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PARP inhibitors are considered promising anti-cancer agents and currently being tested in clinical trials in hereditary breast cancer patients harboring mutations in BRCA1 and BRCA2 genes. In this study, we investigated the antiproliferative effects and mechanism of PARP inhibitors ABT-888 (Veliparib), BSI-201 (Iniparib) and AZD228 (Olaparib) in breast cancer cell lines with BRCA1 or BRCA2 mutations and 9 different BRCA wild-type cell lines with BRCA1 allelic loss. We found that AZD2281 was the most potent in the PARP inhibitors and induces significant growth inhibition (~95%) in BRCA1 mutant (HCC-1937, MDA-MB-436, and SUM-149PT) and BRCA2 mutant (HCC-1428) cell lines. AZD2281 treatment also resulted in growth inhibition ranging from 20 to 50% in cells with BRCA1 allelic loss, including ER(+), HER2/Neu(+) and triple-negative breast cancer (TNBC) cells, but showed no effect in cells without with type BRCA without allelic loss. Knocking down of BRCA1 or BRCA2 in TNBC cells with BRCA1 allelic loss by RNA interference significantly enhanced AZD2281-induced growth inhibition and induced significant autophagy that was associated with mitophagy in cells with BRCA mutations. Inhibition of autophagy by gene knockdown significantly diminished AZD2281-induced mitophagy and apoptosis, indicating that autophagic process mediates some of the downstream effects of PARP inhibitors. In conclusion, our data provide the first evidence of PARP inhibitor AZD2281 autophagy and mitophagy in breast cancer cell lines with BRCA mutations or BRCA-allelic loss. In addition, our results indicate that the patients with BRCA1 allelic loss may also benefit from PARP inhibitor therapy if BRCA is further inhibited.

The identification of germline BRCA1/2 (BRCA) mutations plays an important role in the treatment planning of high-risk breast cancer patients, but genetic testing may be costly or unavailable. The multiparametric breast MRI (mpMRI) features offer noninvasive imaging biomarkers that could support BRCA mutation prediction. In this study, we investigate whether mpMRI features can predict BRCA mutation status in high-risk breast cancer patients. We collected data from 231 consecutive patients (82 BRCA-positive, 149 BRCA-negative) who underwent BRCA mutation testing and preoperative MRI between 2013 and 2019. We used the mpMRI features, including computer-aided diagnosis (CAD)-derived kinetic features, morphologic features, and apparent diffusion coefficient (ADC) values from diffusion-weighted imaging (DWI). In the univariate analysis, higher CAD-derived washout component and peak enhancement, larger tumor size and angio-volume, peritumoral edema on T2-weighted imaging, axillary adenopathy, and minimal or mild background parenchymal enhancement (BPE) were significantly associated with BRCA mutation, while ADC values showed no significant differences. In the multivariate analysis, three significant predictors were washout component ≥ 19.5% (odds ratio [OR] = 3.89, p < 0.001), minimal or mild BPE (OR = 2.57, p = 0.004), and tumor size ≥ 2.5 cm (OR = 2.41, p = 0.004). Using these predictors, we compared the predictive performance of 13 ML models through 30 repeated runs and achieved the highest performance (AUC = 0.72). In conclusion, ML models integrating mpMRI features demonstrated good performance for predicting BRCA mutations in high-risk patients. This noninvasive approach may aid personalized treatment planning and genetic counseling.

Poly (ADP-ribose) polymerase (PARP) inhibitors are a class of targeted agents for the treatment of solid tumors. Concurrent PARP inhibition in Breast Cancer Susceptibility Gene (BRCA)-mutated or homologous recombination-deficient tumor cells can induce \"synthetic lethality\", which targets two DNA repair pathways and induces serious cytotoxicity to tumor cells without damaging normal cells. Currently, PARP inhibitors such as olaparib, rucaparib and niraparib, which improve progression-free survival, particularly in patients harboring BRCA mutations, are approved by the Food and Drug Administration (FDA) and European Medicine Agency (EMA) for the treatment of ovarian cancers. Based on the results of different clinical trials, the indications for these drugs are slightly different. PARP inhibitors have been studied both as single agents and in combination with chemotherapy, antiangiogenic agents, and ionizing radiation. This review summarizes the critical clinical trials of PARP inhibitors that have been completed, provides an overview of the ongoing trials, presents the confirmed conclusions and notes the issues that need to be addressed in future studies.

Background Breast cancer is a common cause for central nervous system (CNS) metastasis, resulting in a significant reduction in overall survival. Germline pathogenic variants (PVs) in BRCA1/2 are the most common genetic risk factor for breast cancer, associated with poor prognostic factors. This study sought to explore the patterns and outcome of CNS metastases in breast cancer patients with germline PVs in BRCA 1/2 genes. Methods A retrospective cohort of 75 breast cancer patients with known BRCA 1/2 mutation status, who were diagnosed with CNS metastases in 2006–2021. Histopathology, characteristics of CNS disease, treatments, and survival were compared between BRCA 1/2 carriers ( n  = 25) and non-carriers ( n  = 50), using propensity score matching (1:2 ratio) to control for the possible influence of tumor receptor status (ER, PR, HER2) and patient age. Pearson chi-square or Fisher exact test and Kaplan-Meier survival curves with log-rank test were used for statistical analyses. Results Patients with PVs in BRCA1/2 had more high-grade tumors (88% vs. 68%, P  = 0.060), were younger at CNS disease diagnosis (median 46.69 vs. 55.02 years, P  = 0.003) and had better ECOG performance status (ECOG PS 0 in 20% vs. 2%, P  = 0.033), but without significant differences in systemic or CNS-directed treatment approaches. BRCA 1/2 mutation was associated with a higher rate of temporal lobe involvement (52% vs. 26%, P  = 0.026) and leptomeningeal spread (40% vs. 20%, P  = 0.020). Survival after diagnosis of CNS disease was shorter (median 8.03 vs. 28.36 months, P  < 0.0001), with no significant differences in time to development of CNS metastases or overall-survival. Conclusion Patients with CNS metastatic breast cancer and PVs in BRCA1/2 showed a higher rate of leptomeningeal and temporal lobe involvement, and a shorter survival with CNS disease. To the best of our knowledge, this is the first study suggesting an exclusive impact of germline BRCA 1/2 mutations in CNS metastatic breast cancer.

Ovarian cancer is the leading cause of gynecologic cancer death in the world, and its prevention and early diagnosis remain the key to its treatment, especially for high‐grade serous carcinoma (HGSC). Accumulating epidemiological and molecular evidence has shown that HGSC originates from fallopian tube secretory cells through serous tubal intraepithelial carcinoma. Comprehensive molecular analyses and mouse studies have uncovered the key driver events for serous carcinogenesis, providing novel molecular targets. Risk‐reducing bilateral salpingo‐oophorectomy (RRSO) has been proposed to reduce the subsequent occurrence of serous carcinoma in high‐risk patients with BRCA mutations. However, there is no management strategy for isolated precursors detected at RRSO, and the role of subsequent surgery or chemotherapy in preventing serous carcinoma remains unclear. Surgical menopause due to RRSO provides a variety of problems related to patients’ quality of life, and the risks and benefits of hormone replacement are under investigation, especially for women without a previous history of breast cancer. An additional surgical option, salpingectomy with delayed oophorectomy, has been proposed to prevent surgical menopause. The number of opportunistic salpingectomies at the time of surgery for benign disease to prevent the future occurrence of HGSC has increased worldwide. Thus, the changing concept of the origin of serous carcinoma has provided us a great opportunity to develop novel diagnostic and therapeutic approaches. Accumulating epidemiological and molecular evidence has shown that high‐grade serous carcinoma originates from fallopian tube secretory cells through serous tubal intraepithelial carcinoma. The changing concept of the origin of serous carcinoma has provided us a great opportunity to develop novel diagnostic and preventive approaches.

Background In women with newly diagnosed ovarian cancer, bevacizumab and poly (ADP-ribose) polymerase inhibitors (PARPi) exhibit improved progression-free survival (PFS) when administered concurrent with chemotherapy and/or maintenance therapy, but no study has directly compared their effects. Therefore, this study aimed to compare the efficacy and safety of bevacizumab and PARPi in women with newly diagnosed ovarian cancer using a network meta-analysis. Methods PubMed, Medline, and Embase databases were searched, and five randomized trials assessing PFS in women with newly diagnosed ovarian cancer treated with either bevacizumab, PARPi, or placebo or no additional agent (controls) were identified. PFS was compared in the overall population with ovarian cancer, women with a BRCA1/2 mutation (BRCAm) and women with homologous-recombination deficiency (HRD). Adverse events (grade ≥ 3) were compared in all populations of the included studies. Results PARPi improved PFS significantly more than bevacizumab in women with a BRCAm (HR 0.47; 95% CI 0.36–0.60) and with HRD (HR 0.66; 95% CI 0.50–0.87). However, in the overall population with ovarian cancer, no significant difference in PFS was observed between women treated with PARPi and those treated with bevacizumab. PARPi exhibited the highest surface under the cumulative ranking probabilities value as the most effective treatment for PFS (PARPi vs. bevacizumab: 98% vs. 52% in the overall population with ovarian cancer; 100% vs. 50% in women with BRCAm; 100% vs. 50% in women with HRD). For adverse events, the risk of all treatments was similar. However, PARPi had a higher adverse risk than the control group (relative risk 2.14; 95% CI 1.40–3.26). Conclusions In women with newly diagnosed ovarian cancer, PARPi might be more effective in terms of PFS compared to bevacizumab. The risk of serious adverse events was similar for PARPi and bevacizumab.

BRCA mutation carriers face various situations that influence their fertility potential. There is still a lack of guideline or expert consensus on Fertility Preservation (FP) in BRCA mutation carriers and the necessity and safety of FP in BRCA mutation carriers is still in dispute. This review aims to focus on the population of BRCA mutation carriers by analyzing the existing FP strategies, comprehensively comparing the pros and cons of each strategy and its applicability. FP is a suggestion for BRCA mutation carriers with birth planning. Different FP strategies have different characteristics. Considering the particularity of BRCA mutation carriers, multiple factors need to be carefully considered. This review focuses on the applicability of each FP method for carriers under various circumstances. Available FP strategies including oocyte cryopreservation, ovarian tissue cryopreservation, preimplantation genetic diagnosis, and egg/embryo donation are analyzed by comparing existing methods comprehensively. In the attempt to provide an up-to-date decision-making guidance. Conditions taking into consideration were the carrier’s age, the risk of breast and ovarian metastasis, plans for oncotherapy, FP outcome, time available for FP intervention and accessibility. Overall, FP is necessary and safe for BRCA mutation carriers. Among all available FP methods, oocyte cryopreservation is the most reliable procedure; ovarian tissue cryopreservation is the only way for preserving both fertility and endocrine function, recommended for pre-pubertal carriers and when time is limited for oocyte stimulation. A clear framework provides frontline clinical practitioners a new thought and eventually benefit thousands of BRCA mutation carriers.

Medullary breast cancer is a rare subtype of invasive breast cancer, representing from 0.2% to 6% of all breast carcinomas, with a higher proportion among women with triple-negative breast cancer and among those with a BRCA1 mutation. This review article aims to investigate the frequency of medullary breast cancer among all breast cancers and to assess its association with BRCA1 mutations. We surveyed studies involving patients diagnosed with breast cancer that report both the histology of the breast cancer as well as the presence of BRCA1 mutations. Among women with medullary breast cancer, the proportion of cases that carry a BRCA1 mutation ranges from 3% up to 35.3%, depending on the study. Among BRCA1 -mutated breast cancers, the proportion that are medullary ranges from 8 to 20%. Given the notable association between medullary breast cancer and BRCA1 mutations, we propose to consider medullary breast cancer as a criterion for genetic testing in order to improve the identification of a larger number of carriers, thereby enhancing screening and prevention strategies.

Approximately 5-10% of all patients diagnosed with breast cancer have germline mutations, which make their disease more susceptible to DNA-damaging agents and a new class of drugs known as poly(ADP-ribose) polymerase (PARP) inhibitors. Talazoparib is a new PARP inhibitor that has been recently approved for use in patients with metastatic breast cancer with germline mutations after a phase III trial showed superior progression-free survival when compared to standard chemotherapy. In this review, we analyze the development of talazoparib as well as its safety profile and the potential role of the combination therapy with standard cytotoxic drugs and with novel therapies.

Reporting the incidence and the variants of /2 mutations in ovarian cancer patients exploring their effects on the treatment outcomes. In total, 104 patients with epithelial ovarian cancer were prospectively recruited to the study. Analysis consisted of the sequencing of all the translated exons and immediately adjacent intronic regions of the genes. Responses to multiple lines of chemotherapy were assessed, as well as the effect of gene mutations on progression-free survival (PFS) and overall survival (OS). Pathogenic / mutations were found in 21.15% of the patients. mutations represented 68.2% of the total mutations. Two novel mutations were identified. Age at diagnosis was a strong predictor of the presence of a pathogenic mutation. Patients with a family history of cancer had a higher incidence of mutations ( =0.005). As high as 72% of the patients with BRCA mutations were diagnosed at advanced stage. High-grade serous tumors have a higher incidence of pathogenic mutation ( =0.07). Response to neoadjuvant chemotherapy was high (93.9%). All patients underwent surgery which was optimal in 73.1% of the patients. As high as 85.6% of the patients received adjuvant chemotherapy. Relapse rate was 45.2%. Visceral metastasis was more often in BRCA carriers ( =0.01). Patients carrying pathogenic BRCA1/2 mutations had a longer median PFS of 42.43 months (95% CI 32.04-52.83) compared to 22.24 months (95% CI 14.83-29.58) for non-carriers ( =0.08). OS was 64.32 months (95% CI 38.09-90.06) for BRCA mutation patients versus 56.63 months (95% CI 50.05-63.21) ( =0.04) for non-carriers. In multivariate analysis, early stage at diagnosis and optimal debulking were the only independent predictors of better PFS and OS. We documented a number of pathogenic and mutations in this patients cohort; two novel mutations were detected. BRCA status seemed to affect survival in ovarian cancer patients.