Germline Mutations In BRCA1 Research Articles

Proteomic signature for detection of high-grade ovarian cancer in germline BRCA mutation carriers.

No current screening methods for high-grade ovarian cancer (HGOC) guarantee effective early detection for high-risk women such as germline BRCA mutation carriers. Therefore, the standard-of-care remains risk-reducing salpingo-oophorectomy (RRSO) around age 40. Proximal liquid biopsy is a promising source of biomarkers, but sensitivity has not yet qualified for clinical implementation. We aimed to develop a proteomic assay based on proximal liquid biopsy, as a decision support tool for monitoring high-risk population. Ninety Israeli BRCA1 or BRCA2 mutation carriers were included in the training set (17 HGOC patients and 73 asymptomatic women), (BEDOCA trial; ClinicalTrials.gov Identifier: NCT03150121). The proteome of the microvesicle fraction of the samples was profiled by mass spectrometry and a classifier was developed using logistic regression. An independent cohort of 98 BRCA mutation carriers was used for validation. Safety information was collected for all women who opted for uterine lavage in a clinic setting. We present a 7-protein diagnostic signature, with AUC >0.97 and a negative predictive value (NPV) of 100% for detecting HGOC. The AUC of the biomarker in the independent validation set was >0.94 and the NPV >99%. The sampling procedure was clinically acceptable, with favorable pain scores and safety. We conclude that the acquisition of Müllerian tract proximal liquid biopsies in women at high-risk for HGOC and the application of the BRCA-specific diagnostic assay demonstrates high sensitivity, specificity, technical feasibility and safety. Similar classifier for an average-risk population is warranted.

Oral Contraceptive Use and Breast Cancer Risk for BRCA1 and BRCA2 Mutation Carriers: Systematic Review and Meta-Analysis of Case-Control Studies.

Simple SummaryThe aim of the present work was to systematically review and meta-analysis the available evidence regarding the effects of oral contraceptives using on breast cancer risk in BRCA germline mutations. The included studies were published between 2002 and 2021. Data were pooled from nine case–control studies, comprising a total of 33,162 woman. The association between oral contraceptive use and risk of breast cancer may differ in breast cancer defined by BRCA mutation status. This meta-analysis showed a diverse effect of oral contraceptive use against breast cancer in BRCA carrier mutations. However, futher case control studies are necessary to examine breast cancer risk.Oral contraceptive use is one of the major modifiable risk factors for breast cancer. To investigate the effect of oral contraceptive taking on breast cancer risk by BRCA 1 and BRCA 2 mutation status, we conducted a systematic review and meta-analysis of case-controlled studies. Therefore, English language articles were retrieved by searching MEDLINE (PubMed), EMBASE and the Cochrane Library up to August 2021. Data were pooled from none case–control studies, comprising a total of 33,162 subjects, including 23,453 who had never used oral contraceptives. Overall meta-analysis indicated a statistically insignificant risk reduction: OR = 0.86, 95% CI: 0.70 to 1.06, p = 0.1594. However, increased breast cancer risk was associated with age at first use of OCs ≥20 years: OR = 1.21, 95% CI:1.07 to 1.36, p = 0.002. Multivariable meta-regression with covariates of age of first OC use (β = 0.21, 95% CI: −0.25 to 0.67, p = 0.3767), duration of OC use (β = −0.08, 95% CI; −0.51 to 0.34, p = 0.7093), and time since last OC use (β = 0.32, 95% CI: −0.22 to 0.85, p = 0.2461) did not have a significant effect on the breast cancer risk. This meta-analysis suggests a diverse effect of oral contraceptive use against breast cancer in BRCA carrier mutation. The association between OC use and breast and ovarian cancers needs more investigation.

Mechanisms of PARP1 inhibitor resistance and their implications for cancer treatment.

The discovery of synthetic lethality as a result of the combined loss of PARP1 and BRCA has revolutionized the treatment of DNA repair-deficient cancers. With the development of PARP inhibitors, patients displaying germline or somatic mutations in BRCA1 or BRCA2 were presented with a novel therapeutic strategy. However, a large subset of patients do not respond to PARPinhibitors. Furthermore, many of those who do respond eventually acquire resistance. As such, combating de novo and acquired resistance to PARPinhibitors remains an obstacle in achieving durable responses in patients. In this review, we touch on some of the key mechanisms of PARPinhibitorresistance, including restoration of homologous recombination, replication fork stabilization and suppression of single-strandedDNA gap accumulation, as well as address novel approaches for overcoming PARPinhibitor resistance.

Germline BRCA mutation carriers are more likely to undergo cytoreductive surgery for relapsed, platinum sensitive, ovarian cancer

ObjectiveBRCA mutations have been associated with improved outcomes in ovarian cancer patients. This study's objective was to compare the secondary cytoreduction surgery (SCS) rates among ovarian cancer patients by BRCA mutation status. MethodsThe study was retrospective and included platinum sensitive recurrent high grade serous ovarian cancer patients from one Canadian center and two Israeli centers from January 1999 to December 2018. Demographic and genetic data, tumor characteristics, patterns of recurrence and surgical and medical treatments were obtained from electronic charts. Patients were grouped according to BRCA mutation status. Logistic regression analyses were used to explore potential prognostic factors of secondary cytoreduction. Results147 patients were enrolled, including 97 from Canada and 50 from Israel. Forty-seven patients (32%) had a BRCA mutation, including 39 (26.5%) germline mutations and 8 (5.5%) somatic mutations. Thirty-one patients (21.1%) underwent SCS. The rate of SCS was 33.3% among the germline BRCA mutation carriers and 15.7% among patients without germline BRCA mutation (p = 0.026). Predictors of secondary cytoreduction included germline BRCA mutation (OR = 2.5, p = 0.03), time to recurrence (OR = 1.004 per month, p < 0.001), absence of lymphatic recurrence (OR = 3.08, p = 0.013), three or fewer lesions at recurrence (OR = 36.74, p < 0.001) and absence of ascites (OR = 9.1, p = 0.034). After adjusting for the number of lesions at recurrence, no other variable remained a significant predictor. ConclusionGermline BRCA mutation carriers are more likely to undergo secondary cytoreduction. This may be mediated in part by lower volume disease at recurrence. This observation should be considered when planning surveillance for these patients after first-line treatment.

Identification of Shared Neoantigens in BRCA1-Related Breast Cancer.

Personalized neoantigen-based cancer vaccines have been shown to be safe and immunogenic in cancer patients; however, the manufacturing process can be costly and bring about delays in treatment. Using off-the-shelf cancer vaccines targeting shared neoantigens may circumvent these problems. Unique mutational signatures and similar phenotypes found among BRCA1-mutated breast cancer make it an ideal candidate for discovering shared neoantigens within the group. We obtained genome sequencing data of breast cancer samples with or without somatic BRCA1 mutations (BRCA1-positive and BRCA1-negative, respectively) from the three public cancer databases; The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Catalogue of Somatic Mutations in Cancer (COSMIC); and from three studies with whole genome/exome sequencing data of samples with germline BRCA1 mutations. Data were analyzed separately within the same database/cohort. We found PIK3CA H1047R, E545K, E542K, and N345K recurrently in BRCA1-negative groups across all databases, whereas recurrent somatic mutations in BRCA1-positive groups were discordant among databases. For germline BRCA1-mutated breast cancer, TP53 R175H was unanimously the most frequent mutation among the three germline cohorts. Our study provides lists of potential shared neoantigens among BRCA1-related breast cancer, which may be used in developing off-the-shelf neoantigen-based vaccines.

BRCA Mutation Status in Triple-Negative Breast Cancer Patients Treated with Neoadjuvant Chemotherapy: A Pivotal Role for Treatment Decision-Making.

Simple SummaryIn this retrospective observational study, we evaluated data from patients with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NACT) in order to better define the impact of germline BRCA1/2 (gBRCA1/2) mutation status on outcomes in this patient population. Our results show that patients with BRCA1/2 mutation had a higher pathologic complete response (pCR) rate than non-mutated patients; nevertheless, the benefit was confirmed only in the subset of patients who received a platinum-based NACT. Furthermore, pCR was associated with improved Event Free Survival (EFS) and Overall Survival (OS), regardless of BRCA1/2 mutation status and type of NACT received. Long-term follow-up analyses are needed to further define the impact of gBRCA mutation status in patients with early-TNBC.Triple-negative breast cancer (TNBC) is characterized by earlier recurrence and shorter survival compared with other types of breast cancer. Moreover, approximately 15 to 25% of all TNBC patients harbor germline BRCA (gBRCA) 1/2 mutations, which confer a more aggressive phenotype. However, TNBC seems to be particularly sensitive to chemotherapy, the so-called ‘triple negative paradox’. Therefore, Neoadjuvant chemotherapy (NACT) is currently considered the preferred approach for early-stage TNBC. BRCA status has also been studied as a predictive biomarker of response to platinum compounds. Although several randomized trials investigated the addition of carboplatin to standard NACT in early-stage TNBC, the role of BRCA status remains unclear. In this retrospective analysis, we evaluated data from 136 consecutive patients with Stage I-III TNBC who received standard NACT with or without the addition of carboplatin, in order to define clinical features and outcomes in BRCA 1/2 mutation carriers and non-carrier controls. Between January 2013 and February 2021, 67 (51.3%) out of 136 patients received a standard anthracyclines/taxane regimen and 69 (50.7%) patients received a platinum-containing chemotherapy regimen. Deleterious germline BRCA1 or BRCA2 mutations were identified in 39 (28.7%) patients. Overall, patients with deleterious gBRCA1/2 mutation have significantly higher pCR rate than non-carrier patients (23 [59%] of 39 vs. 33 [34%] of 97; p = 0.008). The benefit of harboring a gBRCA mutation was confirmed only in the subset of patients who received a platinum-based NACT (17 [65.4%] of 26 vs. 13 [30.2%] of 43; p = 0.005) while no differences were found in the platinum-free subgroup. Patients who achieved pCR after NACT had significantly better EFS (OR 4.5; 95% CI 1.9–10.7; p = 0.001) and OS (OR 3.3; 95% CI 1.3–8.9; p = 0.01) than patients who did not, regardless of BRCA1/2 mutation status and type of NACT received. Our results based on real-world evidence show that TNBC patients with the gBRCA1/2 mutation who received platinum-based NACT have a higher pCR rate than non-carrier patients, supporting the use of this chemotherapy regimen in this patient population. Long-term follow-up analyses are needed to further define the role of gBRCA mutation status on clinical outcomes in patients with early-TNBC.

Impact of BRCA Gene Testing on Ovarian Cancer Management

Ovarian cancer is a diverse disease with several cellular subtypes, the most common of which are high-grade serous ovarian cancer (HGSOC). Ovarian cancer is still primarily treated with chemotherapy and surgery. Recent advances in the hereditary understanding of this disease have revealed that the BRCA gene plays an important role. While only a small percentage of HGSOC patients will have a germline BRCA mutation, many more will have tumor genetic aberrations within BRCA or other homologous recombination proteins. Improved preventative measures and therapeutic development have resulted from genetic screening for these BRCA mutations. This review focuses on BRCA mutations and their relationship to the development of ovarian cancer, as well as future therapeutic targets.

PARP targeted Auger emitter therapy with [125I]PARPi-01 for triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) lacks biomarkers for targeted therapy. Auger emitters display the best therapeutic effect, if delivered directly into the nucleus proximal to DNA. The nuclear protein Poly (ADP-ribose)-Polymerase 1 (PARP1) is a suitable target against which few inhibitors (PARPi) are clinically approved for treatment of breast cancer with germline BRCA mutation (BRCAmut). In this study, a theranostic approach was investigated in a TNBC xenografted mouse model by radiolabelling a close derivative of a PARPi Olaparib (termed PARPi-01) with the Auger emitters 123/125I.MethodsTNBC cell line MDA-MB-231 was subcutaneously implanted in female NOD/SCID mice. At a tumour size of ~ 500mm3, [123I]PARPi-01 was administered intravenously, and SPECT/CT images were obtained at 4 h or 24 h post injection (p.i). A therapy study was performed with [125I]PARPi-01 in 4 doses (10 MBq/dose, 10 days apart). Tumour growth was monitored by CT scans longitudinally once per week. Upon reaching study endpoint, tissues were harvested and stained with TUNEL assay for detection of apoptosis induction.ResultsSPECT/CT images showed rapid hepatobiliary tracer clearance at 4 h post injection (p.i.). Retention in thyroid at 24 h p.i. suggested tracer deiodination in vivo. The tumour and liver uptake were 0.2%ID/g and 2.5%ID/g, respectively. The tumour: blood ratio was 1.3. Endogenous therapy induced a significant delay in tumour growth (doubling time increased from 8.3 to 14.2 days), but no significant survival advantage. Significantly higher apoptosis ratio was observed in [125I]PARPi-01 treated tumour tissues. No radiotoxicity was detected in the liver and thyroid.ConclusionConsidering the radio-cytotoxic effect in the tumour tissue and a delay on tumour doubling time, [125I]PARPi-01 presents a potential radiotherapeutics for treatment of TNBC. Improvements to overcome the suboptimal pharmacokinetics are necessary for its potential clinical application.

Dissection of transcriptome dysregulation and immune characterization in women with germline BRCA1 mutation at single-cell resolution

BackgroundHigh-grade serous carcinoma (HGSC) is the most frequent and lethal type of ovarian cancer. It has been proposed that tubal secretory cells are the origin of ovarian HGSC in women with familial BRCA1/2 mutations. However, the molecular changes underlying malignant transformation remain unknown.MethodWe performed single-cell RNA and T cell receptor sequencing of tubal fimbriated ends from 3 BRCA1 germline mutation carriers (BRCA1 carriers) and 3 normal controls with no high-risk history (non-BRCA1 carriers).ResultsExploring the transcriptomes of 19,008 cells, predominantly from BRCA1+ samples, we identified 5 major cell populations in the fallopian tubal mucosae. The secretory cells of BRCA1+ samples had differentially expressed genes involved in tumor growth and regulation, chemokine signaling, and antigen presentation compared to the wild-type BRCA1 controls. There are several novel findings in this study. First, a subset of the fallopian tubal secretory cells from one BRCA1 carrier exhibited an epithelial-to-mesenchymal transition (EMT) phenotype, which was also present in the mucosal fibroblasts. Second, we identified a previously unreported phenotypic split of the EMT secretory cells with distinct evolutionary endpoints. Third, we observed increased clonal expansion among the CD8+ T cell population from BRCA1+ carriers. Among those clonally expanded CD8+ T cells, PD-1 was significantly increased in tubal mucosae of BRCA1+ patients compared with that of normal controls, indicating that T cell exhaustion may occur before the development of any premalignant or malignant lesions.ConclusionThese results indicate that EMT and immune evasion in normal-looking tubal mucosae may represent early events leading to the development of HGSC in women with BRCA1 germline mutation. Our findings provide a probable molecular mechanism explaining why some, but not all, women with BRCA1 germline mutation present with early development and rapid dissemination of HGSC.

Prognostic role of tumor subtype and germline BRCA mutation in advanced breast cancer patients treated with palbociclib plus endocrine therapy.

Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor which shows promising effect in hormone receptor-positive breast cancer. The purpose of this study is to evaluate the real-world efficacy and toxicity of palbociclib plus endocrine therapy. This is a retrospective study performed in two tertiary referral hospitals in Korea. Advanced breast cancer patients who were treated with 1st-line palbociclib plus endocrine therapy were enrolled. A total of 216 patients were included between August 2016 and May 2019. Median age was 56 (29-89) years old and 75 patients (34.7%) were premenopausal. Median progression-free survival (PFS) was 33.0months [95% confidence interval (CI) 24.7 to 41.3] and objective response rate was 59.3%. Luminal B patients had shorter PFS (33.0months vs. Not reached, p = 0.019) and tendency of lower ORR (58.3 vs. 62.0%, p = 0.19) compared to luminal A patients. Multivariate analysis revealed luminal B (adjusted hazard ratio 1.90, p = 0.038) and germline BRCA mutation (adjusted hazard ratio 5.57, p = 0.002) as an independent poor prognostic factor for PFS. The most common grade 3 or 4 adverse event was neutropenia (86.7%). The efficacy and toxicity of palbociclib in the real world were comparable to those of clinical trials. In addition, palbociclib with endocrine therapy was an effective treatment option for young patients. Luminal B and germline BRCA mutation were associated with inferior outcome.

&lt;i&gt;BRCA&lt;/i&gt;-associated ovarian cancer: a review of the current literature

Ovarian cancer is a heterogeneous disease and is the leading cause of mortality among all gynecological malignancies. The disease is characterized by a high frequency of germline and somatic mutations in BRCA1/2 suppressor genes, which, according to various sources, occur in 10–27 % of all ovarian cancer cases. Determination of mutations in BRCA1 / 2 genes is a mandatory diagnostic criteria and includes performing next generation sequencing. Knowledge of the disease mutational status is important not only in the case of determining treatment plan, but also in the case of prevention of the other malignant neoplasms. The purpose of this review is to summarize the current data on the disease characteristics, diagnosis and treatment of BRCA-associated ovarian cancer. Also, the article presents data from a non-interventional multicenter OvATAR study to assess the prevalence of germline and somatic mutations in BRCA1 / 2 genes in the Russian patient population.

EPIK-O/ENGOT-OV61: alpelisib plus olaparib vs cytotoxic chemotherapy in high-grade serous ovarian cancer (phase III study).

Patients with platinum-resistant or -refractory high-grade serous ovarian cancer (HGSOC) have a poor prognosis, and their management represents a substantial unmet medical need. Preclinical data and results from a phase Ib trial demonstrated the efficacy and tolerability of the combination of the α-specific phosphatidylinositol-3-kinase (PI3K) inhibitor alpelisib plus the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib in platinum-resistant, non-BRCA-mutated ovarian cancer. Here, we describe the study design and rationale for the phase III, multicenter, open-label, randomized, active-controlled EPIK-O/ENGOT-OV61 trial investigating alpelisib in combination with olaparib compared with standard-of-care chemotherapy in patients with platinum-resistant or -refractory HGSOC with no germline BRCA mutation. Progression-free survival (blinded independent review committee) is the primary end point. Overall survival is a key secondary end point. Clinical Trial Registration:: NCT04729387 (ClinicalTrials.gov).

Pancreatic Acinar Cell Carcinoma in the Setting of a BRCA1 Germline Mutation

Pancreatic acinar cell carcinoma (PACC) is a rare neoplasm of the exocrine pancreas. PACC’s molecular and genetic features are poorly elucidated compared with pancreatic ductal cell carcinoma. Here, we present the patient case of a woman in her late 60s, with a BRCA1 germline mutation and a medical history of breast and lung adenocarcinomas diagnosed with PACC. A literature search identified only 2 reported cases of PACC associated with a BRCA1 germline mutation.

1298P Extended overall survival results from the POLO study of active maintenance olaparib in patients with metastatic pancreatic cancer and a germline BRCA mutation

1298P Extended overall survival results from the POLO study of active maintenance olaparib in patients with metastatic pancreatic cancer and a germline BRCA mutation

Maintenance therapy with a poly(ADP-ribose) polymerase inhibitor in patients with newly diagnosed advanced epithelial ovarian cancer: individual patient data and trial-level meta-analysis

BackgroundWe synthesize the efficacy and toxicity of poly(ADP-ribose) polymerase inhibitors (PARPis) in patients with newly diagnosed advanced ovarian cancer.Patients and methodsWe manually extracted individual patient data (IPD) for progression-free survival (PFS) from published survival curves of randomized controlled trials (RCTs) that compared PARPi versus placebo as maintenance therapy in first-line treatment, for whole study populations and subgroups, based on BRCA1/BRCA2 mutation (germline and/or somatic) and homologous recombination deficiency (HRD) status, using WebPlotDigitizer software. The respective PFS curves for each study and combined population were reconstructed from extracted IPD. The primary outcome was PFS in combined whole population and subgroups.ResultsIn IPD analysis of combined population from three RCTs, with 2296 patients and 1287 events, PFS was significantly longer in PARPi versus placebo [median 20.4 (95% confidence interval (CI) 18.6-21.9) versus 14.9 (95% CI 13.9-16.5) months, respectively; hazard ratio (HR) 0.67, 95% CI 0.60-0.75; P < 0.001]. In IPD subgroup analyses from four eligible RCTs (2687 patients and 1485 events), median PFS was significantly longer in PARPi versus placebo arm, in the BRCA-mutated (45.7 versus 17.7 months, respectively; HR 0.38, 95% CI 0.32-0.46; P < 0.001), HRD-positive including BRCA-mutated (34.7 versus 17.9 months, respectively; HR 0.45, 95% CI 0.38-0.54; P < 0.001), and HRD positive excluding BRCA-mutated (22.3 versus 13.1 months, respectively; HR 0.47, 95% CI 0.34-0.65; P < 0.001) subgroups, but not in the HRD-negative (15.0 versus 11.3 months, respectively; HR 0.90, 95% CI 0.76-1.05; P = 0.75) subgroup. Results of trial-level meta-analysis were concordant with IPD analysis in whole population and subgroups.ConclusionsAmong newly diagnosed ovarian cancer patients, PARPi maintenance therapy significantly improves PFS in those with germline and/or somatic BRCA mutation and/or HRD-positive tumor but not in those with HRD-negative tumor.

Brca1L63X /+ rat is a novel model of human BRCA1 deficiency displaying susceptibility to radiation-induced mammary cancer.

Women who are heterozygous for deleterious BRCA1 germline mutations harbor a high risk of hereditary breast cancer. Previous Brca1‐heterozygous animal models do not recapitulate the breast cancer phenotype, and thus all currently used knockout models adopt conditional, mammary‐specific homozygous Brca1 loss or addition of Trp53 deficiency. Herein, we report the creation and characterization of a novel Brca1 mutant rat model harboring the germline L63X mutation, which mimics a founder mutation in Japan, through CRISPR‐Cas9–based genome editing. Homozygotes (Brca1 L63X/L63X) were embryonic lethal, whereas heterozygotes (Brca1 L63X/+) showed apparently normal development. Without carcinogen exposure, heterozygotes developed mammary carcinoma at a comparable incidence rate with their wild‐type (WT) littermates during their lifetime. Intraperitoneal injection of 1‐methyl‐1‐nitrosourea (25 or 50 mg/kg) at 7 weeks of age induced mammary carcinogenesis at comparable levels among the heterozygotes and their littermates. After exposure to ionizing radiation (0.1–2 Gy) at 7 weeks of age, the heterozygotes, but not WT littermates, displayed dose‐dependent mammary carcinogenesis with 0.8 Gy−1 excess in hazard ratio during their middle age; the relative susceptibility of the heterozygotes was more prominent when rats were irradiated at 3 weeks of age. The heterozygotes had tumors with a lower estrogen receptor α immunopositivity and no evidence of somatic mutations of the WT allele. The Brca1 L63X/+ rats thus offer the first single‐mutation, heterozygous model of BRCA1‐associated breast cancer, especially with exposure to a DNA break‐inducing carcinogen. This implies that such carcinogens are causative and a key to breast cancer prevention in individuals who carry high‐risk BRCA1 mutations.

BRCA Mutations in Ovarian and Prostate Cancer: Bench to Bedside.

Simple SummaryDNA damage is one of the hallmarks of cancer. Epithelial ovarian cancer (EOC) —especially the high-grade serous subtype—harbors a defect in at least one DNA damage response (DDR) pathway. Defective DDR results from a variety of lesions affecting homologous recombination (HR) and nonhomologous end joining (NHEJ) for double strand breaks, base excision repair (BER), and nucleotide excision repair (NER) for single strand breaks and mismatch repair (MMR). Apart from the EOC, mutations in the DDR genes, such as BRCA1 and BRCA2, are common in prostate cancer as well. Among them, BRCA2 lesions are found in 12% of metastatic castration-resistant prostate cancers, but very rarely in primary prostate cancer. Better understanding of the DDR pathways is essential in order to optimize the therapeutic choices, and has led to the design of biomarker-driven clinical trials. Poly(ADP-ribose) polymerase (PARP) inhibitors are now a standard therapy for EOC patients, and more recently have been approved for the metastatic castration-resistant prostate cancer with alterations in DDR genes. They are particularly effective in tumours with HR deficiency.DNA damage repair (DDR) defects are common in different cancer types, and these alterations can be exploited therapeutically. Epithelial ovarian cancer (EOC) is among the tumours with the highest percentage of hereditary cases. BRCA1 and BRCA2 predisposing pathogenic variants (PVs) were the first to be associated with EOC, whereas additional genes comprising the homologous recombination (HR) pathway have been discovered with DNA sequencing technologies. The incidence of DDR alterations among patients with metastatic prostate cancer is much higher compared to those with localized disease. Genetic testing is playing an increasingly important role in the treatment of patients with ovarian and prostate cancer. The development of poly (ADP-ribose) polymerase (PARP) inhibitors offers a therapeutic strategy for patients with EOC. One of the mechanisms of PARP inhibitors exploits the concept of synthetic lethality. Tumours with BRCA1 or BRCA2 mutations are highly sensitive to PARP inhibitors. Moreover, the synthetic lethal interaction may be exploited beyond germline BRCA mutations in the context of HR deficiency, and this is an area of ongoing research. PARP inhibitors are in advanced stages of development as a treatment for metastatic castration-resistant prostate cancer. However, there is a major concern regarding the need to identify reliable biomarkers predictive of treatment response. In this review, we explore the mechanisms of DDR, the potential for genomic analysis of ovarian and prostate cancer, and therapeutics of PARP inhibitors, along with predictive biomarkers.

Emerging Role of PARP Inhibitors in Metastatic Prostate Cancer.

We highlight the clinical development of Poly (ADP-Ribose) polymerase (PARP) inhibitors in prostate cancer. Approximately 10 to 30% of metastatic prostate cancer patients carry germline or somatic mutations in DNA repair pathways. BRCA2 is the most commonly mutated gene in DNA damage repair pathways. Because of its critical function in homologous recombination repair (HRR) machinery, deleterious BRCA2 mutation enables synthetic lethality to a PARP inhibitor. Olaparib demonstrated clinical benefit in patients with deleterious mutations in HRR-related genes and most clearly in patients with BRCA2 mutations. Olaparib received the US FDA approval or mCRPC patients with a qualifying HRR gene mutation in May 2020. Rucaparib received an accelerated FDA approval for patients with BRCA1- or BRCA2-mutated mCRPC based on 43% objective response rate in a phase II study. To expand the application of a PARP inhibitor, several trials have evaluated various combination strategies with an androgen receptor signaling inhibitor, immunotherapy, radium-223, and others. While no PARP inhibitor combination regimen has been approved, promising data from a PARP inhibitor and an ASI combination have been reported. PARP inhibitor represents a standard treatment for patient with mCRPC with germline or somatic mutations in BRCA2 and other HRR pathway genes.

Germline and somatic genetic testing trends among women with epithelial ovarian cancer (197)

Objectives: Identifying homologous recombination deficiency (HRD) mutations has significant treatment implications for women with epithelial ovarian cancer (EOC). While germline testing strategies have been well cataloged in clinical practice, and the American Society for Clinical Oncology recommends somatic testing if germline testing is negative, best-practice strategies for obtaining somatic, germline, or combination testing remain unclear. We aimed to trend rates and temporal relationships of germline and somatic genetic testing at an academic institution to identify gaps in equitable access to precision testing. Methods: All patients with EOC were identified from the electronic medical record (EMR) using diagnostic codes at a single urban academic gynecologic oncology group from January 2015 to December 2020. IRB approval was obtained and an EMR review was performed to analyze trends in germline and somatic genetic testing. Descriptive statistics and Chi-square tests were performed. Results: A total of 431 women with EOC were identified. Patients were predominantly White (88%), older women (mean age 68) who had insurance (97%). Most patients had advanced stage disease (80%) with high-grade serous histology (77%). Eighty percent of patients underwent germline testing with 15% having BRCA1/2 mutations identified. The somatic testing rate was 50% with rates increasing each contact year (Figure 1A) and a detection rate of 29.5% for HRD mutations. Combination testing rates also increased per contact year (Figure 1B). Patients with negative germline testing were more likely to undergo somatic testing (60%) compared to those with germline BRCA1 (29%) or BRCA2 (37%) mutations (p = 0.0012). About 12.5% of patients with negative germline testing had a somatic mutation in either BRCA1/2 or loss of heterozygosity. Of patients without germline genetic testing, only 27% had somatic testing performed (22/81). Thirty percent had somatic testing performed after a recurrence; however, 36% of patients experiencing a recurrence never underwent somatic testing. Sixty-nine percent had somatic testing performed on a current tissue specimen as opposed to archived tissue. Conclusions: Somatic testing resulted in actionable HRD mutations in one in three patients in this cohort, with one in eight patients having somatic HRD mutations despite negative germline testing. This illustrates the therapeutic potential of comprehensive genetic profiling and represents how variations in practice may result in missed therapeutic interventions. As somatic testing rates continue to increase, efforts to define barriers and create streamlined, guideline-based strategies for universal testing are warranted to better align with current clinical practice guidelines. Objectives: Identifying homologous recombination deficiency (HRD) mutations has significant treatment implications for women with epithelial ovarian cancer (EOC). While germline testing strategies have been well cataloged in clinical practice, and the American Society for Clinical Oncology recommends somatic testing if germline testing is negative, best-practice strategies for obtaining somatic, germline, or combination testing remain unclear. We aimed to trend rates and temporal relationships of germline and somatic genetic testing at an academic institution to identify gaps in equitable access to precision testing. Methods: All patients with EOC were identified from the electronic medical record (EMR) using diagnostic codes at a single urban academic gynecologic oncology group from January 2015 to December 2020. IRB approval was obtained and an EMR review was performed to analyze trends in germline and somatic genetic testing. Descriptive statistics and Chi-square tests were performed. Results: A total of 431 women with EOC were identified. Patients were predominantly White (88%), older women (mean age 68) who had insurance (97%). Most patients had advanced stage disease (80%) with high-grade serous histology (77%). Eighty percent of patients underwent germline testing with 15% having BRCA1/2 mutations identified. The somatic testing rate was 50% with rates increasing each contact year (Figure 1A) and a detection rate of 29.5% for HRD mutations. Combination testing rates also increased per contact year (Figure 1B). Patients with negative germline testing were more likely to undergo somatic testing (60%) compared to those with germline BRCA1 (29%) or BRCA2 (37%) mutations (p = 0.0012). About 12.5% of patients with negative germline testing had a somatic mutation in either BRCA1/2 or loss of heterozygosity. Of patients without germline genetic testing, only 27% had somatic testing performed (22/81). Thirty percent had somatic testing performed after a recurrence; however, 36% of patients experiencing a recurrence never underwent somatic testing. Sixty-nine percent had somatic testing performed on a current tissue specimen as opposed to archived tissue. Conclusions: Somatic testing resulted in actionable HRD mutations in one in three patients in this cohort, with one in eight patients having somatic HRD mutations despite negative germline testing. This illustrates the therapeutic potential of comprehensive genetic profiling and represents how variations in practice may result in missed therapeutic interventions. As somatic testing rates continue to increase, efforts to define barriers and create streamlined, guideline-based strategies for universal testing are warranted to better align with current clinical practice guidelines.

Optimal Choice of Neoadjuvant Chemotherapy for HER2-Negative Breast Cancer: Clinical Insights.

The neoadjuvant setting provides immense opportunities for translational research and drug development. The acceptance of pathological complete response (pCR) as a surrogate endpoint for clinical benefit has led to the widespread use of neoadjuvant treatment. Optimal neoadjuvant therapies are determined based on their ability to achieve the highest rates of pCR. Predicted rates of pCR for triple negative breast cancer (TNBC) treated with sequential taxane/anthracycline regimens range from 35% to 48%. With the addition of a platinum agent pCR rates of 55% are predicted. Further increases have been observed with the addition of immune checkpoint inhibitors to this standard chemotherapy backbone. In the pivotal KEYNOTE-522 clinical trial pCR rates of 65% and 69% were reported for chemotherapy plus pembrolizumab in the overall and PD-L1-positive subgroup respectively. The role of the neoadjuvant chemotherapy is less clear in hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer. In general, HR–positive cancers have the least chance of achieving a pCR after neoadjuvant chemotherapy, especially if they are low-grade. If neoadjuvant chemotherapy is given for high-risk HR-positive, HER2-negative breast cancer, standard adjuvant anthracycline/taxane regimens are appropriate. Optimum endocrine therapy is the standard-of-care in the adjuvant setting regardless of pCR. There are several genomic signatures available to guide decisions regarding adjuvant chemotherapy use however these assays are not routinely used in the neoadjuvant setting. For high-risk patients meeting the criteria for the monarchE trial adjuvant abemaciclib in addition to endocrine therapy is associated with an improvement in disease free survival (DFS) at 3 years. Based on the OlympiA trial patients with germline BRCA mutations should be considered for adjuvant olaparib therapy. In this article we review neoadjuvant clinical trials that guide optimum treatment options for TNBC and HR-positive, HER2-negative breast cancer.