Male BRCA Mutation Carriers Research Articles

Malignant Abnormalities in Male BRCA Mutation Carriers

This study evaluates the use of a comprehensive screening protocol for prostate, breast, colorectal, and pancreatic cancer and skin malignant abnormalities in male BRCA carriers.

Male BRCA mutation carriers: clinical characteristics and cancer spectrum

BackgroundMutations in BRCA1 and BRCA2 (BRCA1/2) genes are associated with an increased risk of breast and ovarian cancers in women. The cancer characteristics of men with BRCA1/2 mutations are less well studied. This study describes the unique cancer characteristics of male BRCA1/2 mutation carriers at our institution.MethodsWe performed a retrospective chart review on male patients who were seen between January 2004 and December 2014 and tested positive for a BRCA1/2 mutation. We evaluated clinical characteristics, pathology findings, treatment selection and survival.ResultsA total of 102 male patients were identified who tested positive for a BRCA1/2 deleterious mutation. Of these 102 patients, 33 (32%) had a diagnosis of cancer. Of these 33 patients with cancer, the majority (20 patients) were found to carry a BRCA2 mutation. Median age of cancer diagnosis was 65 years (Range: 35-75 years). Of the 33 patients diagnosed with cancer, 8 had two or more cancers, including 1 patient who had 4 cancers. Prostate cancer was the most commonly diagnosed cancer, seen in 13 patients, 11 of whom were BRCA2 positive. These cancers tended to have higher Gleason scores and elevated PSA levels. The majority of these prostate cancer patients were alive and disease free at a median follow-up of 7.4 years. Male breast cancer was the second most common cancer seen in 9 patients, all of whom were BRCA2 positive. The majority of these cancers were high grade, hormone receptor positive and associated with lymph node metastases. There were no breast cancer related deaths. Other cancers included bladder cancer, pancreatic cancer, melanoma and other skin cancers.ConclusionsThis study describes the cancer characteristics and outcomes of male BRCA1/2 mutation carriers. A third of male BRCA1/2 mutation carriers had a diagnosis of cancer. A significant number of patients (mostly BRCA2 mutation positive) developed multiple cancers, which may have important implications for cancer screening and prevention. Despite having high grade histology and advanced stage at diagnosis, male BRCA1/2 mutation carriers with breast and prostate cancer demonstrated a favorable 5-year survival.

Is there a difference in testosterone levels and its regulators in men carrying BRCA mutations?

BackgroundMale BRCA mutation carriers are at risk for an early onset aggressive prostate cancer. No data exist on the association of testosterone levels among these patients. We aimed to analyze testosterone and associated hormonal levels among male BRCA carriers and non-carriers.Patients and methodsOverall 87 male carriers and 43 non-carriers aged 40-70 were prospectively enrolled. Clinical data were collected and all patients were tested for total testosterone (TT), prostate specific antigen (PSA), follicle stimulating hormone (FSH), luteinizing hormone (LH), free androgen index (FAI), sex hormone binding globulin (SHBG) and prolactin. Multivariate linear regression analysis was performed to predict TT levels.ResultsThe median age, mean BMI, comorbidities, PSA, FSH, LH and SHBG levels in both groups were similar. However, mean TT and FAI were higher in the carriers (16.7 nmol/l vs 13.5 nmol/l, p=0.03 and 39.5 vs 34.8, p=0.05, respectively), while prolactin was significantly lower. Multivariate analysis demonstrated that while BMI was inversely correlated to TT levels in both groups, LH was a predictor only in non-carriers.ConclusionsCarriers have higher TT and FAI levels and lower prolactin levels; but LH does not predict their TT levels. Further research in a larger cohort of BRCA carriers with and without prostate cancer should be performed.

Lower Urinary Tract Symptoms and Benign Prostate Hyperplasia Features Among Male BRCA Mutation Carriers

To analyze lower urinary tract symptoms and benign prostate hyperplasia features among male BRCA1 and 2 carriers and an age-matched control group. Male BRCA carriers and noncarriers aged 40-70 years were enrolled in our cross-sectional study. Relevant clinical data were collected, and patients filled the International Prostate Symptom Score. Patients also underwent prostate-specific antigen (PSA) blood testing, digital rectal examination, uroflowmetry, and post-void residual ultrasound examination. As part of their routine follow-up, BRCA carriers underwent prostate magnetic resonance imaging. Overall, 87 carriers and 30 noncarriers were enrolled. The median age, mean body mass index, and comorbidities in both groups were similar. Maximal flow (QMAX) was higher in the noncarrier group (16.9 mL/s vs 12 mL/s, P = .01). Mean prostate volume among all BRCA carriers was 38.8 cc (19.7), but BRCA1 patients had larger glands with higher mean PSA and PSA density than BRCA2 patients (41.8 cc vs 33.1 cc, P = .047, 1.84 ng/mL vs 1.07 ng/mL, P = .006, and .044 vs .032, P = .042, respectively). Multivariate analysis demonstrated age being the sole significant predictor of PSA density in BRCA2 patients. Male carrying BRCA mutations have significantly lower QMAX than healthy men. BRCA1 patients have on average larger prostate glands and higher PSA than BRCA2 patients. Further research is required to decipher the association of lower urinary tract symptoms or benign prostate hyperplasia with BRCA carriers.

236 - Malignancies in male BRCA mutation carriers – results from a prospectively screened cohort of patients enrolled to a dedicated male BRCA clinic

236 - Malignancies in male BRCA mutation carriers – results from a prospectively screened cohort of patients enrolled to a dedicated male BRCA clinic

Abstract P4-15-01: Cost-effectiveness of pre-implantation genetic diagnosis for BRCA mutation carriers

Abstract Introduction: Management of BRCA mutation carriers is very expensive due to preventive surgeries and/or screening tests, as well as greater likelihood of cancer treatment. The related cancer burden and costs continue from generation to generation. One relatively new option for male or female BRCA mutation carriers, who wish to have children, is pre-implantation genetic diagnosis (PGD) of in vitro fertilized embryos. PGD eliminates the mutation from the descendants of these carriers. The purpose of this study was to model the cost-effectiveness of PGD. Methods: We developed a Markov Model using TreeAge Pro 2016 and compared incidence of cancers, cancers-related death, costs, quality adjusted life-years (QALY), and incremental cost-effectiveness ratio (ICER) in the 2nd generation associated with conventional management of BRCA mutation carriers vs. PGD using a U.S. third-party payer's perspective with a lifetime horizon at a discount rate of 3% per year. In the model, health states were implemented to reflect the natural history of breast and ovarian cancer for women, and prostate cancer (and breast cancer in BRCA2 mutation carriers) for men. Model data were obtained from published literature. Costs were determined from published data and insurance payment schedules. Results: Our preliminary results show that for BRCA1 mutation carriers, the PGD with IVF strategy is associated with an increase of 0.29 QALYs and costs an additional $292.68 per person, translating to an ICER of $1,014.25/QALY when compared with “No PGD”, making it highly cost-effective. For BRCA2 mutation carriers, the PGD with IVF strategy is associated with an increase of 0.17 QALYs and costs an additional $4,916.88 per person, translating to an ICER of $28,436.10/QALY when compared with “No PGD”, making it cost-effective. Table 1StrategyCost ($)Incr Cost ($)Eff (QALY)Incr Eff (QALY)Incr C/E ($/QALY) BRCA 1 No PGD323,347.22 28.41 PGD323,639.89292.6828.70.291,014.25BRCA 2 No PGD318,723.02 28.52 PGD323,639.894,916.8828.70.1728,436.10 Conclusion: PGD for both BRCA1 and BRCA2 mutation carriers reduces cancer burden, increases QALYs and, is very cost-effective in the 2nd generation cohort, making this an attractive option from the perspectives of patients and public payers. Our estimates are conservative because the cost-effectiveness of PGD will likely improve further if subsequent generations are included in the model, given the expected further reduction in cancer burden and associated cost-savings in subsequent generations. Citation Format: Lipton JH, Wong WWL, Warner E, Greenblatt EM, Lee EK, Chan KKW. Cost-effectiveness of pre-implantation genetic diagnosis for BRCA mutation carriers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-15-01.

1112 Lower urinary tract symptoms in male BRCA mutation carriers

1112 Lower urinary tract symptoms in male BRCA mutation carriers

Preliminary activity of veliparib (V) in BRCA2-mutated metastatic castration-resistant prostate cancer (mCRPC).

170 Background: Male BRCA mutation carriers have a 2-8-fold increased risk of prostate cancer when compared to the general population, and up to 3% of patients (pts) with prostate cancer carry an inherited mutation in BRCA1 or 2. The therapeutic implications of germline BRCA mutations in prostate cancer are largely unknown. BRCA mutation enhances sensitivity to inhibition of the PARP1 and PARP2 enzymes, due to a synthetic lethal effect on DNA repair. We therefore conducted a phase 1 study of the PARP 1, 2 inhibitor, veliparib (V), in 2 cohorts of pts- BRCA germline mutated (BRCA+) and BRCA-wild type (BRCA-wt; consisting of serous ovarian cancer and triple-negative breast cancer). Methods: A 3+3 dose escalation phase I trial was performed to determine a maximum tolerated dose (MTD) and recommended phase II dose (RP2D). V was administered orally continuously on a 28-day cycle. Results: A total of98 (70 BRCA+ and 28 BRCA-wt) pts were enrolled. The maximum administered dose (MAD) was 500 mg BID and the MTD/RP2D was 400 mg BID. In BRCA+ cohort at doses ≥ 400 mg BID, overall response rate (ORR) defined as complete response (CR)+ partial response (PR) was 37%, and clinical benefit rate (CBR) defined as CR+PR+stable disease (SD) > 6 cycles was 40%. Three pts with BRCA2+ metastatic castration-resistant prostate cancer (mCRPC) were enrolled on the RP2D and were evaluable for response. In these pts, the ORR was 2/3 (66%) and CBR 3/3 (100%) (summarized in table). One pt with rapidly progressive mCRPC involving liver and bone achieved PR and undetectable serum PSA, and remains on therapy at 19+ cycles. The most common adverse effects in these pts were grade 1/2 nausea/vomiting, fatigue, and leukopenia consistent with the overall study population. Conclusions: Single-agent V demonstrates evidence of activity in BRCA2+ mCRPC. These data support the role of genotype-directed therapy in prostate cancer. Clinical trial information: NCT00892736. [Table: see text]

Optimizing recruitment to a prostate cancer surveillance program among male BRCA1 mutation carriers: invitation by mail or by telephone

The effectiveness of a genetics-based public health screening programs depend on the successful recruitment of subjects who qualify for intensified screening by virtue of a positive genetic test. Herein we compare the effectiveness of a mailed invitation and follow-up phone call for non-responding subjects and an initial invitation by telephone addressed to male BRCA1 mutation carriers for prostate screening.The final participation rate was 75% (42 of 56) for men who were initially contacted by mail (and follow-up phone call) and 81% (30 of 37) for men who were initially contacted by telephone. Among the men who were initially contacted by mail, it was necessary to telephone 54% of these patients (30 of 56).After a calculation of the cost-effectiveness related to these results, we conclude that if the costs of the phone call were to exceed the costs of the letter by 2.5 times or more, then savings would be arranged by initiating contact with a mailed invitation.

Aspirin Use is Associated with Lower Prostate Cancer Risk in Male Carriers of BRCA Mutations

Previous studies have shown that male BRCA mutation carriers stand at increased risk of developing prostate cancer and have concerns about developing cancer. Genetic counseling practitioners often discuss strategies for reducing the risk of cancer for patients at high risk due to their genetic background. Addressing modifiable health habits is one such strategy. Unfortunately, modifiable risk factors for prostate cancer have only been documented in the general population and have not yet been studied in the BRCA carrier subpopulation. Therefore, this study aimed to identify modifiable risk factors for prostate cancer in BRCA carriers. We examined prostate cancer risk factors in 74 men who were part of families with a BRCA mutation. This study examined nine dichotomous variables including: exercise, history of vasectomy, smoking history, alcohol use, finasteride use, statin use, aspirin use, coffee use, and vitamin use. The survey was sent to all cases of prostate cancer in the Hereditary Cancer Center Database at Creighton University with a known BRCA status. This study confirmed the protective benefits of daily aspirin use, which have been observed in previous studies of the general population, and suggests its benefit in BRCA carriers. Protective benefits from regular vigorous exercise and daily coffee use trended towards significance, but neither factor withstood the Bonferroni Correction for multiple comparisons.

Interest of individuals from BRCA families to participate in research studies focused on male BRCA carriers

Although men and women are equally likely to carry a mutation in the BRCA1 and BRCA2 (BRCA) genes, the clinical significance of mutations in men remains incompletely defined. We sought evaluate interest of individuals from BRCA families to participate in a research study focused on men from BRCA families. Through an anonymous survey posted on the website of the BRCA patient advocacy organization, facing our risk of cancer empowered (FORCE), data was collected over a 21 month period (August 2010-June 2012) from members of BRCA families. The survey was completed by 405 individuals with known BRCA mutations, including 150 males and 232 females. The median age of survey respondents was 49 years (50 years for males and 48 years for females). Overall, 84% of survey respondents indicated prior BRCA mutation testing (95.2% females, 67.3% males). For the overall group of survey respondents, 84% (86% females, 84% males) indicated they would tell their male relatives about a research study focused on high risk men from BRCA families, and 53% (39% females, 74% males) thought that their male relatives would be interested in participating in such a study. Despite limited studies focused on men from BRCA mutation positive families, our survey suggests that both male and female family members are highly interested in focused on male BRCA mutation carriers. The importance of further studying this topic is underscored by emerging literature that suggest cancer surveillance and treatment decisions may improve outcomes in men with BRCA mutations.

Abstract P3-11-02: Male breast cancer: A comparison between BRCA mutation carriers and non-carriers in Hong Kong, Southern China

Abstract Background: Male breast cancer is suggested to be biologically different from female breast cancer. The differences in clinicopathology between male and female breast cancer raise the issues of establishing specific strategies and treatment regime for male breast cancer patients. The single most significant risk factor for male breast cancer is a mutation in the BRCA2 gene. The lack of information on hereditary breast cancer in male, particularly in Asians, leaves great but forgiven research area on epidemiological studies for this group of patients. Methods: All male breast cancer patients and their family members, from a Hong Kong Hereditary and High Risk Breast Cancer Program since year 2007, were recruited in this study. All received genetic counseling and BRCA mutation testing using DNA extracted from blood samples. A questionnaire was administered at their first visit which included questions on their demographics and socioeconomic status. Other information including family history of breast cancer or other kinds of cancer, method of diagnosis, surgical strategies, pathological results, treatment regime, relapse, metastasis, and outcomes were obtained from their medical records. Descriptive analysis was performed describing the background characteristics. Chi-square test and Student's t-test were applied to calculate the associations between BRCA mutation and risk factors. Survival analysis was performed to look for their survival patterns. Results: Thirty-six male breast cancer patients were recruited between year 2007 and 2012, while 21 were diagnosed before year 2007 (range: 1996 to 2012). Mean, standard deviation, and median follow-up time were 5.75±4.31 and 5.25 years. Seven were found to carry the BRCA mutation. All were BRCA2 mutation and the mutation rate was 19.4% (N = 7). Family history of cancer was found in 52.8% (N = 19). Male BRCA mutation carriers were found to have higher risk of secondary cancer, and their first and second degree family members had higher risk of either breast cancer or other kinds of cancers. T stage in BRCA patients was significantly higher than non-BRCA patients (p = 0.028). All BRCA mutation carriers had ER positive cancers compared with 96.2% who were non-carriers. Half of the male BRCA patients were PR positive compared with higher percentage in non-BRCA patients (50% vs. 80.8%, p = 0.117). Both groups had similar overall (p = 0.962) and disease-free survivals (p = 0.919). The means and standard deviations of 5-year overall survival between BRCA and non-BRCA patients were 2.08±0.25 and 4.24±0.12 years respectively, and 2.08±3.03 and 4.41±1.46 years for disease-free survival. Conclusions: The prevalence of male breast cancer patients with BRCA2 mutation in Hong Kong is comparable with other similar studies. Male breast cancer patients with BRCA2 mutation are suspected to have higher chance of secondary cancer and familial cancer. Although percentage of ER positive cancers are similar to the two groups, BRCA2 mutation carriers tend to have less PR positive cancers which may suggest a poorer prognosis although due to a small sample size this cannot be shown in this cohort. Further collaborative studies to better understand male breast cancer patients carrying the BRCA mutation is warranted. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-11-02.

Germline BRCA1 mutations increase prostate cancer risk

Background:Prostate cancer (PrCa) is one of the most common cancers affecting men but its aetiology is poorly understood. Family history of PrCa, particularly at a young age, is a strong risk factor. There have been previous reports of increased PrCa risk in male BRCA1 mutation carriers in female breast cancer families, but there is a controversy as to whether this risk is substantiated. We sought to evaluate the role of germline BRCA1 mutations in PrCa predisposition by performing a candidate gene study in a large UK population sample set.Methods:We screened 913 cases aged 36–86 years for germline BRCA1 mutation, with the study enriched for cases with an early age of onset. We analysed the entire coding region of the BRCA1 gene using Sanger sequencing. Multiplex ligation-dependent probe amplification was also used to assess the frequency of large rearrangements in 460 cases.Results:We identified 4 deleterious mutations and 45 unclassified variants (UV). The frequency of deleterious BRCA1 mutation in this study is 0.45% three of the mutation carriers were affected at age ⩽65 years and one developed PrCa at 69 years. Using previously estimated population carrier frequencies, deleterious BRCA1 mutations confer a relative risk of PrCa of ∼3.75-fold, (95% confidence interval 1.02–9.6) translating to a 8.6% cumulative risk by age 65.ConclusionThis study shows evidence for an increased risk of PrCa in men who harbour germline mutations in BRCA1. This could have a significant impact on possible screening strategies and targeted treatments.

Breast cancer in a BRCA2 mutation carrier with a history of prostate cancer

A 49-year-old patient with high-risk prostate cancer presented to a specialist. He was treated with neoadjuvant hormonal therapy for 6 months, followed by conformal radiotherapy. Three years later, he had a biochemical recurrence and commenced continuous luteinizing hormone-releasing hormone analog and antiandrogen therapy as part of a clinical trial. Aside from notable gynecomastia, he remained asymptomatic. He has a strong family history of breast cancer with multiple sisters affected. At 58 years of age, the patient underwent BRCA2 germline testing and was found to be a mutation carrier. Following post-test counseling, he was offered clinical breast examination, which was unremarkable except for gynecomastia. Baseline screening mammography identified a 4 mm cluster of microcalcifications and ductal carcinoma in situ (DCIS) was confirmed by stereotactic biopsy. DCIS in a male BRCA2 mutation carrier undergoing androgen deprivation therapy for prostate cancer. The patient was treated with bilateral mastectomy and no additional systemic therapy was recommended. This case report illustrates the importance of implementing screening mammography in male BRCA mutation carriers, particularly in those with a BRCA2 mutation.

Counseling for male BRCA mutation carriers – a review

BRCA mutations in women confer a high risk for breast and ovarian cancers. The risks to male carriers are poorly understood and risk management strategies undescribed. This review summarizes current evidence and gives recommendations for counseling male BRCA mutation carriers. Reported risks for breast, prostate, pancreatic, gastric and hematologic cancers are higher in male BRCA mutation carriers vs non-carriers. Especially in male BRCA2 mutation carriers under age 65 prostate and pancreatic cancer risks are increased. The risk increase for primary cancers of organs like the liver, bone and brain is difficult to assess as these organs are common sites for metastases. Reports on colorectal cancer and melanoma risks are inconclusive. On the current limited evidence available, male BRCA mutation carriers should be regarded as at high risk for breast, prostate, gastric, pancreatic and colorectal cancers; surveillance by appropriate investigations should start at age 40 years.

Breast Cancer Risk Among Male BRCA1 and BRCA2 Mutation Carriers

Men who carry germline mutations in the BRCA2 gene have a higher risk of developing breast carcinoma than men in the general population. Men who carry germline mutations in the BRCA1 gene may also be at a higher risk for breast carcinoma, but this association is not as well established. We evaluated the risks of developing breast carcinoma for male BRCA1 and BRCA2 mutation carriers in the US population based on data from 1939 families with 97 male subjects with breast carcinoma that were collected from eight centers across the National Cancer Institute's Cancer Genetics Network. At all ages, the cumulative risks of male breast cancer were higher in both BRCA1 and BRCA2 mutation carriers than in noncarriers. The relative risks of developing breast cancer were highest for men in their 30s and 40s and decreased with increasing age. Both the relative and cumulative risks were higher for BRCA2 mutation carriers than for BRCA1 mutation carriers. The estimated cumulative risk of breast carcinoma for male BRCA1 mutation carriers at age 70 years was 1.2% (95% confidence interval [CI] = 0.22% to 2.8%) and for BRCA2 mutation carriers, 6.8% (95% CI = 3.2% to 12%).

Clinical factors used to support prophylactic mastectomy for a male BRCA2 mutation carrier

Male breast cancer accounts for less than 1% of male cancers and of all diagnosed breast cancers in the United States. Male breast cancer is treated with mastectomy and, more recently, mastectomy combined with sentinel node surgery. For female BRCA gene mutation carriers requiring mastectomy, the use of prophylactic mastectomy for the contralateral breast is well supported. Whether this should be done for male BRCA mutation carriers has not yet been established. This case report describes the treatment of a male with a known BRCA2 mutation who was found to have breast cancer and had an opposite side prophylactic mastectomy at the time of his breast cancer surgery. His tumor was strongly estrogen receptor positive and moderately progesterone receptor positive, and his estradiol level was elevated. Increased estrogen exposure is a probable risk factor for breast cancer in men and women. Examples of conditions leading to hyperestrogenism in males include cirrhosis of the liver and genetic syndromes such as Klinefelter Syndrome. Some studies support the use of a single measurement of bioavailable estradiol to stratify women into risk categories for breast cancer, although not all re-

Cancer Risks for Male Carriers of Germline Mutations in BRCA1 or BRCA2: A Review of the Literature

Major risks conferred by BRCA1 and BRCA2 in women are for cancers of the breast, ovary, fallopian tube, and peritoneum. Male carriers of mutations in BRCA1 or BRCA2 are also susceptible to cancer; however, their risks remain poorly understood and their optimal clinical management has not yet been defined. This article reviews studies that estimate risk associated with mutations in BRCA1 or BRCA2, with a focus on the cancer sites most relevant to men. Male BRCA1 mutation carriers are at increased risk of cancers of the prostate and breast. Evidence supporting increased susceptibility to colon cancer is limited. In contrast to women, who have a greater lifetime risk of cancer with mutations of the BRCA1 gene, BRCA2 is the more important gene for men. The spectrum of cancers is wide for BRCA2 and some studies report that the overall cancer risk for male BRCA2 carriers exceeds the risk for female carriers. In particular, the relative risk to male BRCA2 mutation carriers is high before age 65 years, largely attributable to breast, prostate, and pancreatic cancers. BRCA2 mutation carriers are also at risk of stomach cancer and melanoma (of the skin and eye). Additional research into risks to male BRCA1 or BRCA2 mutation carriers is necessary, specifically to determine the magnitude of excess cancer risk among BRCA2 carriers and to increase our understanding of the basis for the observed site-specificity in cancer development.

BRCA1 and BRCA2 gene mutations: decision-making dilemmas concerning testing and management.

The identification of the BRCA genes, and their possible etiologic relationship with various forms of inherited cancer, has been recognized universally as a cornerstone in the search of cancer's genetic susceptibility. Female BRCA gene mutation carriers are found to carry an increased risk of developing breast or ovarian cancer and to a lesser degree, colon cancer, and male BRCA mutation carriers are also related to an increased risk of breast, colon, or prostate cancer. Although genetic testing promises a possible future presymptomatic determination and treatment of women who are genetically susceptible to cancer, current data reveal certain dilemmas and uncertainties regarding our ability to interpret the results from testing and offer effective management options. In addition, several complex ethical, legal, and social issues have been revealed with the advent of this new information, which also confirm the need for additional research regarding the most effective use of this genetic information and for the establishment of appropriate clinical management strategies.