Importance:Increasing germline genetic testing rates may impact contralateral prophylactic mastectomy (CPM) rates in patients with newly diagnosed breast cancer. Objective:To quantify the impact of a personalized contralateral breast cancer (CBC) risk counseling tool that incorporates genetic testing results. Design, Setting, and Participants:This randomized clinical trial recruited participants from a single tertiary referral center between June 8, 2020, and December 31, 2022. Patients aged 18 to 80 years with unilateral breast cancer who underwent genetic counseling and surgery were eligible. Exclusion criteria were prior or metastatic breast cancer or prior multigene panel testing. Follow-up was completed June 30, 2023. Intervention:Personalized age-specific CBC risks were estimated based on the presence or absence of pathogenic variants associated with breast cancer and were incorporated into a visual decision support tool. Patients were randomized 1:1 to quantitative counseling via the tool vs standard counseling without personalized CBC risk estimates. Main Outcomes and Measures:Co-primary end points included patients' personal CBC risk knowledge and propensity to undergo CPM, before and after counseling, by randomization arm. The secondary end point was CPM rate. Sample size calculations assumed postcounseling CBC risk self-assessments would be 5% different from baseline (SD, 20%). A total of 199 patients in each arm would achieve 80% power and 5% type I error (based on a 2-sample t test). Univariate and multivariate analyses were performed for each end point. Results:A total of 400 patients were randomized (mean [SD] age, 54 [11] years), and 54 were excluded after randomization, leaving 346 patients. Among 341 patients with data available, 21 (6.2%) were Asian or Pacific Islander, 18 (5.3%) were Black, 295 (86.5%) were White, and 7 (2.1%) were of other race; 33 of 330 patients with available data (10.0%) were of Ashkenazi Jewish ancestry. Seventy-five of 346 patients (21.7%) had a first-degree relative with breast cancer. Patients who received quantitative counseling more accurately reported their CBC risk estimates than those who received standard counseling by univariate (coefficient, -9.39; 95% CI, -14.86 to -3.93; P < .001) and multivariate (coefficient, -9.52; 95% CI, -16.50 to -2.51; P = .008) analyses. The type of counseling did not significantly impact perception of risk, self-reported propensity to undergo CPM, or CPM rates. Conclusions and Relevance:In this randomized clinical trial, patients more accurately described their calculated CBC risk after quantitative counseling. This improved knowledge did not impact decisions to undergo CPM. The CBC risk assessment tool is publicly available and can be used for preoperative discussions. Trial Registration:ClinicalTrials.gov Identifier: NCT04245176.

Background/Objectives. The performance of contralateral prophylactic mastectomy significantly reduces the risk of contralateral breast cancer but has also been linked to higher rates of unplanned future operations and psychological stress. The risks of undergoing contralateral prophylactic mastectomy after diagnosis of unilateral primary breast cancer should be weighed against the benefit of risk reduction, which varies widely based on the presence of pathogenic or likely pathogenic variants in high and moderate penetrance genes. In the absence of these mutations, contralateral breast cancer risk varies based on characteristics such as family history, primary tumor characteristics, precursor lesions and other risk factors. Physicians and patients can benefit from risk prediction tools that provide patients personalized risk estimates. Our goal was to develop such a decision support tool to help facilitate informed discussions with breast cancer patients and their clinicians, to make optimal surgical decisions regarding contralateral prophylactic mastectomy. Methods. For carriers of BRCA1, BRCA2, CHEK2, ATM, PALB2, TP53 data was abstracted from published studies to estimate conditional age-specific contralateral breast cancer risk, which was then used to estimate future risk. For non-carriers, a previously developed and validated contralateral breast cancer risk model was adapted. Results. We developed an easy-to-use web application that can estimate lifetime and age-conditional risks for both carriers of relatively common breast cancer-related high and moderate penetrance genes as well as for non-carriers. Conclusions. Our developed tool immediately provides individualized contralateral breast cancer risk estimates and could be extremely helpful during surgical discussions, especially regarding whether or not to perform contralateral prophylactic mastectomy. The tool will be evaluated in a forthcoming randomized controlled trial.

It is unclear whether the American Society of Breast Surgeons’ (ASBrS) guideline to offer genetic testing (GT) to all patients with breast cancer (BC) impacted contralateral prophylactic mastectomy (CPM) rates. We sought to describe the trends of GT and CPM rates and to determine predictors of CPM uptake. After retrospective review of two prospectively maintained institutional databases, we identified patients with unilateral stage 0–III BC who underwent surgery between January 2016 and July 2020. Trends in GT and CPM rates were described and multivariable logistic regression determined factors associated with CPM utilization. Among 6062 women identified, 3242 (53.4

Traditional models for genetic testing have included pre- and post-test genetic counseling. To expand access in cancer care, alternative models have been developed that provide brief pre-test education for informed consent. The VERDI (Video Education with Result Dependent Disclosure) study is examining ways to adapt pre-test video education for historically underserved communities. The impact of alternative models on the genetic counseling workforce is unknown. Insights from qualitative interviews with cancer genetic counselors (GCs) about how to optimally implement this approach will help inform a national survey of GCs about using pre-test video education emphasizing post-test counseling.

Abstract Background: It is unclear whether the release of the American Society of Breast Surgeons’ (ASBrS) guideline to offer germline genetic testing to all patients with breast cancer impacted contralateral prophylactic mastectomy (CPM) rates. The objective of this study was to describe trends of germline testing and CPM rates, and to determine predictors of CPM uptake. Methods: This is a retrospective review of two prospectively maintained single institutional databases: Dana-Farber/Brigham Cancer Center’s surgical database, merged with Dana-Farber Cancer Institute’s Genetics and Prevention database. Trends in germline testing and CPM rates were described, in relation to the February 2019 ASBrS guideline release, and a multivariable logistic regression model was used to determine factors associated with CPM utilization. Patients with unilateral stage 0-III breast cancer who underwent surgery between January 2016 and July 2020 were included. Patients were considered “tested” if they underwent germline genetic testing and results were disclosed before their index operation. CPM was defined as contralateral mastectomy performed at index operation or anytime thereafter, excluding mastectomy for a new contralateral breast cancer event. Results: Among 6,064 women in the cohort, 2,455 (40.5%) had germline genetic testing before their index surgery. Rates of testing significantly increased over the study period from 33.7% in 2016 to 64.9% in 2020 (p< 0.001). A total of 783/6,064 (12.9%) patients underwent CPM which was 40.7% (783/1,926) of the patients who underwent mastectomy. The CPM rate was 13.3% before the guideline release (2016 – January 2019) and 12.5% after (February 2019 – 2020). There was no significant change in CPM rate over time (p=0.527), including before (p=0.380) and after (p=0.220) the 2019 guideline release. The following factors were associated with increased CPM rates on multivariable logistic regression: identification of a pathogenic/likely pathogenic variant in a breast cancer predisposition gene (Adjusted Odds Ratio [Adj. OR] 24.43), genetic testing with a negative test result (Adj. OR 1.52), number of relatives with breast/ovarian cancer (Adj. OR 1.18 and 1.39, respectively for each additional relative), younger age (Adj. OR 0.97 if pre-menopausal, 0.91 if post-menopausal, for each year decrement), and cT2-3 tumors (Adj. OR 1.53 and 1.94, respectively as compared to other cT stages); all p< 0.05. Conclusions: Despite increasing germline genetic testing rates, CPM rates were stable over time, indicating that offering genetic testing to more patients does not increase CPM rates in our experience. Selection bias is most certainly contributing to the apparent association between CPM and genetic testing, even if there is a negative test result, as the classic indications for genetic testing are similar to those for CPM. Citation Format: Anna Weiss, Stephen Knapp, Danielle Braun, Brenna Barton, Monica McGrath, Samantha Stokes, Alison Laws, Laura Warren, Stefania Morganti, Filipa Lynce, Brittany Bychkovsky, Huma Rana, Dillon Davis, Jill Stopfer, Judy Garber, Tari King. Are contralateral prophylactic mastectomy rates impacted by ASBrS guidelines to offer germline genetic testing to all patients with breast cancer? Results from a large, prospective, single-institution cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-22-10.

BACKGROUND:Prior to COVID-19, little was known about how risks associated with such a pandemic would compete with and influence patient decision making regarding cancer risk reducing medical decision making. We investigated how the pandemic affected preferences for medical risk-reducing strategies among women at elevated risk of breast or ovarian cancer. METHODS:We conducted a discrete choice experiment. Women about to undergo genetic testing and counseling at 2 medical centers participated. Enrollment occurred between 2019 and 2022, allowing us to investigate changes in preferences from before the pandemic to after the pandemic. Women chose from permuted scenarios that specified type of surgery, age of menopause, quality of menopausal symptoms, and risk of ovarian cancer, heart disease, or osteoporosis. RESULTS:A total of 355 women, with a median age of 36 y, participated. In 2019, women were less likely to choose prevention scenarios with higher ovarian cancer risk (odds ratio [OR] = 0.42 per 10-point increase in risk, 95% confidence interval [CI] 0.22-0.61). In June 2020, the effect of higher ovarian cancer risk scenarios on choice was attenuated (OR = 0.86, 95% CI 0.68-1.04), with the effect becoming more salient again by July 2021 (OR = 0.59, 95% CI 0.52-0.67) (P = 0.039 for test of temporal interaction). No other attribute demonstrated a temporal trend. CONCLUSION:The risks associated with the COVID-19 pandemic may have attenuated the impact of risk of ovarian cancer on choice of risk-reducing prevention strategies for ovarian cancer. The maximum attenuation occurred at the beginning of the pandemic when access to risk-reducing surgery was most restricted. Our findings highlight how individuals evaluate competing health risks and adjust their uptake of cancer prevention strategies when faced with a future pandemic or similar global crisis. HIGHLIGHTS:In this discrete choice experiment, women were much less likely to choose prevention scenarios that had higher ovarian cancer risk prior to the COVID-19 pandemic than after the pandemic.The attenuation of preferences may have persisted through 2022.COVID-19 may have altered the relative importance of factors that motivate women to undergo risk-reducing surgeries.

BACKGROUND & AIMS:Genetic testing uptake for cancer susceptibility in family members of patients with cancer is suboptimal. Among relatives of patients with pancreatic ductal adenocarcinoma (PDAC), The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated 2 online genetic education/testing delivery models and their impact on patient-reported psychological outcomes. METHODS:Eligible participants had ≥1 first-degree relative with PDAC, or ≥1 first-/second-degree relative with PDAC with a known pathogenic germline variant in 1 of 13 PDAC predisposition genes. Participants were randomized by family, between May 8, 2019, and June 1, 2021. Arm 1 participants underwent a remote interactive telemedicine session and online genetic education. Arm 2 participants were offered online genetic education only. All participants were offered germline testing. The primary outcome was genetic testing uptake, compared by permutation tests and mixed-effects logistic regression models. We hypothesized that Arm 1 participants would have a higher genetic testing uptake than Arm 2. Validated surveys were administered to assess patient-reported anxiety, depression, and cancer worry at baseline and 3 months postintervention. RESULTS:A total of 424 families were randomized, including 601 participants (n = 296 Arm 1; n = 305 Arm 2), 90% of whom completed genetic testing (Arm 1 [87%]; Arm 2 [93%], P = .014). Arm 1 participants were significantly less likely to complete genetic testing compared with Arm 2 participants (adjusted ratio [Arm1/Arm2] 0.90, 95% confidence interval 0.78-0.98). Among participants who completed patient-reported psychological outcomes questionnaires (Arm 1 [n = 194]; Arm 2 [n = 206]), the intervention did not affect mean anxiety, depression, or cancer worry scores. CONCLUSIONS:Remote genetic education and testing can be a successful and complementary option for delivering genetics care. (Clinicaltrials.gov, number NCT03762590).

Supplementary Figure 2 PDF file 78K, This figure depicts the assay used to visualize repair proteins at DNA double-strand breaks

Supplementary Figure 1 from The Relative Contribution of Point Mutations and Genomic Rearrangements in BRCA1 and BRCA2 in High-Risk Breast Cancer Families

Supplementary Figure 4 from Common Familial Colorectal Cancer Linked to Chromosome 7q31: A Genome-Wide Analysis

Background: The COVID-19 pandemic influenced patient health care decisions, but there is little information about the pandemic’s impact on decisions about cancer risk reduction. This includes women at elevated risk of breast or ovarian cancer considering risk-reducing salpingo-oophorectomy (RRSO), risk-reducing salpingectomy (RRS), or other preventive measures. During the pandemic patients needed to balance their concerns about cancer risk reduction with their risks associated with elective health procedures, a risk which changed as vaccines became available. Methods: To address the impact of the COVID-19 pandemic on cancer prevention decision making, we recruited N=396 pre-menopausal women with a personal history of breast cancer or familial history suggestive of increased breast and/or ovarian cancer risk between 4/2019 and 3/2022. We conducted a discrete choice experiment in which patients were asked to choose between two scenarios that specified type of surgery (RRSO, RRS vs. non-surgical surveillance), age of menopause (natural versus immediate), quality of menopausal symptoms (mild, moderate, severe), and risk of ovarian cancer, heart disease, or osteoporosis. Risk of ovarian cancer for the scenarios provided varied in discrete intervals from 0% to 40%. We examined temporal trends during the pandemic using interactions with time coinciding approximately with the beginning of pandemic, peak vaccination period, and the Omicron wave. Results: We identified significant temporal interactions on a woman’s prevention decisions. In 2019, women at higher risk of ovarian cancer were more likely to choose prevention scenarios that favored lower ovarian cancer risk (odds ratio [OR] = 0.48; 95% CI = 0.37, 0.69 per 10% increase in ovarian cancer risk difference). This association decreased through the pre-vaccine period of 2020 by OR=2.61/month (95% CI = 1.21, 5.65). By June 2020, the effect of a 10% increase in ovarian cancer risk on intervention choice had attenuated substantially (OR=0.84, 95% CI 0.67, 1.00). By January 2022, the effect strengthened (OR= 0.69, 95% CI .49, .88), but had not reached pre-pandemic levels. Before 3/2020, natural age of menopause (versus immediate) had a strong impact on the choice of a scenario (OR=3.56, 95% CI 1.65-7.65). At the beginning of the pandemic, the effect was reduced by 0.47/month (95% CI 0.22-0.99). The rate of attenuation slowed over time, such that the effect of having a natural age of menopause on choice was OR= 1.56 (95% CI 0.65, 2.46) by January 2022. Tests for temporal interactions were statistically significant for both ovarian cancer risk and age of menopause. Conclusions: Our results suggest that over the course of the pandemic, women seemed more accepting of higher risks of ovarian cancer and immediate (post treatment) menopause when considering preventive options. There was an inverse U shape curve of the effect of ovarian cancer risk on choices over time (Figure A), but the strength of the relationship had not reached pre-pandemic levels by January 2022. This may reflect patient tolerance for side effects as the pandemic evolved. These results suggest that factors such as ovarian cancer risk and delay of menopause influenced personal prevention choices, but that these choices were influenced by events related to events that hallmarked the COVID-19 pandemic. Citation Format: Brian Egleston, Mary Daly, Kaitlyn Lew, Lisa Bealin, Alexander Husband, Jill Stopfer, Pawel Przybysz, Olga Tchuvatkina, Yu-Ning Wong, Judy Garber, Timothy Rebbeck. Changes in preferences for ovarian cancer prevention strategies during the COVID-19 pandemic: Results of a discrete choice experiment. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-03-16.

Supplementary Figures 1-4. Supplementary Figure S1: Full Pedigrees from TP53 c.1000G>C;p.G334R clinically ascertained families. Fam ID allows reference to Table 1; Supplementary Figure S2: Constructs encoding p53 wild-type (TP53-WT), p53-R175H (TP53-R175H), and p53-G334R (c.1000G>A and c.1000G>C) were transiently transfected into p53 deficient Saos-2 cells; Supplementary Figure S3: p53 levels after treatment with 10uM cisplatin (CDDP); Supplementary Figure S4: Heatmap showing fold activation of a canonical p53 signature at 24 hours post nutlin with wildtype versus mutant lymphoblastoid cell lines.

Table of Demographic and Socioeconomic characteristics

Supplementary Table 1 PDF file 38K, This table summarizes all additional V1736A pedigrees

Supplementary Methods PDF file 61K, This document describes the methods for all supplemental data

Supplementary Tables 1-2 from The Relative Contribution of Point Mutations and Genomic Rearrangements in BRCA1 and BRCA2 in High-Risk Breast Cancer Families

Educational Content on the Color Genomics Website