Hereditary breast cancer and ancestry in the Madeira archipelago: an exploratory study.

Access to genetic testing and counselling in remote areas such as the Madeira archipelago, in the Northern Atlantic Ocean, may be complex. Different counselling methods, including telegenetics, should be explored. In this study, we characterise the Hereditary Breast/Ovarian Cancer (HBOC) families with Madeira ancestry enrolled in our programme. Of a total of 3,566 index patients tested between January 2000 and June 2018, 68 had Madeira ancestry and 22 were diagnosed with a pathogenic germline variant (PV). As in the whole group, BRCA2 PV were more frequent in Madeira patients (68.4%: c.9382C>T (26.3%), c.658_659del (21%), c.156_157insAlu (10.5%), c.793+1G>A (5.3%) and c.298A>T (5.3%). However, the most frequently diagnosed PV in Madeira patients was the BRCA1 c.3331_3334del (31.6%). BRCA1/2 detection rates were 27.9% and 10.5% for Madeira and the whole group, respectively. This study is the first characterisation of HBOC patients with Madeira ancestry. A distinct pattern of BRCA1/2 variants was observed, and the geographic clustering of BRCA1 c.3331_3334del variant may support the possibility of a founder mutation previously described in Northern Portugal. The high detection rate observed reinforces the need to reduce gaps in access to genetic testing in Madeira and other remote areas. According to current guidelines, timely identification of HBOC patients can contribute to their ongoing care and treatment.

ATM germline variants and male breast cancer.

Male breast cancer is rare and has been frequently associated with cancer predisposing variants, particularly in BRCA 1 and BRCA 2 genes. ATM pathogenic variants may also increase risk for breast and other cancers. However, less than 10 cases relating ATM mutations and male breast cancer have been previously reported. Therefore, risk estimates and surveillance recommendations are not well established. We report a case of a male patient with breast cancer found to be heterozygous for a pathogenic ATM variant after multigene testing. We also review the literature regarding increased cancer risk associated with ATM germline variants, with emphasis on potential recommendations for surveillance and follow-up.

Men seeking counselling in a Breast Cancer Risk Evaluation Clinic.

BACKGROUND: Hereditary breast and ovary cancer syndrome affects both genders but little is known about the uptake of genetic services by men. The objective of this study is to characterise the male population counselled through a multidisciplinary breast/ovarian program. METHODS: Descriptive analysis of male patients counselled from January 2000 to December 2015. Data in this analysis include new cancer diagnoses during prospective follow up. RESULTS: From 4,320 families registered, 362 male patients were identified: 236 (65.2%) from hereditary cancer families (HCF) and 126 (34.8%) from non-HCF. In HCF, 121 patients (51.3%) were mutation carriers (MC): BRCA2 - 102 (84.3%), BRCA1 - 16 (13.2%), CHEK2 - 1 (0.8%) and TP53 - 2 (1.7%). Non-HCF included 126 patients: 85 (67.5%) belonged to families without pathogenic mutations or with variants of unknown clinical significance; 22 (17.5%) refused testing after counselling and 19 (15.0%) did not meet criteria for testing. Both HCF and non-HCF included patients with previous cancer diagnoses: HCF- Breast Cancer (BC) - 18; prostate cancer (PC) - 13; melanoma - 1; others - 7) and non-HCF (BC - 77; PC - 20; gastric cancer (GC) - 1; melanoma - 8; bladder cancer - 1; others - 22). From the 121 MC identified (including the TP53 and CHEK2 carriers), 97 patients (80.2%) adhered to prospective surveillance. With a median follow-up of 36.9 months, 17 cancers were diagnosed in 14 patients, PC being the most frequently diagnosed neoplasia (5 cases). Eleven patients (78.6%) are alive and three patients died of advanced cancer (2 with GC, 1 with disseminated adenocarcinoma). CONCLUSION: We observed a high adherence to counselling, genetic testing and active surveillance by men belonging to hereditary BC families. Male carriers of pathogenic DNA variants are at risk for several cancers and should be included in prospective follow-up studies.

Candidate comprehension of key concepts in kidney transplantation.

BACKGROUND: Although kidney transplant candidates receive education regarding transplantation and donation, little is known about the extent of their comprehension. We aimed to identify factors that affect patient comprehension of important concepts regarding kidney transplantation. MATERIAL AND METHODS: We performed a cross-sectional survey of consecutive adult kidney transplant candidates seen at our center between July 2013 and October 2013 for initial evaluation (n=100) or for reevaluation (n=117). The main outcome measure was a Knowledge Assessment Questionnaire completed by patients. We assessed factors affecting patient understanding of key kidney transplant concepts as measured by mean knowledge score. RESULTS: Mean knowledge scores of those at evaluation (72±21) and those at reevaluation (70±20; p=0.4769) were similar; therefore the entire cohort was analyzed as a single group. Compared to the high-scoring group, low-scorers (<75%; median value) were significantly more likely to be older, Hispanic, with lower education attainment, and have end-stage renal disease due to hypertension or diabetes rather than other etiologies. On multivariate analysis, independent risk factors for low-scores were increasing age (aOR 1.03 (95% CI 1.01-1.06) and educational level (less than high school; aOR 4.23, 95%CI 1.82-9.80; high school or GED aOR2.85, 95% CI 1.43-5.70 compared to some college or technical school). Of 139 candidates that consented to receive ECD and 152 consenting to CDCHR kidneys, 52% and 27%, respectively, answered the high-risk-specific question incorrectly. CONCLUSIONS: Educational level and older age are independent risk factors for poor comprehension. Kidney candidate knowledge of organs with increased risks is suboptimal despite previous consent to receive such organs.

Bevacizumab in the treatment of metastatic breast cancer: three case reports.

Case reports are presented for three patients with metastatic breast cancer who received first-line treatment with bevacizumab in combination with taxanes in clinical trials. Two patients showed peak reductions in lesion size of 49 and 70%, respectively. In one patient, subsequent treatment with bevacizumab in combination with capecitabine [Xeloda (after discontinuation of paclitaxel due to asthenia)] yielded peak reductions in target lesion size of 78%. One patient experienced a progression-free survival time of 16 months. In all three patients, bevacizumab was well tolerated and mostly displayed only mild toxicities.

Screening for a BRCA2 rearrangement in high-risk breast/ovarian cancer families: evidence for a founder effect and analysis of the associated phenotypes.

PURPOSE: BRCA2 rearrangements are rare genetic events. A large BRCA2 genomic insertion was recurrently observed in our participants, and we sought to characterize it at the molecular and phenotypic level. PATIENTS AND METHODS: We studied 210 high-risk breast/ovarian cancer families. Fifty-three probands were fully screened for BRCA1/2 mutations, and three of 53 had a large insertion in exon 3 of BRCA2. This finding was analyzed by polymerase chain reaction (PCR), reverse transcriptase PCR (RT-PCR), and sequencing. An additional 157 consecutive families were screened for this mutation by a three-step PCR method. Phenotype and haplotype analysis was also performed. RESULTS: Sixteen BRCA mutations were observed in 19 of 53 patients (36% detection rate). A recurrent Alu motif insertion in position c.156_157 was observed after sequencing of an abnormal fragment obtained after the amplification of BRCA2 exon 3. RT-PCR revealed exon 3 skipping. Screening of this rearrangement identified 14 additional families (out of 157). In total, 17 (8%) of 210 high-risk families ascertained in our clinic were positive for this mutation. Segregation of a common haplotype (from D13S260 to D13S1695) confirmed a common origin, estimated to have occurred 2,400 to 2,600 years ago. The following four cancer phenotypes were observed in the 17 positive families: female breast (n = 9), male breast (n = 4), breast/ovarian (n = 2), and heterogeneous (n = 2). Male breast cancer was more frequently observed in c.156_157insAlu-positive families compared with negative families (23% v 12%, respectively), and 33% of all male breast cancer families with an identified BRCA mutation were c.156_157insAlu positive. CONCLUSION: c.156_157insAlu is a founder mutation of Portuguese origin and is the most frequent BRCA2 rearrangement described to date.