Elias Obeid

Genetic testing for hereditary cancer predisposition: BRCA1/2, Lynch syndrome, and beyond

Obstetrician/gynecologists and gynecologic oncologists serve an integral role in the care of women at increased hereditary risk of cancer. Their contribution includes initial identification of high risk patients, screening procedures like bimanual exam, trans-vaginal ultrasound and endometrial biopsy, prophylaxis via TAH and/or BSO, and chemoprevention. Further, gynecologists also serve a central role in the management of the secondary repercussions of efforts to mitigate increased cancer risks, including vasomotor symptoms, sexual function, bone health, cardiovascular disease, and mental health. The past several years has seen multiple new high and moderate penetrance genes introduced into the clinical care of women at increased risk of gynecologic malignancy. Awareness of these new genes and the availability of new multi-gene panel tests is critical for providers on the front-line of womens health.

Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.

Comparison of Adjuvant Radiation Therapy Alone Versus Radiation Therapy and Endocrine Therapy in Elderly Women With Early-Stage, Hormone Receptor-Positive Breast Cancer Treated With Breast-Conserving Surgery

BACKGROUND Randomized data examining adjuvant radiation therapy (RT) alone in elderly women with low-risk, hormone receptor-positive (HR(+)) breast cancer is lacking. We investigated the outcomes for elderly women treated with adjuvant RT alone versus RT plus endocrine therapy (ET) after breast-conserving surgery. PATIENTS AND METHODS We queried our institutional breast cancer database for the following patients: age > 65 years, stage T1-T2N0, HR(+), and treatment with breast-conserving surgery, including adjuvant RT. The χ(2) analysis identified significant baseline differences between the groups. Cox proportional hazard methods identified predictors of endpoints on multivariate analysis. Kaplan-Meier estimates of survival were compared using the log-rank test. RESULTS A total of 504 patients were identified, 311 had undergone RT plus ET (62%) and 193, RT alone (38%). The median follow-up time was 88 months. The RT-alone group versus RT plus ET group had different median age (72 vs.71 years, P < .001), different median tumor size (1 vs. 1.3 cm, P < .001), lower grade (40% vs. 29%, P = .05), and fewer close or positive margins (11% vs. 19%, P = .01). The adherence rate to prescribed ET was 70%. Tumor size predicted an increased risk of distant metastasis (DM) (hazard ratio, 1.96; 95% confidence interval [CI], 1.23-3.13) and worse disease-free survival (DFS) (hazard ratio, 1.86; 95% CI, 1.22-2.86). ET nonadherence versus adherence predicted for risk of DM (hazard ratio, 5.03; 95% CI, 1.98-12.66) and DFS (HR, 4.24; 95% CI, 1.9-10.3). Of the women with DM, 83.8% had tumors > 1 cm in size. CONCLUSION ET nonadherence and tumor size > 1 cm predicted an increased risk of DM and worse DFS, favoring the addition of ET in this group. However, RT alone for women with tumors less than or equal to 1 cm may be appropriate.

Inherited Mutations in Men Undergoing Multigene Panel Testing for Prostate Cancer: Emerging Implications for Personalized Prostate Cancer Genetic Evaluation

PurposeMultigene panels are commercially available for the evaluation of prostate cancer (PCA) predisposition, which necessitates tailored genetic counseling (GC) for men. Here we describe emerging results of Genetic Evaluation of Men, prospective multigene testing study in PCA to inform personalized genetic counseling, with emerging implications for referrals, cancer screening, and precision therapy.Patients and MethodsEligibility criteria for men affected by or at high risk for PCA encompass age, race, family history (FH), and PCA stage/grade. Detailed demographic, clinical, and FH data were obtained from participants and medical records. Multigene testing was conducted after GC. Mutation rates were summarized by eligibility criteria and compared across FH data. The 95% CI of mutation prevalence was constructed by using Poisson distribution.ResultsOf 200 men enrolled, 62.5% had PCA. Eleven (5.5%; 95% CI, 3.0% to 9.9%) had mutations; 63.6% of mutations were in DNA repair genes. FH of breast cancer was si...

Understanding of multigene test results among males undergoing germline testing for inherited prostate cancer: Implications for genetic counseling

Genetic testing (GT) for prostate cancer (PCA) is rising, with limited insights regarding genetic counseling (GC) needs of males. Genetic Evaluation of Men (GEM) is a prospective multigene testing study for inherited PCA. Men undergoing GC were surveyed on knowledge of cancer risk and genetics (CRG) and understanding of personal GT results to identify GC needs.

Abstract B01: Testing a multilevel risk prediction model in high risk men enrolled in a prostate cancer early detection program

Background: Health disparities play a major role in prostate cancer (PCa). African American (AA) compared to European American (EA) men are twice as likely to die of and be diagnosed with PCa. Multilevel factors from societal/neighborhood exposures down to genetics likely contribute to racial disparities, but few PCa risk prediction models include multilevel factors and consider race/ethnic differences. Objective: We sought to: 1) develop a multilevel risk prediction model for time to PCa diagnosis, that includes neighborhood variables, individual-level socioeconomic and clinical factors (education, race, digital rectal exam or DRE), and biologic variables (prostate specific antigen or PSA level, and percent West African genetic ancestry) in men at high risk for prostate cancer (defined as AA men and/or men with a PCa family history); 2) compare our multilevel model to a more standard prediction model that includes only age, race, PSA, and DRE (abnormal/normal). Methods: A total of 443 high risk, cancer-free men between 35 and 69 years of age with complete socioeconomic, racial, and genetic ancestry data were identified from the Prostate Risk Assessment Program (PRAP) at Fox Chase Cancer Center. Their data were geocoded and linked to 17 neighborhood variables at the census tract level (from the Year 2000 U.S. Census) that were previously associated with advanced PCa in EA men in a novel neighborhood-wide association study(NWAS) our study team developed. These variables generally represent neighborhood transportation, poverty, income, social support, immigration, renting/owning a house, and employment. Men were followed from time of program (PRAP) entry to PCa diagnosis or censoring, with annual follow-up visits that included PSA and DRE screening. Men with elevated PSA or other indications for PCa were referred to Urology for evaluation and potential biopsy according to PRAP protocols. Univariate analyses of neighborhood variables, and the interaction of each variable with PSA and race, were evaluated in Cox regression models, using robust standard errors to adjust for clustering by census tract, in order to inform the final multivariate, multilevel model. Harrell9s C Index (C Statistic) was used to compare the multilevel risk prediction model to a standard prediction model. Results: With a median follow-up time of 71 months, PCa diagnosis occurred in 69 participants. The final multilevel risk prediction model included 3 neighborhood variables related to transportation, social support, and poverty, along with education, age, race, baseline PSA, baseline DRE, and PCa family history. Significant interactions between the top hit from the NWAS and PSA were noted in the full study population (neighborhood mode of transportation to work X PSA, p-value Conclusion: This study is the first to investigate the role of neighborhood in PCa risk prediction. While risk prediction models show little change, significant neighborhood effects in multilevel models warrant additional study and could inform future health disparity studies. Citation Format: Shannon M. Lynch, Elizabeth Handorf, Elizabeth Blackman, Lisa Bealin, Shiju Daniel, Veda N. Giri, Elias Obeid, Camille Ragin, Mary B. Daly. Testing a multilevel risk prediction model in high risk men enrolled in a prostate cancer early detection program. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B01.

Effects of a randomized trial comparing standard and enhanced counseling for men at high risk of prostate cancer as a function of race and monitoring style

Despite conflicting guidelines, a significant subset of high-risk men decide to undergo routine prostate cancer screening. Yet, there is a scarcity of available programs, and no studies evaluating interventions to support men in dealing with the psychosocial impact of screening. In this study, one of the first to explore the responses of high-risk men enrolling in a Prostate Cancer Risk Assessment Program (N = 128), patients underwent a prostate cancer risk counseling visit immediately followed by either a cognitive–affective preparation session designed to help them process the information they received or a general health education session. All men in this self-selected sample chose to participate in prostate cancer screening. Men were assessed 3 weeks and 6 months post-counseling. The impact of the enhanced counseling condition on knowledge, perceived risk, expectancies, and intrusive ideation was a function of racial and coping style group. Implications for tailored interventions to maximize preparedness for risk and screening counseling are discussed.