Multigene panel testing results in patients with multiple breast cancer primaries.

Currently, the NCCN guidelines recommend testing of BRCA1 and BRCA2 for females with multiple breast primaries, if her first diagnosis was ≤50 years old. With the increase in uptake of multigene panels, testing for genes outside of BRCA1 and BRCA2 has become more prevalent. This study looked at a single institution's cohort of women with multiple primary breast cancers that underwent panel testing to determine the rates of pathogenic mutations in non-BRCA genes. The genetic testing results for each individual were reviewed, along with patient characteristics. Descriptive analysis and two-tailed Z tests were used to analyze the data. Out of 85 eligible women, 33 (38.8%) tested positive for a pathogenic mutation in a cancer predisposition gene: 9 BRCA1, 5 BRCA2, 5 ATM, 1 BARD1, 4 CHEK2, 1 MSH2, 1 MSH6, 2 PALB2, 1 PMS2, 1 PTEN and 3 TP53. Overall, 17.6% tested positive for a non-BRCA breast cancer predisposition gene. There was no difference in the age of first or second breast cancer diagnosis in comparison with genetic testing outcomes. This study found a high positive rate for all individuals with multiple breast cancers, regardless of age, for both BRCA1 and BRCA2 and non-BRCA genes. Future studies should investigate whether individuals with multiple breast cancer primaries that do not meet BRCA1 and BRCA2 testing criteria should undergo genetic testing, regardless of the age of diagnosis.

Genetic counseling considerations for men with prostate cancer.

Genetic counseling for men with prostate cancer has unique considerations. While the main components of the genetic counseling session are similar to other indications, specific attention to penetrance differences among hereditary cancer genes for male versus female-related cancer risks and future cancer surveillance among prostate cancer patients should be included. Limitations in discerning the contribution to prostate cancer and risks to relatives dependent on specific gene mutations, or absence of identifiable genetic cause, must be reviewed.

Pazopanib in patients with von Hippel-Lindau disease: a single-arm, single-centre, phase 2 trial.

BACKGROUND: No approved systemic therapy exists for von Hippel-Lindau disease, an autosomal dominant disorder with pleiotropic organ manifestations that include clear cell renal cell carcinomas; retinal, cerebellar, and spinal haemangioblastomas; pheochromocytomas; pancreatic serous cystadenomas; and pancreatic neuroendocrine tumours. We aimed to assess the activity and safety of pazopanib in patients with von Hippel-Lindau disease. METHODS: In this non-randomised, single-centre, open-label, phase 2 trial, adult patients with clinical manifestations of von Hippel-Lindau disease were recruited from the University of Texas MD Anderson Cancer Center (Houston, TX, USA) and were treated with pazopanib (800 mg orally daily) for 24 weeks, with an option to continue treatment if desired by the patient and treating physician. Primary endpoints were the proportion of patients who achieved an objective response and safety in the per-protocol population. The objective response was measured for each patient and each lesion type. Radiographic assessments were done at baseline and every 12 weeks throughout the study. Activity and safety were assessed with continuous monitoring and a Bayesian design. This study is registered with ClinicalTrials.gov, number NCT01436227, and is closed to accrual. FINDINGS: Between Jan 18, 2012, and Aug 10, 2016, we screened 37 patients with genetically confirmed or clinical features consistent with von Hippel-Lindau disease, of whom 31 eligible patients were treated with pazopanib. The proportion of patients who achieved an objective response was 42% (13 of 31 patients). By lesion sites responses were observed in 31 (52%) of 59 renal cell carcinomas, nine (53%) of 17 pancreatic lesions, and two (4%) of 49 CNS haemangioblastomas. Seven (23%) of 31 patients chose to stay on the treatment after 24 weeks. Four (13%) of 31 patients withdrew from the study because of grade 3 or 4 transaminitis, and three (10%) discontinued study treatment because of treatment intolerance with multiple intercurrent grade 1-2 toxicities. Treatment-related serious adverse events included one case each of appendicitis and gastritis and one patient had a fatal CNS bleed. INTERPRETATION: Pazopanib was associated with encouraging preliminary activity in von Hippel-Lindau disease, with a side-effect profile consistent with that seen in previous trials. Pazopanib could be considered as a treatment choice for patients with von Hippel-Lindau disease and growing lesions, or to reduce the size of unresectable lesions in these patients. The safety and activity of pazopanib in this setting warrants further investigation. FUNDING: Novartis Inc and NIH National Cancer Institute core grant.

Genetic Counseling Referral Rates in Long-Term Survivors of Triple-Negative Breast Cancer.

Background: Inherited BRCA gene mutations (pathogenic variants) cause 10% of breast cancers. BRCA pathogenic variants predispose carriers to triple-negative breast cancer (TNBC); around 30% of patients with TNBC carry BRCA pathogenic variants. The 2018 NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian recommend genetic counseling referrals for patients with TNBC diagnosed at age ≤60 years. This study sought to describe genetic counseling referral patterns among long-term TNBC survivors at The University of Texas MD Anderson Cancer Center. Methods: This single-institution retrospective analysis of female long-term (disease-free for ≥5 years) TNBC survivors sought to determine the rate of genetic counseling referral among patients diagnosed at age ≤60 years between 1992 and 2008. Patients who underwent treatment and surveillance visits at our institution and were followed until 2017 were included. We collected BRCA pathogenic variant status among tested patients. Descriptive statistical methods and a univariate analysis were used to identify patient characteristics associated with genetic counseling referral. Results: We identified 646 female long-term TNBC survivors with a median age at diagnosis of 47 years. Of these, 245 (38%) received a recommendation for a genetic counseling referral. Among those referred, 156 (64%) underwent genetic testing, and 35% of those tested had BRCA pathogenic variants. Interestingly, among those referred, 20% declined genetic testing. The rate of genetic referrals improved over time, from 25% among TNBC survivors whose last surveillance visit was between 2011 and 2013 to 100% among those whose last surveillance visit was between 2014 or later. Younger age and premenopausal status at diagnosis and a family history of breast or ovarian cancer were associated with an increased rate of referral for genetic counseling. Conclusions: Among long-term TNBC survivors, the rate of referral to genetic counseling increased over time, and among those tested, 35% carried a BRCA pathogenic variant. Survivorship care provides an excellent opportunity to refer eligible patients for genetic counseling.

Hereditary breast cancer syndromes and genetic testing.

Only 5% of breast cancers are explained by highly penetrant multisystem autosomal dominant hereditary disorders. Though another 20-30% has a familial presentation, the genetic and other etiologies are still not well understood. Genetic testing is now widely available and multiple professional societies have published guidelines for testing and management. Genetic testing trends include utilization of multi-gene panels that take advantage of next-generation sequencing as well as testing for low- and moderate-penetrance susceptibility genes.

Breast cancer, BRCA mutations, and attitudes regarding pregnancy and preimplantation genetic diagnosis.

BACKGROUND: Women with premenopausal breast cancer may face treatment-related infertility and have a higher likelihood of a BRCA mutation, which may affect their attitudes toward future childbearing. METHODS: Premenopausal women were invited to participate in a questionnaire study administered before and after BRCA genetic testing. We used the Impact of Event Scale (IES) to evaluate the pre- and post-testing impact of cancer or carrying a BRCA mutation on attitudes toward future childbearing. The likelihood of pursuing prenatal diagnosis (PND) or preimplantation genetic diagnosis (PGD) was also assessed in this setting. Univariate analyses determined factors contributing to attitudes toward future childbearing and likelihood of PND or PGD. RESULTS: One hundred forty-eight pretesting and 114 post-testing questionnaires were completed. Women with a personal history of breast cancer had less change in IES than those with no history of breast cancer (p = .003). The 18 BRCA-positive women had a greater change in IES than the BRCA-negative women (p = .005). After testing, 31% and 24% of women would use PND and PGD, respectively. BRCA results did not significantly affect attitudes toward PND/PGD. CONCLUSION: BRCA results and history of breast cancer affect the psychological impact on future childbearing. Intentions to undergo PND or PGD do not appear to change after disclosure of BRCA results. Additional counseling for patients who have undergone BRCA testing may be warranted to educate patients about available fertility preservation options.

Pilot study of dovitinib in patients with von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease is an autosomal dominant disease occurring in 1 in 35,000 births and leads to an increased risk of a phenotypically diverse array of tumor types including, but not limited to, clear cell renal cell carcinoma (ccRCC) and hemangioblastomas (HBs). Previous studies of patients with VHL disease treated with the tyrosine kinase inhibitor (TKI) sunitinib did not show clinical response in HBs. Interestingly, VHL-related HBs displayed increased fibroblast growth factor receptor 3 (FGFR3) protein expression when compared to VHL-related ccRCCs. Therefore, in this pilot study, we assessed the safety and efficacy profile of TKI 258 (dovitinib), a multi-tyrosine kinase inhibitor of VEGF receptor and fibroblast growth factor (FGF), in patients with VHL disease who had measureable HBs. The trial was stopped after six patients enrolled after the toxicity stopping rule was triggered. With regards to safety, 6/6 subjects had at least one adverse event (AE). Best response in 6/6 subjects was stable disease (SD) in HBs. While the negative safety and efficacy results of this pilot study do not favor the use of dovitinib for the treatment of asymptomatic HBs in VHL disease patients, further investigation into alternative scheduling and other FGFR inhibitors for the treatment of HBs in VHL disease patients is warranted given the promising pre-clinical and molecular data.

Service Delivery Model and Experiences in a Cancer Genetics Clinic for an Underserved Population.

This report describes a genetics clinic for hereditary breast and ovarian cancer (HBOC) in an underserved population. Genetic counseling was provided to 151 patients, and 131 underwent BRCA genetic testing. This was a unique, group-based establishment of an HBOC genetics clinic, which to our knowledge had not previously been reported.

Breast cancer in the young: role of the geneticist.

The genetics professional plays an important role in the care of young women with breast cancer by providing counseling on issues specific to these young women. The issues addressed in counseling include hereditary predisposition to cancer, fertility and reproductive options in the context of hereditary cancer, and the impact and implications of their history of early breast cancer on close family members. A thorough risk assessment and counseling session address the patient's personal and family history, with particular attention paid to benign and malignant findings that suggest the need for genetic testing. Genetics professionals, especially genetic counselors, also address the physical and emotional implications of an increased risk of cancer with patients and family members. This review highlights the unique aspects of care provided by these specialized healthcare providers.