Ashley Henriksen Woodson

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. J. Surg. Oncol. 2015 111:66–80.

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.

High incidence of germline BRCA mutation in patients with ER low-positive/PR low-positive/HER-2 neu negative tumors.

The 2015 National Comprehensive Cancer Network guidelines recommend that genetic counseling and germline BRCA mutation testing be offered to women under age 60 with triple‐negative breast cancer (TNBC). As a result of the 2010 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines for breast cancer, patients with breast cancers that are estrogen receptor (ER) or progesterone receptor (PR) low‐positive (1%‐9% on immunohistochemistry) are no longer strictly considered to have TNBC and may not be referred for genetic counseling. However, the incidence of BRCA mutation in patients with hormone receptor (HR) low‐positive breast cancers remains unknown, and current ASCO/CAP guidelines may result in undertesting for BRCA mutations.

Genotype–Phenotype Correlations by Ethnicity and Mutation Location in BRCA Mutation Carriers

The genotype–phenotype correlations of the specific BRCA1 and BRCA2 mutations in multi‐ethnic populations in USA have not yet been fully investigated. This study was designed to evaluate the effects of ethnicity at specific mutation locations and breast/ovarian cancer phenotypes. Our cohort included 445 women with different ethnic backgrounds who underwent BRCA genetic testing between 1997 and 2010. Known clinical and pathologic characteristics were compared with Chi‐Square Analysis or Fishers Exact test as appropriate. The three most common mutation locations in BRCA1 (exons 2, 11, and 20) and BRCA2 (exons 10, 11, and 25) genes were chosen. Prevalence of BRCA1 exon 2 mutations were significantly higher in Ashkenazi Jewish (AJ) women compared to Caucasians (41% versus 15%; p = 0.001). Similarly, AJ women with breast cancer were more likely to have BRCA1 exon 2 mutation (47% positivity in AJ women versus 0–12.5% positivity in other ethnicities; p = 0.004). Women carrying the exon 20 BRCA1 mutation had the highest probability of having combined breast and ovarian cancers compared to women carrying other exon mutations (p = 0.05). The median age at initial cancer diagnosis, phenotypic features of breast cancer tumors, and overall survival did not vary significantly by ethnicity or mutation location. Our data suggest that ethnicity does not affect age of onset, overall survival or confer different risks of breast and ovarian cancer development in BRCA carriers. These results also suggest that women carrying the exon 20 BRCA1 mutation may warrant mutation‐specific counseling and be more aggressively managed for risk reduction.

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 patients 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.

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.

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.

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.

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.

Abstract P5-13-03: Factors associated with prophylactic mastectomy among BRCA-positive patients with no personal history of breast cancer

Background: The rate of prophylactic mastectomy (PM) has recently increased1. A deleterious mutation in the BRCA1 or BRCA 2 genes is among the major reasons why patients pursue PM 2, 3. Women with BRCA1 or BRCA2 gene mutations have up to an 87% risk to develop an invasive breast cancer (BC), and up to 45% risk for ovarian cancer (OC)2, 3. Most studies evaluating predictors of PM in BRCA mutation carriers are performed among women with breast cancer; however, accurate predictors for PM among unaffected BRCA mutation carriers are less defined. In a single institution study we aimed to evaluate predictors of PM among BRCA carriers with no personal history of breast cancer. Method: One hundred seventy seven women with no personal history of BC, who tested positive for a BRCA1 or BRCA 2 germline mutation, were included in the study. Patients’ characteristics were obtained from a prospectively maintained research database under an IRB approved protocol at UT MD Anderson Cancer Center. Univariate analyses using chi-square and logistic regression analysis were used to determine predictive factors associated with PM. The patient characteristics examined included age, martial and educational status, bilateral salphingo-oophorectomy (BSO), family history of 1st and 2nd degree relatives with breast (BC) and ovarian cancer (OC), race, and BRCA genetic test result. Results: Out of the 177 BRCA1 and BRCA 2 positive patients, 51 (29%) elected for PM. The average age for the cohort was 44 years (range 23-91). The majority were Caucasian (81%), and married (72%) with a college degree (64%). One hundred sixty-four (92%) patients had 1st and 2nd degree relatives with BC, 93 (53%) had 1st and 2nd degree relatives with OC, and 85 (48%) had undergone BSO. A logistic regression model was run to identify factors associated with undergoing PM, including family history of OC, family history of BC, BSO and age. Patients with a family history of OC were 2.5 times more likely than those without to have had a PM (p = 0.0125), and patients who had a BSO were 0.137 times less likely to have had a PM (p <.0001). Only 12 patients did not have a family history of BC and none of those patients had a PM, so an Odds Ratio could not be calculated. However, it was determined through the Fishers exact test that patients with a family history of BC were more likely to undergo a PM (p = 0.0198). Conclusion: The rate of PM in our cohort was slightly lower than expected. Factors associated with PM included a family history of BC and OC. Interestingly, having had a BSO was associated with lower likelihood of undergoing PM (menopausal status will be further evaluated); possibly due to the knowledge that BSO reduces breast cancer risk. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-03.