Jessica M. Long

Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2 negative patients with early onset breast cancer

Purpose:Clinical testing for germ-line variation in multiple cancer susceptibility genes is available using massively parallel sequencing. Limited information is available for pretest genetic counseling regarding the spectrum of mutations and variants of uncertain significance in defined patient populations.Methods:We performed massively parallel sequencing using targeted capture of 22 cancer susceptibility genes in 278 BRCA1/2-negative patients with early-onset breast cancer (diagnosed at younger than 40 years of age).Results:Thirty-one patients (11%) were found to have at least one deleterious or likely deleterious variant. Seven patients (2.5% overall) were found to have deleterious or likely deleterious variants in genes for which clinical guidelines exist for management, namely TP53 (4), CDKN2A (1), MSH2 (1), and MUTYH (double heterozygote). Twenty-four patients (8.6%) had deleterious or likely deleterious variants in a cancer susceptibility gene for which clinical guidelines are lacking, such as CHEK2 and ATM. Fifty-four patients (19%) had at least one variant of uncertain significance, and six patients were heterozygous for a variant in MUTYH.Conclusion:These data demonstrate that massively parallel sequencing identifies reportable variants in known cancer susceptibility genes in more than 30% of patients with early-onset breast cancer. However, only few patients (2.5%) have definitively actionable mutations given current clinical management guidelines.Genet Med 17 8, 630–638.

Development of a tiered and binned genetic counseling model for informed consent in the era of multiplex testing for cancer susceptibility

Purpose:Multiplex genetic testing, including both moderate- and high-penetrance genes for cancer susceptibility, is associated with greater uncertainty than traditional testing, presenting challenges to informed consent and genetic counseling. We sought to develop a new model for informed consent and genetic counseling for four ongoing studies. Methods:Drawing from professional guidelines, literature, conceptual frameworks, and clinical experience, a multidisciplinary group developed a tiered-binned genetic counseling approach proposed to facilitate informed consent and improve outcomes of cancer susceptibility multiplex testing.Results:In this model, tier 1 “indispensable” information is presented to all patients. More specific tier 2 information is provided to support variable informational needs among diverse patient populations. Clinically relevant information is “binned” into groups to minimize information overload, support informed decision making, and facilitate adaptive responses to testing. Seven essential elements of informed consent are provided to address the unique limitations, risks, and uncertainties of multiplex testing.Conclusion:A tiered-binned model for informed consent and genetic counseling has the potential to address the challenges of multiplex testing for cancer susceptibility and to support informed decision making and adaptive responses to testing. Future prospective studies including patient-reported outcomes are needed to inform how to best incorporate multiplex testing for cancer susceptibility into clinical practice.Genet Med 17 6, 485–492.

Patient feedback and early outcome data with a novel tiered-binned model for multiplex breast cancer susceptibility testing

Purpose:The risks, benefits, and utilities of multiplex panels for breast cancer susceptibility are unknown, and new counseling and informed consent models are needed. We sought to obtain patient feedback and early outcome data with a novel tiered-binned model for multiplex testing.Methods:BRCA1/2-negative and untested patients completed pre- and posttest counseling and surveys evaluating testing experiences and cognitive and affective responses to multiplex testing.Results:Of 73 patients, 49 (67%) completed pretest counseling. BRCA1/2-negative patients were more likely to proceed with multiplex testing (86%) than those untested for BRCA1/2 (43%; P < 0.01). Many patients declining testing reported concern for uncertainty and distress. Most patients would not change anything about their pre- (76%) or posttest (89%) counseling sessions. Thirty-three patients (72%) were classified as making an informed choice, including 81% of those who proceeded with multiplex testing. Knowledge increased significantly. Anxiety, depression, uncertainty, and cancer worry did not significantly increase with multiplex testing.Conclusion:Some patients, particularly those without prior BRCA1/2 testing, decline multiplex testing. Most patients who proceeded with testing did not experience negative psychological responses, but larger studies are needed. The tiered-binned approach is an innovative genetic counseling and informed consent model for further study in the era of multiplex testing.Genet Med 18 1, 25–33.

Randomized Noninferiority Trial of Telephone vs In-Person Disclosure of Germline Cancer Genetic Test Results

Background Germline genetic testing is standard practice in oncology. Outcomes of telephone disclosure of a wide range of cancer genetic test results, including multigene panel testing (MGPT) are unknown. Methods Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone disclosure (TD) of genetic test results with usual care, in-person disclosure (IPD) after tiered-binned in-person pretest counseling. Primary noninferiority outcomes included change in knowledge, state anxiety, and general anxiety. Secondary outcomes included cancer-specific distress, depression, uncertainty, satisfaction, and screening and risk-reducing surgery intentions. To declare noninferiority, we calculated the 98.3% one-sided confidence interval of the standardized effect; t tests were used for secondary subgroup analyses. Only noninferiority tests were one-sided, others were two-sided. Results A total of 1178 patients enrolled in the study. Two hundred eight (17.7%) participants declined random assignment due to a preference for in-person disclosure; 473 participants were randomly assigned to TD and 497 to IPD; 291 (30.0%) had MGPT. TD was noninferior to IPD for general and state anxiety and all secondary outcomes immediately postdisclosure. TD did not meet the noninferiority threshold for knowledge in the primary analysis, but it did meet the threshold in the multiple imputation analysis. In secondary analyses, there were no statistically significant differences between arms in screening and risk-reducing surgery intentions, and no statistically significant differences in outcomes by arm among those who had MGPT. In subgroup analyses, patients with a positive result had statistically significantly greater decreases in general anxiety with telephone disclosure (TD -0.37 vs IPD +0.87, P = .02). Conclusions Even in the era of multigene panel testing, these data suggest that telephone disclosure of cancer genetic test results is as an alternative to in-person disclosure for interested patients after in-person pretest counseling with a genetic counselor.

Psychosocial, Ethical, and Legal Implications for Mutation Carriers

This chapter aims to highlight the seminal as well as emerging literature regarding psychosocial, ethical, and legal considerations for individuals with hereditary breast and ovarian cancer (HBOC) syndrome due to inherited BRCA1 and BRCA2 gene mutations. While cancer risk may be mitigated by enhanced surveillance, chemoprevention, and/or risk-reducing surgery, careful attention must be paid to psychosocial aspects of genetic testing, risk communication within families, and the impact of the psychosocial experience on medical management decisions. Among BRCA1 and BRCA2 mutation carriers, worry and other emotional states remain strong predictors of health behaviors. In addition, this chapter underscores unique ethical and legal considerations that influence the lived experience of a person with HBOC. These include legislative milestones like the Genetic Information Non-discrimination Act (GINA), concerns about genetic testing for adult-onset susceptibility in minors, and the delicate balance between provider–patient privacy and the importance of disseminating predictive genetic health information to at-risk relatives (duty to warn). Understanding of these issues may change over time, given the rapidly evolving field of cancer genetics. Moreover, as medical management and cancer treatment options improve, the psychosocial landscape of individuals living with HBOC will likely adjust in parallel. The journey traveled by individuals with HBOC is typically marked by significant milestones of personal experience with cancer in themselves and/or their relatives; it is vital for healthcare providers working with families with HBOC to fully appreciate the psychosocial experience of HBOC in order to provide compassionate and effective care.

Abstract P2-09-01: Patient reported outcomes of multiplex breast cancer susceptibility testing utilizing a tiered-binned counseling and informed consent model in BRCA1/2 negative patients

Background :The risks, benefits and utilities of multiplex panels for breast cancer susceptibility are unknown and new counseling and informed consent models are needed. We sought to obtain patient reported outcomes of multiplex testing in BRCA1/2 negative patients utilizing a novel, previously piloted tiered-binned counseling model for multiplex testing. Methods: BRCA1/2 negative participants completed pre(V1) and post-test counseling(V2) and surveys evaluating cognitive, affective and behavioral responses to a 25-gene multiplex testing panel. We used linear regressions with estimation by GEE where appropriate. Results: 376 patients have been approached. To date, 124 participants(33%) have consented to the study, 21(6%) declined and 231(61%) are considering. Of 95 who have completed pre-test counseling(V1), 88(93%) elected to proceed with 25-gene panel testing and (81%) were classified as making an informed choice after tiered-binned counseling. 6/53(11%) participants received a positive result, including 1 mutation in MSH2 and 5 in moderate penetrance genes (2 ATM, 1 BARD1, 1 CHEK2, 1 PALB2 ). 22/53(42%) participants received a variant of unknown significance(VUS). General anxiety and perceived utility decreased significantly with pre-test counseling and after results (Table 1). Knowledge increased with pre-test counseling; cancer worry increased after receipt of multiplex results. Higher cancer worry was associated only with lower income (2.6 points/income category, p Conclusions: Many BRCA1/2 -negative patients proceed with 25-gene cancer susceptibility testing if offered and most make informed choices utilizing a tiered-binned genetic counseling model. The tiered-binned counseling model is associated with increased knowledge, decreases in general anxiety and uncertainty after pre-test counseling and disclosure of results, but an increase in cancer worry after result disclosure. The clinical utility, long-term outcomes and differences in patient reported outcomes by test result remain unknown. Citation Format: Bradbury AR, Patrick-Miller L, Egleston BE, Maxwell KN, Brandt A, Brower J, DiGiovanni L, Long JM, Powers J, Stopfer J, Nathanson KL, Domchek SM. Patient reported outcomes of multiplex breast cancer susceptibility testing utilizing a tiered-binned counseling and informed consent model in BRCA1/2 negative patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-01.

Abstract 4663: Identification of germline variants in cancer susceptibility genes in patients with multiple primary cancers

The occurrence of multiple primary (MP) cancers in a patient suggests a genetic predisposition to tumor formation. Multiplex panel testing may be an efficient way of evaluating MP patients for the presence of germline mutations in cancer susceptibility genes. However the spectrum of mutations in many cancer susceptibility genes in the MP patient population is largely unknown. We performed massively parallel sequencing using targeted capture of 15 genes with well-established risks of breast and/or other cancers, specifically TP53, CDH1, PTEN, STK11, ATM, CHEK2, MRE11A, NBN, RAD50, PALB2, MLH1, MSH2, MSH6, PMS2, and MUTYH. Our patient cohort consisted of 221 BRCA1/2 negative patients diagnosed with breast cancer and at least one other primary cancer, excluding non-melanoma skin cancer. Patients diagnosed with contralateral breast cancer were included. Thirty patients (14%) were found to have at least one deleterious variant in these 15 genes. Deleterious variants were found in CHEK2 (16 patients, 7.2%), TP53 (4, 1.8%), MSH6 (3, 1.4%), ATM (2, 0.9%) and one patient each had deleterious variants in CDKN2A, PTEN, PMS2, PALB2, BRIP1 and NBN. In addition, six patients (2.7%) were found to be heterozygous carriers of a MUTYH mutation. In comparison, deleterious variants were identified in 9% of 341 patients with breast cancer only, indicating a small but nonsignificant increase in the rate of deleterious variants in MP patients. The rate of MUTYH heterozygous mutations was also non-significantly different in patients with breast cancer only (1.2%). There was a significant increase in the rate of CHEK2 and MSH6 mutations in the MP versus breast-only patients (7.2% vs 3.5%, p = 0.04 for CHEK2 and 1.4% vs 0%, p = 0.05 for MSH6). As a corollary study, a subset of MP patients (n = 165) were assayed on a panel including TET2. Deleterious TET2 mutations were identified in 2 of 165 patients (1.2%) at allele frequencies of 0.17 and 0.36. These patients blood samples were ascertained at ages 77 and 72, respectively. These preliminary data show that in our cohort of patients with multiple primary cancers, over 16% of patients were found to have deleterious variants in 15 cancer susceptibility genes. In addition, approximately 1% of MP patients have deleterious variants in TET2 that may be due to age-related clonal hematopoiesis, although it is unknown if these mutations are related to the development of the tumors in these individuals. Further analysis of variants in less well-characterized cancer susceptibility genes and unclassified variants is ongoing. Discovery of clinically relevant mutations can potentially guide future treatment practices for those with similar diagnoses to our patients. Citation Format: Brandon Wenz, Kara N. Maxwell, Bradley Wubbenhorst, Kurt D9Andrea, Bradley Garman, Jessica M. Long, Jacquelyn Powers, Jill E. Stopfer, Angela R. Bradbury, Angela DeMichele, Susan M. Domchek, Katherine L. Nathanson. Identification of germline variants in cancer susceptibility genes in patients with multiple primary cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4663. doi:10.1158/1538-7445.AM2015-4663

Abstract P4-12-10: Uptake and outcomes of multiplex testing for breast cancer susceptibility

Background : New counseling models for multiplex genetic testing for breast cancer susceptibility are needed. Further, the risks, benefits and utilities of multiplex genetic panels are unknown. Purpose: To obtain stakeholder feedback on an innovative tiered-binned model for pretest counseling and informed consent for multiplex testing and to evaluate the uptake of, cognitive and affective responses to and perceived utility of panel testing. Methods: Patients previously BRCA1/2- or BRCA1/2 untested completed in-person pre-test (V1) and post-test counseling (V2) and surveys regarding the novel counseling model and evaluating cognitive and affective responses to, and perceived utility of the 26 gene Myriad MyRisk panel for cancer susceptibility. Results: 49 patients (62% of eligible) enrolled and completed V1. 38% of decliners were not interested in panel testing. BRCA1/2- were more likely to proceed with MyRisk (89%) than BRCA1/2 untested (48%, p Conclusion: With a tiered-binned counseling model, patients experience increased knowledge. Uptake of panel testing varies by prior testing and potentially by patient affective factors. Most patients do not experience negative psychological responses, although this may vary by test result. Declines in satisfaction and perceived utility may also vary by test result and may reflect the current unclear utility and uncertainty of multiplex testing. Citation Format: Angela R Bradbury, Linda Patrick-Miller, Brian L Egleston, Amanda Brandt, Jessica Long, Jacquelyn Powers, Jill Stopfer, Laura DiGiovanni, Jamie Brower, Susan M Domchek. Uptake and outcomes of multiplex testing for breast cancer susceptibility [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-10.