Susan M Domchek

An eHealth Delivery Alternative for Cancer Genetic Testing for Hereditary Predisposition in Patients With Metastatic Cancers: Protocol for a Randomized Trial

Background Germline BRCA1 and BRCA2 testing is a standard evidence-based practice, with established risk reduction and cancer screening guidelines for genetic carriers. With Food and Drug Administration approval for poly (adenosine diphosphate ribose) polymerase (PARP) inhibitors in patients with metastatic breast, ovarian, pancreatic, and prostate cancer, there is an additional therapeutic rationale for testing all patients with these cancers for germline BRCA1 and BRCA2 mutations. However, many at-risk patients do not have access to genetic services, leaving many genetic carriers unidentified. Objective The eREACH (A Randomized Study of an eHealth Delivery Alternative for Cancer Genetic Testing for Hereditary Predisposition in Metastatic Breast, Ovarian, Prostate, and Pancreatic Cancer Patients) study evaluates the effectiveness of a theoretically and stakeholder-informed eHealth (eg, digital) delivery alternative to traditional genetic counseling for patients with metastatic breast or prostate cancer or advanced or metastatic ovarian or pancreatic cancer referred for genetic testing to determine whether they are candidates for a PARP inhibitor. Methods The eREACH study is a randomized noninferiority study using a 2 × 2 design to test a self-directed digital intervention to deliver clinical genetic testing for patients with metastatic cancers. The traditional standard-of-care pretest (visit 1) and posttest (visit 2—disclosure) counseling delivered by a genetic counselor is replaced with our patient-informed digital intervention. The four arms were as follows: arm A, genetic counselor for visits 1 and 2; arm B, genetic counselor for visit 1 and digital intervention for visit 2; arm C, digital intervention for visit 1 and genetic counselor for visit 2; and arm D, digital intervention for both visits. Participants were adults with advanced or metastatic breast, ovarian, pancreatic, and prostate cancer. The primary outcomes of this study were change in genetic knowledge and anxiety from baseline to postdisclosure assessment. We will test whether the digital intervention is noninferior to standard-of-care counseling with a genetic counselor using a modified noninferiority ANOVA of the posttest disclosure minus baseline change scores. In secondary analyses, we will test pairwise differences among the 4 groups. Results As of January 2025, we have completed enrollment of 229 participants. Data analysis is ongoing, and we expect the results to be published in 2025. Conclusions Increasing indications for BRCA1 and BRCA2 testing create a pressing need to evaluate alternative delivery models to increase access and uptake of these tests while maintaining adequate patient cognitive, affective, and behavioral outcomes. The eREACH study evaluates the effectiveness of an interactive, patient-centered digital intervention to deliver clinical genetic testing to patients with metastatic cancers. We expect that this work will inform evidence-based guidelines and the standard of care for delivery of genetic testing, and it is designed to be broadly applicable and easily adaptable for other populations and settings even beyond oncology. Trial Registration ClinicalTrials.gov NCT04353973; https://clinicaltrials.gov/study/NCT04353973 International Registered Report Identifier (IRRID) DERR1-10.2196/72515

Early Detection of Ovarian Cancer Using Cell-Free DNA Fragmentomes and Protein Biomarkers

Abstract Ovarian cancer is a leading cause of death for women worldwide, in part due to ineffective screening methods. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker [cancer antigen 125 (CA-125) and human epididymis protein 4 (HE4)] analyses to evaluate 591 women with ovarian cancer, with benign adnexal masses, or without ovarian lesions. Using a machine learning model with the combined features, we detected ovarian cancer with specificity >99% and sensitivities of 72%, 69%, 87%, and 100% for stages I to IV, respectively. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100%, and HE4 alone detected 28%, 27%, 67%, and 100% of ovarian cancers for stages I to IV, respectively. Our approach differentiated benign masses from ovarian cancers with high accuracy (AUC = 0.88, 95% confidence interval, 0.83–0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation. Significance: There is an unmet need for effective ovarian cancer screening and diagnostic approaches that enable earlier-stage cancer detection and increased overall survival. We have developed a high-performing accessible approach that evaluates cfDNA fragmentomes and protein biomarkers to detect ovarian cancer.

Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Mutations in BRCA1 and BRCA2

PURPOSE It is uncertain whether, and to what extent, hormonal contraceptives increase breast cancer (BC) risk for germline BRCA1 or BRCA2 mutation carriers. METHODS Using pooled observational data from four prospective cohort studies, associations between hormonal contraceptive use and BC risk for unaffected female BRCA1 and BRCA2 mutation carriers were assessed using Cox regression. RESULTS Of 3,882 BRCA1 and 1,509 BRCA2 mutation carriers, 53% and 71%, respectively, had ever used hormonal contraceptives for at least 1 year (median cumulative duration of use, 4.8 and 5.7 years, respectively). Overall, 488 BRCA1 and 191 BRCA2 mutation carriers developed BC during median follow-up of 5.9 and 5.6 years, respectively. Although for BRCA1 mutation carriers, neither current nor past use of hormonal contraceptives for at least 1 year was statistically significantly associated with BC risk (hazard ratio [HR], 1.40 [95% CI, 0.94 to 2.08], P = .10 for current use; 1.16 [0.80 to 1.69], P = .4, 1.40 [0.99 to 1.97], P = .05, and 1.27 [0.98 to 1.63], P = .07 for past use 1-5, 6-10, and >10 years before, respectively), ever use was associated with increased risk (HR, 1.29 [95% CI, 1.04 to 1.60], P = .02). Furthermore, BC risk increased with longer cumulative duration of use, with an estimated proportional increase in risk of 3% (1%-5%, P = .002) for each additional year of use. For BRCA2 mutation carriers, there was no evidence that current or ever use was associated with increased BC risk (HR, 0.70 [95% CI, 0.33 to 1.47], P = .3 and 1.07 [0.73 to 1.57], P = .7, respectively). CONCLUSION Hormonal contraceptives were associated with increased BC risk for BRCA1 mutation carriers, especially if used for longer durations. Decisions about their use in women with BRCA1 mutations should carefully weigh the risks and benefits for each individual.

Biallelic BRCA Loss and Homologous Recombination Deficiency in Nonbreast/Ovarian Tumors in Germline BRCA1/2 Carriers

PURPOSE Breast and ovarian tumors in germline BRCA1/2 carriers undergo allele-specific loss of heterozygosity, resulting in homologous recombination deficiency (HRD) and sensitivity to poly-ADP-ribose polymerase (PARP) inhibitors. This study investigated whether biallelic loss and HRD also occur in primary nonbreast/ovarian tumors that arise in germline BRCA1/2 carriers. METHODS A clinically ascertained cohort of BRCA1/2 carriers with a primary nonbreast/ovarian cancer was identified, including canonical (prostate and pancreatic cancers) and noncanonical (all other) tumor types. Whole-exome sequencing or clinical sequencing results (n = 45) were analyzed. A pan-cancer analysis of nonbreast/ovarian primary tumors from germline BRCA1/2 carriers from The Cancer Genome Atlas (TCGA, n = 73) was used as a validation cohort. RESULTS Ages of nonbreast/ovarian cancer diagnosis in germline BRCA1/2 carriers were similar to controls for the majority of cancer types. Nine of 45 (20%) primary nonbreast/ovarian tumors from germline BRCA1/2 carriers had biallelic loss of BRCA1/2 in the clinical cohort, and 23 of 73 (32%) in the TCGA cohort. In the combined cohort, 35% and 27% of primary canonical and noncanonical BRCA tumor types, respectively, had biallelic loss. High HRD scores (HRDex > 42) were detected in 81% of tumors with biallelic BRCA loss compared with 22% ( P < .001) of tumors without biallelic BRCA loss. No differences in genomic profile, including mutational signatures, mutation spectrum, tumor mutational burden, or microsatellite instability, were found in primary nonbreast/ovarian tumors with or without biallelic BRCA1/2 loss. CONCLUSION A proportion of noncanonical primary tumors have biallelic loss and evidence of HRD. Our data suggest that assessment of biallelic loss and HRD could supplement identification of germline BRCA1/2 mutations in selection of patients for platinum or PARP inhibitor therapy.

WHAM—A Prospective Study of Weight and Body Composition After Risk-Reducing Bilateral Salpingo-oophorectomy

Abstract Context Body weight and composition may change over the natural menopause transition. Whether surgical menopause has similar effects, and the impact of hormone replacement therapy (HRT), are unknown. Understanding the metabolic effects of surgical menopause will inform clinical care. Objective To prospectively measure weight and body composition over 24 months following surgical menopause compared with a similar comparison group who retained their ovaries. Methods Prospective observational study of weight change from baseline to 24 months in 95 premenopausal women at elevated risk of ovarian cancer planning risk-reducing salpingo-oophorectomy (RRSO) and 99 comparators who retained their ovaries. Change in body composition from baseline to 24 months was also assessed by dual-energy x-ray absorptiometry in a subgroup of 54 women who underwent RRSO and 81 comparators who retained their ovaries. In the subgroup, weight, fat mass, lean mass, and abdominal fat measures were compared between groups. Results At 24 months both groups had gained weight (RRSO 2760 ± 4860 g vs comparators 1620 ± 4540 g) with no difference between groups (mean difference 730 g; 95% CI 920 g to 2380 g; P = .383). In the body composition subgroup, there was no difference in weight between groups at 24 months (mean difference 944 g; 95% CI −1120 g to 2614 g; P = .431). RRSO women may have gained slightly more abdominal visceral adipose tissue (mean difference 99.0 g; 95% CI 8.8 g to 189.2 g; P = .032) but there were no other differences in body composition. There were also no differences in weight or body composition between HRT users and nonusers at 24 months. Conclusion 24 months after RRSO, there was no difference in body weight compared with women who retained their ovaries. RRSO women gained more abdominal visceral adipose tissue than comparators, but there were no other differences in body composition. Use of HRT following RRSO had no effect on these outcomes.

C ombination A TR (ceralasertib) and P A R P (olaparib) I nhibitor (CAPRI) Trial in Acquired PARP Inhibitor–Resistant Homologous Recombination–Deficient Ovarian Cancer

Abstract Purpose: Addition of ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) to PARP inhibitors (PARPi) overcomes PARPi resistance in high-grade serous ovarian cancer (HGSOC) cell and mouse models. We present the results of an investigator-initiated study of combination PARPi (olaparib) and ATRi (ceralasertib) in patients with acquired PARPi-resistant HGSOC. Patients and Methods: Eligible patients had recurrent, platinum-sensitive BRCA1/2 mutated or homologous recombination (HR)–deficient (HRD) HGSOC and clinically benefited from PARPi (response by imaging/CA-125 or duration of maintenance therapy; > 12 months first-line or > 6 months ≥ second-line) before progression. No intervening chemotherapy was permitted. Patients received olaparib 300 mg twice daily and ceralasertib 160 mg daily on days 1 to 7 of a 28-day cycle. Primary objectives were safety and objective response rate (ORR). Results: Thirteen patients enrolled were evaluable for safety and 12 for efficacy; 62% (n = 8) had germline BRCA1/2 mutations, 23% (n = 3) somatic BRCA1/2 mutations, and 15% (n = 2) tumors with positive HRD assay. Prior PARPi indication was treatment for recurrence (54%, n = 7), second-line maintenance (38%, n = 5) and first-line treatment with carboplatin/paclitaxel (8%, n = 1). There were 6 partial responses yielding an ORR of 50% (95% confidence interval, 0.15–0.72). Median treatment duration was 8 cycles (range 4–23+). Grade (G) 3/4 toxicities were 38% (n = 5); 15% (n = 2) G3 anemia, 23% (n = 3) G3 thrombocytopenia, 8% (n = 1) G4 neutropenia. Four patients required dose reductions. No patient discontinued treatment due to toxicity. Conclusions: Combination olaparib and ceralasertib is tolerable and shows activity in HR-deficient platinum-sensitive recurrent HGSOC that benefited and then progressed with PARPi as the penultimate regimen. These data suggest that ceralasertib resensitizes PARPi-resistant HGSOCs to olaparib, warranting further investigation.

PTEN Loss and BRCA1 Promoter Hypermethylation Negatively Predict for Immunogenicity in BRCA-Deficient Ovarian Cancer

PURPOSE Ovarian cancers can exhibit a prominent immune infiltrate, but clinical trials have not demonstrated substantive response rates to immune checkpoint blockade monotherapy. We aimed to understand genomic features associated with immunogenicity in BRCA1/2 mutation–associated cancers. MATERIALS AND METHODS Using the Cancer Genome Atlas whole-exome sequencing, methylation, and expression data, we analyzed 66 ovarian cancers with either germline or somatic loss of BRCA1/2 and whole-exome sequencing, immunohistochemistry, and CyTOF in 20 ovarian cancers with germline BRCA1/2 pathogenic variants from Penn. RESULTS We found two groups of BRCA1/2 ovarian cancers differing in their immunogenicity: (1) 37 tumors significantly enriched for PTEN loss (11, 30%) and BRCA1 promoter–hypermethylated (10, 27%; P = .0016) and (2) PTEN wild-type (28 of 29 tumors) cancers, with the latter group having longer overall survival (OS; P = .0186, median OS not reached v median OS = 66.1 months). BRCA1/2-mutant PTEN loss and BRCA1 promoter–hypermethylated cancers were characterized by the decreased composition of lymphocytes estimated by gene expression ( P = .0030), cytolytic index ( P = .034), and cytokine expression but higher homologous recombination deficiency scores ( P = .00013). Large-scale state transitions were the primary discriminating feature ( P = .001); neither mutational burden nor neoantigen burden could explain differences in immunogenicity. In Penn tumors, PTEN loss and high homologous recombination deficiency cancers exhibited fewer CD3+ ( P = .05), CD8+ ( P = .012), and FOXP3+ ( P = .0087) T cells; decreased PRF1 expression ( P = .041); and lower immune costimulatory and inhibitory molecule expression. CONCLUSION Our study suggests that within ovarian cancers with genetic loss of BRCA1/2 are two subsets exhibiting differential immunogenicity, with lower levels associated with PTEN loss and BRCA hypermethylation. These genomic features of BRCA1/2-associated ovarian cancers may inform considerations around how to optimally deploy immune checkpoint inhibitors in the clinic.

Comprehensive RAD51C ovarian cancer variant analysis uncouples homologous recombination and replicative functions

RAD51C is a tumor suppressor gene with over 285 variants of unknown significance (VUS) found in primary ovarian tumors. RAD51C is a paralog of the recombinase RAD51, and it forms complexes with other paralogs to regulate RAD51 activity. We screened 27 ovarian cancer-derived RAD51C VUS to identify those that affect the assembly of functional tetrameric RAD51B-C-D-XRCC2 (BCDX2) complex. With yeast 3-hybrid and biochemical analyses, we identify a mutation cluster of the RAD51C Walker B region affecting protein interactions with other RAD51 paralogs. By further analyzing these variants for homologous recombination (HR), replication fork regression, DNA binding and ATPase activity, and RAD51 filament formation, we identified separation-of-function alleles that uncouple RAD51C distinct enzymatic activities with HR and replication. Thus, our analysis of RAD51C identifies additional VUS with functional defects, which will aid in pathogenicity classification and inform future strategies to treat individuals harboring RAD51C loss-of-function alleles.

Functional evaluation and clinical classification of BRCA2 variants

Germline BRCA2 loss-of function variants, which can be identified through clinical genetic testing, predispose to several cancers

Olaparib plus Durvalumab, with or without Bevacizumab, as Treatment in PARP Inhibitor-Naïve Platinum-Sensitive Relapsed Ovarian Cancer: A Phase II Multi-Cohort Study

Abstract Purpose: Early results from the phase II MEDIOLA study (NCT02734004) in germline BRCA1- and/or BRCA2-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) showed promising efficacy and safety with olaparib plus durvalumab. We report efficacy and safety of olaparib plus durvalumab in an expansion cohort of women with gBRCAm PSROC (gBRCAm expansion doublet cohort) and two cohorts with non-gBRCAm PSROC, one of which also received bevacizumab (non-gBRCAm doublet and triplet cohorts). Patients and Methods: In this open-label, multicenter study, PARP inhibitor-naïve patients received olaparib plus durvalumab treatment until disease progression; the non-gBRCAm triplet cohort also received bevacizumab. Primary endpoints were objective response rate (ORR; gBRCAm expansion doublet cohort), disease control rate (DCR) at 24 weeks (non-gBRCAm cohorts), and safety (all cohorts). Results: The full analysis and safety analysis sets comprised 51, 32, and 31 patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively. ORR was 92.2% [95% confidence interval (CI), 81.1–97.8] in the gBRCAm expansion doublet cohort (primary endpoint); DCR at 24 weeks was 28.1% (90% CI, 15.5–43.9) in the non-gBRCAm doublet cohort (primary endpoint) and 74.2% (90% CI, 58.2–86.5) in the non-gBRCAm triplet cohort (primary endpoint). Grade ≥ 3 adverse events were reported in 47.1%, 65.6%, and 61.3% of patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively, most commonly anemia. Conclusions: Olaparib plus durvalumab continued to show notable clinical activity in women with gBRCAm PSROC. Olaparib plus durvalumab with bevacizumab demonstrated encouraging clinical activity in women with non-gBRCAm PSROC. No new safety signals were identified.