Homologous recombination deficiency and ovarian cancer

The discovery that PARP inhibitors block an essential pathway of DNA repair in cells harbouring a BRCA mutation has opened up a new therapeutic avenue for high-grade ovarian cancers. BRCA1 and BRCA2 proteins are essential for high-fidelity repair of double-strand breaks of DNA through the homologous recombination repair (HRR) pathway. Deficiency in HRR (HRD) is a target for PARP inhibitors. The first PARP inhibitor, olaparib, has now been licensed for BRCA-mutated ovarian cancers. While mutated BRCA genes are individually most commonly associated with HRD other essential HRR proteins may be mutated or functionally deficient potentially widening the therapeutic opportunities for PARP inhibitors. HRD is the first phenotypically defined predictive marker for therapy with PARP inhibitors in ovarian cancer. Several different PARP inhibitors are being trialled in ovarian cancer and this class of drugs has been shown to be a new selective therapy for high-grade ovarian cancer. Around 20% of high-grade serous ovarian cancers harbour germline or somatic BRCA mutations and testing for BRCA mutations should be incorporated into routine clinical practice. The expanded use of PARP inhibitors in HRD deficient (non-BRCA mutant) tumours using a signature of HRD in clinical practice requires validation.     

Japanese nationwide observational multicenter study of tumor BRCA1/2 variant testing in advanced ovarian cancer

The association between germline BRCA1 and BRCA2 pathogenic variants (mutations: gBRCAm) and ovarian cancer risk is well established. Germline testing alone cannot detect somatic BRCA1/2 pathogenic variants (sBRCAm), which is calculated based on the proportion of tumor BRCAm (tBRCAm) from tumor samples and gBRCAm. Homologous recombination deficiency (HRD) results mainly from genetic/epigenetic alterations in homologous recombination repair-related genes and can be evaluated by genomic instability status. In Japan, the prevalence of tBRCAm, sBRCAm, and HRD remains unclear. This multicenter, cross-sectional, observational study, CHaRacterIzing the croSs-secTional approach to invEstigate the prevaLence of tissue BRCA1/2 mutations in newLy diagnosEd advanced ovarian cancer patients (CHRISTELLE), evaluated the prevalence of tBRCAm, sBRCAm, and HRD in tumor specimens from newly diagnosed patients with ovarian cancer who underwent gBRCA testing. Of the 205 patients analyzed, 26.8% had a tBRCAm, including tBRCA1m (17.6%) and tBRCA2m (9.3%). The overall prevalence of tBRCAm, gBRCAm, sBRCAm, and HRD-positive status was 26.8%, 21.5%, 6.3%, and 60.0%, respectively. The calculated sBRCAm/tBRCAm ratio was 23.6% (13/55), and the prevalence of gBRCA variant of uncertain significance was 3.9%. These results suggest gBRCA testing alone cannot clearly identify the best course of treatment, highlighting the importance of sBRCA testing in Japan. The present results also suggest that testing for tBRCA and HRD should be encouraged in advanced ovarian cancer patients to drive precision medicine.     

BRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation

Mutations in BRCA1/2 increase the risk of developing breast and ovarian cancer. Germline BRCA1/2 mutations occur in 8.6–13.7% of unselected epithelial ovarian cancers, somatic mutations are also frequent. BRCA1/2 mutated or dysfunctional cells may be sensitive to PARP inhibition by synthetic lethality. The aim of this study is to comprehensively characterise the BRCA1/2 status of a large panel of ovarian cancer cell lines available to the research community to assist in biomarker studies of novel drugs and in particular of PARP inhibitors.The BRCA1/2 genes were sequenced in 41 ovarian cell lines, mRNA expression of BRCA1/2 and gene methylation status of BRCA1 was also examined. The cytotoxicity of PARP inhibitors olaparib and veliparib was examined in 20 cell lines.The cell line SNU-251 has a deleterious BRCA1 mutation at 5564G > A, and is the only deleterious BRCA1/2 mutant in the panel. Two cell lines (UPN-251 and PEO1) had deleterious mutations as well as additional reversion mutations that restored the protein functionality. Heterozygous mutations in BRCA1/2 were relatively common, found in 14.6% of cell lines. BRCA1 was methylated in two cell lines (OVCAR8, A1847) and there was a corresponding decrease in gene expression. The BRCA1 methylated cell lines were more sensitive to PARP inhibition than wild-type cells. The SNU-251 deleterious mutant was more sensitive to PARP inhibition, but only in a long-term exposure to correct for its slow growth rate. Cell lines derived from metastatic disease are significantly more resistant to veliparib (2.0 fold p = 0.03) compared to those derived from primary tumours. Resistance to olaparib and veliparib was correlated Pearsons-R 0.5393, p = 0.0311.The incidence of BRCA1/2 deleterious mutations 1/41 cell lines derived from 33 different patients (3.0%) is much lower than the population incidence. The reversion mutations and high frequency of heterozygous mutations suggest that there is a selective pressure against BRCA1/2 in cell culture similar to the selective pressure seen in the clinic after treatment with chemotherapy. PARP inhibitors may be useful in patients with BRCA1 deleterious mutations or gene methylation.     

Cancer treatment according to BRCA1 and BRCA2 mutations

Identification of germline mutations associated with significant cancer susceptibility has the potential to change all aspects of an individual's care, from screening to cancer treatment. For example, women with germline mutations in BRCA1 and BRCA2 have markedly elevated risks of breast and ovarian cancer and the identification of these germline mutations has led to specific screening and prevention strategies. More recently, advances in the understanding of the biological function of BRCA1 and BRCA2 have led to clinical trials testing targeted therapies in this population, particularly poly(ADP-ribose) polymerase (PARP) inhibitors. Unfortunately, the development of PARP inhibitors has not been as rapid as anticipated and has been more challenging than expected. Somatic mutations identified in many cancer types have allowed the development of therapeutics that target these mutated genes, and many of these agents obtained rapid regulatory approval and are currently in widespread clinical practice. Diagnostic testing has a central role in targeted cancer therapeutics for both somatic and germline mutations. Although the era of molecular medicine and targeted therapies has led to significant changes in the practice of oncology, new challenges continue to arise.     

Rapid Progression of Metastatic Pancreatic Adenocarcinoma During Platinum-Based Therapy in a Patient Harboring a Pathogenic BRCA2 Germline Variant

Familial pancreatic adenocarcinoma (PDAC) is most commonly related to inheritance of a pathogenic BRCA variant (J Med Genet 2005;42:711–719). The National Comprehensive Cancer Network recommends germline testing for patients diagnosed with PDAC and recommends platinum-based chemotherapy as the preferred initial systemic therapy for patients harboring a pathogenic BRCA germline variant with PDAC ( https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455 ). PDACs related to pathogenic BRCA germline variants typically demonstrate BRCA loss of heterozygosity (LOH), which results in ineffective DNA damage repair due to a lack of normal BRCA gene product activity. By causing DNA damage, platinum-based therapies have been shown to be highly effective therapies (Cancer Cell 2010;18:499–509, Gen Med 2015;17:569). In contrast, platinum-based therapies would be predicted to be significantly less effective for PDACs in patients with pathogenic BRCA germline variants who have cancers that lack BRCA LOH. Poly (ADP-ribose) polymerase 1 (PARP) is also key to effective DNA repair. The Food and Drug Administration has approved PARP inhibitors for patients carrying germline pathogenic BRCA variants and metastatic breast cancer or ovarian cancer (Ann Oncol 2019;30:558–566, J Clin Oncol 2015;33:244–250). PARP inhibitors would again be expected to be far less effective in patients who carry pathogenic BRCA germline variants with breast and ovarian cancers (those that lack BRCA LOH) than in those with BRCA-related breast and ovarian cancers (which typically demonstrate BRCA LOH), because PARP is involved in DNA repair. Here, we present a patient harboring a pathogenic BRCA germline variant whose PDAC grew rapidly during platinum-based therapy and lacked BRCA LOH and therefore was not likely BRCA related. Given the molecular fingerprint of BRCA-related PDAC in patients with pathogenic BRCA germline variants and the mechanism of action of platinum-based therapies and PARP inhibitors, this case underscores the importance of future studies aimed at determining whether the lack of BRCA LOH in PDACs in pathogenic BRCA germline variant carriers is a biomarker of less responsiveness to platinum-based chemotherapy and PARP inhibitors.

Key Points

• Platinum-based therapy or Poly (ADP-ribose) polymerase 1 (PARP) inhibitor therapies are highly effective systemic therapy options for most patients with pancreatic adenocarcinoma who carry a germline pathogenic BRCA variant.
• In the case presented here, a patient carrying a germline pathogenic BRCA variant saw rapid progression of his pancreatic adenocarcinoma while on platinum-based therapy. Next-generation sequencing confirmed that his pancreatic cancer was likely not related to BRCA loss of heterozygosity (LOH).
• Studies are needed to determine, in patients who harbor germline pathogenic BRCA variants, whether similar cancers (i.e., those that lack BRCA LOH) are less responsive to platinum-based or PARP inhibitor therapies than are those more common BRCA-related cancers (i.e., those that demonstrate LOH).

     

PARP Inhibitors and Prostate Cancer: To Infinity and Beyond BRCA

The U.S. Food and Drug Administration recently approved two poly‐adenosine diphosphate‐ribose polymerase (PARP) inhibitors, olaparib and rucaparib, for treatment of biomarker‐positive metastatic castrate resistant prostate cancer. The benefits of PARP inhibition have been well characterized in patients who have BRCA1 and BRCA2 mutations in several forms of cancer. BRCA1 and BRCA2 occupy key roles in DNA damage repair, which is comprised of several different pathways with numerous participants. Patients with mutations in other key genes within the DNA damage repair pathway may also respond to treatment with PARP inhibitors, and identification of these alterations could significantly increase the percentage of patients that may benefit from PARP inhibition. This review focuses on the potential for synthetically lethal interactions between PARP inhibitors and non‐BRCA DNA damage repair genes.Implications for PracticeThe treatment potential of PARP inhibition has been well characterized in patients with BRCA1 and BRCA2 mutations, but there is compelling evidence for expanding the use of PARP inhibitors to mutations of other non‐BRCA DNA damage repair (DDR) genes. This could increase the percentage of patients that may benefit from treatment with PARP inhibitors alone or in combination with other therapies. Understanding the significance of PARP inhibitor‐sensitizing alterations in other common non‐BRCA DDR genes will help guide clinical decisions to provide targeted treatment options to a wider population of patients.     

PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions

Poly(ADP-ribose) polymerase (PARP) inhibitors cause targeted tumour cell death in homologous recombination (HR)-deficient cancers, including BRCA-mutated tumours, by exploiting synthetic lethality. PARP inhibitors are being evaluated in late-stage clinical trials of ovarian cancer (OC). Recently, olaparib was the first PARP inhibitor approved in the European Union and United States for the treatment of advanced BRCA-mutated OC. This paper reviews the role of BRCA mutations for tumorigenesis and PARP inhibitor sensitivity, and summarises the clinical development of PARP inhibitors for the treatment of patients diagnosed with OC. Among the five key PARP inhibitors currently in clinical development, olaparib has undergone the most extensive clinical investigation. PARP inhibitors have demonstrated durable antitumour activity in BRCA-mutated advanced OC as a single agent in the treatment and maintenance setting, particularly in platinum-sensitive disease. PARP inhibitors are well tolerated; however, further careful assessment of moderate and late-onset toxicity is mandatory in the maintenance and adjuvant setting, respectively. PARP inhibitors are also being evaluated in combination with chemotherapeutic and novel targeted agents to potentiate antitumour activities. Current research is extending the use of PARP inhibitors beyond BRCA mutations to other sensitising molecular defects that result in HR-deficient cancer, and is defining an HR-deficiency signature. Trials are underway to determine whether such a signature will predict sensitivity to PARP inhibitors in women with sporadic OC.     

PARP inhibitors in breast cancer: Bringing synthetic lethality to the bedside

Individuals with breast and ovarian cancer susceptibility gene 1 (BRCA1) or BRCA2 germline mutations have a significantly increased lifetime risk for breast and ovarian cancers. BRCA‐mutant cancer cells have abnormal homologous recombination (HR) repair of DNA. In these tumors, the base excision repair (BER) pathway is important for cell survival. The poly(adenosine diphosphate‐ribose) polymerase (PARP) enzymes play a key role in BER, and PARP inhibitors are effective in causing cell death in BRCA‐mutant cells while sparing normal cells—a concept called synthetic lethality. PARP inhibitors are the first cancer therapeutics designed to exploit synthetic lethality. Recent clinical trials in BRCA‐mutant, metastatic breast cancer demonstrated improved outcomes with single‐agent PARP inhibitors (olaparib and talazoparib) over chemotherapy. However, resistance to PARP inhibitors remains a challenge. Primarily due to myelosuppression, the combination of PARP inhibitors with chemotherapy has been difficult. Novel combinations with chemotherapy, immunotherapy, and other targeted therapies are being pursued. In this review, the authors discuss current knowledge of PARP inhibitors in BRCA‐mutant breast cancer and potential future directions for these agents. Cancer 2018;124:2498‐506 . © 2018 American Cancer Society.     

PARP Inhibitors in BRCA Gene-Mutated Ovarian Cancer and Beyond

Poly(ADP-ribose)polymerase (PARP) inhibitors are showing considerable promise for the treatment of BRCA mutation–associated ovarian and breast cancer. This approach exploits a synthetic lethal strategy to target the specific DNA repair pathway in cancers that harbor mutations in the BRCA1 or BRCA2 genes. Accumulating evidence suggests that PARP inhibitors may have a wider application in the treatment of sporadic, high-grade serous ovarian cancers and other cancers including endometrial cancer. In this review, we discuss the clinical development of PARP inhibitors in ovarian cancer and explore challenges that need to be addressed if the full potential of these agents is to be realized.     

Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer

Introduction  

BRCA1 or BRCA2 germline mutations increase the risk of developing breast cancer. Tumour cells from germline mutation carriers have frequently lost the wild-type allele. This is predicted to result in genomic instability where cell survival depends upon dysfunctional checkpoint mechanisms. Tumorigenic potential could then be acquired through further genomic alterations. Surprisingly, somatic BRCA mutations are not found in sporadic breast tumours. BRCA1 methylation has been shown to occur in sporadic breast tumours and to be associated with reduced gene expression. We examined the frequency of BRCA1 methylation in 143 primary sporadic breast tumours along with BRCA1 copy number alterations and tumour phenotype.     

Recent advances in targeting DNA repair pathways for the treatment of ovarian cancer and their clinical relevance

Poly (ADP-ribose) polymerase (PARP) inhibitors have attracted much attention as one of the major molecular-targeted therapeutics for inhibiting DNA damage response. The PARP inhibitor, olaparib, has been clinically applied for treating certain recurrent ovarian cancer patients with BRCA1/2 mutations in Europe and the United States. It was also designated on 24 March 2017 as an orphan drug in Japan for similar clinical indications. In this review, we discuss (i) the prevalence of BRCA1/2 mutations in ovarian cancer, (ii) clinical trials of PARP inhibitors in ovarian cancer, (iii) genetic counseling for hereditary breast and ovarian cancer patients, and (iv) non-BRCA genes that may be associated with homologous recombination deficiency.     

High prevalence of deleterious <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> germline mutations in arab breast and ovarian cancer patients

Purpose

The BRCA1 and BRCA2 (BRCA) genes are heavily involved in mammalian cell DNA repair processes. Germline pathogenic mutations in BRCA increase the lifetime risk of developing breast and/or ovarian cancer in women. In the Arabian Peninsula, most breast and ovarian cancers are diagnosed as early-onset cases, some of which may be due to germline variants in BRCA genes. To identify the BRCA germline mutation frequency and spectrum in the Arab breast and ovarian cancers, we have sequenced the protein-coding exons of these genes.

Methods

All BRCA coding exons were sequenced using genomic DNA isolated from lymphocytes in 173 Arab breast and ovarian cancer patients by a massively parallel sequencing technology and verified by Sanger sequencing.

Results

We identified a total of 17 distinct pathogenic mutations, of which four were novel, in 28 patients; nine out of 108 breast (8.3%) and 19 out of 65 ovarian cancer (29.2%) patients. Thirteen of the 17 mutations were detected in BRCA1 and four mutations were found in BRCA2 gene. Four pathogenic BRCA1 mutations (c.1140dupG, c.4136_4137delCT, c.5095C>T, and c.5530delC) accounted for 54% of all the mutations detected in our patient cohort. Additionally, we identified a likely pathogenic BRCA1 missense variant in two of 108 breast (1.9%) and a BRCA2 missense variant in one of 65 ovarian cancer (1.5%) patients.

Conclusions

The overall frequencies of the BRCA germline mutations were 10.2% in breast and 30.7% in ovarian cancer patients. These data shed new light into the prevalence of BRCA mutations in the Arab women population.

     

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.     

Olaparib Use in Patients With Metastatic Breast Cancer Harboring Somatic BRCA1/2 Mutations or Mutations in Non-BRCA1/2, DNA Damage Repair Genes

BackgroundPoly-ADP ribose polymerase (PARP) inhibitors (PARPi) are active in patients with germline BRCA1/2 (gBRCA1/2)-mutated breast cancer, accounting for 5% to 10% of all breast cancers. Another 5% to 10% harbor somatic BRCA1/2 (sBRCA1/2) mutations or mutations in non-BRCA1/2, homologous recombination repair (HRR) genes but until recently, there were no data for the use of PARPi in these patients. This study examines the use of olaparib in patients with metastatic breast cancer harboring sBRCA1/2 or germline or somatic non-BRCA1/2, HRR mutations and demonstrates potential activity of PARPi in this setting.MethodsIn this retrospective, single institution study, patients who were treated with off-label, off-protocol olaparib for metastatic breast cancer harboring sBRCA1/2 or germline or somatic non-BRCA1/2, HRR mutations were identified. The primary aim was to describe these patients’ demographics, tumor characteristics, mutations, safety and tolerability, response rates, progression free survival, PARPi-associated survival and subsequent treatment.ResultsSeven patients were treated off-label, off-trial with olaparib for sBRCA1/2-mutated cancers (n = 4) or non-BRCA1/2, HRR-mutated cancers (n = 3). All patients with sBRCA1/2-mutated cancers responded to PARP inhibition; patients with non-BRCA1/2, HRR-mutated cancers did not respond. The median progression free survival in patients with a sBRCA1/2 mutation was 6.5 months (range 5-9 months) vs. 3 months (range 2-4 months) in patients with non-BRCA1/2, HRR mutations.ConclusionThis single institution experience adds to recent larger reports confirming evidence for PARPi therapy in patients with metastatic breast cancer harboring sBRCA1/2 mutations. No activity was observed in patients with either germline or somatic non-BRCA1/2, HRR-mutated cancers.     

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.     

The performance of BRCA1 immunohistochemistry for detecting germline,somatic, and epigenetic BRCA1 loss in high-grade serous ovarian cancer

BackgroundBRCA1 expression can be lost by a variety of mechanisms including germline or somatic mutation and promotor hypermethylation. Given the potential importance of BRCA1 loss as a predictive and prognostic biomarker in high-grade serous ovarian cancer, we sought to evaluate the utility of BRCA1 immunohistochemistry (IHC) in screening for BRCA1 loss by germline, somatic, and epigenetic mechanisms.Patients and methodsPatients with advanced high-grade serous ovarian cancer who had previously undergone germline BRCA1 testing were identified. Samples from each tumor were stained for BRCA1 and reviewed independently by two pathologists blinded to BRCA status. Tumors with abnormal BRCA1 IHC and wild-type germline testing underwent further evaluation for somatic BRCA1 mutations and promoter hypermethylation. McNemar's test was used to determine the association of BRCA1 IHC with germline BRCA1 mutations and BRCA1 loss through any mechanism. Kaplan–Meier methods were used to estimate overall survival (OS), and the log-rank test was used to assess differences between groups.ResultsInter-rater reliability between the two pathologists on BRCA IHC interpretation was very good (kappa coefficient 0.865, P = 0.16; McNemar's test). BRCA1 IHC was abnormal in 36% (48/135) of cases. When compared with germline BRCA1 status, BRCA1 IHC had a high negative predictive value (95.4%) but a low positive predictive value (PPV, 52.1%). When accounting for promoter hypermethylation and somatic mutations as alternative methods of BRCA1 loss, the PPV rose to 87.5%. Five-year OS rate was 49.6% [95% confidence interval (CI) 26.3% to 69.3%] for patients with germline BRCA1 mutations, 50.4% (95% CI 27.5% to 69.5%) for germline wild-type BRCA1 and abnormal IHC, and 52.1% (95% CI 38.4% to 64.2%) for germline wild-type BRCA1 and normal IHC (P = 0.92).ConclusionsBRCA1 IHC interpretation was a highly reproducible and accurate modality for detecting germline, somatic, or epigenetic mechanisms of BRCA1 loss. These results support further development of BRCA1 IHC as a potential biomarker for BRCA1 loss in high-grade serous ovarian cancer.     

Somatic mutations in the BRCA1 gene in Chinese women with sporadic breast cancer

Recent studies suggested that breast cancer patients who carry a BRCA1 germline mutation benefit from poly (ADP-ribose) polymerase (PARP) inhibitors; therefore, it would be of great interest to detect BRCA1 somatic mutations in sporadic breast cancers. In this study, we detected BRCA1 somatic mutations in tumor cDNA from 144 Chinese women with sporadic breast cancer by using polymerase chain reaction (PCR)-direct sequencing assay. In total, eight BRCA1 alterations (three nonsense mutations and five missense mutations) were identified in this cohort of 144 sporadic breast cancers. We further confirmed that 5 out of 144(3.5%) sporadic breast cancer cases carried a BRCA1 somatic mutation, including two novel nonsense mutations (c.191_212del22 and c.2963C>G) resulting in a truncated protein and three missense mutations (c.114G>T, c.925A>C, and c.824G>A). The two cases with BRCA1 somatic truncating mutations also contained a TP53 somatic mutation in the tumors. Our study suggested that a small subset of sporadic breast cancers do harbor BRCA1 somatic mutations; these patients who carry a BRCA1 somatic mutation may be potential candidates for treatment with PARP inhibitors.     

Poly(ADP-Ribose) Inhibition: Exploring a New Approach to Breast Cancer Prevention in <Emphasis Type="Italic">BRCA1/2</Emphasis> Mutation Carriers

Carriers of deleterious BRCA1 and BRCA2 mutations face an elevated risk of developing breast cancer. This risk warrants consideration of prevention interventions. Currently, the only proven prevention intervention for BRCA mutation carriers is risk-reducing surgery. Inhibitors of poly(ADP-ribose) polymerase (PARP) are a new class of drugs that appear to be effective in treating BRCA mutation–associated cancers and triple-negative breast cancers. PARP inhibitors may offer a new approach to breast cancer prevention in BRCA mutation carriers. This article reviews current breast cancer prevention interventions for BRCA mutation carriers and discusses the rationale for investigating new chemoprevention agents in this population. The mechanism of action of PARP inhibitors and the rationale for studying them in BRCA mutation carriers is reviewed. Published clinical trials regarding PARP inhibitors and ongoing research regarding PARP inhibitors and breast cancer prevention are reviewed.     

Methylation not a frequent “second hit” in tumors with germline BRCA mutations

Mutations in tumor suppressor genes BRCA1 and BRCA2 confer an increased lifetime risk of breast and ovarian cancer. Loss of heterozygosity (LOH) of the wildtype allele has been observed in ~80% of tumors from BRCA1 carriers and 70% of tumors from BRCA2 carriers and accounts for the majority of the “second-hits” occurring in BRCA-related tumors. Few sporadic tumors have been reported to have mutations in BRCA. Some sporadic tumors do show LOH of BRCA1 and BRCA2. BRCA1 promoter methylation has also been observed in sporadic ovarian and breast tumors; however, BRCA2 promoter methylation has not been reported in sporadic tumors. The relationship between BRCA LOH and BRCA promoter methylation has not been well characterized in tumors from BRCA germline mutation carriers. The goal of this study was to determine if BRCA1 and BRCA2 promoter hypermethylation serves as a “second-hit” in tumors from mutation carriers that do not show LOH. We studied 38 tumors from BRCA1 carriers and 23 tumors from BRCA2 carriers for LOH. To determine if BRCA1 and BRCA2 promoter hypermethylation serves as a “second-hit” in tumors with germline mutations, we tested 15 tumors lacking LOH and nine tumors with LOH for BRCA1 or BRCA2 promoter methylation. We identified seven BRCA1 tumors and nine BRCA2 tumors lacking LOH. Of these, only one tumor with a BRCA2 mutation showed promoter methylation. These data indicate that promoter methylation is a not a frequent “second-hit” in tumors from BRCA1 or BRCA2 carriers.