN guidelines recommend the procedure as a risk-management option to consider (34% uptake, 33/97). These individuals comprised 73% of all mastectomies (33/45) and had surgery, on average, at age 44 years (range: 25–70 years) and 391 days following genetic testing (range: 73–1,599 days). Cohort members completing bilateral mastectomy also included individuals testing negative (16% of mastectomies, 7/45), with P/LP variants in genes without specific mastectomy recommendations (7% of mastectomies, 3/45), and with VUS, only (4% of mastectomies, 2/45) (Table 3, Supplemental Table 3).
Table 3.
Risk-reducing surgeries by genetic test results and NCCN guidelines.
| Surgery N (Col %) | No surgery N (Col %) | Uptake (Row %) | Age at surgery Mean (Range), years | Time to surgery Mean (Range), days | |
|---|---|---|---|---|---|
| Bilateral mastectomy | 45 (100) | 952 (100) | (5) | 44 (25, 70) | 365 (42, 1599) |
| P/LP | |||||
| Consider: BRCA1, BRCA2, PALB2, TP53 | 33 (73) | 64 (7) | (34) | 44 (25, 70) | 391 (73, 1599) |
| No specific recommendation: all other genes | 3a (7) | 60 (6) | (5) | 48 (34, 59) | 277 (72, 577) |
| VUS only | 2b (4) | 139 (15) | (<2) | 37 (36, 37) | 238 (119, 456) |
| Negative | 7 (16) | 689 (72) | (<2) | 45 (40, 51) | 303 (42, 1066) |
| Bilateral salpingo-oophorectomy | 37 (100) | 929 (100) | (4) | 45 (29, 76) | 278 (3, 1879) |
| P/LP | |||||
| Recommend: BRCA1, BRCA2 | 23 (62) | 71 (8) | (24) | 42 (29, 76) | 232 (18, 1061) |
| Consider: BRIP1, EPCAM, RAD51C, MLH1, MSH2, MSH6, RAD51D | 2c (5) | 16 (<2) | (11) | 43 (33, 54) | 156 (124, 188) |
| No specific recommendation: all other genes | 2d (5) | 46 (5) | (4) | 43 (36, 50) | 341 (12, 671) |
| VUS only | 1e (3) | 134 (14) | (<1) | 64 | 188 |
| Negative | 9 (24) | 662 (71) | (<2) | 51 (36, 67) | 419 (3, 1879) |
| Total hysterectomy | 34 (100) | 931 (100) | (4) | 44 (31, 76) | 310 (11, 1396) |
| P/LP | |||||
| Consider: EPCAM, MLH1, MSH2, MSH6, PMS2 | 1f (3) | 11 (<2) | (8) | 33 | 124 |
| No specific recommendation: all other genes | 18g (53) | 129 (14) | (12) | 43 (31, 76) | 261 (12, 1061) |
| VUS only | 0 (0) | 132 (15) | (0) | NA | NA |
| Negative | 15 (44) | 659 (71) | (2) | 47 (36, 60) | 401 (11, 1396) |
Abbreviations: P/LP: pathogenic or likely pathogenic; NCCN: National Comprehensive Cancer Network; VUS: variant of uncertain significance; Col: column; NA: not applicable.
CHECK2 (N=3);
BRCA1 (N=1), RAD51C (N=1);
MLH1 (N=1), MSH2 (N=1);
APC (N=2);
MSH6 (N=1);
MLH1 (N=1);
APC (N=2), BRCA1 (N=9), BRCA2 (N=7)
Exploratory analyses of the 64 individuals with P/LP variants in BRCA1, BRCA2, PALB2, or TP53 who did not have a mastectomy (66% of 97 identified) showed that 34 received any breast MRI during study follow-up and only one initiated chemoprevention (began tamoxifen three months after genetic testing) (Supplemental Table 4).
Bilateral salpingo-oophorectomy
Four percent (37/929) of individuals with intact ovaries had BSO during study follow-up (Table 3). BSO uptake was highest among those with P/LP variants in BRCA1 and BRCA2, for whom NCCN guidelines recommend surgery beginning at age 35 or at the conclusion of childbearing (24% uptake, 23/94). These individuals comprised 62% of all BSO procedures (23/37) and completed surgery, on average, at age 42 years (range: 29–76 years) with a mean time to surgery of 232 days after genetic testing (range: 18–1,061 days). Individuals who had BSO during follow-up also included those with negative test results (24% of BSO procedures, 9/37), P/LP variants in MLH1 or MSH2, where NCCN guidelines recommend considering BSO (5% of BSO procedures, 2/37), and P/LP variants in APC, which has no BSO recommendations (5% of BSO procedures, 2/37). One person with VUS, only, also had a BSO (3% of BSO procedures, 1/37) (Table 3, Supplemental Table 3).
Seventy-one individuals who learned they had P/LP variants in BRCA1 or BRCA2 did not complete BSO during study follow-up (76% of 94 identified). Fifty-six percent (40/71) were age 35 years or older when they received genetic testing (Supplemental Table 5). Additionally, 16 individuals with P/LP variants in genes for which NCCN guidelines recommend considering surgery (BRIP1, EPCAM, MLH1, MSH2, MSH6, RAD51C, and RAD51D) did not complete BSO (89% of 18 identified). Sixty-nine percent (11/16) were age 35 years or older when they received genetic testing (Supplemental Table 5).
Total hysterectomy
Four percent (34/931) of individuals with an intact uterus had total hysterectomy during study follow-up (Table 3). Hysterectomy uptake was highest among those with P/LP variants in BRCA1, BRCA2, and APC, for which NCCN guidelines do not include specific hysterectomy recommendations (12% uptake, 18/147). These individuals comprised 53% of all hysterectomies during follow-up (18/34) and underwent surgery, on average, at age 43 years (range: 31–76 years) and 261 days following genetic testing (range: 12–1,061 days). An additional 15 individuals that tested negative completed hysterectomy during study follow-up (44% of hysterectomies, 15/34). Exploratory analyses showed that 73% of hysterectomies in these two groups (24/33) were concurrent with BSO (Supplemental Table 3).
Genetic testing identified twelve individuals with P/LP variants in EPCAM, MLH1, MSH2, MSH6, or PMS2, for whom NCCN guidelines recommend considering hysterectomy to reduce endometrial cancer risk. One of these individuals completed total hysterectomy during study follow-up (8% uptake, 1/12). The remaining eleven individuals who were candidates for surgery per genetic test results and NCCN guidelines, but did not have hysterectomy, had a mean age at genetic testing of 36 years (range: 19–53 years) (Supplemental Table 4).
Variation in Surgery Uptake
Age at testing, years of study follow-up, and the year the individual received genetic testing were independently associated with BSO uptake (Table 4). Individuals who were younger than 35 years when tested were 82% less likely to have BSO during follow-up than those 35 years or older when tested (OR: 0.18, 95% CI: 0.05, 0.66). A one-year increase in study follow-up was associated with a 35% increase in likelihood of having completed BSO (OR: 1.35, 95% CI: 1.06, 1.71), while a one-year increase in the year the member received testing (i.e., secular trend) was associated with a 28% decrease (OR: 0.72, 95% CI: 0.55, 0.95). A one-year increase in study follow-up was associated with a 26% increase in likelihood of having completed bilateral mastectomy (OR: 1.26, 95% CI: 1.01, 1.58).
Table 4.
Adjusted associations between patient-level characteristics and uptake of risk-reducing surgery.
| aOR | ||
|---|---|---|
| Bilateral mastectomya N=97 |
BSOb N=112 |
|
| Index test result | ||
| BRCA1, BRCA2 | Ref | - |
| PALB2, TP53 | 0.78 (0.12, 4.96) | - |
| Age at index test | ||
| ≥35 years | - | Ref |
| <35 years | - | 0.18 (0.05, 0.66) |
| Age at index test (one-year increase) | 1.03 (0.99, 1.07) | - |
| Follow-up data (one-year increase) | 1.26 (1.01, 1.58) | 1.35 (1.06, 1.71) |
| Index test year (one-year increase) | 1.06 (0.85, 1.34) | 0.72 (0.55, 0.94) |
| Prior health plan enrollment (one-year increase) | 0.98 (0.93, 1.04) | 0.96 (0.88, 1.05) |
p < 0.05
Abbreviations: aOR = adjusted odds ratio; BSO: bilateral salpingo-oophorectomy; Ref: reference; P/LP: pathogenic or likely pathogenic.
Model includes individuals with intact breasts and P/LP variants in BRCA1, BRCA2, PALB2, TP53. Model adjusted for index test results, age at index test, follow-up data, index test year (secular trend), and prior health plan enrollment.
Model includes individuals with intact ovaries and P/LP variants in BRCA1, BRCA2, BRIP1, EPCAM, RAD51C, MLH1, MSH2, MSH6, RAD51D. Model adjusted for age at index test, follow-up data, index test year, and prior health plan enrollment.
DISCUSSION
In this sample of unaffected individuals who received cancer genetic testing as part of usual care, patterns of bilateral mastectomy and BSO largely followed available, gene-specific clinical practice guidelines. Namely, individuals with P/LP variants making them candidates for prophylactic surgery per NCCN guidelines accounted for 73% of bilateral mastectomies and 68% of BSOs that occurred during follow-up. Use of total hysterectomy following testing, however, was highest among individuals with P/LP variants in genes with limited evidence about endometrial cancer risk and no strong surgery recommendations (e.g., APC, BRCA1, BRCA2) and among individuals who received negative test results (53% and 44% of hysterectomies, respectively).
NCCN guidelines recommend that individuals with P/LP variants in EPCAM, MLH1, MSH2, MSH6, & PMS2—the genes that cause Lynch syndrome (LS)—consider prophylactic total hysterectomy as a risk-management option.2 Only one of 12 individuals with P/LP variants in LS-related genes in our sample completed hysterectomy following genetic testing. This rate (8%) is lower than observed in prior studies.21–23 However, our sample of individuals with LS was quite small and almost half received genetic testing in 2018. Thus, they were followed for less time than in previous studies and may have still been considering total hysterectomy at the end of the study follow-up period. NCCN guidelines advise discussing risks and benefits of concurrent hysterectomy at the time of BSO with individuals with BRCA1 and BRCA2 P/LP variants.3 This advice is based on limited data suggesting a slight increased risk of serous uterine cancer in BRCA1 and BRCA2 P/LP variant heterozygotes. Our findings suggest that at least a proportion of those with BRCA1 and BRCA2 P/LP variants pursue concurrent hysterectomy and BSO—as well as some individuals with P/LP variants in APC. It is possible these individuals or their providers see benefits to concurrent gynecologic surgery beyond or in addition to cancer risk-management or that hysterectomy use was motivated by other indications.
Almost three-quarters of our sample was tested with a multigene panel and only slightly fewer individuals received VUS results (n=146) than learned they had a P/LP variant (n=176). In other words, with the transition to panel testing, a meaningful number of individuals received genetic test results with unclear clinical implications. While we cannot definitively determine appropriateness of individual surgery decisions, it does not appear that this transition led to substantial “overtreatment” or guideline-discordant surgeries in this setting. Only three individuals with VUS had risk-reducing surgery during follow-up—less than the number of individuals with negative test results who completed surgery (n=22). Further, surgery uptake in this cohort could have been motivated by cancer family history or other health conditions not captured in our data.24 Our results therefore suggest that while counseling and provider education to prevent downstream harms of uncertain genetic test results—including confusion and over interpretation—is undoubtedly important, there may be a greater need to focus attention and limited research dollars on developing interventions that educate individuals identified with hereditary cancer syndromes (and their providers) about available cancer prevention interventions and support recommended shared decision-making processes.25
To this point, the proportion of individuals with P/LP variants in BRCA1 and BRCA2 who underwent BSO following genetic testing was lower in our study than in prior research.26 Chai et al. reported BSO rates were 45% for BRCA1 and 34% for BRCA2 by age 40 and 86% for BRCA1 and 71% for BRCA2 by age 50.13 More recent data from Marcinkute et al. showed BSO uptake two, five, and ten years after genetic testing of 37%, 50%, and 64%, respectively.14 It is possible our lower BSO rates were because some P/LP variant heterozygotes we considered candidates for surgery were in fact ineligible due to procedures that occurred prior to joining the health system that were not captured in our data. More likely, our results indicate that uptake and timing of BSO continue to be suboptimal. Further, this may be a particular challenge in community settings with less infrastructure for longitudinal case management than specialty cancer centers where most prior research has been conducted. Health plan members who learned they had P/LP variants in BRCA1 or BRCA2 after age 35, but did not have BSO during study follow-up, outnumbered those who did complete BSO by almost two-fold and comprised close to 4% of the total population that had genetic testing. Bilateral mastectomy rates were also low, but more comparable with prior studies given the distributions of age and follow-up time in our cohort.13,14 Based on our exploratory analyses, it does not appear, however, that high-risk individuals identified through genetic testing consistently pursued other types of breast cancer risk-management (chemoprevention or surveillance MRI) if they chose not to complete bilateral mastectomy (Supplemental Table 4).
Finally, individuals had risk-reducing surgery at a range of ages—including as young as 25 and as old as 76—and completed surgeries both shortly following and years after undergoing cancer genetic testing. Health plan members were more likely to have BSO if they had genetic testing after the age of 35, the lowest age bound where NCCN guidelines recommend BSO. Independent of the age at which they had testing, the more years of follow-up data we had available for an individual, the more likely we were to observe bilateral mastectomy and BSO. This is not surprising and suggests, again, that individuals continue to process their hereditary cancer diagnosis and make decisions about risk management approaches years after genetic testing. The secular trend we identified, where individuals who received genetic testing more recently were less likely to have BSO, adjusting for age and years of study follow-up, deserves additional exploration, as it conflicts with temporal trends seen in prior studies.14,27
This study’s key strength is its use of a novel health plan database to study a contemporary sample of individuals who received cancer genetic testing as part of usual care. Further, our robust clinical and administrative data infrastructure and stable membership increase our confidence in our data’s completeness and quality.19,20 However, we may miss cancer diagnoses, genetic tests, and surgeries that individuals received before they joined or outside of the health system. We did not have detailed data on family cancer history or indications for genetic testing, which would have helped us better classify surgery eligibility and understand surgery behavior. We did not account for changes in NCCN recommendations that occurred during the study period; notably, guidelines did change for PALB2 P/LP variant heterozygotes near the end of the study period. Individuals should have been counseled on new risk-management recommendations, although we know anecdotally that there are few formalized processes for tracking high risk patients in the health system. We excluded women with prior breast, ovarian, or endometrial cancer from our sample. Our results may therefore differ from studies using different definitions of unaffected (for example cancer site-specific), as surgery uptake can vary by personal cancer history.28 Finally, we were limited in the sociodemographic factors we could include in logistic regression models due to small cell sizes. It should be noted that while our study was not designed to evaluate the representativeness of genetic test delivery in the health system, non-Hispanic White individuals were over-represented in the population receiving genetic testing relative to KPNW’s overall membership demographics (87% vs. 69%).
In conclusion, our study results call into question return on investments to expand cancer genetic testing that are not accompanied by similar investments in risk-management support for identified high-risk patients. Centralized high-risk clinics are one approach to providing long-term follow-up to individuals with inherited risk factors, but leaner, more flexible delivery models are also needed.29 Given the limitations of current ovarian and endometrial cancer screening modalities, it is particularly important that we better understand how to support high-risk individuals in making challenging risk-management decisions that are inextricably linked to their fertility and sexual health. Honoring patients’ preferences for use and timing of prophylactic surgery while addressing multilevel access and knowledge barriers will be essential to using predictive genetic testing to decrease cancer morbidity and mortality.
Supplementary Material
Funding:
This work was funded as part of the Clinical Sequencing Evidence-Generating Research (CSER) consortium funded by the National Human Genome Research Institute with co-funding from the National Institute on Minority Health and Health Disparities (NIMHD) and the National Cancer Institute (NCI). The CSER consortium represents a diverse collection of projects investigating the application of genome-scale sequencing in different clinical settings including pediatric and adult subspecialties, germline diagnostic testing and tumor sequencing, and specialty and primary care. This work was supported by a grant from the National Human Genome Research Institute (U01HG007292; MPIs: Wilfond, Goddard), with additional support from U24HG007307 (Coordinating Center). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Conflict of interest: The authors made no disclosures.
REFERENCES
- 1.Owens DK, Davidson KW, Krist AH, et al. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2019;322(7):652–665. [DOI] [PubMed] [Google Scholar]
- 2.Gupta S, Weiss JM, Axell L, et al. NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2021. 05/11/2021.
- 3.Daly MB, Pal T, Buys SS, et al. NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2022. 08/11/2021.
- 4.Ludwig KK, Neuner J, Butler A, Geurts JL, Kong AL. Risk reduction and survival benefit of prophylactic surgery in BRCA mutation carriers, a systematic review. Am J Surg. 2016;212(4):660–669. [DOI] [PubMed] [Google Scholar]
- 5.Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010;304(9):967–975. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Schmeler KM, Lynch HT, Chen LM, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med. 2006;354(3):261–269. [DOI] [PubMed] [Google Scholar]
- 7.Li X, You R, Wang X, et al. Effectiveness of Prophylactic Surgeries in BRCA1 or BRCA2 Mutation Carriers: A Meta-analysis and Systematic Review. Clin Cancer Res. 2016;22(15):3971–3981. [DOI] [PubMed] [Google Scholar]
- 8.Anderson K, Jacobson JS, Heitjan DF, et al. Cost-effectiveness of preventive strategies for women with a BRCA1 or a BRCA2 mutation. Ann Intern Med. 2006;144(6):397–406. [DOI] [PubMed] [Google Scholar]
- 9.Sroczynski G, Gogollari A, Conrads-Frank A, et al. Cost-Effectiveness of Early Detection and Prevention Strategies for Endometrial Cancer-A Systematic Review. Cancers (Basel). 2020;12(7). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Kwon JS, Sun CC, Peterson SK, et al. Cost-effectiveness analysis of prevention strategies for gynecologic cancers in Lynch syndrome. Cancer. 2008;113(2):326–335. [DOI] [PubMed] [Google Scholar]
- 11.Jeffers L, Reid J, Fitzsimons D, Morrison PJ, Dempster M. Interventions to improve psychosocial well-being in female BRCA-mutation carriers following risk-reducing surgery. Cochrane Database Syst Rev. 2019;10(10):Cd012894. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Etchegary H, Dicks E, Tamutis L, Dawson L. Quality of life following prophylactic gynecological surgery: experiences of female Lynch mutation carriers. Fam Cancer. 2018;17(1):53–61. [DOI] [PubMed] [Google Scholar]
- 13.Chai X, Friebel TM, Singer CF, et al. Use of risk-reducing surgeries in a prospective cohort of 1,499 BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat. 2014;148(2):397–406. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Marcinkute R, Woodward ER, Gandhi A, et al. Uptake and efficacy of bilateral risk reducing surgery in unaffected female BRCA1 and BRCA2 carriers. J Med Genet. 2021. [DOI] [PubMed] [Google Scholar]
- 15.Berchuck A, Havrilesky LJ, Kauff ND. Is There a Role for Ovarian Cancer Screening in High-Risk Women? J Clin Oncol. 2017;35(13):1384–1386. [DOI] [PubMed] [Google Scholar]
- 16.Hall MJ, Forman AD, Pilarski R, Wiesner G, Giri VN. Gene panel testing for inherited cancer risk. J Natl Compr Canc Netw. 2014;12(9):1339–1346. [DOI] [PubMed] [Google Scholar]
- 17.Welsh JL, Hoskin TL, Day CN, et al. Clinical Decision-Making in Patients with Variant of Uncertain Significance in BRCA1 or BRCA2 Genes. Ann Surg Oncol. 2017;24(10):3067–3072. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Eleje GU, Eke AC, Ezebialu IU, Ikechebelu JI, Ugwu EO, Okonkwo OO. Risk-reducing bilateral salpingo-oophorectomy in women with BRCA1 or BRCA2 mutations. Cochrane Database Syst Rev. 2018;8(8):Cd012464. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Sengupta S, Bachman D, Laws R, et al. Data Quality Assessment and Multi-Organizational Reporting: Tools to Enhance Network Knowledge. EGEMS (Wash DC). 2019;7(1):8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Chubak J, Ziebell R, Greenlee RT, et al. The Cancer Research Network: a platform for epidemiologic and health services research on cancer prevention, care, and outcomes in large, stable populations. Cancer Causes Control. 2016;27(11):1315–1323. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Seppälä TT, Dominguez-Valentin M, Crosbie EJ, et al. Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report. Eur J Cancer. 2021;148:124–133. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Yurgelun MB, Mercado R, Rosenblatt M, et al. Impact of genetic testing on endometrial cancer risk-reducing practices in women at risk for Lynch syndrome. Gynecol Oncol. 2012;127(3):544–551. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Mittendorf KF, Hunter JE, Schneider JL, et al. Recommended care and care adherence following a diagnosis of Lynch syndrome: a mixed-methods study. Hered Cancer Clin Pract. 2019;17:31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.The American College of Obstetricians and Gynecologists. FAQs: Hysterectomy. 2020; https://www.acog.org/womens-health/faqs/hysterectomy. Accessed 07/01/2021, 2021. [Google Scholar]
- 25.Domchek SM, Bradbury A, Garber JE, Offit K, Robson ME. Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? J Clin Oncol. 2013;31(10):1267–1270. [DOI] [PubMed] [Google Scholar]
- 26.Makhnoon S, Tran G, Levin B, et al. Uptake of cancer risk management strategies among women who undergo cascade genetic testing for breast cancer susceptibility genes. Cancer. 2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Surgical Decision Making in the BRCA-Positive Population: Institutional Experience and Comparison with Recent Literature. The Breast Journal; 2015. 10.1111/tbj.12521. Accessed 7/01/2021. [DOI] [PubMed] [Google Scholar]
- 28.Schwartz MD, Isaacs C, Graves KD, et al. Long-Term Outcomes of BRCA1/BRCA2 Testing: Risk Reduction and Surveillance. Cancer. 2012; 118:510–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Laws A, Mulvey TM. Implementation of a High-Risk Breast Clinic for Comprehensive Care of Women With Elevated Breast Cancer Risk Identified by Risk Assessment Models in the Community. JCO Oncol Pract. 2021;17(2):e217–e225. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.