Abstract
PURPOSE
Recommendations for clinical management of women with germline pathogenic variants (PVs) in breast cancer susceptibility genes vary by gene. The goal of this study was to examine the utilization of risk-reducing strategies and treatments in women with germline PVs in breast cancer susceptibility genes.
METHODS
This cross-sectional study identified women with a PV in at least one of 13 breast cancer susceptibility genes from germline panel testing at a single commercial laboratory between 2015 and 2023. Paired health care claims data for 12 months after genetic testing were evaluated to estimate the utilization of risk-reducing mastectomy and salpingo-oophorectomy, breast magnetic resonance imaging (MRI), and pancreatic screening (magnetic resonance cholangiopancreatography or endoscopic ultrasound) in these women. Multivariable logistic regression models were used to evaluate the association of clinicodemographic factors and genetic testing results with intervention utilization.
RESULTS
Of 3,959 women with a PV (2,088 cancer-free; 1,871 with primary breast cancer diagnosed ≤120 days before genetic testing), the average age at testing was 45 years, 67% were White, and 90% reported a family history of cancer. Breast MRI was used by 33% of cancer-free women and 31% of women with breast cancer after genetic testing; pancreatic screening occurred in <11% of the eligible population. Women with PVs in BRCA1/2 versus other breast cancer susceptibility genes had higher odds of risk-reducing mastectomy (cancer-free: odds ratio 7.2 [95% CI, 3.5 to 14.5]; with cancer: 6.0 [95% CI, 4.2 to 8.5]) and salpingo-oophorectomy (cancer-free: 7.2 (95% CI, 4.6 to 11.3]; with cancer: 13.8 [95% CI, 9.7 to 19.7]).
CONCLUSION
Utilization of risk-reducing surgery was highest in women with BRCA1/2 PV. Pancreatic screening was low in all patients. Future studies are needed to examine the factors underlying these trends.
BACKGROUND
Guidelines from the National Comprehensive Cancer Network (NCCN) recognize BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, and TP53 as high-risk and ATM, BARD1, CHEK2, NF1, RAD51C, and RAD51D as moderate-risk breast cancer susceptibility genes.1 Precision medicine–based strategies include risk-reducing surgeries, early detection, and treatment for individuals with germline pathogenic variants (PVs) in these genes.
CONTEXT
Key Objective
To examine the utilization of risk-reducing strategies and surveillance in women with germline pathogenic variants (PV) in at least one of 13 breast cancer susceptibility genes.
Knowledge Generated
Within the year following identification of a PV in a breast cancer susceptibility gene, approximately one third of women (with and without cancer) pursued increased breast surveillance using magnetic resonance imaging, while <11% of the eligible women pursued pancreatic screening. Women with BRCA1/2 PVs were more likely to pursue risk-reducing surgery compared with women with PVs in other breast cancer susceptibility genes.
Relevance
Tools and programs may be needed to aid improving awareness of and compliance with appropriate surveillance/surgical recommendations for women with PV in breast cancer susceptibility genes.
Risk-reducing strategies vary by gene. For example, NCCN guidelines advise consideration of risk-reducing mastectomy (RRM) for women with high-risk breast cancer gene PVs, yet not for women with moderate-risk gene PVs.1 Risk-reducing salpingo-oophorectomies (RRSO) are recommended for women with PVs in ovarian cancer risk genes: BRCA1, BRCA2, PALB2, RAD51C, and RAD51D.
For early breast cancer detection, women with high- or moderate-risk gene PVs are recommended to have breast magnetic resonance imaging (MRI) in addition to mammogram.1 ATM, BRCA1, BRCA2, PALB2, STK11, and TP53 PVs confer increased risk of pancreatic cancer, and endoscopic ultrasound (EUS) and/or magnetic resonance cholangiopancreatography (MRCP) are offered for early detection.1
After breast cancer diagnosis, genetic results also inform treatment; for example, poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum chemotherapy with BRCA1 or BRCA2 PVs.1,2 Radiation therapy (RT) is relatively contraindicated in patients with TP53 PVs due to risk of radiation-induced sarcomas1,3; thus, mastectomy is advised rather than breast conservation.1,2 Cancer treatment decisions are also influenced by age, family history, and other patient factors.4 In this study, we examined clinical management patterns, including risk-reducing surgeries, surveillance strategies, and treatment approaches, in a real-world cohort of women with and without breast cancer who had PVs in any of 13 breast cancer predisposition genes.
METHODS
Data Sources
This retrospective study used deidentified genetic testing data from women who underwent multigene panel testing (2015-2023) at a commercial laboratory (Invitae, now part of Labcorp, San Francisco, CA) linked to insurance claims data from the Komodo Healthcare Map (Komodo Healthcare, New York, NY) as previously described.5 The study was approved by the Western-Copernicus Group Institutional Review Board (IRB; study number 1167406) and the requirement for individual informed consent was waived due to the minimal risk of using deidentified data. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.5
Study Population
This study focused on two subpopulations: women with PVs in any of 13 breast cancer susceptibility genes who had no International Classification of Diseases (ICD) codes (10th edition) associated with cancer diagnosis and those diagnosed with breast cancer (or ductal carcinoma in situ [DCIS]) followed by germline genetic testing (herein genetic testing) within 120 days (Data Supplement, Table S1). All women had ≥12 months of continuous claims data before and after genetic testing.
Study Variables
Risk-reducing surgeries (RRM and RRSO), surveillance (breast MRI and EUS/MRCP), and treatments (RT, PARPi, and platinum chemotherapy) were identified in claims data using Current Procedural Terminology codes, the Healthcare Common Procedure Coding System (HCPCS), and National Drug Codes (NDC) as previously described (Data Supplement, Table S1).5 A diagnosis of cancer (any type) or DCIS, family history of cancer, and lymph node or distant metastasis were defined by ICD-10 codes. Surgeries for breast cancer treatment (lumpectomy or unilateral mastectomy in the absence of contralateral RRM) were not classified as RRM. Breast MRI performed during the study period was considered surveillance (Data Supplement, Table S1). Insurance type and US region were also extracted from claims data.
Age at testing (continuous), year of genetic testing (continuous), and clinician-reported race, ethnicity, and sex were obtained from the genetic testing requisition form. This form had nine discrete race and ethnicity categories (Ashkenazi Jewish, Asian, Black, French Canadian, Hispanic, Native American, Pacific Islander, Sephardic Jewish, and White) and an open-ended “other” option. The race and ethnicity provided by the clinician informed the categories reported herein: Ashkenazi Jewish, Asian, Black, Hispanic, White, Multiple (≥2 categories selected), and other/unknown (category proportion <2% or unknown).
Use of risk-reducing surgeries, surveillance, and treatments during the year after genetic testing was evaluated for women with ≥1 PV in any of 13 breast cancer susceptibility genes: ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53. For use by gene, women with PVs in >1 of these genes were counted in a separate “multiple” group. Women with a PV classified as possibly mosaic were excluded from all analyses because follow-up testing and information regarding which tissues were affected were not widely available.
In cancer-free women, for RRM, RRSO, and EUS/MRCP, genes were grouped as BRCA1/2, non-BRCA1/2 guideline-indicated (use to be discussed, considered, or recommended), or insufficient evidence, based on the NCCN guidelines for each intervention (Fig 1).1 For breast MRI, genes were grouped as BRCA1/2 or non-BRCA1/2 guideline-indicated (use recommended or considered).1 Women with PVs in >1 breast cancer susceptibility genes were grouped according to the highest-risk PV for analyses of use by gene group. Women with RRM were excluded from the breast MRI analysis. For RRM, RRSO, and EUS/MRCP analyses, women with prior use of an intervention were excluded from the postgenetic testing analysis of that intervention (Fig 1).5 Genes requiring family history of certain cancers were included in the BRCA1/2 or non-BRCA1/2 guideline-indicated category regardless of documented family history, recognizing that ICD-10 family history documentation is often incomplete.
FIG 1.
Exclusion criteria and gene categories evaluated for risk-reducing surgeries and surveillance approaches. EUS/MRCP, endoscopic ultrasound and/or magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging; RRM, risk-reducing mastectomy; RRSO, risk-reducing salpingo-oophorectomy.
As a subanalysis, we assessed intervention use in women with PVs based on guideline stipulations about starting age (RRSO: BRCA1 ≥35, BRCA2 ≥40, PALB2/RAD51C/RAD51D ≥45) and/or family history of pancreatic cancer (EUS/MRCP: STK11 ≥30, ATM/BRCA2 ≥50, BRCA1/PALB2/TP53 ≥50 and family history). Longer-term trends in risk-reducing surgeries 2 and 3 years after genetic testing were assessed. Women without continuous enrollment for the entire year or with utilization the prior year were excluded from the 2- and 3-year analyses.
For women with nonmetastatic breast cancer, rates of risk-reducing surgeries and surveillance were evaluated as described above (Fig 1). Women with bilateral breast cancer or without any documented breast surgery in the year pre- and post-genetic testing (suggesting that they might not be healthy enough to undergo surgery) were excluded from the RRM analysis. Use of PARPi (olaparib or talazoparib) and platinum chemotherapy (carboplatin or cisplatin) were evaluated in women with distantly metastatic breast cancer; RT use was evaluated in women without distantly metastatic breast cancer after excluding those with a breast cancer diagnosis at age 70+ years, RRM, or lack of documented breast surgery (Fig 2). Genes indicated (BRCA1/2 for PARPi and platinum chemotherapy) or contraindicated (TP53 for RT) for breast cancer treatment were compared with all other susceptibility genes.
FIG 2.
Exclusion criteria and gene categories evaluated for each of the treatment approaches in women with breast cancer. DCIS, ductal carcinoma in situ; PARPi, poly (ADP-ribose) polymerase inhibitors; RT, radiation therapy.
Statistical Analyses
Proportions across gene groups were compared using chi-square or Fisher's exact tests. For use by gene, 95% CIs were calculated using Wilson's method. The association of gene groups and clinicodemographic factors with use of risk-reducing surgeries, surveillance, and treatment was assessed with multivariable logistic regression.
For all women, clinicodemographic factors in the model included: clinician-reported race and ethnicity, year of and age at genetic testing, age in years squared (accounting for the nonlinear effect of age), family cancer history (breast or ovarian for RRSO, pancreatic for EUS/MRCP, and breast for all other outcomes), insurance type, and US geographic region. For women with breast cancer, lymph node metastasis and log-transformed time from diagnosis to genetic testing were also included. All analyses were performed using R Statistical Software (v4.2.1; R Core Team 2022) and P < .05 was considered statistically significant.
RESULTS
Cohort Characteristics
Among 2,088 cancer-free women with 2,116 PVs (Data Supplement, Fig S1), mean testing age was 40.2 years; most were White (65.5%), had family history of cancer (92.7%), and commercial insurance (73.0%; Table 1). In 1,871 women with breast cancer (1,905 PVs), average testing age was 50.2 years, median time from diagnosis to testing was 33 days, and demographics were similar to cancer-free women (Table 1; Data Supplement, Fig S1).
TABLE 1.
Demographic Characteristics of Women With Pathogenic Variants in Breast Cancer Susceptibility Genes
| Characteristic | Pathogenic Variant, Cancer-Free | Pathogenic Variant, Breast Cancer Diagnosis |
|---|---|---|
| Total, n | 2,088 | 1,871 |
| Age at testing, years | ||
| Mean (standard deviation) | 40.2 (13.3) | 50.2 (11.6) |
| Median (range) | 38 (18-90) | 50 (21-90) |
| Race and ethnicity, No. (%) | ||
| Asian | 75 (3.6) | 61 (3.3) |
| Ashkenazi Jewish | 76 (3.6) | 39 (2.1) |
| Black | 75 (3.6) | 140 (7.5) |
| Hispanic | 112 (5.4) | 97 (5.2) |
| White | 1,367 (65.5) | 1,303 (69.6) |
| Multiple | 245 (11.7) | 129 (6.9) |
| Other/unknown | 138 (6.6) | 102 (5.5) |
| Family history of breast cancer, No. (%) | ||
| Yes | 1,819 (87.1) | 1,381 (73.8) |
| No | 269 (12.9) | 490 (26.2) |
| Family history of ovarian cancer, No. (%) | ||
| Yes | 632 (30.3) | 310 (16.6) |
| No | 1,456 (69.7) | 1,561 (83.4) |
| Family history of pancreatic cancer, No. (%) | ||
| Yes | 812 (38.9) | 654 (35.0) |
| No | 1,276 (61.1) | 1,217 (65.0) |
| Family history of any cancer, No. (%) | ||
| Yes | 1,936 (92.7) | 1,608 (85.9) |
| No | 152 (7.3) | 263 (14.1) |
| Insurance type, No. (%) | ||
| Commercial | 1,525 (73.0) | 1,319 (70.5) |
| Medicaid/Managed Medicaid | 435 (20.8) | 311 (16.6) |
| Medicare/Medicare Advantage | 114 (5.5) | 239 (12.8) |
| Other/unknown | 14 (0.7) | <5 (<0.3) |
| Geographic region, No. (%) | ||
| Northeast | 475 (22.7) | 388 (20.7) |
| Midwest | 540 (25.9) | 520 (27.8) |
| South | 461 (22.1) | 521 (27.8) |
| West | 602 (28.8) | 434 (23.2) |
| Unknown | 10 (0.5) | 8 (0.4) |
| Days between breast cancer diagnosis and genetic testing report, days | ||
| Mean (standard deviation) | NA | 40.5 (25.4) |
| Median (range) | NA | 33 (0, 120) |
| Lymph node metastasis, No. (%) | ||
| Yes | NA | 626 (33.5) |
| No | NA | 1,245 (66.5) |
| Distant metastasis, No. (%) | ||
| Yes | NA | 164 (8.8) |
| No | NA | 1,707 (91.2) |
| Continuous enrollment after genetic testing, months | 12.0-97.1 | |
| Mean (standard deviation) | 29.9 (15.5) | 33.7 (18.0) |
| Median (range) | 25.1 (12.0-99.2) | 28.6 (12.0-97.1) |
| Continuous enrollment categorical after genetic testing, months, No. (%) | ||
| 12-24 | 981 (47.0) | 722 (38.6) |
| ≥24-36 | 520 (24.9) | 459 (24.5) |
| ≥36-48 | 286 (13.7) | 276 (14.8) |
| ≥48 | 301 (14.4) | 414 (22.1) |
| Year of genetic testing, No. (%) | ||
| 2015/2016 | 16 (0.8) | 37 (2.0) |
| 2017 | 53 (2.5) | 89 (4.8) |
| 2018 | 157 (7.5) | 196 (10.5) |
| 2019 | 280 (13.4) | 275 (14.7) |
| 2020 | 315 (15.1) | 289 (15.4) |
| 2021 | 540 (25.9) | 416 (22.2) |
| 2022 | 636 (30.4) | 477 (25.5) |
| 2023 | 91 (4.4) | 92 (4.9) |
NOTE. Demographic-related cells with values <5 have been suppressed for patient privacy.
Use of Risk-Reducing Surgeries and Surveillance in Cancer-Free Women
Cancer-free women had the highest rates of breast MRI use (33.2%) versus other interventions (Data Supplement, Table S2). For women with BRCA1/2 PVs, use differed by intervention, with highest rates for breast MRI (BRCA1: 41.9% [95% CI, 36.5% to 47.4%]; BRCA2: 39.9% [95% CI, 35.2% to 44.7%]) and lowest for EUS/MRCP (BRCA1: 1.5%, [95% CI, 0.7% to 3.6%]; BRCA2: 3.1% [95% CI, 1.8% to 5.2%]; Data Supplement, Figs S2 and S3).
Cancer-free women with PVs in non-BRCA1/2 guideline-indicated genes did not have significantly different RRM rates versus those with BRCA1/2 PVs (<3.0% v 4.9%, P = .050) or insufficient evidence genes (<3.0% v <1.3%, P = .678; Table 2). Women with non-BRCA1/2 guideline-indicated gene PVs had higher rates of RRSO than those with insufficient evidence gene PVs (11.5% v 3.3%, P < .001), but rates were not different compared with those with BRCA1/2 PVs (11.5% v 12.6%, P = .730). Women with BRCA1/2 versus other gene PVs had higher rates of breast MRI (40.8% v 28.9%, P < .001). Women with non-BRCA1/2 guideline-indicated gene PVs had significantly higher rates of EUS/MRCP compared with those with BRCA1/2 PVs (7.9% v 2.3%, P < .001) or insufficient evidence gene PVs (7.9% v 2.3%, P < .001).
TABLE 2.
Rates of Preventative Intervention and Breast Cancer Treatment in the First Year After Genetic Testing by Gene-Directed Recommendation Groups
| Risk-Reducing Strategies and Treatments | Pathogenic Variant, Cancer-Free | Pathogenic Variant, Breast Cancer Diagnosis | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Gene Groups | P | Gene Groups | P | |||||||||
| BRCA1/2 | Non-BRCA1/2 Guideline-Indicateda | Otherb | BRCA1/2 v Other | Non-BRCA1/2 Guideline-Indicated v Other | BRCA1/2 v Non-BRCA1/2 Guideline-Indicated | BRCA1/2 | Non-BRCA1/2 Guideline-Indicated | Other | BRCA1/2 v Other | Non-BRCA1/2 Guideline-Indicated v Other | BRCA1/2 v Non-BRCA1/2 Guideline-Indicated | |
| Risk-reducing surgical procedures, No. (%) | ||||||||||||
| RRM | 38/771 (4.9) | <5/168 (<3.0) | <15/1,142 (<1.3) | 1.6 × 10 − 7 | .678 | .050 | 307/375 (81.9) | 48/96 (50.0) | 212/517 (41.0) | <2 × 10 − 16 | .127 | 2.4 × 10 − 10 |
| RRSO | 97/768 (12.6) | 28/243 (11.5) | 34/1,038 (3.3) | 7.1 × 10 − 14 | 1.7 × 10 − 7 | .730 | 277/659 (42.0) | 46/203 (22.7) | 58/775 (7.5) | <2 × 10 − 16 | 9.6 × 10 − 10 | 9.4 × 10 − 7 |
| Surveillance strategies, No. (%) | ||||||||||||
| EUS/MRCP | 18/768 (2.3) | 37/470 (7.9) | 19/815 (2.3) | 1.0 | 5.5 × 10 − 6 | 9.0 × 10 − 6 | 44/666 (6.6) | 30/338 (8.9) | 19/629 (3.0) | .004 | 1.4x10 − 4 | .241 |
| Breast MRI | 299/733 (40.8) | 375/1,297 (28.9) | NA | NA | NA | 6.3 × 10 − 8 | 52/133 (39.1) | 145/502 (28.9) | NA | NA | NA | .031 |
| Breast cancer treatment, No. (%) | ||||||||||||
| Indicated: BRCA1/2 | Not indicatedc | BRCA1/2 v not indicated | ||||||||||
| Platinum agent | NA | 23/82 (28.0) | 16/74 (21.6) | .459 | ||||||||
| PARPi | NA | >16/82 (>19.5) | <5/74 (<6.8) | 7.0 × 10 − 5 | ||||||||
| Indicatedd | Contraindicated: TP53 | Indicated vs TP53 | ||||||||||
| RT | NA | 277/>320 (>85.2) | 0/<5 (0.0) | .021 | ||||||||
NOTE. Values in bold indicate a significant P value <.05. Procedure-related cells with values <5 and related subgroups have been suppressed for patient privacy.
Abbreviations: EUS/MRCP, endoscopic ultrasound and/or magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging; PARPi, poly (ADP-ribose) polymerase inhibitors; RRM, risk-reducing mastectomy; RRSO, risk-reducing salpingo-oophorectomy; RT, radiation therapy.
Non-BRCA1/2 guideline-indicated = CDH1, PALB2, PTEN, STK11, and TP53 for risk-reducing mastectomy; PALB2, RAD51C, and RAD51D for risk-reducing salpingo-oophorectomy; ATM, PALB2, STK11, and TP53 for endoscopic ultrasound and/or magnetic resonance cholangiopancreatography; and ATM, BARD1, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53 for breast MRI.
Other = insufficient evidence (ATM, BARD1, CHEK2, NF1, RAD51C, and RAD51D for risk-reducing mastectomy; ATM, BARD1, CDH1, CHEK2, NF1, PTEN, STK11, and TP53 for risk-reducing salpingo-oophorectomy; and BARD1, CDH1, CHEK2, NF1, PTEN, RAD51C, and RAD51D for endoscopic ultrasound and/or magnetic resonance).
Not indicated for platinum agents or PARPi = ATM, BARD1, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53.
Indicated for radiation therapy = ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, and STK11.
In cancer-free women with PVs in guideline-eligible genes based on age and/or family history, EUS/MRCP use was 10.4% (95% CI, 7.0% to 15.3%) and RRSO use was 24.7% (95% CI, 20.8% to 29.0%). For longer-term trends in risk-reducing surgeries, 7.3% (95% CI, 4.2% to 12.3%) and 2.5% (95% CI, 0.7% to 8.6%) of guideline-eligible cancer-free women had RRSO during years 2 and 3, respectively. RRM rates were 2.7% (95% CI, 1.5% to 4.6%) in year 2 and 2.2% (95% CI, 0.9% to 5.0%) in year 3 for women with guideline-indicated gene PVs (BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, or TP53).
In multivariable analyses, intervention utilization for cancer-free women was higher for those with BRCA1/2 (v insufficient evidence gene) PVs for RRM (odds ratio [OR], 7.2 [95% CI, 3.5 to 14.5]), RRSO (OR, 7.2 [95% CI, 4.6 to 11.3]), and breast MRI (OR, 2.6 [95% CI, 2.1 to 3.2]), and with non-BRCA1/2 guideline-indicated (v insufficient evidence) gene PVs for RRSO (OR, 3.9 [95% CI, 2.2 to 6.7]) and EUS/MRCP (OR, 3.6 [95% CI, 2.0 to 6.6]) (Table 3). With each additional year of age, odds of undergoing RRSO (OR, 1.6 [95% CI, 1.4 to 1.9]), EUS/MRCP (OR, 1.2 [95% CI, 1.0 to 1.5]), and breast MRI (OR, 1.2 [95% CI, 1.2 to 1.3]) increased. Women with family cancer history had higher odds of RRSO (breast: OR, 4.1 [95% CI, 1.6 to 10.6]; ovarian: OR, 1.8 [95% CI, 1.3 to 2.7]), EUS/MRCP (pancreatic: OR, 5.1 [95% CI, 2.8 to 9.2]), and breast MRI (breast: OR, 3.8 [95% CI, 2.6 to 5.6]) than those without family history; odds of EUS/MRCP use increased with each calendar year (OR, 1.2 [95% CI, 1.0 to 1.4]). By contrast, having Medicaid versus commercial insurance was associated with decreased likelihood of breast MRI (OR, 0.6 [95% CI, 0.5 to 0.8]).
TABLE 3.
Factors Associated With Use of Risk-Reducing Surgery and Surveillance
| Factor | Odds Ratio (95% CI) | |||||||
|---|---|---|---|---|---|---|---|---|
| Pathogenic Variant, Cancer-Free | Pathogenic Variant, Breast Cancer Diagnosis | |||||||
| RRM | RRSO | EUS/MRCP | Breast MRI | RRM | RRSO | EUS/MRCP | Breast MRI | |
| Gene group (reference:a insufficient evidenceb) | ||||||||
| BRCA1/2 | 7.2 (3.5 to 14.5) | 7.2 (4.6 to 11.3) | 1.7 (0.8 to 3.4) | 2.6 (2.1 to 3.2) | 6.0 (4.2 to 8.5) | 13.8 (9.7 to 19.7) | 2.5 (1.4 to 4.4) | 1.5 (1.0 to 2.3) |
| Non-BRCA1/2 guideline-indicatedc | 1.3 (0.3 to 6.1) | 3.9 (2.2 to 6.7) | 3.6 (2.0 to 6.6) | NA | 1.6 (1.0 to 2.6) | 4.9 (3.1 to 7.8) | 3.2 (1.8 to 6.0) | NA |
| Age at genetic testing (years, continuous) | 1.1 (0.9 to 1.3) | 1.6 (1.4 to 1.9) | 1.2 (1.0 to 1.5) | 1.2 (1.2 to 1.3) | 1.0 (0.9 to 1.1) | 1.5 (1.3 to 1.6) | 1.2 (1.0 to 1.4) | 1.0 (0.9 to 1.2) |
| Age (nonlinear effect of age) | 1.0 (1.0 to 1.0) | 0.995 (0.994 to 0.997) | 0.9982 (0.9964 to 0.9999) | 0.998 (0.997 to 0.998) | 1.0 (1.0 to 1.0) | 0.996 (0.995 to 0.997) | 1.0 (1.0 to 1.0) | 1.0 (1.0 to 1.0) |
| Race and ethnicity (reference: White) | ||||||||
| Ashkenazi Jewish | 0.3 (0.0 to 2.4) | 1.5 (0.7 to 3.4) | 0.5 (0.1 to 2.2) | 1.3 (0.8 to 2.1) | 0.7 (0.2 to 1.8) | 0.1 (0.0 to 0.6) | 0.0 (0.0 to Inf) | 2.0 (0.7 to 5.8) |
| Asian | 0.0 (0.0 to Inf) | 1.2 (0.6 to 2.8) | 0.6 (0.2 to 2.0) | 0.8 (0.5 to 1.4) | 0.6 (0.2 to 1.3) | 0.5 (0.2 to 1.0) | 0.9 (0.3 to 2.8) | 2.8 (1.0 to 7.6) |
| Black | 0.0 (0.0 to Inf) | 0.4 (0.1 to 1.4) | 0.3 (0.0 to 2.4) | 0.9 (0.5 to 1.6) | 0.9 (0.5 to 1.6) | 0.6 (0.4 to 1.1) | 1.1 (0.4 to 2.8) | 1.8 (0.9 to 3.6) |
| Hispanic | 0.2 (0.0 to 1.8) | 0.5 (0.2 to 1.4) | 0.7 (0.2 to 2.4) | 0.8 (0.5 to 1.3) | 2.1 (1.0 to 4.5) | 0.8 (0.5 to 1.5) | 0.7 (0.2 to 2.4) | 0.8 (0.3 to 2.3) |
| Multiracial | 1.1 (0.5 to 2.4) | 1.0 (0.6 to 1.8) | 0.4 (0.1 to 1.1) | 1.1 (0.8 to 1.5) | 0.8 (0.4 to 1.4) | 1.2 (0.7 to 1.9) | 2.3 (1.2 to 4.6) | 0.7 (0.3 to 1.4) |
| Unknown/other | 0.6 (0.2 to 2.1) | 0.5 (0.2 to 1.1) | 0.4 (0.1 to 1.5) | 1.0 (0.6 to 1.4) | 1.6 (0.8 to 3.5) | 1.0 (0.5 to 1.8) | 0.2 (0.0 to 1.8) | 1.3 (0.6 to 3.0) |
| Family history of breast cancer (reference: no) | 6.0 (0.8 to 43.8) | 4.1 (1.6 to 10.6) | NA | 3.8 (2.6 to 5.6) | 1.3 (0.9 to 1.8) | 1.4 (1.0 to 2.0) | NA | 1.3 (0.9 to 1.9) |
| Family history of ovarian cancer (reference: no) | NA | 1.8 (1.3 to 2.7) | NA | NA | NA | 1.1 (0.8 to 1.6) | NA | NA |
| Family history of pancreatic cancer (reference: no) | NA | NA | 5.1 (2.8 to 9.2) | NA | NA | NA | 2.7 (1.7 to 4.2) | NA |
| Insurance type (reference: commercial) | ||||||||
| Medicaid | 1.0 (0.5 to 2.0) | 1.3 (0.8 to 2.1) | 0.8 (0.4 to 1.6) | 0.6 (0.5 to 0.8) | 0.6 (0.4 to 1.0) | 0.6 (0.4 to 1.0) | 0.4 (0.2 to 0.9) | 0.6 (0.4 to 1.1) |
| Medicare | 0.3 (0.0 to 3.2) | 0.5 (0.2 to 1.5) | 0.5 (0.1 to 2.0) | 0.6 (0.4 to 1.1) | 0.6 (0.4 to 1.1) | 1.4 (0.8 to 2.4) | 0.6 (0.2 to 1.4) | 0.4 (0.2 to 0.9) |
| Other | 0.0 (0.0 to Inf) | 0.0 (0.0 to Inf) | 0.0 (0.0 to Inf) | 0.7 (0.1 to 8.3) | 0.0 (0.0 to Inf) | 0.0 (0.0 to Inf) | 0.0 (0.0 to Inf) | 0.0 (0.0 to Inf) |
| US geographic region (reference: Northeast) | ||||||||
| Midwest | 1.5 (0.6 to 3.5) | 0.9 (0.5 to 1.4) | 0.5 (0.2 to 1.0) | 0.6 (0.5 to 0.8) | 1.2 (0.8 to 1.8) | 1.1 (0.7 to 1.6) | 0.9 (0.5 to 1.7) | 0.9 (0.5 to 1.5) |
| South | 1.4 (0.6 to 3.4) | 0.8 (0.5 to 1.3) | 0.6 (0.3 to 1.2) | 0.7 (0.5 to 0.9) | 1.1 (0.7 to 1.7) | 1.1 (0.8 to 1.7) | 0.5 (0.3 to 1.0) | 0.6 (0.4 to 1.1) |
| West | 1.1 (0.5 to 2.7) | 0.5 (0.3 to 0.9) | 0.8 (0.4 to 1.4) | 0.6 (0.4 to 0.8) | 1.4 (0.9 to 2.2) | 1.1 (0.7 to 1.6) | 0.7 (0.4 to 1.4) | 1.1 (0.6 to 1.8) |
| Year of genetic testing (continuous) | 1.0 (0.8 to 1.2) | 1.0 (0.9 to 1.1) | 1.2 (1.0 to 1.4) | 1.0 (1.0 to 1.1) | 1.0 (1.0 to 1.1) | 1.0 (0.9 to 1.1) | 1.3 (1.1 to 1.5) | 1.0 (0.9 to 1.1) |
| Days between breast cancer diagnosis and return of genetic testing results (log-transformed) | NA | NA | NA | NA | 0.3 (0.2 to 0.6) | 0.7 (0.4 to 1.2) | 0.7 (0.3 to 1.7) | 0.9 (0.5 to 1.8) |
| Lymph node metastasis (reference: no) | NA | NA | NA | NA | 1.6 (1.1 to 2.2) | 0.7 (0.5 to 1.0) | 0.5 (0.3 to 0.9) | 0.9 (0.6 to 1.5) |
| DCIS (reference: no) | NA | NA | NA | NA | 1.4 (0.9 to 2.1) | 1.3 (0.9 to 1.8) | 0.9 (0.5 to 1.7) | 0.6 (0.4 to 1.1) |
NOTE. Values in bold indicate a significant P value (<.05).
Abbreviations: DCIS, ductal carcinoma in situ; EUS/MRCP, endoscopic ultrasound and/or magnetic resonance cholangiopancreatography; Inf, infinity; MRI, magnetic resonance imaging; RRM, risk-reducing mastectomy; RRSO, risk-reducing salpingo-oophorectomy.
For breast MRI, the reference group is non-BRCA1/2 guideline-indicated.
Insufficient evidence = ATM, BARD1, CHEK2, NF1, RAD51C, and RAD51D for risk-reducing mastectomy; ATM, BARD1, CDH1, CHEK2, NF1, PTEN, STK11, and TP53 for risk-reducing salpingo-oophorectomy; and BARD1, CDH1, CHEK2, NF1, PTEN, RAD51C, and RAD51D for endoscopic ultrasound and/or magnetic resonance cholangiopancreatography.
Non-BRCA1/2 guideline-indicated = CDH1, PALB2, PTEN, STK11, and TP53 for risk-reducing mastectomy; PALB2, RAD51C, and RAD51D for risk-reducing salpingo-oophorectomy; ATM, PALB2, STK11, and TP53 for endoscopic ultrasound and/or magnetic resonance cholangiopancreatography; and ATM, BARD1, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53 for breast MRI.
Use of Risk-Reducing Surgeries, Surveillance, and Treatment in Women With Breast Cancer
For women with breast cancer, RRM use was 57.4%, exceeding use of RRSO and all screening interventions (Data Supplement, Table S2). For women with BRCA1/2 PVs, the highest rates of intervention use were for RRM (BRCA1: 83.6%, [95% CI, 77.1% to 88.6%]; BRCA2: 81.1% [95% CI, 75.2% to 85.8%]) while the lowest were for EUS/MRCP (BRCA1: 4.7% [95% CI, 2.8% to 7.9%]; BRCA2: 8.0% [95% CI, 5.7% to 11.2%]; Data Supplement, Figs S4 and S5). RT was the most used treatment (277/325, 85.2%) and PARPi the least (21/156, 13.5%; Data Supplement, Table S2 and Data Supplement, Fig S6).
Women with breast cancer and non-BRCA1/2 guideline-indicated gene PVs had lower RRM rates than women with BRCA1/2 PVs (50.0% v 81.9%, P < .001), with no difference from women with insufficient evidence gene PVs (50.0% v 41.0%, P = .127; Table 2). Women with non-BRCA1/2 guideline-indicated gene PVs had lower RRSO rates than women with BRCA1/2 PVs (22.7% v 42.0%, P < .001) and higher rates than women with insufficient evidence gene PVs (22.7% v 7.5%, P < .001). Women with BRCA1/2 PVs versus other gene PVs had higher rates of breast MRI (39.1% v 28.9%, P = .031). Women with non-BRCA1/2 guideline-indicated gene PVs versus insufficient evidence gene PVs had higher rates of EUS/MRCP (8.9% v 3.0%, P < .001), but did not differ from women with BRCA1/2 PVs (8.9% v 6.6%, P = .241).
In women with cancer and PVs in guideline-eligible genes based on age and/or family history, use of EUS/MRCP was 10.9% (95% CI, 8.0% to 14.6%) and of RRSO was 42.7% (95% CI, 39.0% to 46.5%). For longer-term risk-reducing surgery trends, 30.9% (95% CI, 25.5% to 36.9%) and 10.7% (85/5 CI, 6.1% to 18.1%) of guideline-eligible women with cancer had RRSO during years 2 and 3, respectively. For women with guideline-indicated gene PVs, RRM rates were 19.7% (95% CI, 11.9% to 30.8%) in year 2 and 3.2% (95% CI, 0.6% to 16.2%) in year 3.
In multivariable analyses, factors associated with use of risk-reducing surgeries and surveillance strategies in women with breast cancer included having BRCA1/2 (v insufficient evidence gene) PVs for RRM (OR, 6.0 [95% CI, 4.2 to 8.5]), RRSO (OR, 13.8 [95% CI, 9.7 to 19.7]), and EUS/MRCP (OR, 2.5 [95% CI, 1.4 to 4.4]) as well as having non-BRCA1/2 guideline-indicated (v insufficient evidence) gene PVs for RRM (OR, 1.6 [95% CI, 1.0 to 2.6]), RRSO (OR, 4.9 [95% CI, 3.1 to 7.8]), and EUS/MRCP (OR, 3.2 [95% CI, 1.8 to 6.0]) (Table 3). Compared with White women, multiracial women were more likely to undergo EUS/MRCP (OR, 2.3 [95% CI, 1.2 to 4.6]) and Asian women were more likely to undergo breast MRI (OR, 2.8 [95% CI, 1.0 to 7.6]), while Ashkenazi Jewish women were less likely to undergo RRSO (OR, 0.1 [95% CI, 0.0 to 0.6]). Women with lymph node metastasis (v without) had higher use of RRM (OR, 1.6 [95% CI, 1.1 to 2.2]) but lower use of RRSO (OR, 0.7 [95% CI, 0.5 to 1.0]) and EUS/MRCP (OR, 0.5 [95% CI, 0.3 to 0.9]). Odds of RRSO use (OR, 1.5 [95% CI, 1.3 to 1.6]) were higher with each additional year of age. Compared with women with commercial insurance, those with Medicaid were less likely to have RRSO (OR, 0.6 [95% CI, 0.4 to 1.0]) and EUS/MRCP (OR, 0.4 [95% CI, 0.2 to 0.9]) and those with Medicare were less likely to have breast MRI (OR, 0.4 [95% CI, 0.2 to 0.9]). Women with (v without) a family history of pancreatic cancer (OR, 2.7 [95% CI, 1.7 to 4.2]) and more recent (v earlier) genetic testing (OR, 1.3 [95% CI, 1.1 to 1.5]) were more likely to undergo EUS/MRCP.
For breast cancer treatments, odds of PARPi use were higher for women with BRCA1/2 PVs (OR, 31.4 [95% CI, 3.8 to 260.3]) versus those with other gene PVs (Data Supplement, Table S3).
DISCUSSION
Women with breast cancer susceptibility gene PVs face a complex and evolving landscape of options to manage their cancer risks. Use of these interventions may have unintended consequences, such as increased risk of second malignant neoplasms in women with TP53 PVs who undergo RT,6 or missed opportunities for early detection with EUS/MRCP in women with ATM or BRCA2 PVs.7 In this study, risk-reducing surgery, surveillance, and treatment varied by gene and with cancer-intrinsic and noncancer factors.
We found that cancer-free women with BRCA1/2 PVs were seven times more likely to undergo RRM and RRSO than women with insufficient evidence gene PVs, suggesting that physicians' guideline-concordant recommendations inform women's choices. Similarly, women with cancer and BRCA1/2 PVs had greater use of RRM, RRSO, and breast MRI than women with non-BRCA1/2 guideline-indicated gene PVs, in agreement with several other publications8-15 and likely reflecting the abundant evidence base for BRCA1/2 PVs.2,9 We found no higher RRM use in cancer-free women with non-BRCA1/2 guideline-indicated gene PVs versus insufficient evidence gene PVs, and no demographic factor was associated with RRM. A study from the Inherited Cancer Registry also did not detect significant associations between age, race, or family history of breast cancer and RRM, but did identify correlates unaccounted for in this study, such as income and cancer worry.16
In women with breast cancer, RRSO use was <50% in guideline-eligible patients, despite the established morbidity and mortality benefits (particularly with estrogen receptor [ER]+ breast cancer).17-19 However, ER/progesterone receptor status was not available in this study.
Breast MRI use was low in women with and without cancer (31.0% and 33.2%, respectively). Prior literature suggests that factors including claustrophobia, time and travel constraints, financial concerns, and procedure intolerance may contribute to low breast MRI use.20
To our knowledge, this is the first study to evaluate EUS/MRCP use in women with breast cancer susceptibility gene PVs. Although women with non-BRCA1/2 guideline-indicated gene PVs were three times more likely than women with insufficient evidence gene PVs to undergo EUS/MRCP, EUS/MRCP use was the lowest among all evaluated risk-reducing and surveillance interventions. These low rates may reflect the recent evolution of guidelines for EUS/MRCP.1,7,21 Accordingly, both having a family history of pancreatic cancer (previously required for all high-risk genes) and more recent genetic testing were associated with use of EUS/MRCP.
In women with cancer, platinum chemotherapy use for metastatic breast cancer was not significantly higher with BRCA1/2 versus other gene PVs. Metastatic breast cancer treatment decisions depend not only on PV status, but also on overall health, tumor subtype, and the location and extent of metastases.22 Notably, PARPi use was <25% in women with distantly metastatic breast cancer and BRCA1/2 PVs, despite guideline recommendations.
This study had limitations. We used a cross-sectional design, analyzing patients referred for clinical genetic testing over nearly decade, during which guidelines evolved. Additionally, the number of patients with continuous claims data for two or more years after genetic testing was relatively low. For some genes (CDH1, PTEN, and STK11), PVs were rare and data limited.
We lacked information about patient preferences, clinician recommendations, tumor biomarkers and somatic mutations, and full demographic/family history information, which influence intervention timing and utilization.1,23-31 We were limited by ambiguities of real-world data in differentiating between breast MRI use for screening versus diagnosis or monitoring. These limitations were balanced by considerable strengths. This was a large, contemporary, real-world study of high-risk women, with genetic information derived directly from the testing laboratory; as such, its results are relevant to patients having clinical genetic testing for breast cancer risk.
These results have implications for clinical practice. Reassuringly, use of RRM, RRSO, and breast surveillance was highest in women with BRCA1/2 PVs, for whom the evidence of benefit is strongest. However, we observed little difference in RRM use between cancer-free women with PVs in genes that did not, versus genes that did, meet guidelines for this invasive procedure. RRSO was too low, even among cancer-free women eligible by gene and age, despite strong evidence of morbidity and mortality reduction.17-19 Pancreatic cancer screening was also low (<11%), regardless of guidelines. Future studies are needed to understand the patient, clinician, and health care system factors that underlie these trends, and to align intervention use with evidence-based guidelines.
Emily M. Russell
Employment: Invitae, Labcorp
Stock and Other Ownership Interests: Invitae, Labcorp
Sarah M. Nielsen
Employment: Invitae, Labcorp
Stock and Other Ownership Interests: Invitae, Labcorp
Travel, Accommodations, Expenses: Invitae, Labcorp
Rachel E. Ellsworth
Stock and Other Ownership Interests: Illumina
Heidi Chwan Ko
Employment: Labcorp
Stock and Other Ownership Interests: Labcorp, Gilead Sciences
Honoraria: Illumina
Speakers' Bureau: Illumina
Rebecca A. Previs
Employment: Labcorp
Stock and Other Ownership Interests: Labcorp
Travel, Accommodations, Expenses: Labcorp
Daniel E. Pineda-Alvarez
Employment: Invitae, GeneDx/BioReference (I), Variantyx (I), Menarini Silicon Biosystems (I), Labcorp, Illumina
Stock and Other Ownership Interests: Invitae
Edward D. Esplin
Employment: Invitae, Labcorp, Biocartis
Consulting or Advisory Role: Taproot Health Inc, Exir Bio, ROM Tech
Travel, Accommodations, Expenses: Velsera
Kevin Hughes
Honoraria: RMMS Legal Services Chicago
Consulting or Advisory Role: Targeted Medical Education, Inc
Nadine M. Tung
Consulting or Advisory Role: AstraZeneca, Jazz Pharmaceuticals, Daiichi Sankyo/Lilly
Research Funding: AstraZeneca (Inst)
Stacy W. Gray
This author is a member of the JCO Precision Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.
Consulting or Advisory Role: Autolomous (I)
Allison W. Kurian
Other Relationship: Ambry Genetics, Color Genomics, GeneDx/BioReference, Invitae, Genentech, Myriad Genetics, Adela, Merck, Gilead Sciences, Foundation Medicine
Uncompensated Relationships: JScreen, Primum, Roon
No other potential conflicts of interest were reported.
PRIOR PRESENTATION
Presented in part at the ASCO Annual Meeting, Chicago, IL, May 31-June 4, 2024; the ASCO Annual Meeting, Chicago, IL, May 29-June 2, 2025; the American Society of Human Genetics (ASHG) Annual Meeting, Denver, CO, November 5-9, 2024; the American Society of Breast Surgeons (ASBrS) Annual Meeting, Las Vegas, NV, May 1-4, 2025; The National Society of Genetic Counselors (NSGC) Annual Meeting, Seattle, WA, November 7-10, 2025; and the Montreal BRCA Symposium, Montreal, QC, May 6-9, 2025.
SUPPORT
Supported by Labcorp (formerly Invitae Corp).
E.M.R. and S.M.N. contributed equally to this work.
AUTHOR CONTRIBUTIONS
Conception and design: Emily M. Russell, Sarah M. Nielsen, Daniel E. Pineda-Alvarez, Kevin Hughes, Allison W. Kurian
Administrative support: Sarah M. Nielsen, Daniel E. Pineda-Alvarez
Provision of study materials or patients: Sarah M. Nielsen
Collection and assembly of data: Sarah M. Nielsen, Kevin Hughes, Stacy W. Gray, Nadine M. Tung
Data analysis and interpretation: Emily M. Russell, Sarah M. Nielsen, Rachel E. Ellsworth, Heidi Chwan Ko, Rebecca A. Previs, Daniel E. Pineda-Alvarez, Edward D. Esplin, Kevin Hughes, Stacy W. Gray, Allison W. Kurian
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Emily M. Russell
Employment: Invitae, Labcorp
Stock and Other Ownership Interests: Invitae, Labcorp
Sarah M. Nielsen
Employment: Invitae, Labcorp
Stock and Other Ownership Interests: Invitae, Labcorp
Travel, Accommodations, Expenses: Invitae, Labcorp
Rachel E. Ellsworth
Stock and Other Ownership Interests: Illumina
Heidi Chwan Ko
Employment: Labcorp
Stock and Other Ownership Interests: Labcorp, Gilead Sciences
Honoraria: Illumina
Speakers' Bureau: Illumina
Rebecca A. Previs
Employment: Labcorp
Stock and Other Ownership Interests: Labcorp
Travel, Accommodations, Expenses: Labcorp
Daniel E. Pineda-Alvarez
Employment: Invitae, GeneDx/BioReference (I), Variantyx (I), Menarini Silicon Biosystems (I), Labcorp, Illumina
Stock and Other Ownership Interests: Invitae
Edward D. Esplin
Employment: Invitae, Labcorp, Biocartis
Consulting or Advisory Role: Taproot Health Inc, Exir Bio, ROM Tech
Travel, Accommodations, Expenses: Velsera
Kevin Hughes
Honoraria: RMMS Legal Services Chicago
Consulting or Advisory Role: Targeted Medical Education, Inc
Nadine M. Tung
Consulting or Advisory Role: AstraZeneca, Jazz Pharmaceuticals, Daiichi Sankyo/Lilly
Research Funding: AstraZeneca (Inst)
Stacy W. Gray
This author is a member of the JCO Precision Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.
Consulting or Advisory Role: Autolomous (I)
Allison W. Kurian
Other Relationship: Ambry Genetics, Color Genomics, GeneDx/BioReference, Invitae, Genentech, Myriad Genetics, Adela, Merck, Gilead Sciences, Foundation Medicine
Uncompensated Relationships: JScreen, Primum, Roon
No other potential conflicts of interest were reported.
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