Targeted BRCA1/2 population screening among Ashkenazi Jewish individuals using a web-enabled medical model: An observational cohort study.

PURPOSE: This study aimed to evaluate uptake and follow-up using internet-assisted population genetic testing (GT) for BRCA1/2 Ashkenazi Jewish founder pathogenic variants (AJPVs). METHODS: Across 4 cities in the United States, from December 2017 to March 2020, individuals aged ≥25 years with ≥1 Ashkenazi Jewish grandparent were offered enrollment. Participants consented and enrolled online with chatbot and video education, underwent BRCA1/2 AJPV GT, and chose to receive results from their primary care provider (PCP) or study staff. Surveys were conducted at baseline, at 12 weeks, and annually for 5 years. RESULTS: A total of 5193 participants enrolled and 4109 (79.1%) were tested (median age = 54, female = 77.1%). Upon enrollment, 35.1% of participants selected a PCP to disclose results, and 40.5% of PCPs agreed. Of those tested, 138 (3.4%) were AJPV heterozygotes of whom 21 (15.2%) had no significant family history of cancer, whereas 86 (62.3%) had a known familial pathogenic variant. At 12 weeks, 85.5% of participants with AJPVs planned increased cancer screening; only 3.7% with negative results and a significant family history reported further testing. CONCLUSION: Although continued follow-up is needed, internet-enabled outreach can expand access to targeted GT using a medical model. Observed challenges for population genetic screening efforts include recruitment barriers, improving PCP engagement, and increasing uptake of additional testing when indicated.

Challenges and Opportunities in Engaging Primary Care Providers in BRCA Testing: Results from the BFOR Study.

PURPOSE: Engaging primary care providers (PCPs) in BRCA1/2 testing and results disclosure would increase testing access. The BRCA Founder OutReach (BFOR) study is a prospective study of BRCA1/2 founder mutation screening among individuals of Ashkenazi Jewish descent that sought to involve participants' PCPs in results disclosure. We used quantitative and qualitative methods to evaluate PCPs' perspectives, knowledge, and experience disclosing results in BFOR. METHODS: Among PCPs nominated by BFOR participants to disclose BRCA1/2 results, we assessed the proportion agreeing to disclose. To examine PCP's perspectives, knowledge, and willingness to disclose results, we surveyed 501 nominated PCPs. To examine PCPs' experiences disclosing results in BFOR, we surveyed 101 PCPs and conducted 10 semi-structured interviews. RESULTS: In the BFOR study overall, PCPs agreed to disclose their patient's results 40.5% of the time. Two hundred thirty-four PCPs (46.7%) responded to the initial survey. Responding PCPs were more likely to agree to disclose patients' results than non-responders (57.3% vs. 28.6%, p<0.001). Among all respondents, most felt very (19.7%) or somewhat (39.1%) qualified to share results. Among PCPs declining to disclose, insufficient knowledge was the most common reason. In multivariable logistic regression, feeling qualified was the only variable significantly associated with agreeing to disclose results (OR 6.53, 95% CI 3.31, 12.88). In post-disclosure surveys (response rate=55%), PCPs reported largely positive experiences. Interview findings suggested that although PCPs valued the study-provided educational materials, they desired better integration of results and decision support into workflows. CONCLUSION: Barriers exist to incorporating BRCA1/2 testing into primary care. Most PCPs declined to disclose their patients' BFOR results, although survey respondents were motivated and had positive disclosure experiences. PCP training and integrated decision support could be beneficial. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03351803), November 24, 2017.

Comparison of up-front cash cards and checks as incentives for participation in a clinician survey: a study within a trial.

BACKGROUND: Evidence is needed regarding effective incentive strategies to increase clinician survey response rates. Cash cards are increasingly used as survey incentives; they are appealing because of their convenience and because in some cases their value can be reclaimed by investigators if not used. However, their effectiveness in clinician surveys is not known. In this study within the BRCA Founder OutReach (BFOR) study, a clinical trial of population-based BRCA1/2 mutation screening, we compared the use of upfront cash cards requiring email activation versus checks as clinician survey incentives. METHODS: Participants receiving BRCA1/2 testing in the BFOR study could elect to receive their results from their primary care provider (PCP, named by the patient) or from a geneticist associated with the study. In order to understand PCPs' knowledge, attitudes, experiences and willingness to disclose results we mailed paper surveys to the first 501 primary care providers (PCPs) in New York, Boston, Los Angeles and Philadelphia who were nominated by study participants to disclose their BRCA1/2 mutation results obtained through the study. We used alternating assignment stratified by city to assign the first 303 clinicians to receive a $50 up-front incentive as a cash card (N = 155) or check (N = 148). The cash card required PCPs to send an activation email in order to be used. We compared response rates by incentive type, adjusting for PCP characteristics and study site. RESULTS: In unadjusted analyses, PCPs who received checks were more likely to respond to the survey than those who received cash cards (54.1% versus 41.9%, p = 0.046); this remained true when we adjusted for provider characteristics (OR for checks 1.61, 95% CI 1.01, 2.59). No other clinician characteristics had a statistically significant association with response rates in adjusted analyses. When we included an interaction term for incentive type and city, the favorable impact of checks on response rates was evident only in Los Angeles and Philadelphia. CONCLUSIONS: An up-front cash card incentive requiring email activation may be less effective in eliciting clinician responses than up-front checks. However, the benefit of checks for clinician response rates may depend on clinicians' geographic location. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03351803 ), November 24, 2017.

TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline BRCA Carriers With HER2-Negative Breast Cancer (the INFORM trial).

PURPOSE: Platinum compounds have activity in triple-negative breast cancer (TNBC) in germline BRCA mutation carriers (BRCA carriers). Limited data exist for estrogen receptor (ER)-positive (+) breast cancer among BRCA carriers. INFORM is a randomized, multicenter, phase II trial comparing pathologic complete response (pCR) rates (ypT0/is, N0) after neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin-cyclophosphamide (AC) in BRCA carriers with stage I-III human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Secondary objectives included residual cancer burden scores (RCB) of 0 or 1 (combined) and toxicity. The goal was to determine whether pCR was ≥ 20% higher with CDDP than AC. PATIENTS AND METHODS: BRCA carriers with cT1-3 (≥ 1.5 cm), cN0-3 HER2-negative breast cancer were randomly assigned to preoperative CDDP (75 mg/m2 every 3 weeks × 4 doses) or AC (doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2 every 2-3 weeks × 4 doses) followed by surgery. Pathologic responses were confirmed by central review. RESULTS: A total of 118 patients were randomly assigned; 117 were included in outcome analyses. Mean age was 42 years (range, 24-73 years); 69% were BRCA1+, 30% were BRCA2+, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% had nodal involvement at baseline. Seventy percent had TNBC. Clinical and tumor characteristics were well matched between treatment arms. The pCR rate was 18% with CDDP and 26% with AC, yielding a risk ratio (RR) of 0.70 (90% CI, 0.39 to 1.2). The risk of RCB 0 or 1 (RCB 0/1) was 33% with CDDP and 46% with AC (RR, 0.73; 90% CI, 0.50 to 1.1). Both regimens were generally well tolerated without unexpected toxicities. CONCLUSION: pCR or RCB 0/1 is not significantly higher with CDDP than with AC in BRCA carriers with stage I-III HER2-negative breast cancer for both TNBC and ER+/HER2-negative disease.

TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes.

PURPOSE: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in germline (g)BRCA1/2 mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s)BRCA1/2 mutations or g/s mutations in homologous recombination (HR)-related genes other than BRCA1/2. METHODS: Eligible patients had MBC with measurable disease and germline mutations in non-BRCA1/2 HR-related genes (cohort 1) or somatic mutations in these genes or BRCA1/2 (cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS). RESULTS: Fifty-four patients enrolled. Seventy-six percent had estrogen receptor-positive HER2-negative disease. Eighty-seven percent had mutations in PALB2, sBRCA1/2, ATM, or CHEK2. In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with gPALB2 (ORR, 82%) and sBRCA1/2 (ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable [NA]) for gPALB2 and 6.3 months (90% CI, 4.4 months to NA) for sBRCA1/2 mutation carriers. No responses were observed with ATM or CHEK2 mutations alone. CONCLUSION: PARP inhibition is an effective treatment for patients with MBC and gPALB2 or sBRCA1/2 mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond gBRCA1/2 mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.