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Background: In this article, we delineate a loosely selected cohort comprising patients with a history of early‐onset breast cancer and/or a familial occurrence of cancer. The aim of this study was to gain insights into the presence of breast cancer‐related gene variants in a population from a micro‐region in southern Brazil, specifically the Metropolitan Region of Curitiba. This area exhibits a highly genetically mixed population, mirroring the general characteristics of the Brazilian people. Methods: Comprehensive next‐generation sequencing (NGS) multigene panel testing was conducted on 12 patients from the region, utilizing three different library preparation methods. Results: Two pathogenic variants and one candidate pathogenic variant were identified: BRCA2 c.8878C>T, p.Gln2960Ter; CHEK2 c.1100del, p.Thr367Metfs15, and BRCA2 c.3482dup, p.Asp1161Glufs3. Conclusion: BRCA2 c.3482dup, a novel candidate pathogenic variant, previously unpublished, is reported. The prevalence of pathogenic variants in this small cohort is similar to that described in the literature. All different library preparation methods were equally proficient in enabling the detection of these variants. [ABSTRACT FROM AUTHOR]

Abstract Background In this article, we delineate a loosely selected cohort comprising patients with a history of early‐onset breast cancer and/or a familial occurrence of cancer. The aim of this study was to gain insights into the presence of breast cancer‐related gene variants in a population from a micro‐region in southern Brazil, specifically the Metropolitan Region of Curitiba. This area exhibits a highly genetically mixed population, mirroring the general characteristics of the Brazilian people. Methods Comprehensive next‐generation sequencing (NGS) multigene panel testing was conducted on 12 patients from the region, utilizing three different library preparation methods. Results Two pathogenic variants and one candidate pathogenic variant were identified: BRCA2 c.8878C>T, p.Gln2960Ter; CHEK2 c.1100del, p.Thr367Metfs15, and BRCA2 c.3482dup, p.Asp1161Glufs3. Conclusion BRCA2 c.3482dup, a novel candidate pathogenic variant, previously unpublished, is reported. The prevalence of pathogenic variants in this small cohort is similar to that described in the literature. All different library preparation methods were equally proficient in enabling the detection of these variants.

Abstract Background Penile squamous cell carcinoma (PSCC) is a highly aggressive malignancy with a poor prognosis. BRCA1/2 mutations are associated with impaired DNA double-strand break repair and are among the common mutations in penile cancer, potentially paving the way for poly ADP-ribose polymerase inhibitor therapy. Case presentation We report a 65-year-old male with PSCC who progressed to thigh metastasis at 10 months after partial penectomy. Next-generation sequencing showed that the penis primary lesion and metastatic thigh lesion harboured a BRCA2 mutation. Chemotherapy plus immunotherapy was used for treatment, and the thigh metastasis was found to involve no tumour. Progression-free survival (PFS) lasted for 8 months until the appearance of lung metastasis. Afterwards, the patient benefited from second-line therapy of olaparib with pembrolizumab and anlotinib, and his disease was stable for 9 months. The same BRCA2 was identified in the lung biopsy. Given the tumour mutation burden (TMB, 13.97 mutation/Mb), the patient received third-line therapy with nivolumab plus ipilimumab, but PFS only lasted for 3 months, with the appearance of right frontal brain metastasis. Then, the patient was treated with radiation sequential fluzoparib therapy as fourth-line treatment, and the treatment efficacy was evaluated as PR. Currently, this patient is still alive. Conclusions This is the first report of penile cancer with BRCA2 mutation, receiving a combination treatment with olaparib and experiencing a benefit for 9 months. This case underscores the pivotal role of BRCA2 in influencing treatment response in PSCC, providing valuable insights into the application of targeted therapies in managing recurrent PSCC with BRCA2 alterations. This elucidation establishes a crucial foundation for further research and clinical considerations in similar cases.

Abstract BRCA2-mutated carriers have a high lifetime risk of breast cancer (BC), an early age of onset, and an increased risk of other cancers (including ovarian, pancreatic, and prostate cancer). Almost 70–80% of BRCA2-mutated BC are estrogen receptor (ER)-positive, which is a particular type of ER-positive BC that differs from sporadic ER-positive BC. This article reviews the clinicopathological features, treatment, and prognosis of ER-positive and BRCA2-mutated BC to provide a reference for clinical decision-making.

Abstract Objective To investigate the prevalence of BRCA1/2 gene variants and evaluate the clinical and pathological characteristics associated with these variants in Chinese Hakka breast cancer patients. Methods A total of 409 breast cancer patients were analyzed based on next-generation sequencing results, with 337 categorized as non-carriers and 72 as carriers of BRCA1/2 variants. Data on the patients’ BRCA1/2 gene mutation status, clinical and pathological characteristics, as well as menstrual and reproductive information, were collected, analyzed, compared, and tabulated. Logistic regression analysis was performed to explore the relationship between clinical characteristics and pathogenic variants. Results Among the patients, 72 were identified as carriers of pathogenic or likely pathogenic variants in BRCA1/2, while 337 had likely benign or benign mutations. The BRCA1 c.2635G > T (p. Glu879*) variant was detected at a high frequency, accounting for 12.5% (4/32) of the BRCA1 mutations, while the c.5164_5165del (p.Ser1722Tyrfs*4) variant was common among the BRCA2 mutations, accounting for 17.5% (7/40). It was observed that a higher proportion of BRCA1 carriers had the triple-negative breast cancer subtype, whereas more BRCA2 carriers exhibited estrogen receptor (ER) + and progesterone receptor (PR) + subtypes. Multivariate logistic regression analysis revealed that a family history of cancer (OR = 2.36, 95% CI = 1.00–5.54), bilateral cancer (OR = 4.78, 95% CI 1.61–14.20), human epidermal growth factor receptor 2 (HER2)- (OR = 8.23, 95% CI 3.25–20.84), and Ki67 ≥ 15% (OR = 3.88, 95% CI 1.41–10.65) were associated with BRCA1/2 mutations, with the age at diagnosis, age at menarche, and premenopausal status serving as covariates. Conclusions The most common pathogenic variant of the BRCA1 and BRCA2 in breast cancer patients was c.2635G > T and c.5164_5165del, respectively. Additionally, a family history of cancer, bilateral cancer, HER2-, and Ki67 ≥ 15% were identified as independent predictors of BRCA1/2 pathogenic variants.

BRCA2-mutated carriers have a high lifetime risk of breast cancer (BC), an early age of onset, and an increased risk of other cancers (including ovarian, pancreatic, and prostate cancer). Almost 70–80% of BRCA2-mutated BC are estrogen receptor (ER)-positive, which is a particular type of ER-positive BC that differs from sporadic ER-positive BC. This article reviews the clinicopathological features, treatment, and prognosis of ER-positive and BRCA2-mutated BC to provide a reference for clinical decision-making. [ABSTRACT FROM AUTHOR]

Objective: To investigate the prevalence of BRCA1/2 gene variants and evaluate the clinical and pathological characteristics associated with these variants in Chinese Hakka breast cancer patients. Methods: A total of 409 breast cancer patients were analyzed based on next-generation sequencing results, with 337 categorized as non-carriers and 72 as carriers of BRCA1/2 variants. Data on the patients' BRCA1/2 gene mutation status, clinical and pathological characteristics, as well as menstrual and reproductive information, were collected, analyzed, compared, and tabulated. Logistic regression analysis was performed to explore the relationship between clinical characteristics and pathogenic variants. Results: Among the patients, 72 were identified as carriers of pathogenic or likely pathogenic variants in BRCA1/2, while 337 had likely benign or benign mutations. The BRCA1 c.2635G > T (p. Glu879*) variant was detected at a high frequency, accounting for 12.5% (4/32) of the BRCA1 mutations, while the c.5164_5165del (p.Ser1722Tyrfs*4) variant was common among the BRCA2 mutations, accounting for 17.5% (7/40). It was observed that a higher proportion of BRCA1 carriers had the triple-negative breast cancer subtype, whereas more BRCA2 carriers exhibited estrogen receptor (ER) + and progesterone receptor (PR) + subtypes. Multivariate logistic regression analysis revealed that a family history of cancer (OR = 2.36, 95% CI = 1.00–5.54), bilateral cancer (OR = 4.78, 95% CI 1.61–14.20), human epidermal growth factor receptor 2 (HER2)- (OR = 8.23, 95% CI 3.25–20.84), and Ki67 ≥ 15% (OR = 3.88, 95% CI 1.41–10.65) were associated with BRCA1/2 mutations, with the age at diagnosis, age at menarche, and premenopausal status serving as covariates. Conclusions: The most common pathogenic variant of the BRCA1 and BRCA2 in breast cancer patients was c.2635G > T and c.5164_5165del, respectively. Additionally, a family history of cancer, bilateral cancer, HER2-, and Ki67 ≥ 15% were identified as independent predictors of BRCA1/2 pathogenic variants. [ABSTRACT FROM AUTHOR]

Background: Mutations in the human breast cancer susceptibility gene 2 (breast cancer 2, BRCA2) increase the risk of breast, ovarian and other cancers. Olaparib, an oral poly[adenosine diphosphate (ADP)-ribose] polymerase (PARP) inhibitor, is usually prescribed to treat BRCA mutated tumors, especially breast and ovarian cancers. Programmed cell death-1 (PD-1) inhibitors have revolutionized the treatment of lung cancer and many other cancers by destroying the interaction between receptors with ligands in the tumor-immune microenvironment and enabling T cells to recognize and attack cancer cells. Case description: In our study, we report a patient with advanced BRCA2 lung squamous cell carcinoma who received platinum-based chemotherapy combined with paclitaxel. Seven months later, the disease progressed. BRCA2 mutations were detected in peripheral blood by next-generation sequencing. After 2 months of treatment with Olaparib combined with Cindilimab, the patient was in partial remission and the progression-free survival (PFS) lasted for 6 months, but the patient developed immune renal damage. Conclusions: This study adds to the clinical data for the treatment of BRCA2 mutant non-small cell lung cancer by demonstrating that lung squamous cell carcinoma has a good response to PARP inhibitors. It also serves as a reminder that there may still be some negative effects from targeted superimposed immunotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Despite major advances in surveillance and management, advanced cholangiocarcinoma (CCA) still carries a dismal prognosis. In recent years, several actionable genomic alterations in pancreatobiliary malignancies have been identified. For instance, homologous recombination deficiency (HRD) has been considered a predictive biomarker of clinical response to platinum and poly (ADP-ribose) polymerase (PARP) inhibitors. Case Report: A 53-year-old man with a stage 3 (T4N0M0) BRCA2-mutant CCA developed intolerable toxicity after 44 cycles of gemcitabine/cisplatin. In light of his HRD positivity, treatment was switched to single-agent olaparib. The patient showed a partial radiological response, which was maintained after 8 months of olaparib discontinuation (progression-free survival >36 months). Conclusion: Given the durable response observed, olaparib can be a valuable therapeutic tool in BRCA-mutant CCAs. Ongoing and future clinical trials are needed to confirm the role of PARP inhibition in similar patients and to define the clinicopathological and molecular profile of the individuals most likely to benefit. [ABSTRACT FROM AUTHOR]

Metastatic colorectal cancer (mCRC) has a poor prognosis. Combining chemotherapy with targeted therapy constitutes a basic form of mCRC treatment. Immune checkpoint inhibitors have been recommended for microsatellite instability mCRC, while most patients harboring microsatellite stability (MSS) or proficient mismatch repair (pMMR) are less responsive to immunotherapy. Combinational targeted therapy, including poly-ADP ribose polymerase (PARP) inhibitors, has been considered a promising way to reverse immunotherapy resistance; however, there is no clear and consistent conclusions can be drawn from the current research. Here, we report the case of a 59-year-old woman diagnosed with stage IVB MSS mCRC who received three courses of capecitabine/oxaliplatin chemotherapy combined with bevacizumab as a first-line treatment, resulting in an overall evaluation of stable disease (−25.7%). However, the occurrence of adverse events of intolerable grade 3 diarrhea and vomiting forced the cessation of this therapy. A germline BRCA2 mutation was found by next-generation sequencing, and the patient further received a combination of olaparib, tislelizumab, and bevacizumab. This treatment regime resulted in a complete metabolic response and a partial response (−50.9%) after 3 months of treatment. Mild asymptomatic interstitial pneumonia and manageable hematologic toxicity were two adverse events associated with this combination therapy. This study provides new insights into the combination of PARP inhibitors and immunotherapy for MSS mCRC patients carrying germline BRCA2 mutations. [ABSTRACT FROM AUTHOR]

Introduction Treatment‐emergent small cell/neuroendocrine prostate cancer occurs predominantly in advanced or metastatic castration‐resistant prostate cancer that arises when prostate adenocarcinoma is transformed after androgen deprivation therapy. The clinical course for the pathogenesis involved or associated genetic information have not been clearly elucidated. Case presentation A Japanese male, 63‐year‐old, underwent a para‐aortic lymph biopsy due to sudden severe bilateral leg edema, with a final diagnosis of stage IV prostate adenocarcinoma. He was initially responsive to upfront abiraterone with androgen deprivation therapy; however, relapse occurred in the liver and bone 10 months after initial treatment, with serum neuron‐specific enolase elevation and without prostate‐specific antigen elevation. Pathological findings of liver tumor revealed treatment‐emergent small cell/neuroendocrine prostate cancer. FoundationOne® CDx was used for cancer‐related gene profiling of liver tumor specimen; a BRCA2 mutation was identified. Conclusion Early detection of this transformation and pathological diagnosis can improve patient survival when genetic mutations, including BRCA 1/2.

Backgraound. High-grade serous ovarian carcinoma (HGSOC) is the most common type of ovarian cancer. The prevalence of BRCA1/2 germline mutations is the highest in HGSOC. patients with germline BRCA gene mutations are more likely to respond to platinum-based chemotherapy. Clinical trials demonstrate the effectiveness of PARP inhibitors in the treatment of BRCA-associated ovarian cancer. Re-administration of PARP inhibitors after response to platinum-based chemotherapy demonstrates an increase in progression-free survival rates regardless of BRCA status. it is important for understanding the development of molecular mechanisms of resistance to platinum drugs and PARP inhibitors, as well as for developing new treatment strategies and tools to overcome resistance. Case description. This clinical case of BRCA-associated hereditary ovarian cancer demonstrates the efficacy and good tolerability of PARP inhibitor maintenance therapy following the treatment of the first relapse, as well as the efficacy of re-administration of PARP inhibitors following the treatment of the second relapse. The short-course of re-treatment with PARP inhibitors was accompanied by the development of multidrug resistance. the overall survival time was 112 months. Conclusion. The presence of mutations in BRCA1/2 genes is a promising justification for the administration of maintenance therapy with PARP inhibitors. Re-administration of PARP inhibitor maintenance therapy for relapsed ovarian cancer is currently being considered as a possible therapeutic option. deciphering the molecular mechanisms of resistance to PARP inhibitors is of paramount importance for the development of new treatment strategies and tools to overcome chemoresistance, re-sensitization of the tumor to platinum-based drugs or PARP inhibitors.

Abstract Background Women with BRCA1/2 mutations have a higher risk of developing breast and ovarian cancer compared to women of the general population. Various preventive options are available to deal with the increased risk of developing cancer. These include intensified breast cancer screening and risk-reducing bilateral mastectomy and salpingo-oophorectomy. The choice of a preventive option can lead to increased decisional conflict. To support these women in their decision-making process, two evidence-based decision aids were developed in an upstream research process and adapted to the German healthcare context. These will be evaluated within a randomised controlled trial (RCT) in terms of their effects on decision-making, women’s level of information and psychological outcome variables. Methods A sample of 310 women carrying BRCA1/2 mutations (A) without a history of cancer or (B) with a history of unilateral breast cancer who have received post-test genetic counselling will be enrolled. Upon study consent, women will be randomly assigned to either the intervention or the control group. All participants will receive standard care including a physician’s letter summarising the counselling content. After baseline data collection (t0), the intervention group receives the respective decision aid while the control group receives standard care only. The primary outcome variable assessed at a 3-month follow-up (t1) is the change of extent in decisional conflict (measured with the Decisional Conflict Scale). Secondary outcome variables comprise the stage of decision-making, self-reported symptoms of anxiety, depression and stress due to the genetic test result, and knowledge regarding cancer risks and preventive options. At t1, the extent of preparation for decision-making and acceptability of the decision aids will also be examined. Another secondary outcome variable assessed at 6-month follow-up (t2) is the extent of decision regret. Discussion These will be the first decision aids available for BRCA1/2 mutation carriers in Germany to be evaluated regarding their effectiveness and acceptability in clinical use within an RCT. Subsequently, they are to be integrated into the care concept of the centres of the German Consortium for Hereditary Breast and Ovarian Cancer and the affiliated breast centres. Trial registration {2a} DRKS DRKS00015823 . Retrospectively registered on 14 June 2019

Introduction Deoxyribonucleic acid repair gene mutations are now being studied in a variety of solid tumors, with the hope of predicting prognosis, pathogenesis, and treatment outcomes. Case presentation We report the case of a Japanese patient with advanced castration‐resistant prostate cancer who exhibited a prominent response to platinum therapy and had coexisting BRCA2 and PTEN mutations according to retrospective multigene panel analysis. Conclusion Through a review of clinical outcomes and genetic/pathologic profiling, the presented case provides insights into future management strategies based on the tumor genetic status.

Metastatic colorectal cancer (mCRC) has a poor prognosis. Combining chemotherapy with targeted therapy constitutes a basic form of mCRC treatment. Immune checkpoint inhibitors have been recommended for microsatellite instability mCRC, while most patients harboring microsatellite stability (MSS) or proficient mismatch repair (pMMR) are less responsive to immunotherapy. Combinational targeted therapy, including poly-ADP ribose polymerase (PARP) inhibitors, has been considered a promising way to reverse immunotherapy resistance; however, there is no clear and consistent conclusions can be drawn from the current research. Here, we report the case of a 59-year-old woman diagnosed with stage IVB MSS mCRC who received three courses of capecitabine/oxaliplatin chemotherapy combined with bevacizumab as a first-line treatment, resulting in an overall evaluation of stable disease (−25.7%). However, the occurrence of adverse events of intolerable grade 3 diarrhea and vomiting forced the cessation of this therapy. A germline BRCA2 mutation was found by next-generation sequencing, and the patient further received a combination of olaparib, tislelizumab, and bevacizumab. This treatment regime resulted in a complete metabolic response and a partial response (−50.9%) after 3 months of treatment. Mild asymptomatic interstitial pneumonia and manageable hematologic toxicity were two adverse events associated with this combination therapy. This study provides new insights into the combination of PARP inhibitors and immunotherapy for MSS mCRC patients carrying germline BRCA2 mutations.

Background: Women with BRCA1/2 mutations have a higher risk of developing breast and ovarian cancer compared to women of the general population. Various preventive options are available to deal with the increased risk of developing cancer. These include intensified breast cancer screening and risk-reducing bilateral mastectomy and salpingo-oophorectomy. The choice of a preventive option can lead to increased decisional conflict. To support these women in their decision-making process, two evidence-based decision aids were developed in an upstream research process and adapted to the German healthcare context. These will be evaluated within a randomised controlled trial (RCT) in terms of their effects on decision-making, women's level of information and psychological outcome variables. Methods: A sample of 310 women carrying BRCA1/2 mutations (A) without a history of cancer or (B) with a history of unilateral breast cancer who have received post-test genetic counselling will be enrolled. Upon study consent, women will be randomly assigned to either the intervention or the control group. All participants will receive standard care including a physician's letter summarising the counselling content. After baseline data collection (t0), the intervention group receives the respective decision aid while the control group receives standard care only. The primary outcome variable assessed at a 3-month follow-up (t1) is the change of extent in decisional conflict (measured with the Decisional Conflict Scale). Secondary outcome variables comprise the stage of decision-making, self-reported symptoms of anxiety, depression and stress due to the genetic test result, and knowledge regarding cancer risks and preventive options. At t1, the extent of preparation for decision-making and acceptability of the decision aids will also be examined. Another secondary outcome variable assessed at 6-month follow-up (t2) is the extent of decision regret. Discussion: These will be the first decision aids available for BRCA1/2 mutation carriers in Germany to be evaluated regarding their effectiveness and acceptability in clinical use within an RCT. Subsequently, they are to be integrated into the care concept of the centres of the German Consortium for Hereditary Breast and Ovarian Cancer and the affiliated breast centres. Trial registration {2a}: DRKS DRKS00015823. Retrospectively registered on 14 June 2019 [ABSTRACT FROM AUTHOR]

While combined immunotherapy and anti-angiogenic therapy have demonstrated efficacy in renal cell carcinoma, non-small cell lung cancer and hepatocellular carcinoma, the efficacy of first-line treatment for pancreatic ductal adenocarcinoma (PDAC) with germline BRCA2 mutation remains unproven. We described a BRCA2-mutated patient with PDAC who presented with posterior cardiac metastasis 8 months after surgery. After receiving four cycles of anlotinib combined with tislelizumab, abdominal CT scans indicated a complete response. The patient sustained this response for over 14 months on the combination regimen, with no reported adverse events. In conclusion, the combination of tislelizumab and anlotinib may offer a viable therapeutic option for recurrent metastatic BRCA2-mutated PDAC. [ABSTRACT FROM AUTHOR]

Poly (ADP-ribose) polymerase inhibitors exhibit strong activity for treating the DNA damage repair defect in patients with prostate carcinoma (PCa). Although conventional DNA-damaging agents can theoretically lead to synthetic antitumoral effects, no report has clearly mentioned the clinical use of cisplatin for treating PCa patients with the breast cancer gene (BRCA)2 mutation. We administered 80 mg/m2 cisplatin triweekly to a patient with metastatic castration-resistant PCa (mCRPC) with the BRCA2 mutation, and after ten cycles, the prostate-specific antigen was dramatically decreased. We suggest that BRCA2 mutations may indicate the use of cisplatin for treating patients with mCRPC.

Combined hepatocellular cholangiocarcinoma (cHCC-CC) is a rare subtype of primary liver malignancy characterized by aggressive behavior and poor prognosis. Radial surgical resection is the standard curative treatment. However, effective therapeutic options for recurrent or metastatic cHCC-CC are still lacking, mainly because of an insufficient understanding of the molecular and genomic alterations of cHCC-CC, preventing the discovery of specialized targeting therapy. Here, we present the case of a patient with metastatic cHCC-CC on first-line treatment of gemcitabine, cisplatin, and nab-paclitaxel. A comprehensive genomic profile revealed four clinically relevant single nucleotide variants (BRCA2, PIK3C2G, RET, and TP53), two amplified genomic regions (CRKL and MAPK1), and 11 heterozygous genomic deletions (BAP1, CDKN2A, PTCH1, TSC1, BRCA2, RB1, RAD51, PALB2, TSC2, SMAD4, and STK11). The patient underwent olaparib treatment and achieved a remarkable and sustained tumor response. Our experience indicates that BRCA2 mutations could be a potential therapeutic target for patients with cHCC-CC. [ABSTRACT FROM AUTHOR]

Pancreatic squamous cell carcinoma (SCC) is a rare primary pancreatic malignancy with a poor prognosis. The median overall survival (OS) for metastatic setting is only 4 months and the optimal management remains poorly defined. In the present study, we report a 52-year-old female patient with stage IV primary SCC of the pancreas harboring a deleteous BRCA2 somatic mutation. After 10 cycles of chemotherapy of cisplatin combined with nanoparticle albumin-bound paclitaxel, metastatic lesions in the liver and lymph nodes achieved radiographic complete responses and pancreatic lesion shrank from 5.7 to 1.5 cm in diameter. The patient subsequently underwent a posterior radical antegrade modular pancreatosplenectomy with R0 resection and residual liver lesions were also resected. After 3 months, a tumor relapsed in the liver. She was then treated with olaparib combined with pembrolizumab and achieved stable disease on the liver lesion. The patient eventually died from cerebral hemorrhage with a long OS of 21 months. Our case demonstrated a favorable clinical activity and survival advantage of the combined cisplatin and nanoparticle albumin-bound paclitaxel, which might serve as a therapeutic option for the patient with BRCA-mutant pancreatic SCC.

Pancreatic squamous cell carcinoma (SCC) is a rare primary pancreatic malignancy with a poor prognosis. The median overall survival (OS) for metastatic setting is only 4 months and the optimal management remains poorly defined. In the present study, we report a 52-year-old female patient with stage IV primary SCC of the pancreas harboring a deleteous BRCA2 somatic mutation. After 10 cycles of chemotherapy of cisplatin combined with nanoparticle albumin-bound paclitaxel, metastatic lesions in the liver and lymph nodes achieved radiographic complete responses and pancreatic lesion shrank from 5.7 to 1.5 cm in diameter. The patient subsequently underwent a posterior radical antegrade modular pancreatosplenectomy with R0 resection and residual liver lesions were also resected. After 3 months, a tumor relapsed in the liver. She was then treated with olaparib combined with pembrolizumab and achieved stable disease on the liver lesion. The patient eventually died from cerebral hemorrhage with a long OS of 21 months. Our case demonstrated a favorable clinical activity and survival advantage of the combined cisplatin and nanoparticle albumin-bound paclitaxel, which might serve as a therapeutic option for the patient with BRCA -mutant pancreatic SCC. [ABSTRACT FROM AUTHOR]

Purpose: Twelve percent of women in the USA will develop invasive breast cancer in their lifetime, and that risk increases to 80% if they carry a BRCA1 or BRCA2 mutation. BRCA1/2 mutations are thought to potentially affect ovarian reserve and/or fertility. Methods: PubMed and PubMed Central were searched for publications on ovarian reserve–related outcomes (i.e., AMH and response to controlled ovarian hyperstimulation (COH) protocols) that were reported in relation to BRCA1 and/or BRCA2 mutations from 1950 through May 2019. A meta-analysis was conducted to create forest plots and summary effect measures using Review Manager 5.3. Results: This article reviews the 16 qualifying publications. There were several fundamental methodological differences in the study designs and outcome details reported in AMH studies. Summary statistics found no difference in AMH levels between BRCA1/2+ women as compared with controls (Z overall test effects p ≥ 0.45). Regarding responses to COH, there were overall non-significantly fewer total and mature numbers of oocytes retrieved in BRCA1/2+ cases as compared with controls (meta-analysis Z overall test effects p ≥ 0.40). Conclusions: While the summary measures indicate no significant differences in AMH levels between BRCA1/2+ cases and controls, readers should be aware that there are significant methodological differences in the AMH reports. Additionally, the response to COH protocols does not seem to be significantly lower in BRCA1/2 mutation carriers in the existing literature. Continued research on both of these clinical parameters would be beneficial for patient counseling. [ABSTRACT FROM AUTHOR]

The performance of breast cancer risk models for women with a family history but negative BRCA1 and/or BRCA2 mutation test results is uncertain. We calculated the cumulative 10-year invasive breast cancer risk at cohort entry for 14 657 unaffected women (96.1% had an affected relative) not known to carry BRCA1 or BRCA2 mutations at baseline using three pedigree-based models (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, BRCAPRO, and International Breast Cancer Intervention Study). During follow-up, 482 women were diagnosed with invasive breast cancer. Mutation testing was conducted independent of incident cancers. All models underpredicted risk by 26.3%-56.7% for women who tested negative but whose relatives had not been tested (n = 1363; 63 breast cancers). Although replication studies with larger sample sizes are needed, until these models are recalibrated for women who test negative and have no relatives tested, caution should be used when considering changing the breast cancer risk management intensity of such women based on risk estimates from these models. [ABSTRACT FROM AUTHOR]

Men who carry a BRCA2 mutation (BRCA2+ men or BRCA2 carriers) have an increased risk for prostate cancer, also tumors are more aggressive. The results of the international IMPACT study show that the BRCA2+ men can have benefit from screening. A total of 2,932 men were recruited. After four screening rounds, BRCA2 carriers have been shown to have a statistically significant higher risk of prostate cancer, 19 per 1,000, compared to non-carriers, 12 per 1,000 (p = 0.03). It is also more often clinically significant prostate cancer (77%) compared to 49% in the general population. Based on the results of the IMPACT study, it was decided to actively discuss the possibility of screening for prostate cancer with BRCA2+ men in the Netherlands. [ABSTRACT FROM AUTHOR]

There remains debate about whether risk-reducing salpingo-oophorectomy (RRSO), which reduces ovarian cancer risk, also reduces breast cancer risk. We examined the association between RRSO and breast cancer risk using a prospective cohort of 17 917 women unaffected with breast cancer at baseline (7.2% known carriers of BRCA1 or BRCA2 mutations). During a median follow-up of 10.7 years, 1046 women were diagnosed with incident breast cancer. Modeling RRSO as a time-varying exposure, there was no association with breast cancer risk overall (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 0.87 to 1.24) or by tertiles of predicted absolute risk based on family history (HR = 0.68, 95% CI = 0.32 to 1.47, HR = 0.94, 95% CI = 0.70 to 1.26, and HR = 1.10, 95% CI = 0.88 to 1.39, for lowest, middle, and highest tertile of risk, respectively) or for BRCA1 and BRCA2 mutation carriers when examined separately. There was also no association after accounting for hormone therapy use after RRSO. These findings suggest that RRSO should not be considered efficacious for reducing breast cancer risk. [ABSTRACT FROM AUTHOR]

Background: BRCA2 mutation carriers are at increased risk for multiple cancers including pancreatic adenocarcinoma (PAC). Our goal was to compare the effectiveness of different PAC screening strategies in BRCA2 mutation carriers, from the standpoint of life expectancy. Methods: A previously published Markov model of PAC was updated and extended to incorporate key aspects of BRCA2 mutation carrier status, including competing risks of breast- and ovarian-cancer specific mortality. BRCA2 mutation carriers were modeled and analyzed as the primary cohort for the analysis. Additional higher risk BRCA2 cohorts that were stratified according to the number of first-degree relatives (FDRs) with PAC were also analyzed. For each cohort, one-time screening and annual screening were evaluated, with screening starting at age 50 in both strategies. The primary outcome was net gain in life expectancy (LE) compared to no screening. Sensitivity analysis was performed on key model parameters, including surgical mortality and MRI test performance. Findings: One-time screening at age 50 resulted in a LE gain of 3.9 days for the primary BRCA2 cohort, and a gain of 5.8 days for those with BRCA2 and one FDR. Annual screening resulted in LE loss of 12.9 days for the primary cohort and 1.3 days for BRCA2 carriers with 1 FDR, but resulted in 20.6 days gained for carriers with 2 FDRs and 260 days gained for those with 3 FDRs. For patients with ≥3 FDRs, annual screening starting at an earlier age (i.e. 35–40) was optimal. Interpretation: Among BRCA2 mutation carriers, aggressive screening regimens may be ineffective unless additional indicators of elevated risk (e.g., 2 or more FDRs) are present. More clinical studies are needed to confirm these findings. Funding: American Cancer Society – New England Division – Ellison Foundation Research Scholar Grant (RSG-15-129-01-CPHPS).

Pancreatic acinar cell carcinoma (ACC) is a rare entity. Herein we present the case of a 50-year-old male patient with an unlimited mass on the pancreatic corpus and tail with peripancreatic effusion and multiple metastases in the liver and spleen. A liver biopsy showed a pancreatic ACC. The patient received 9 cycles of gemcitabine plus oxaliplatin (GEMOX regimen), which had to be stopped because of a persistent grade 2 neuropathy. A CT scan showed complete response after 14 years. At the age of 61 years, a localized prostatic cancer was diagnosed, treated by prostatectomy. The patient carried a BRCA2 mutation. None of the precedent case reports describe a chemosensibility to the GEMOX regimen. In spite of the lack of study in these patients, chemotherapy with oxaliplatin seems to be the most effective. Long survival can be expected.

Abstract: This study aims to estimate the pathologic complete response (pCR) rate after neo‐adjuvant chemotherapy and to compare disease‐free survival (DFS) and overall survival (OS) between pCR and non‐pCR groups of patients with triple‐negative breast cancer (TNBC) and deleterious BRCA1 or BRCA2 mutation. We carried out a retrospective analysis of 53 patients including 46 BRCA1, 6 BRCA2, and 1 combined BRCA1 and BRCA2 mutation. All patients had been diagnosed with triple‐negative breast cancer (TNBC) between 1997 and 2014. Neo‐adjuvant therapy consisted of regimens that were based on anthracycline or an anthracycline‐taxane doublet. DFS included any relapse or second cancer. The Kaplan‐Meier method and the log‐rank test were used to compare pCR and non‐pCR groups. A pCR was observed in 23 (42.6% [95% CI, 29.2%‐56.8%]) of the TNBC included. The pCR rate was 38.3% [95% CI, 26%‐55%] among BRCA1 mutation carriers, and 66% among the 6 BRCA2 mutation carriers. Median follow‐up was 4.4 years (range 0.62‐16.2 years) and did not differ between the groups (P = .25). Fifteen relapses and six second cancers were recorded during the follow‐up period. Eleven deaths occurred, all of which were in the non‐pCR group. DFS (P < .01) and OS (P < .01) were significantly better in the pCR group than the non‐pCR group. This study shows a high pCR rate after neo‐adjuvant therapy in BRCA‐mutated triple‐negative breast cancer, and the survival results confirm the prognostic value of pCR in this group. These outcomes should be considered as a basis of comparison to be used by future studies about new therapies in this domain. [ABSTRACT FROM AUTHOR]

Anthracycline-based cardiotoxicity is concerning for women with breast cancer and portends a dose-dependent risk of developing left ventricular dysfunction. Overall, the prevalence of heart failure (HF) is ≈2% of the total US population; however, BRCA-deficient mice have shown increased HF. We evaluated for the inherent risk of HF in women with BRCA mutations to determine whether treatment with anthracycline-based therapy increased this risk. We obtained results on BRCA mutation carriers regarding cancer treatment and HF, identified through the BRCA patient advocacy organization Facing Our Risk for Cancer Empowered (FORCE) and the Moffitt-based Inherited Cancer Registry. In our patient group (232 BRCA1 and 159 BRCA2 patients; 10 with both mutations), 7.7% reported HF, with similar proportions in BRCA1 versus BRCA2 carriers (7.4% and 8.2%, respectively). These proportions are significantly higher than published rates (p < 0.001). There was no statistically significant difference in HF rates comparing anthracycline-treated versus anthracycline-naïve patients however (7.1% vs. 8.3%; p = 0.67). In addition, 9.1% of BRCA1 carriers and 8.2% of BRCA2 carriers reported arrhythmias. BRCA mutation carriers showed increased risk of cardiotoxicity versus the general population and an overall increased risk of cardiotoxicity from anthracycline-based therapy. Our study supports data that BRCA carriers have increased non-cancer mortality from cardiotoxicity. A prospective trial to determine HF and conduction abnormalities in this population is warranted. [ABSTRACT FROM AUTHOR]

The aim of the present study is to investigate mutations in tumor suppressor BRCA1 and BRCA2 genes and P53 gene polymorphism in high-voltage power station workers and to determine the distribution of this polymorphism among these workers. This study carried out on 35 high-voltage transmission line (HVTL) workers with a mean age of 36.6 ± 6.8 years. The data obtained from the exposure group were compared to the control group. Control group was created from volunteers who have same age range (35.4 ± 6.4 years) and sociocultural level except occupational extremely low frequency magnetic field (ELFMF) exposure. DNAs were isolated from the blood samples collected from both groups and BRCA1 and BRCA2 gene mutations and p53 gene polymorphism were investigated. Isolated DNAs were used to amplify the mutation regions of exon 2 and exon 20 regions for BRCA1 and exon 2 for BRCA2 with polymerase chain reaction (PCR) and the single-strand conformational polymorphism (SSCP) method was used to detect the mutations. PCR and Restriction Fragment Length Polymorphism (RFLP) were used to determine P53 codon 72 Arg/Pro gene polymorphism. The exon 2 mutation of BRCA1 was detected in only 1 worker in the occupational exposure group. It should be noted that the worker was also cancer and receiving treatment. It remains unclear whether the mutation was cancer-related or a result of occupational exposure. However, the investigation on P53 gene polymorphism did not indicate any difference between the groups (p >0.05). In conclusion, BRCA1 and BRCA2 mutations were not observed among the high-voltage transmission line workers except one in this study. However, P53 gene polymorphism also showed no difference between groups. Finally, further studies are required to clarify the underlying causes of the mutation detected in a worker in this study group. [ABSTRACT FROM AUTHOR]

Variation in the worldwide prevalence of BRCA1 and BRCA2 mutations is well recognized. We analyzed BRCA mutation type variability in 585 BRCA-tested epithelial ovarian cancer patients from different ethnic populations. Of these patients, 98 (16.8%) were carriers of the BRCA1 mutation, and 34 (5.8%) were carriers of BRCA2. Among the BRCA1/2 carriers, there were 29 mutation types. The widest variation in mutation types was in non-Jewish Caucasians. Our analysis showed statistically improved overall survival and a tendency towards improved first progression-free survival across all BRCA mutation subtypes, compared to non-carriers. [ABSTRACT FROM AUTHOR]

Background: Follicular dendritic cell sarcoma is a rare tumour with clinical behaviour covering a spectrum from indolent to aggressive disease. Treatment recommendations are currently based on case reports and small series describing combinations of surgery, chemotherapy and radiotherapy providing the best patient outcomes. Recent knowledge on molecular aberrations in this disease have not yet impacted on therapeutic decisions. Case presentation: We describe a case of progressive follicular dendritic cell sarcoma of the lung and pleura, treated based on knowledge of the tumour's molecular aberrations. The patient was initially treated with surgery, chemotherapy and radiotherapy and developed disease progression. Mutation testing by Caris molecular intelligence demonstrated a breast cancer 2 gene mutation and further treatment with carboplatin and veliparib achieved disease stabilisation. Conclusion: Understanding of the molecular profile of rare tumours is key to improve therapeutic decision making and patient outcomes. [ABSTRACT FROM AUTHOR]

Breast cancer occurs rarely in male patient. BRCA1 gene mutation seems to be related to male breast cancer, but its role is not clearly defined. We have identified in a male patient affected by breast cancer the BRCA1 gene variant p.P142H. We performed a literature research using the keywords 'male breast cancer', 'male breast cancer mutations' and ' BRCA' and we reviewed the cases. We found ew other studies regarding BRCA1 variant p.P142H, about female subjects. At the moment, BRCA1 gene variant p.P142H is not certainly classified as neutral or deleterious. Genetic testing for BRCA1 and BRCA2 and PALB2 mutation gene has been performed on our patient. Segregation analysis for this p.P142H BRCA1 variant has been extended to the second generation of the family. Genetic tests revealed a clear inheritance regarding the BRCA1 gene p. P142H variant. Of the eight patients with this specific genetic mutation, four presented breast cancer (bilateral in one case), two female and two male. None of the subjects in the family without the BRCA1 gene variant p. P142H presented breast cancer or other BRCA1 gene mutation-related cancers. Our analysis suggests that the BRCA1 gene variant p.P142H mutation is related with male breast cancer. Starting from these data, it can be inferred that more studies on MBC and its relation with the BRCA1 gene mutation P142H variant must be undertaken to improve prognostic and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Male breast cancer (MBC) is an uncommon disease that has been the focus of limited research. It is estimated that approximately 10% of men with breast cancer have a genetic predisposition, with BRCA2 being the most prevalent genetic mutation. Here we describe the case of MBC in a 64-year-old man who presented on physical examination a nodule in his left breast and declared to have an extensive family history of cancer. Methods and results: The patient was firstly diagnosed with an invasive ductal carcinoma (IDC) with histological grade III, nuclear grade 3, pT4N2Mx and positive for hormonal receptors and HER2. Exome sequencing was performed by massive parallel sequencing which had detected a novel BRCA2 germline mutation that is a large genomic deletion of 3,492 nucleotides including BRCA2 exon 14, and this deletion is out of frame and is predicted to lead to a stop codon in exon 15 at codon 2,496. Conclusion: Large rearrangements in BRCA1 and BRCA2 occur in a small percentage (<1%) of patients tested for hereditary breast and ovarian cancer. This is the first report of the mutation del3492 in BRCA2 exon 14, which leads to a truncated protein and therefore is clinically relevant. Mutation segregation analysis should be further done in the Brazilian population. Herein we highlight the importance of next-generation sequencing in the detection of large genomic deletions. [ABSTRACT FROM AUTHOR]

Background: Because up to 30% of breast cancer cases may relapse, understanding the biology of recurrent breast cancer is imperative in preventing these poor outcomes. Thus, we present this unusual case of a BRCA2 carrier who presented seven years after her initial diagnosis of breast adenocarcinoma with a new lump in the left axillary tail, which proved to be small cell carcinoma. The second cancer bore no morphologic or immunohistochemical resemblance to the first. However, we aimed to understand whether the two cancers could have been related. Methods: We performed targeted Next Generation Sequencing on both cancer specimens in order to determine whether there was a genomic relationship between the two cancers. Results: We found that the initial breast adenocarcinoma was positive for a heterozygous mutation in PIK3CA (c. 1624 G > A, p.E42K) and a heterozygous 13-basepair deletion in TP53 (c.639-651del, p.H214fs). The small cell cancer was positive for the same mutation in PIK3CA, but negative for the mutation in TP53. Conclusion: We concluded that the small cell cancer may have arisen from a clone within the initial cancer, since they carried an identical genetic mutation. Furthermore, we postulate that the unusual morphology of the second cancer may be due, in part, to the patient's germline BRCA mutation. [ABSTRACT FROM AUTHOR]

Pancreatic acinar cell carcinoma (ACC) is a rare entity. Herein we present the case of a 50- year-old male patient with an unlimited mass on the pancreatic corpus and tail with peripancreatic effusion and multiple metastases in the liver and spleen. A liver biopsy showed a pancreatic ACC. The patient received 9 cycles of gemcitabine plus oxaliplatin (GEMOX regimen), which had to be stopped because of a persistent grade 2 neuropathy. A CT scan showed complete response after 14 years. At the age of 61 years, a localized prostatic cancer was diagnosed, treated by prostatectomy. The patient carried a BRCA2 mutation. None of the precedent case reports describe a chemosensibility to the GEMOX regimen. In spite of the lack of study in these patients, chemotherapy with oxaliplatin seems to be the most effective. Long survival can be expected. [ABSTRACT FROM AUTHOR]

Background Veliparib is a potent small molecule inhibitor of PARP-1/2, which is cytotoxic in tumor cells with deficiencies in BRCA1 or BRCA2. We studied the clinical activity and toxicity of veliparib in ovarian cancer patients carrying a germline BRCA1 or BRCA2 mutation (gBRCA). Methods Eligibility included three or fewer prior chemotherapy regimens, measurable disease and no prior use of a PARP inhibitor. Veliparib was administered at 400 mg orally BID with one cycle being 28 days. The two-stage Simon design was capable of detecting a 25% response probability with 90% power while controlling alpha = 10% (at a 10% assumed null response probability). Results The median age of the 50 eligible patients was 57 years (range 37-94) and 14, 18, and 18 patients had 1, 2, and 3 prior therapies respectively. Thirty patients (60%) were platinum-resistant. The median number of cycles administered was 6 (1-27). There was one grade 4 thrombocytopenia. Grade 3 adverse events were: fatigue (n = 3), nausea (2), leukopenia (1), neutropenia (1), dehydration (1), and ALT (1). Grade 2 events > 10% were: nausea (46%), fatigue (26%), vomiting (18%), and anemia (14%). The proportion responding was 26% (90% CI: 16%-38%, CR: 2, PR: 11); for platinum-resistant and platinum-sensitive patients the proportion responding was 20% and 35%, respectively. The most common reason for treatment discontinuation was progression (62%). Twenty-nine patients are alive; two with SD remain on veliparib. The median PFS is 8.18 months. Conclusions The single agent efficacy and tolerability of veliparib for BRCA mutation-associated recurrent ovarian cancer warrants further investigation. [ABSTRACT FROM AUTHOR]

Background Male breast cancer (MBC) is an uncommon disease that has been the focus of limited research. It is estimated that approximately 10% of men with breast cancer have a genetic predisposition, with BRCA2 being the most prevalent genetic mutation. Here we describe the case of MBC in a 64-year-old man who presented on physical examination a nodule in his left breast and declared to have an extensive family history of cancer. Methods and results The patient was firstly diagnosed with an invasive ductal carcinoma (IDC) with histological grade III, nuclear grade 3, pT4N2Mx and positive for hormonal receptors and HER2. Exome sequencing was performed by massive parallel sequencing which had detected a novel BRCA2 germline mutation that is a large genomic deletion of 3,492 nucleotides including BRCA2 exon 14, and this deletion is out of frame and is predicted to lead to a stop codon in exon 15 at codon 2,496. Conclusion Large rearrangements in BRCA1 and BRCA2 occur in a small percentage (<1%) of patients tested for hereditary breast and ovarian cancer. This is the first report of the mutation del3492 in BRCA2 exon 14, which leads to a truncated protein and therefore is clinically relevant. Mutation segregation analysis should be further done in the Brazilian population. Herein we highlight the importance of next-generation sequencing in the detection of large genomic deletions. [ABSTRACT FROM AUTHOR]

There is a significant variation in the uptake of cancer risk reducing options by women with a BRCA1 or BRCA2 mutation. It is currently unclear why these differences exist and it is possible that recommendations vary between providers and these influence patient decisions. Eligible health care providers who provide genetic counseling for hereditary breast and ovarian cancer families in Canada were identified. Each provider was asked to complete a study specific questionnaire that included their opinion of various cancer risk reduction options and their recommendations for specific cases. Respondents recommended prophylactic oophorectomy more often than prophylactic mastectomy or tamoxifen for women with a BRCA1 or BRCA2 mutation (p < 0.0001). Fewer than half of the respondents agreed with the recommendation for prophylactic mastectomy, and a minority of the respondents supported the recommendation for tamoxifen for chemoprevention. The majority of Canadian genetics health care providers adhere to the National Comprehensive Cancer Network ( NCCN) Guideline of recommending prophylactic oophorectomy to mutation carriers, however, the minority of genetics health care providers recommend either prophylactic mastectomy or tamoxifen. [ABSTRACT FROM AUTHOR]

It is not well known to what extent carrying a BRCA2 mutation affects the survival of women with breast cancer and prognostic factors among BRCA2-positive women warrant investigation. Using a record linkage approach we compared the long-term survival in carriers and noncarriers of an inherited BRCA2 founder mutation (999del5), and sought to identify prognostic factors among the BRCA2 mutation-positive subset, including markers of genetic instability (aneuploidy) and mitotic activity (S-phase fraction). We established the genetic status of 2,967 Icelandic breast cancer patients (215 mutation carriers and 2,752 noncarriers) diagnosed from 1955 to 2004, representing 72 % of all cases diagnosed in the country during this period. Tumour ploidy and S-phase fraction were assessed on tumour cells by DNA flow cytometry. Prognostic factors were assessed blindly with respect to mutation status. Univariate and multivariate hazard ratios (HR) were estimated for breast cancer-specific survival by BRCA2 status, using Cox regression. After a median follow-up of 9.5 years, BRCA2 mutation carriers had a higher risk of death from breast cancer than noncarriers (HR 1.64, 95 % CI 1.24-2.16, p < 0.001). The risk increase was restricted to women with diploid tumours (HR 3.03, 95 % CI 1.91-4.79, p < 0.001). Among breast cancer patients with aneuploid tumours, survival of carriers was similar to that of noncarriers (HR 0.76, 95 % CI 0.41-1.41, p = 0.38). Increased tumour size and a positive nodal status predicted worse prognosis in all patients, whereas the highly correlated prognostic factors diploidy, low proliferative activity and a positive estrogen receptor status had reverse effects in mutation carriers and noncarriers. Breast cancer patients who carry the Icelandic founder BRCA2 mutation have inferior long-term survival than noncarriers, but the adverse prognosis is restricted to mutation carriers with diploid, slowly proliferating tumours. [ABSTRACT FROM AUTHOR]

It has been known for decades that nulliparity is associated with an increased risk for certain reproductive malignancies, including breast, ovarian and uterine cancers. A recent commentary in The Lancet summarized the available evidence based on data in nulliparous women and concluded that the risk of nulliparity was related to the increased number of ovulatory cycles, and so might be preventable by utilization of oral contraceptives. That communication described significant differences in age-dependent cancer mortality in nulliparous nuns, as well as in parous controls, between breast, ovarian and uterine cancers. Moreover, the steep inclines in cancer mortality in nuns are only observed decades after the menopause. Taken together, these observations make it appear unlikely that the number of ovulations is associated aetiologically with increased cancer risks in nulliparous nuns. Here are postulated other possible primary mechanisms that could be responsible for the reported age-related increase in cancer risks in nulliparous women, such as nuns, and conclude that a better understanding of such mechanisms may offer important new insights into tumour initiation in general. [ABSTRACT FROM AUTHOR]

Increasing awareness of the hereditary component of breast and ovarian cancer has driven interest in creating clinics for the patient population at high risk for these cancers. Identifying adequate space and appropriate staff, coordinating multiple providers' schedules, establishing referral criteria, and addressing billing and reimbursement concerns are just some of the issues that are involved in the creation of a multidisciplinary high risk breast and ovarian cancer program. We provide an overview of the clinic structure at the Magee-Womens Hospital High Risk Breast and Ovarian Cancer Program (HRBOCP), which was created in 2002 due to recognition of a need for a more coordinated model of providing care for women at increased risk for breast and ovarian cancer. The goals of the HRBOCP are to evaluate women at high risk for breast and ovarian cancer and to organize their clinical care in a multidisciplinary setting staffed by experts in the field; to provide updates on new data regarding screening recommendations, prevention options, and risk factors pertinent to an individual's cancer risk; to provide ongoing support to patients and to coordinate family communication when appropriate; and to facilitate enrollment in appropriate research studies and registries. [ABSTRACT FROM AUTHOR]

Background: The BRCA2 gene is responsible for a high number of hereditary breast and ovarian cancers, and studies of the BRCA2 biological functions are limited by the lack of models that resemble the patient's tumour features. The aim of this study was to establish and characterise a new human breast carcinoma xenograft obtained from a woman carrying a germline BRCA2 mutation.Methods: A transplantable xenograft was obtained by grafting a breast cancer sample into nude mice. The biological and genetic profiles of the xenograft were compared with that of the patient's tumour using histology, immunohistochemistry (IHC), BRCA2 sequencing, comparative genomic hybridisation (CGH), and qRT-PCR. Tumour response to standard chemotherapies was evaluated.Results: Histological profile identified the tumour as a basal-like triple-negative breast cancer. Targeted BRCA2 DNA sequencing of the xenograft showed the presence of the mutation previously identified in the carrier. Comparative genomic hybridisation array profiles of the primary tumour and the xenograft revealed a high number of similar genetic alterations. The therapeutic assessment of the xenograft showed sensitivity to anthracyclin-based chemotherapy and resistance to docetaxel. The xenograft was also highly sensitive to radiotherapy and cisplatin-based treatments.Conclusions: This study describes a new human breast cancer xenograft obtained from a BRCA2-mutated patient. This xenograft provides a new model for the pre-clinical drug development and for the exploration of the drug response biological basis. [ABSTRACT FROM AUTHOR]

The incidence of esophageal squamous cell carcinoma (ESCC) is very high in the northeast region of India. An earlier study from China and Iran suggested that mutations in BRCA2 gene may play a role in the etiology of familial ESCC. However, the frequency of BRCA2 gene germ line mutations and its contribution to risk of familial aggregation of ESCC in high-risk region of India are not known. In the current study of 317 cases of esophageal cancer, 92 (29%) cases had a family history of esophageal and/or other cancers. Of these 92 patients, 45 (49%) patients had a family history of esophageal cancer. The risk of developing esophageal cancer was higher in cases where family history showed occurrence of cancers in first-degree relatives (odds ratio [OR]: 3.1; confidence interval [CI]: 1.9–5.3) than in second-degree relatives (OR: 1.3; CI: 0.25–3.2). Moreover, the risk of developing esophageal cancer was higher in subjects whose predegree suffered from esophageal cancer (OR: 2.4; CI: 1.1–4.1) than from any other cancers (OR: 1.1; CI: 0.32–3.3). The subjects with family history of cancer were more likely to develop ESCC if they were tobacco chewers (OR: 4.2; CI: 2.1–5.8) and betel quid users (OR: 3.6; CI: 1.8–4.6). Screening for mutations of the BRCA2 gene in the germ line DNA was carried out for 20 familial and 80 nonfamilial ESCC patients. One hundred unrelated healthy controls from the same population were included in this study. Nonsynonymous variants in exon 18 (K2729N) and exon 27 (I3412V) of BRCA2 gene were found in 3 of 20 patients with familial ESCC. No sequence alterations were found in 80 nonfamilial ESCC cases ( P= 0.01) and 100 healthy controls ( P= 0.0037), suggesting that germ line BRCA2 gene mutation may play a role in familial aggregation of ESCC in high-risk region of India. [ABSTRACT FROM AUTHOR]

Abstract: To evaluate the potential contribution of mutations in the BRCA1 and BRCA2 genes to male breast cancer (MBC), we expanded a previous study to screen a total of 261 Israeli men diagnosed with breast carcinoma. A total of 21 BRCA2 6174delT and 8 BRCA1 185delAG mutations were found. Similar frequencies of BRCA1 and BRCA2 mutation carriers were found among Ashkenazi (12.8%) and non-Ashkenazi Jews (9.1%). The combined prevalence of BRCA1/BRCA2 founder mutations among Ashkenazi Jewish men is slightly higher than for women, due to a higher frequency of BRCA2 mutations. [Copyright &y& Elsevier]

Germ line mutations in BRCA1 and BRCA2 account for a large proportion of inherited breast and ovarian cancer. Both genes are involved in DNA repair by homologous recombination and are thought to play a vital role in maintaining genomic stability. A major drawback for long-term functional studies of BRCA in general and BRCA2 in particular has been a lack of representative human breast epithelial cell lines. In the present study, we have established three cell lines from two patients harboring the 999del5 germ line founder mutation in the BRCA2 gene. Primary cultures were established from cellular outgrowth of explanted tissue and subsequently transfected with a retroviral construct containing the HPV-16 E6 and E7 oncogenes. Paired cancer-derived and normal-derived cell lines were established from one patient referred to as BRCA2-999del5-2T and BRCA2-999del5-2N, respectively. In addition, one cell line was derived from cancer-associated normal tissue from another patient referred to as BRCA2-999del5-1N. All three cell lines showed characteristics of breast epithelial cells as evidenced by expression of breast epithelial specific cytokeratins. Cytogenetic analysis showed marked chromosomal instability with tetraploidy and frequent telomeric association. In conclusion, we have established three breast cpithelial cell lines from two patients carrying the BRCA2 Icelandic 999del5 founder mutation. These cell lines from the basis for further studies on carcinogenesis and malignant progression of breast cancer on a defined genetic background. [ABSTRACT FROM AUTHOR]

A retrospective study was performed to assess the histopathologic findings in high-risk women undergoing bilateral prophylactic (salpingo)-oophorectomy. The medical files of BRCA1 or BRCA2 mutation carriers and members of a hereditary breast/ovarian cancer (HBOC) family, who had undergone prophylactic surgery, were reviewed. In all, 38 women underwent a bilateral oophorectomy (26 BRCA1, three BRCA2 and nine HBOC, respectively). A total of 90 women underwent bilateral salpingo-oophorectomy (58 BRCA1, six BRCA2, one BRCA1 and 2, 25 HBOC, respectively). At the time of salpingo-oophorectomy, five of 58 BRCA1 carriers (8.6%) were diagnosed with an occult carcinoma: two fallopian tube carcinomas, two ovarian carcinomas and one case was defined as a fallopian tube/ovarian carcinoma. No occult carcinomas were found in the other groups. Of the 38 patients, who underwent a bilateral oophorectomy (mean follow-up 45 months), three of 26 BRCA1 mutation carriers (3.4 in 100 women-years) developed peritoneal papillary serous carcinoma (PPSC) during follow-up. So far, no PPSC have occurred in the 90 women, who underwent a salpingo-oophorectomy (mean follow-up 12 months), including 58 BRCA1 carriers (0 in 60 in women-years). These results contribute to the thesis that BRCA1 germline mutation carriers are not only at risk for ovarian cancer, but also for fallopian tube carcinoma and peritoneal papillary serous carcinoma. Our data suggest that PPSC risk among BRCA2 carriers is lower than among BRCA1 carriers.British Journal of Cancer (2004) 90, 1492-1497. doi:10.1038/sj.bjc.6601692 www.bjcancer.com Published online 16 March 2004 [ABSTRACT FROM AUTHOR]