Germline Mutations In BRCA1 Research Articles

Matched cohort study of germline BRCA mutation carriers with triple negative breast cancer in brightness

In the BrighTNess trial, carboplatin added to neoadjuvant chemotherapy (NAC) was associated with increased pathologic complete response (pCR) rates in patients with stage II/III triple-negative breast cancer (TNBC). In this matched cohort study, cases with a germline BRCA1/2 mutation (gBRCA; n = 75) were matched 1:2 with non-gBRCA controls (n = 150) by treatment arm, lymph node status, and age to evaluate pCR rates and association of benefit from platinum/PARP inhibitors with validated RNA expression-based immune, proliferation, and genomic instability scores among gBRCA with the addition of carboplatin ± veliparib to NAC. Among the well-matched cohorts, odds of pCR were not higher in gBRCA cancers who received standard NAC with carboplatin (OR 0.24, 95% CI [0.04-1.24], p = 0.09) or with carboplatin/veliparib (OR 0.44, 95% CI [0.10-1.84], p = 0.26) compared to non-gBRCA cancers. Higher PAM50 proliferation, GeparSixto immune, and CIN70 genomic instability scores were each associated with higher pCR rate in the overall cohort, but not specifically in gBRCA cases. In this study, gBRCA carriers did not have higher odds of pCR than non-gBRCA controls when carboplatin ± veliparib was added to NAC, and showed no significant differences in molecular, immune, chromosomal instability, or proliferation gene expression metrics.

Concordance of BRCA mutation detection in tumor versus blood, and frequency of bi-allelic loss of BRCA in tumors from patients in the phase III SOLO2 trial

ObjectiveMaintenance olaparib provided a progression-free survival benefit in the phase III SOLO2 trial (NCT01874353) in patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation (BRCAm). However, questions remain regarding tumor versus germline BRCA testing and the impact of heterozygous versus bi-allelic loss of BRCA1 or BRCA2 in the tumor. MethodsBlood and tumor samples were analyzed. A concordance analysis of germline BRCAm status (BRACAnalysis® CLIA test) and tumor BRCAm status (myChoice® CDx test) was conducted (Myriad Genetic Laboratories, Inc.). Bi-allelic loss of BRCA1 and BRCA2 and a genomic instability score (GIS) (myChoice® CDx test) were also determined. Results289 of 295 enrolled patients had a germline BRCAm confirmed centrally and tumor BRCAm status was evaluable in 241 patients. There was 98% and 100% concordance between tumor and germline testing for BRCA1m and BRCA2m, respectively, with discordance found in four cases. Of 210 tumor samples evaluable for BRCA zygosity, 100% of germline BRCA1-mutated tumors (n = 144) and 98% of germline BRCA2-mutated tumors (n = 66) had bi-allelic loss of BRCA. One patient with a heterozygous BRCA2m had a GIS of 53, was progression free for 911 days and remained on olaparib at data cut-off. ConclusionsVery high concordance was demonstrated between tumor and germline BRCA testing, supporting wider implementation of tumor BRCA testing in ovarian cancer. Near 100% rates of bi-allelic loss of BRCA in platinum-sensitive relapsed ovarian tumors suggest routine testing for BRCA zygosity is not required in this population and reflects BRCA loss being a driver of tumorigenesis.

BRCA1/2 Mutation Types Do Not Affect Prognosis in Ovarian Cancer Patients.

Background: High grade serous ovarian carcinoma (HGSOC) is the most lethal type of epithelial ovarian cancer, with a prevalence of germline BRCA1/2 mutations as high as 20%. Our objective is to determine whether the location of mutations in the different domains of the BRCA1/2 genes affects the clinical outcome of HGSOC patients. Methods: A total of 51 women with BRCA1 or BRCA2 mutated ovarian cancer were identified. Progression-free survival (PFS) and overall survival (OS) were analyzed. Results: In our study cohort, 35 patients were carriers of germline mutations in BRCA1 and 16 in BRCA2. The median PFS time following completion of the primary therapy was 23.8 months (95% CI 20.1–27.5) and the median OS was 92.9 months (95% CI 69.8–116.1) in all BRCA carriers. After multivariate analysis, no significant association among the location or type of BRCA1/2 mutation with PFS or OS was identified. Notably, significant differences in PFS between carriers of identical mutations in the same BRCA gene were detected. Conclusions: Among HGSOC patients, BRCA1/2 carriers with mutations in different locations of the genes show no significant difference in survival outcomes, in terms of PFS and OS, suggesting the potential effect of other genetic abnormalities and co-contributing risk factors.

Cost-effectiveness analysis of olaparib and niraparib as maintenance therapy for women with recurrent platinum-sensitive ovarian cancer

ABSTRACT Objective We evaluated the cost-effectiveness of olaparib and niraparib as maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer.Methods: A decision analysis model compared the costs and effectiveness of olaparib and niraparib versus placebo for patients with or without germline BRCA mutations. Resource use and associated costs were estimated from the 2020 National Health Insurance Administration reimbursement price list. Clinical effectiveness was measured in progression-free survival per life-years (PFS-LY) based on the results of clinical trials SOLO2/ENHOT-Ov21 and ENGOT-OV16/NOVA. The incremental cost-effectiveness ratio (ICER) was estimated from a single-payer perspective. Results In the base case, olaparib was the more cost-effective treatment regimen. The ICERs for olaparib and niraparib compared to placebo were NT$1,804,785 and NT$2,340,265 per PFS-LY, respectively. Tornado analysis showed that PFS and the total resource use cost of niraparib regimen for patients without gBRCA were the most sensitive parameters impacting the ICER. The ICERs for both drugs in patients with a gBRCA mutation were lower than in patients without a gBRCA mutation. Probabilistic sensitivity analysis indicated that olaparib was more cost-effective than niraparib at the willingness-to-pay threshold of NT$2,602,404 per PFS life-year gained. Conclusion Olaparib was estimated to be less cost and more effective compared to niraparib as maintenance therapy for patients with recurrent platinum-sensitive ovarian cancer.

Adjuvant Olaparib Improves Outcomes in High-Risk, HER2-Negative Early Breast Cancer Patients With Germline BRCA1 and BRCA2 Mutations

Adjuvant Olaparib Improves Outcomes in High-Risk, HER2-Negative Early Breast Cancer Patients With Germline BRCA1 and BRCA2 Mutations

New Roles of Poly(ADP-Ribose) Polymerase Inhibitors in the Treatment of Breast Cancer.

Since the proof of concept of synthetic lethality between poly(ADP-ribose) polymerase inhibition and loss of BRCA1/2 homologous recombination (HR) function in preclinical models and early phase clinical trials, poly(ADP-ribose) polymerase inhibitors (PARPi) are increasing part of standard-of-care treatment for advanced breast cancers with BRCA gene mutations. The field has also recently seen benefits for PARPi in early breast cancer in those with germline BRCA1 and BRCA2 pathogenic mutations, and signals that synthetic lethal affects may occur in tumors with deficiencies in HR caused by germline, somatic, or epigenetic dysregulation of a number of HR genes. Despite the evidence of the synthetic lethal effects of PARPi, they are not always effective in HR defective cancers, and as they become part of standard of care in breast cancer, the study of prevalence of distinct mechanisms of resistance to PARPi and cross-resistance with other DNA-damaging agents such as platinum in breast cancer will be important and may inform therapy choices.

Prevalence and clinical characterization of BRCA1 and BRCA2 mutations in Korean patients with epithelial ovarian cancer.

This study was performed to investigate the prevalence, clinical characteristics, and treatment response according to BRCA1 and BRCA2 (BRCA) mutations in Korean patients with epithelial ovarian cancer (EOC). Two‐hundred and ninety‐eight Korean women diagnosed with high‐grade serous and/or endometrioid EOC from 2010 to 2015 were tested for germline and 86 specimens for somatic BRCA mutations, regardless of the family history. Clinical characteristics including survival outcomes were compared in patients with and without BRCA mutations (NCT02963688). A total of 43 different germline BRCA mutations were identified in 78 patients among 298 patients (26.2%). Somatic BRCA mutations were identified in 11 (12.8%) patients among patients without germline BRCA mutations. Haplotype analysis demonstrated no founder mutations in our Korean patient cohort. Insignificant differences in age at diagnosis, primary site, and residual disease after surgery were observed between patients with and without BRCA mutations. In multivariate analysis for overall survival (OS), the presence of BRCA mutation was significantly associated with OS (P = .049) in addition to platinum sensitivity (P < .001), indicating it is an independent prognostic factor for survival regardless of platinum sensitivity to first‐line chemotherapy. In addition, a higher response rate to subsequent chemotherapy after recurrence was observed in EOC patients with BRCA mutations resulting in better OS. In the current study, the prevalence of BRCA mutations in Korean patients with EOC was higher than previously reported in other ethnic groups. We demonstrated characteristics and treatment response in Korean EOC patients with BRCA mutations. These findings may provide valuable information to be considered in future clinical trials including Asian patients.

BRCA1/Trp53 heterozygosity and replication stress drive esophageal cancer development in a mouse model

BRCA1 germline mutations are associated with an increased risk of breast and ovarian cancer. Recent findings of others suggest that BRCA1 mutation carriers also bear an increased risk of esophageal and gastric cancer. Here, we employ a Brca1/Trp53 mouse model to show that unresolved replication stress (RS) in BRCA1 heterozygous cells drives esophageal tumorigenesis in a model of the human equivalent. This model employs 4-nitroquinoline-1-oxide (4NQO) as an RS-inducing agent. Upon drinking 4NQO-containing water, Brca1 heterozygous mice formed squamous cell carcinomas of the distal esophagus and forestomach at a much higher frequency and speed (∼90 to 120 d) than did wild-type (WT) mice, which remained largely tumor free. Their esophageal tissue, but not that of WT control mice, revealed evidence of overt RS as reflected by intracellular CHK1 phosphorylation and 53BP1 staining. These Brca1 mutant tumors also revealed higher genome mutation rates than those of control animals; the mutational signature SBS4, which is associated with tobacco-induced tumorigenesis; and a loss of Brca1 heterozygosity (LOH). This uniquely accelerated Brca1 tumor model is also relevant to human esophageal squamous cell carcinoma, an often lethal tumor.

S95 BRCA Mutations and Pancreatic Cancer: A Systematic Review and Meta-Analysis

Introduction: Pancreatic cancer (PC) carries a high mortality and is a leading cause of cancer death in the United States. The lifetime risk of PC in the population is 1.3%, approaching >5% in high-risk individuals such as those with mutations in BRCA genes. We conducted a systematic review and meta-analysis to assess the incidence of PC in BRCA-1 and BRCA-2 mutation carriers and estimate their incidence in patients with PC. Methods: Major databases were searched until January 2021. A random-effects model was used to calculate the pooled rates and 95% confidence intervals (CI). Outcomes assessed were pooled proportion of BRCA-1 and BRCA -2 mutations in PC and incidence of PC in these mutation carriers. Results: Nine studies reported on the incidence of BRCA-1 and BRCA-2 mutations in PC patients, whereas, thirteen studies reported the incidence of PC among BRCA mutation carriers. In 4462 patients with PC, 47 were found to have germline mutation in BRCA-1. Pooled proportion of mutation carriers was 1.1% (CI 0.3-1.8; I2=58.88%). Among 4426 patients with PC, 158 were found to have germline mutations in BRCA-2. Pooled proportion of mutation carriers was 7.9% (CI 4.8-11; I2=91.15%). Among 27,501 BRCA-1 mutation carriers, 121 developed PC. Pooled incidence ratio was 1.78 (CI 1.4-2.26; I2=13%). A total of 144 out of 16,256 BRCA-2 mutation carriers developed PC. Pooled incidence ratio was 3.98 (CI 1.26-12.52; I2=96%). Conclusion: Our results support the current recommendations of PC screening in high-risk individuals such as those with mutations in BRCA-1 and BRCA-2 genes.Figure 1.: BRCA 2.

Prognostic Prediction of BRCA Mutations by 18F-FDG PET/CT SUVmax in Breast Cancer

Objectives:This study aimed to investigate the prognostic prediction of germline BRCA1 and BRCA2 mutations by comparing the maximum standardized uptake value (SUVmax) obtained from 18fluoride-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT), which is considered a prognostic factor in breast cancer (BC).Methods:Retrospective interdisciplinary laboratory results of 92 patients with BC who had germline BRCA1 or BRCA2 mutation profiles and underwent 18F-FDG PET/CT were compared. Genotyping was made by next-generation sequencing, and PET/CT scans were re-evaluated. The histopathological data, genetic results, and clinical demographics of all patients were recorded. Patients were divided into two groups in accordance with the presence of germline BRCA1 and/or BRCA2 mutations. Between-group statistical comparison was performed.Results:In PET/CT performed for primary staging, patients with BRCA-positive BC had significantly higher SUVmax (p=0.039), larger tumor size (p=0.025), and presence of axillary nodal metastases (p=0.023) than patients with BRCA-negative BC. Although the Ki-67 index was higher in the BRCA-positive group than BRCA-negative group, this difference was not significant (p=0.157). Moreover, in the BRCA-positive and negative groups, SUVmax, Ki-67 index, and tumor size, grade, and stage were significantly correlated with each other.Conclusion:The results of this study showed a strong association between BRCA mutations and SUVmax, which indicates the poor prognosis of BC.

Integrating PARP inhibitors into the management of breast cancer: where are we?

During the last 2 decades, extensive research has focused on the molecular functions of BRCA1 and BRCA2 genes. This has led to the development of Poly(ADP-ribose) polymerase inhibitors (PARPi), as effective target therapies, based on their preferential cytotoxicity in tumor cells harboring germline BRCA1 and BRCA2 mutations. At the present time, 2 PARPi (Olaparib and Talazoparib) are approved as single agent for the treatment of patients with metastatic HER2-ve breast cancer, who have BRCA germline mutations. The clinical benefit of these agents might be also anticipated in patients harboring germline mutations in some additional genes involved in the process of homologous recombination repair (HRR) other than BRCA1/BRCA2. In this review, we summarize the molecular rational for the therapeutic development of PARPi and the clinical evidence supporting their use as anticancer drugs in breast cancer patients with BRCA1/BRCA2 germline mutations. We also discuss the role of platinum-based chemotherapy and how it compares with PARPi in the management of these patients. We will go through some relevant clinical trials of various combinations of PARPi with cytotoxic or immunotherapeutic agents, which may potentially provide better treatment results, compared to what is already achieved with their use as monotherapy.

Association between pathogenic germline mutations in BRCA2 and ATM and tumor-infiltrating lymphocytes in primary prostate cancer.

Pathogenic mutations in homologous recombination (HR) DNA repair genes may be associated with increased tumor mutational burden and numbers of tumor-infiltrating lymphocytes (TIL). Though HR-deficient prostate tumors have been anecdotally associated with improved responses to immunotherapy, it is unclear whether HR mutations or HR deficiency (HRD) scores predict for increased T-cell densities in this cancer. We evaluated 17 primary prostate tumors from patients with pathogenic germline BRCA2 mutations (gBRCA2) and 21 primary prostate tumors from patients with pathogenic germline ATM (gATM) mutations, which were compared to 19 control tumors lacking HR gene mutations, as well as the TCGA prostate cancer cohort. HRD score was estimated by targeted sequencing (gBRCA2 and gATM) or by SNP microarray (TCGA). Tumor-associated T-cell densities were assessed using validated automated digital image analysis of CD8 and FOXP3 immunostaining (gBRCA2 or gATM) or by methylCIBERSORT (TCGA). CD8 + and FOXP3 + T-cell densities were significantly correlated with each other in gBRCA2 and gATM cases. There was no significant difference between CD8 + or FOXP3 + TIL densities in gBRCA2 or gATM cases compared to controls. In the TCGA cohort, HRD score was associated with predicted CD8 + and FOXP3 + TILs. Associations were also seen for HRD score and TIL density among the germline-mutated cases. In contrast to mismatch repair-deficient primary prostate tumors, cancers from germline BRCA2 or ATM mutation carriers do not appear to be associated with elevated TIL density. However, measures of genomic scarring, such as HRD score, may be associated with increased tumor-infiltrating T-cells.

Cancer Spectrum, Family History of Cancer and Overall Survival in Men with Germline BRCA1 or BRCA2 Mutations.

BACKGROUND: Men with germline BRCA1/2 mutations are not well studied compared to their female counterparts. This study evaluates the cancer characteristics, family history of cancer, and outcomes of male BRCA1/2 mutation carriers. METHODS: All men with germline BRCA1/2 mutations who attended genetic assessment between October 1995 and October 2019 at the Medical University of Vienna were identified. Clinicohistopathological features, family history of cancer, and outcomes were assessed by mutation status. RESULTS: Of the 323 men included, 45 (13.9%) had a primary cancer diagnosis, many of whom were BRCA2 carriers (75.5%). Breast cancer (BC) was the most common cancer (57.8%) followed by prostate cancer (15.6%). Invasive ductal carcinoma and hormone receptor positive tumors were the most common. Among 26 BC-affected patients, 42% did not have any relatives with cancer. Parent of origin was only known in half of the 26 men, with 42% of them inherited through the maternal lineage versus 8% through the paternal. BRCA2 carriers and those with a family history of BC had worse overall survival (20 y vs. 23 y BRCA1 carriers; P = 0.007; 19 y vs. 21 y for those without family history of BC; P = 0.036). CONCLUSION: Male BRCA2 carriers were most likely to develop cancer and had worse prognosis. In our dataset, BC was the most common cancer, likely due to referral bias. Not all mutation carriers present with BC or have a family history of cancer to warrant genetic testing.

Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations.

Among men with metastatic prostate cancer, about 10% have germline alterations in DNA damage response genes. Most studies have examined BRCA2 alone or an aggregate of BRCA1/2 and ATM. Emerging data suggest that ATM mutations may have distinct biology and warrant individual evaluation. The objective of this study is to determine whether response to prostate cancer systemic therapies differs between men with germline mutations in ATM (gATM) and BRCA2 (gBRCA2). This is an international multicenter retrospective matched cohort study of men with prostate cancer harboring gATM or gBRCA2. PSA50 response (≥50% decline in prostate-specific antigen) was compared using Fisher's exact test. The study included 45 gATM and 45 gBRCA2 patients, matched on stage and year of germline testing. Patients with gATM and gBRCA2 had similar age, Gleason grade, and PSA at diagnosis. We did not observe differences in PSA50 responses to abiraterone, enzalutamide, or docetaxel in metastatic castration resistant prostate cancer between the two groups; however, 0/7 with gATM and 12/14 with gBRCA2 achieved PSA50 response to PARPi (p < .001). Median (95% confidence interval) overall survival from diagnosis to death was 10.9 years (9.5-not reached) versus 9.9 years (7.1-not reached, p = .07) for the gATM and gBRCA2 cohorts, respectively. Limitations include the retrospective design and lack of mutation zygosity data. Conventional therapies can be effective in gATM carriers and should be considered before PARPi, which shows limited efficacy in this group. Men with gATM mutations warrant prioritization for novel treatment strategies.

Biological Role and Clinical Implications of microRNAs in BRCA Mutation Carriers.

Women with pathogenic germline mutations in BRCA1 and BRCA2 genes have an increased risk to develop breast and ovarian cancer. There is, however, a high interpersonal variability in the modality and timing of tumor onset in those subjects, thus suggesting a potential role of other individual’s genetic, epigenetic, and environmental risk factors in modulating the penetrance of BRCA mutations. MicroRNAs (miRNAs) are small noncoding RNAs that can modulate the expression of several genes involved in cancer initiation and progression. MiRNAs are dysregulated at all stages of breast cancer and although they are accessible and evaluable, a standardized method for miRNA assessment is needed to ensure comparable data analysis and accuracy of results. The aim of this review was to highlight the role of miRNAs as potential biological markers for BRCA mutation carriers. In particular, biological and clinical implications of a link between lifestyle and nutritional modifiable factors, miRNA expression and germline BRCA1 and BRCA2 mutations are discussed with the knowledge of the best available scientific evidence.

Analysis of mutation status and homologous recombination deficiency in tumors of patients with germline BRCA1 or BRCA2 mutations and metastatic breast cancer: OlympiAD

Presence of a germline BRCA1 and/or BRCA2 mutation (gBRCAm) may sensitize tumors to poly(ADP-ribose) polymerase (PARP) inhibition via inactivation of the second allele, resulting in gene-specific loss of heterozygosity (gsLOH) and homologous recombination deficiency (HRD). Here we explore whether tissue sample testing provides an additional route to germline testing to inform treatment selection for PARP inhibition. In this prespecified exploratory analysis, BRCA1 and/or BRCA2 mutations in blood samples (gBRCAm) and tumor tissue (tBRCAm) were analyzed from patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer and known gBRCAm, enrolled in the phase III OlympiAD trial. The frequency and nature of tBRCAm, HRD score status [HRD-positive (score ≥42) versus HRD-negative (score <42) using the Myriad myChoice® CDx test] and rates of gsLOH were determined, and their impact on clinical efficacy (objective response rate and progression-free survival) was explored. Tissue samples from 161/302 patients yielded tBRCAm, HRD and gsLOH data for 143 (47%), 129 (43%) and 125 (41%) patients, respectively. Concordance between gBRCAm and tBRCAm was 99%. gsLOH was observed in 118/125 (94%) patients [BRCA1m, 73/76 (96%); BRCA2m, 45/49 (92%)]. A second mutation event was recorded for two of the three BRCA1m patients without gsLOH. The incidence of HRD-negative was 16% (21/129) and was more common for BRCA2m (versus BRCA1m) and/or for hormone receptor-positive (versus triple-negative) disease. Olaparib antitumor activity was observed irrespective of HRD score. gBRCAm identified in patients with HER2-negative metastatic breast cancer by germline testing in blood was also identified by tumor tissue testing. gsLOH was common, indicating a high rate of biallelic inactivation in metastatic breast cancer. Olaparib activity was seen regardless of gsLOH status or HRD score. Thus, additional tumor testing to inform PARP inhibitor treatment selection may not be supported for these patients.

Rucaparib is a safe and effective maintenance therapy for advanced pancreatic cancer

Select patients with advanced pancreatic cancer may have another effective treatment option for maintenance therapy. New data show that rucaparib is effective in stopping tumor growth or substantially shrinking tumors in the majority of patients with select biomarkers enrolled in a phase II trial by researchers at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia.1 The open-label, single-arm, single-stage, phase II study was conducted to test the hypothesis that rucaparib, a poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi), would confer at least 60% progression-free survival at 6 months as maintenance therapy in patients with platinum-sensitive advanced pancreatic cancer with select biomarkers. The study included 46 patients with locally advanced or metastatic pancreatic cancer with confirmed or likely pathogenic germline or somatic pathogenic variants in BRCA1, BRCA2, or PALB2 genes. Patients were aged at least 18 years and had received prior treatment with platinum-based chemotherapy; 34 patients received at least 16 weeks or more, whereas 8 patients received less than 16 weeks. All patients were treated with rucaparib at a dose of 600 mg delivered orally twice a day during every day of a 28-day cycle until disease progression or unacceptable toxicity. For the 42 patients available for evaluation, the progression-free survival rate at 6 months was 59.5%, and the median progression-free survival was 13.1 months. When disease control was examined, 41.7% of the patients, including 3 of 6 patients with the variant PALB2 and 1 of 2 patients with a somatic BRCA2 mutation, experienced either a complete response or a partial response. Kim A. Reiss, MD, assistant professor at the Abramson Cancer Center and lead author of the study, says that these findings expand on prior results from the phase III POLO study showing the efficacy of maintenance olaparib, the first poly(adenosine diphosphate ribose) polymerase 1 (PARP1) agent to be used as maintenance therapy for advanced pancreatic cancer, in select patients with germline BRCA mutations and platinum-sensitive metastatic pancreatic cancer.2 “Our study showed efficacy in patients with additional variants,” she says. “The role of maintenance PARP inhibition may possibly be expanded to patients with germline PALB2 mutations and those with somatic BRCA mutations.” Dr. Reiss also notes the efficacy of rucaparib for patients with locally advanced disease and patients who did not receive a full 4 months of prior platinum therapy. “Although platinum sensitivity is key for PARPi efficacy, a full 4 months of treatment may not be required prior to switching to maintenance therapy,” she says. This finding is important because of toxicities of platinum-based chemotherapy that typically emerge before the completion of 16 weeks of therapy.

1468P POLO: Subsequent therapy after maintenance olaparib in patients with a germline BRCA mutation and metastatic pancreatic cancer

In the phase III POLO trial (NCT02184195), progression-free survival was significantly prolonged on maintenance olaparib (O) relative to placebo (P) in patients (pts) with a germline BRCA mutation and metastatic pancreatic cancer whose disease had not progressed after ≥ 16 weeks of first-line platinum-based chemotherapy. Here, we present subsequent therapies received after discontinuation of study treatment.

1467P POLO: Long-term safety and tolerability of olaparib for patients with a germline BRCA mutation and metastatic pancreatic cancer

The phase III POLO trial (NCT02184195) compared maintenance PARP inhibitor therapy with olaparib (O) to placebo (P) in patients (pts) with a germline BRCA mutation and metastatic pancreatic cancer. We describe safety and tolerability results for pts with an overall survival (OS) of ≥ 2 years.

Evidence for accelerated aging in mammary epithelia of women carrying germline BRCA1 or BRCA2 mutations

During aging in the human mammary gland, luminal epithelial cells lose lineage fidelity by expressing markers normally expressed in myoepithelial cells. We hypothesize that loss of lineage fidelity is a general manifestation of epithelia that are susceptible to cancer initiation. In the present study, we show that histologically normal breast tissue from younger women who are susceptible to breast cancer, as a result of harboring a germline mutation in BRCA1, BRCA2 or PALB2 genes, exhibits hallmarks of accelerated aging. These include proportionately increased luminal epithelial cells that acquired myoepithelial markers, decreased proportions of myoepithelial cells and a basal differentiation bias or failure of differentiation of cKit+ progenitors. High-risk luminal and myoepithelial cells are transcriptionally enriched for genes of the opposite lineage, inflammatory- and cancer-related pathways. We have identified breast-aging hallmarks that reflect a convergent biology of cancer susceptibility, regardless of the specific underlying genetic or age-dependent risk or the associated breast cancer subtype.