Angela R. Bradbury

Genetic susceptibility to breast cancer

Deleterious mutations in two breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2 have been identified in breast and ovarian cancer families. Women with a BRCA1 or BRCA2 mutation are candidates for additional risk reduction measures such as intensive screening, prophylactic surgery or chemoprevention. Additional susceptibility genes have been identified, including PTEN, ATM, TP53, CHEK2, CASP8, PBRL and BRIP1. Yet, many women with a personal or family history suggestive of a hereditary susceptibility to breast cancer undergo genetic testing and no significant genetic alteration is found. Thus, there are other susceptibility genes that have not been identified, and it is likely that the remaining familial contribution to breast cancer will be explained by the presence of multiple low penetrance alleles that coexist to confer high penetrance risks (a polygenic model). The American Cancer Society has identified cancer prevention as a key component of cancer management and there is interest in developing individualized cancer prevention focused on identifying high risk individuals who are most likely to benefit from more aggressive risk reduction measures. Breast cancer risk assessment and genetic counseling are currently provided by genetic counselors, oncology nurse specialist, geneticists, medical and surgical oncologists, gynecologists and other health care professionals, often working within a multidisciplinary clinical setting. Current methods for risk assessment and predictive genetic testing have limitations and improvements in molecular testing and risk assessment tools is necessary to maximize individual breast cancer risk assessment and to fulfill the promise of cancer prevention.

Cancer Genetic Risk Assessment and Referral Patterns in Primary Care

PURPOSEnThis study was undertaken to describe cancer risk assessment practices among primary care providers (PCPs).nnnMETHODSnAn electronic survey was sent to PCPs affiliated with a single insurance carrier. Demographic and practice characteristics associated with cancer genetic risk assessment and testing activities were described. Latent class analysis supported by likelihood ratio tests was used to define PCP profiles with respect to the level of engagement in genetic risk assessment and referral activity based on demographic and practice characteristics.nnnRESULTSn860 physicians responded to the survey (39% family practice, 29% internal medicine, 22% obstetrics/gynecology (OB/GYN), 10% other). Most respondents (83%) reported that they routinely assess hereditary cancer risk; however, only 33% reported that they take a full, three-generation pedigree for risk assessment. OB/GYN specialty, female gender, and physician access to a genetic counselor were independent predictors of referral to cancer genetics specialists. Three profiles of PCPs, based upon referral practice and extent of involvement in genetics evaluation, were defined.nnnCONCLUSIONnProfiles of physician characteristics associated with varying levels of engagement with cancer genetic risk assessment and testing can be identified. These profiles may ultimately be useful in targeting decision support tools and services.

Learning of your parent's BRCA mutation during adolescence or early adulthood: a study of offspring experiences

Objective: To examine the experience, comprehension and perceptions of learning of a parents BRCA mutation during adolescence and early adulthood, and explore the impact on offsprings physical and psychosocial well‐being.

A high response rate to liposomal doxorubicin is seen among women with BRCA mutations treated for recurrent epithelial ovarian cancer

OBJECTIVEnTen percent of ovarian cancer is attributed to hereditary syndromes, most commonly to mutations in the BRCA1 or BRCA2 genes. These cancers are characterized by a prolonged sensitivity to platinum agents in spite of presentation at advanced stages. We hypothesized that women with BRCA-associated ovarian cancer would also show a high response rate to pegylated liposomal doxorubicin (Doxil).nnnMETHODSnA retrospective cohort study was conducted to compare the response rate, progression-free, and overall survival among women with BRCA-associated or sporadic ovarian cancer who were treated with Doxil.nnnRESULTSnA response to Doxil was seen in 13 of 23 patients with BRCA mutations (56.5%; 3 by RECIST criteria and 10 by CA125 levels) compared with only 8 of 41 women with non-hereditary cancers (19.5%; 2 by RECIST criteria and 6 by CA125 levels; p=0.004). This was associated with an improved progression-free and overall survival as measured from the time of Doxil administration. Notably, platinum sensitivity did not directly correlate with a response to Doxil.nnnCONCLUSIONSnWomen with BRCA-associated ovarian tumors demonstrate a greater sensitivity to cytotoxic therapy with Doxil than has previously been reported in unselected cases.

Should genetic testing for BRCA1/2 be permitted for minors? Opinions of BRCA mutation carriers and their adult offspring†

Although professional guidelines recommend against testing minors for adult‐onset genetic conditions, the genetic testing of minors for BRCA1/2 alterations has been debated in the literature. To better understand the opinions of BRCA mutation carriers regarding the genetic testing of minors and the cognitive and affective processes underlying these opinions, we interviewed BRCA mutation carriers and their adult offspring who had learned of their parents BRCA mutation. Semi‐structured interviews were conducted with 53 parents and 22 offspring. In response to a closed‐ended question, 52% (nu2009=u200939) of participants were opposed to the testing of minors. Responses to an open‐ended question indicate that many participants (24%, nu2009=u200918) feel that testing could be permitted for some minor offspring. Psychological risks and the insufficient maturity of minors were frequent concerns of participants opposed to testing minors. The potential to impact health behaviors was frequently cited as a reason to support the genetic testing of minors. These preliminary results suggest that many BRCA mutation carriers and their adult offspring have concerns about, or are opposed to the genetic testing of minors. However, a significant minority in our study would support testing minors. Greater support for testing among offspring could indicate increasing requests for early genetic diagnosis. Further research is necessary to explore the risks and benefits of providing genetic testing to minors for adult‐onset hereditary cancer syndromes in order to inform clinical practice and public policy and to ensure optimal psychosocial and medical outcomes for all members in families at risk for genetically determined disease.

Genetic counselor opinions of, and experiences with telephone communication of BRCA1/2 test results

Bradbury AR, Patrick‐Miller L, Fetzer D, Egleston B, Cummings SA, Forman A, Bealin L, Peterson C, Corbman M, O’Connell J, Daly MB. Genetic counselor opinions of, and experiences with telephone communication of BRCA1/2 test results.

Controversies in Communication of Genetic Risk for Hereditary Breast Cancer

Abstract:u2002 Increased availability and heightened consumer awareness of “cancer genes” has increased consumer interest in, and demand for breast cancer risk assessment, and thus a pressing need for providers to identify effective, efficient methods of communicating complicated genetic information tou2003consumers and their potentially at‐risk relatives. With increasing direct‐to‐consumer and ‐physician marketing of predictive genetic tests, there has been considerable growth in web‐ and telephone‐based genetic services. There is urgent need to further evaluate the psychosocial and behavioral outcomes (i.e., risks and benefits) of telephone and web‐based methods of delivery before they become fully incorporated into clinical care models. Given the implications of genetic test results for family members, and the inherent conflicts in health care providers’ dual responsibilities to protect patient privacy and to “warn” those at‐risk, new models for communicating risk to at‐risk relatives are emerging. Additional controversies arise when the at‐risk relative is a minor. Research evaluating the impact of communicating genetic risk to offspring is necessary to inform optimal communication of genetic risk for breast cancer across the lifespan. Better understanding the risks and benefits associated with each of these controversial areas in cancer risk communication are crucial to optimizing adherence to recommended breast cancer risk management strategies and ensuring psycho‐social well‐being in the clinical delivery of genetic services for breast cancer susceptibility.

Effects of Cancer Chemotherapy on Gonadal Function

During the past 20 years, major strides have been made in the treatment of neoplastic disease with cytotoxic chemotherapy. Progress in understanding tumor cell biology and mechanisms of drug resistance, the introduction of new, effective antineoplastic drugs and technological advances that allow for more detailed and complete pharmacogenetic studies have all contributed to the successful application of cancer chemotherapy. Many patients with Hodgkin’s disease, acute leukemia, non-Hodgkin’s lymphoma, testicular cancer and other tumors now regularly achieve sustained clinical remissions and cures. Moreover, adjuvant chemotherapy is now commonly employed for treatment of micrometastatic disease in clinically well patients with breast cancer, colorectal cancer, lung cancer and soft tissue sarcoma and decreases the relapse rate and prolongs survival for many individuals. Thus many more patients currently receive chemotherapy than ever before and, of greater significance, many more individuals are cured of their tumors and survive to experience the potential late adverse effects of such treatment. Among these, infertility and mutagenesis are often of particular concern to cancer survivors who have new hopes and expectations for a return to normal life style. This chapter will review the effects of cancer chemotherapy on the gonadal function, sexuality and progeny of patients treated for malignant disease.

Telephone disclosure of BRCA1/2 test results: a survey of genetic counselors.

Abstract #1098 Disclosure of BRCA1/2 test results has historically been conducted in person by a certified genetic counselor (GC) and/or other health care professional. Due to increasing demand for and access to BRCA1/2 testing, there has been interest in providing genetic counseling services, including disclosure of test results, by telephone and internet. The practice of telephone disclosure among certified genetic counselors has not been described. We conducted semi-structured interviews with GCs to determine current prevalence of, and future interest in, telephone disclosure (TD) of BRCA1/2 test results. Surveys were self-administered and completed via a secure web site. Participants were recruited through the NSGC Cancer Special Interest Group. 195 GCs completed the survey (25% response rate). 23% of respondents have provided pre-test counseling by telephone. 98% reported having provided genetic test results by telephone, although many (48%) conduct TD rarely ( BRCA1/2 test results in their practice. Given provider interest and the expansion of testing for BRCA1/2 and other hereditary cancer syndromes, further research evaluating the cognitive, affective and behavioral responses to telephone disclosure is warranted. Understanding the impact of telephone disclosure on factors such as, comprehension, risk perception, communication and performance of risk reducing behaviors and their mediators will be critical for the development of telephone disclosure policy and procedures that will optimize adaptive responses to receiving genetic test results via telephone or internet. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1098.

Prophylactic oophorectomy in BRCA1/2 carriers

1012 Background: Women who carry a BRCA1 or BRCA2 mutation are at increased risk for breast and ovarian cancer. Bilateral prophylactic oophorectomy (BPO) has been shown to decrease the risk of ovarian cancer by 85-96%, and the risk of breast cancer by 50%. Therefore, for mutation carriers, prophylactic oophorectomy is recommended after completion of childbearing. Recent studies have found disparate rates of BPO among BRCA1/2 carriers, ranging from 27 to 60%. We conducted a review to determine the rate of BPO use among our BRCA1/2 carrier population.nnnMETHODSnClinical charts were reviewed to evaluate the use of BPO among our population of BRCA1/2 carriers. Participants included female BRCA1/BRCA2 carriers registered at the Cancer Risk Clinic. Women with a history of ovarian cancer, therapeutic oophorectomy and metastatic breast cancer at the time of genetic testing were excluded.nnnRESULTSn80 BRCA1 or BRCA2 carriers in the Cancer Risk Clinic between January 1996 and December 2003 were included. The age at genetic testing ranged from 25 to 71 years old, and 75% were older than 35 at the time of genetic testing. 69 (86%) women were Caucasian, 9 (11%) were African-American and 2 (3%) were Hispanic. 55 (69%) were BRCA1 carriers and 25 (31%) were BRCA2 carriers. All participants received genetic counseling regarding risk reduction options including surveillance, prophylactic surgeries and chemoprevention. 9 (11%) women had a BPO prior to genetic testing, based on family history alone. An additional 32 women (40%) had undergone BPO at the time of analysis. 21 (66%) of these women had a BPO within 12 months of receiving their test results. 29 (53%) of the BRCA1 carriers and 12 (48%) of the BRCA2 carriers underwent BPO. Of the 9 African-American carriers 3 (33%) had a BPO, while neither of the 2 Hispanic carriers underwent BPO.nnnCONCLUSIONSnOver 50% of our BRCA1 and BRCA2 carriers underwent bilateral prophylactic oophorectomy due to a family history suggestive of hereditary breast and ovarian cancer or genetic testing revealing a BRCA1/2 mutation. BPO is an acceptable method of risk reduction. Extended follow-up is necessary, as one-third of women delayed their decision to have BPO over one year after test disclosure. No significant financial relationships to disclose.