Germline Mutations In BRCA1 Research Articles

Large-scale copy number alterations are enriched for synthetic viability in BRCA1/BRCA2 tumors

BackgroundPathogenic BRCA1 or BRCA2 germline mutations contribute to hereditary breast, ovarian, prostate, and pancreatic cancer. Paradoxically, bi-allelic inactivation of BRCA1 or BRCA2 (bBRCA1/2) is embryonically lethal and decreases cellular proliferation. The compensatory mechanisms that facilitate oncogenesis in bBRCA1/2 tumors remain unclear.MethodsWe identified recurrent genetic alterations enriched in human bBRCA1/2 tumors and experimentally validated if these improved proliferation in cellular models. We analyzed mutations and copy number alterations (CNAs) in bBRCA1/2 breast and ovarian cancer from the TCGA and ICGC. We used Fisher’s exact test to identify CNAs enriched in bBRCA1/2 tumors compared to control tumors that lacked evidence of homologous recombination deficiency. Genes located in CNA regions enriched in bBRCA1/2 tumors were further screened by gene expression and their effects on proliferation in genome-wide CRISPR/Cas9 screens. A set of candidate genes was functionally validated with in vitro clonogenic survival and functional assays to validate their influence on proliferation in the setting of bBRCA1/2 mutations.ResultsWe found that bBRCA1/2 tumors harbor recurrent large-scale genomic deletions significantly more frequently than histologically matched controls (n = 238 cytobands in breast and ovarian cancers). Within the deleted regions, we identified 277 BRCA1-related genes and 218 BRCA2-related genes that had reduced expression and increased proliferation in bBRCA1/2 but not in wild-type cells in genome-wide CRISPR screens. In vitro validation of 20 candidate genes with clonogenic proliferation assays validated 9 genes, including RIC8A and ATMIN (ATM-Interacting protein). We identified loss of RIC8A, which occurs frequently in both bBRCA1/2 tumors and is synthetically viable with loss of both BRCA1 and BRCA2. Furthermore, we found that metastatic homologous recombination deficient cancers acquire loss-of-function mutations in RIC8A. Lastly, we identified that RIC8A does not rescue homologous recombination deficiency but may influence mitosis in bBRCA1/2 tumors, potentially leading to increased micronuclei formation.ConclusionsThis study provides a means to solve the tumor suppressor paradox by identifying synthetic viability interactions and causal driver genes affected by large-scale CNAs in human cancers.

Immunotherapy Prior to a Liver Transplant: Literature Review and a Case Report of Hepatocellular Carcinoma With BRCA1 Mutation

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality worldwide. The effectiveness of its standard treatment in some cases remains poor.We report a case of a patient with Barcelona Clinic Liver Cancer stage C cryptogenic HCC whose life duration was 26 months after diagnosis.A 46-year-old woman, a former smoker, presented with elevated alpha-fetoprotein and a left liver lobe mass diagnosed as HCC. Pulmonary nodules (presumably metastatic) were previously found and remained stable. The left lobe of the liver was resected. Intrahepatic recurrence developed 1.5 months later. Lenvatinib+pembrolizumab therapy was prescribed and later switched to olaparib following the detection of somatic and germline BRCA1 mutation. The patient underwent a liver transplant and was prescribed a combination of tacrolimus and everolimus, later supplemented with extracorporeal photopheresis. Pulmonary nodules that were found to be metastases were treated with radiation therapy. A lethal outcome occurred 21.3 months after the transplant.The first literature review related to this case report discusses the problem of neoadjuvant immune checkpoint inhibitor therapy prior to a liver transplant. More than 100 patients have been described in 40 articles and 113 patients, in 2 multicenter studies. Although 16.7%-27.7% of patients developed rejection, such approach may be effective in downstaging the disease.

Management of BRCA-associated breast cancer patients in low and middle-income countries: a review.

Breast cancer poses a significant global health challenge, with higher incidence rates in developed countries. However, low- and middle-income countries (LMICs) suffer from higher mortality rates due to various factors, including limited screening programs, delayed diagnosis and inadequate access to healthcare and advanced treatments. Approximately 5%-10% of breast cancer cases stem from germline mutations in BRCA-1/2 genes. A positive BRCA1/2 status obtained through genetic testing significantly influences surgical and medical treatment decisions. Therefore, genetic counseling, proper surveillance and customized interventions for BRCA1/2 carriers are essential to maximizing the benefits of monitoring, chemoprevention and risk-reducing surgeries for breast and ovarian cancers. Identification of BRCA mutations also impacts treatment strategies, leading to the integration of chemotherapeutic agents like platinum-based chemotherapy and PARP inhibitors. However, implementing these advanced treatment guidelines in LMICs with complex, fragmented and underfunded healthcare systems presents numerous challenges. In this review, we explore the current status and obstacles associated with managing BRCA1/2-associated breast cancer in LMICs.

The guidelines for clinical practice for carriers of germline mutations in hereditary breast, ovarian, prostate, and pancreatic cancer predisposition genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 (4.2024).

The Guidelines for Clinical Practice for carriers of pathogenic variants in clinically relevant cancer predisposition genes define the steps of primary and secondary prevention that should be provided to these individuals at high risk of developing hereditary cancer in the Czech Republic. The drafting of the guidelines was organized by the Oncogenetics Working Group of the Society for Medical Genetics and Genomics of J. E. Purkyně Czech Medical Society (SLG ČLS JEP) in cooperation with the representatives of oncology and oncogynecology. The guidelines are based on the current recommendations of the National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO) and take into account the capacity of the Czech healthcare system.

Efficacy of a platinum-based chemotherapy rechallenge for platinum-sensitive recurrence after PARP inhibitor maintenance

ObjectivePlatinum-free interval (PFI) is the period from the end of platinum-based chemotherapy to the date of recurrence. If the PFI is > 6 months, a platinum-based chemotherapy rechallenge is considered; however, its efficacy after poly adenosine 5′-diphosphate-ribose polymerase (PARP) inhibitor maintenance therapy is unknown. This study aimed to examine the efficacy of a platinum-based chemotherapy rechallenge after PARP inhibitor therapy. MethodsWe retrospectively evaluated patients with ovarian cancer with a PFI≥6 months with PARP inhibitor maintenance therapy, receiving platinum-based chemotherapy. Duration of PARP inhibitor therapy, best response to subsequent platinum chemotherapy rechallenge, and clinical characteristics were collected from medical records. Tumor response was assessed according to RECIST 1.1. Correlations were calculated using Spearman’s correlation coefficients. ResultsAmong the 10 included patients, seven (70 %) received PARP inhibitors after primary chemotherapy, and three (30 %) received chemotherapy for platinum-sensitive relapse. One and five patients harbored a germline BRCA1 and BRCA wild-type mutations, respectively, and two had homologous recombination proficiency. The median PFI was 303.5 (182–602) days, and PARP inhibitor therapy duration was 249 (147–570) days. Platinum chemotherapy rechallenge efficacy was complete and partial response and stable disease in one (10 %), six (60 %), and three (30 %) patients, respectively. The longer the duration of PARP inhibitor treatment, better the response to platinum agents (Spearman correlation coefficient 0.284, p = 0.0288). ConclusionPlatinum-based chemotherapy rechallenge is reasonable for patients with platinum-sensitive disease, using the traditional PFI cutoff of 6 months, even when the PFI is obtained with a maintenance PARP inhibitor.

Alterations in the expression of homologous recombination repair (HRR) genes in breast cancer tissues considering germline BRCA1/2 mutation status

IntroductionHomologous recombination (HR) is a crucial DNA-repair mechanism, and its disruption can lead to the accumulation of mutations that initiate and promote cancer formation. The key HR genes, BRCA1 and BRCA2, are particularly significant as their germline pathogenic variants are associated with a hereditary predisposition to breast and/or ovarian cancer.Materials and methodsThe study was performed on 45 FFPE breast cancer tissues obtained from 24 and 21 patients, with and without the germline BRCA1/2 mutation, respectively. The expression of 11 genes: BRCA1, BRCA2, ATM, BARD1, FANCA, FANCB, FANCI, RAD50, RAD51D, BRIP1, and CHEK2 was assessed using Custom RT2 PCR Array (Qiagen), and results were analysed using R.ResultsCancer tissues from patients with BRCA1 or BRCA2 germline mutations displayed no significant differences in the expression of the selected HR genes compared to BRCA1 or BRCA2 wild-type cancer tissues. In BRCA1mut cancer tissues, BRCA1 expression was significantly higher than in BRCA2mut and BRCA wild-type cancer tissues.ConclusionsIn cancer tissues harbouring either BRCA1 or BRCA2 germline mutations, no significant differences in expression were observed at the mRNA level of any tested HR genes, except BRCA1. However, the significant differences observed in BRCA1 expression between germline BRCA1mut, germline BRCA2mut and BRCA1/2wt tissues may indicate a compensatory mechanism at the mRNA level to mitigate the loss of BRCA1 function in the cells.

Somatic and germline aberrations in homologous recombination repair genes among Chinese high-risk breast cancer patients by multi-gene next-generation sequencing.

Recently, genes involved in homologous recombination repair (HRR) pathway have been extensively studied. However, the landscapes of HRR gene mutations remain poorly defined in Chinese high-risk breast cancer (BC) patients. Our study aims to identify the status of germline and somatic HRR gene mutations and their association with clinicopathological features in these patients. A total of 100 high-risk BC patients from our institution who underwent paired peripheral blood germline and BC tissues somatic 26 genes next-generation sequencing (NGS) from January 2018 to July 2023 were enrolled for retrospective analysis. Out of 100 high-risk BC patients, 55 (55%) had at least one germline or somatic mutation in HRR genes. Among them, 22% carried germline pathogenic variants (19 BRCA1/2 and 3 non-BRCA genes), 9% harbored somatic pathogenic mutations (3 BRCA1/2 and 6 non-BRCA genes). Among high-risk factors, family history and early onset BC showed a correlation with HRR gene mutations (p < 0.05). BRCA1 germline and HRR gene somatic mutations showed a correlation with TNBC, but BRCA2 germline mutations were associated with Luminal B/HER2-negative BC (p < 0.05). Patients with HRR gene somatic pathogenic variant more likely had a lympho-vascular invasion and distant metastasis (p < 0.05). The prevalence of HRR gene germline and somatic mutations were higher in Chinese BC patients with high risk factors. We strongly recommend that these high-risk BC patients receive comprehensive gene mutation testing, especially HRR genes, which are not only related to genetic consultation for BC patients and provide a theoretical basis for necessary prevention and individualized treatment.

Low testing rates and high BRCA prevalence: Poly (ADP-ribose) polymerase inhibitor use in Middle East BRCA/homologous recombination deficiency-positive cancer patients.

Poly (ADP-ribose) polymerase inhibitors (PARPis) are approved as first-line therapies for breast cancer gene (BRCA)-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer. They are also effective for new and recurrent ovarian cancers that are BRCA- or homologous recombination deficiency (HRD)-positive. However, data on these mutations and PARPi use in the Middle East are limited. To assess BRCA/HRD prevalence and PARPi use in patients in the Middle East with breast/ovarian cancer. This was a single-center retrospective study of 57 of 472 breast cancer patients tested for BRCA mutations, and 25 of 65 ovarian cancer patients tested for HRD. These adult patients participated in at least four visits to the oncology service at our center between August 2021 and May 2023. Data were summarized using descriptive statistics and compared using counts and percentages. Response to treatment was assessed using Response Evaluation Criteria in Solid Tumors criteria. Among the 472 breast cancer patients, 12.1% underwent BRCA testing, and 38.5% of 65 ovarian cancer patients received HRD testing. Pathogenic mutations were found in 25.6% of the tested patients: 26.3% breast cancers had germline BRCA (gBRCA) mutations and 24.0% ovarian cancers showed HRD. Notably, 40.0% of gBRCA-positive breast cancers and 66.0% of HRD-positive ovarian cancers were Middle Eastern and Asian patients, respectively. PARPi treatment was used in 5 (33.3%) gBRCA-positive breast cancer patients as first-line therapy (n = 1; 7-months progression-free), for maintenance (n = 2; > 15-months progression-free), or at later stages due to compliance issues (n = 2). Four patients (66.6%) with HRD-positive ovarian cancer received PARPi and all remained progression-free. Lower testing rates but higher BRCA mutations in breast cancer were found. Ethnicity reflected United Arab Emirates demographics, with breast cancer in Middle Eastern and ovarian cancer in Asian patients.

Prevalence of BRCA mutation in breast and ovarian cancer among women in India: A systematic review and meta-analysis protocol.

We present a methodically devised protocol for conducting a systematic review and meta-analysis aimed at ascertaining the prevalence of BReast CAncer gene (BRCA) mutations in breast and ovarian cancer (BOC) among women in India. The review will include cross-sectional, cohort, case-series, and registry-based studies focusing on females clinically diagnosed with any stage of BOC, tested for BRCA germline mutation and undergone any form of treatment. A Cochrane literature search will be carried out to identify all the published and unpublished articles available in English from 2010 till date across various electronic databases including PubMed, Psych Info, SCI, Cochrane Central, Embase, Scopus, IND Med and Google Scholar. A step-by-step process will be followed to select all the relevant studies for final inclusion using Rayyan software. The selection process of the review will be reported based on Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA) checklist. The protocol has been registered in PROSPERO (ID: CRD42023463452). Joanna Briggs Institute Critical Appraisal Checklist will be used to evaluate the methodological quality of the included studies. The outcome measure will be the prevalence of BRCA1/2 gene mutation in this population. Meta-analysis will be performed to report the pooled prevalence along with 95% confidence interval. The results of this review study will provide valuable insights for clinicians, and policy makers, enabling them to formulate guidelines that underscore the importance of screening for BRCA mutations in cases of BOC.

Susceptibility gene mutations in germline and tumors of patients with HER2-negative advanced breast cancer

Germline mutations in BRCA1 and BRCA2 (gBRCA1/2) are required for a PARP inhibitor therapy in patients with HER2-negative (HER2−) advanced breast cancer (aBC). However, little is known about the prognostic impact of gBRCA1/2 mutations in aBC patients treated with chemotherapy. This study aimed to investigate the frequencies and prognosis of germline and somatic BRCA1/2 mutations in HER2- aBC patients receiving the first chemotherapy in the advanced setting. Patients receiving their first chemotherapy for HER2- aBC were retrospectively selected from the prospective PRAEGNANT registry (NCT02338167). Genotyping of 26 cancer predisposition genes was performed with germline DNA of 471 patients and somatic tumor DNA of 94 patients. Mutation frequencies, progression-free and overall survival (PFS, OS) according to germline mutation status were assessed. gBRCA1/2 mutations were present in 23 patients (4.9%), and 33 patients (7.0%) had mutations in other cancer risk genes. Patients with a gBRCA1/2 mutation had a better OS compared to non-mutation carriers (HR: 0.38; 95%CI: 0.17–0.86). PFS comparison was not statistically significant. Mutations in other risk genes did not affect prognosis. Two somatic BRCA2 mutations were found in 94 patients without gBRCA1/2 mutations. Most frequently somatic mutated genes were TP53 (44.7%), CDH1 (10.6%) and PTEN (6.4%). In conclusion, aBC patients with gBRCA1/2 mutations had a more favorable prognosis under chemotherapy compared to non-mutation carriers. The mutation frequency of ~5% with gBRCA1/2 mutations together with improved outcome indicates that germline genotyping of all metastatic patients for whom a PARP inhibitor therapy is indicated should be considered.

TP53 somatic evolution in cervical liquid-based cytology and blood from individuals with and without ovarian cancer and BRCA1 or BRCA2 germline mutations.

Somatic TP53 mutations are prevalent in normal tissue but little is known about their association with cancer risk. Cervical liquid-based cytology (LBC), commonly known as Pap test, provides an accessible gynecological sample to test the value of TP53 somatic mutations as a biomarker for high-grade serous ovarian cancer (HGSC), a cancer type mostly driven by TP53 mutations. We used ultra-deep duplex sequencing to analyze TP53 mutations in LBC and blood samples from 70 individuals (30 with and 40 without HGSC) undergoing gynecologic surgery, 30 carrying BRCA1 or BRCA2 germline pathogenic variants (BRCApv). Only 30% of the tumor mutations were found in LBC samples. However, TP53 pathogenic mutations were identified in nearly all LBC and blood samples, with only 5.4% of mutations in LBC (20/368) also found in the corresponding blood sample. TP53 mutations were more abundant in LBC than in blood and increased with age in both sample types. BRCApv carriers with HGSC had more TP53 clonal expansions in LBC than BRCApv carriers without cancer. Our results show that, while not useful for direct cancer detection, LBC samples capture TP53 mutation burden in the gynecological tract, presenting potential value for cancer risk assessment in individuals at higher hereditary risk for ovarian cancer.

Case report of two long term ovarian cancer survivors with brain metastases following multimodal treatment including chemotherapy, radiotherapy and maintenance olaparib: An institutional case series and literature review

Brain metastasis from ovarian cancer is a very rare condition with a poor prognosis. However, due to its rarity, there is no established treatment strategy. We present a case series of brain metastasis with ovarian cancer, focusing on two long-term survivors treated with multimodal therapy. Among the nine cases, the median survival time after brain metastases was six months (range: 0–58 months). Eight patients had high-grade serous carcinoma (HGSC). Three of the four patients who underwent genetic testing tested positive for germline BRCA2 (gBRCA2) mutation. Two patients survived longer than 4 years after the diagnosis of brain metastases. Both of these patients received chemotherapy, radiation therapy, and olaparib, a molecularly targeted drug, as maintenance therapy. This case series suggests that patients with gBRCA2 mutation-positive HGSC may be at a high risk of developing brain metastases. A multidisciplinary approach, including PARP inhibitors, may improve the prognosis of patients with brain metastases from ovarian cancer.

LGG-24. PEDIATRIC GANGLIOGLIOMA WITH GERMLINE BRCA2 MUTATION

Abstract BACKGROUND BRCA1 and BRCA2 are genes associated with breast and ovarian cancer development in adults. Their influence on brain tumor formation is less understood. METHODS Retrospective review RESULTS An 11 year-old girl was diagnosed with ganglioglioma after presenting with seizures. Tumor sequencing revealed three mutations: a PDAP1-BRAF fusion, a BRAF-HIP1 non-canonical fusion, and a pathogenic BRCA2 variant D252*fs. Upon further review, a family history of breast cancer in the grandmother and several great-aunts was identified, and genetic testing confirmed this mutation to be germline. We then conducted an institutional review and identified a second pediatric low-grade glioma (pilocytic astrocytoma) patient with a pathogenic mutation in BRCA2 (T3085Fs*26) in addition to a BRAF-KIAA1549 fusion; the family declined germline BRCA2 testing. BRCA1/2 knockout models have demonstrated that both genes play a role in brain development. Concurrent BRCA2 and TP53 loss triggers formation of early onset murine medulloblastoma, a finding not observed with TP53 loss alone. In human patients, heterozygous and biallelic mutations in BRCA2 were identified as risk factors for medulloblastoma development in a recent integrative genomic analysis. Retrospective review CONCLUSION We report two cases of BRCA2 mutation in pediatric low-grade gliomas, one of which was confirmed to be germline. While somatic variants of BRCA2 have been reported in both high- and low-grade glioma, their role in these tumors has not been established to date. The BRCA2 tumor predisposition syndrome increases the risk of some types of brain tumors such as medulloblastoma, although the risk remains low compared to the risk of developing breast or ovarian cancer later in life. More evidence is required to determine whether BRCA2 germline mutations can similarly increase the risk of glioma formation.

DIPG-48. PRECISION GUIDED THERAPY PROVIDES CLINICAL BENEFIT IN H3K27-ALTERED DIFFUSE MIDLINE GLIOMA

Abstract BACKGROUND The utility of precision-guided therapeutic approaches to H3K27-altered diffused midline glioma (DMG) remains uncertain. The Australian Zero Childhood Cancer (ZERO) program combines molecular profiling (whole-genome sequencing (WGS), whole-transcriptome sequencing (RNAseq), and DNA methylation profiling), with in vitro high-throughput drug screening (HTS) and patient-derived xenograft (PDX) drug-efficacy testing in patients with high-risk cancer. METHODS We report on the cohort of patients enrolled with a DMG in the ZERO clinical trial between 2017 and 2023. RESULTS 68 patients were enrolled, predominantly at diagnosis (87%), with pontine lesions (66%) at a mean age of 8.7 years. 59 (87%) patients had WGS + RNAseq successfully performed. Most tumors harbored an H3F3A mutation (n=50), followed by HIST1H3B (n=11), HIST1H3C (n=2), HIST2H3C (n=1) and EZHIP overexpression (n=4). 37 samples were suitable for cell culture, with HTS successfully performed in 25 cases, and PDXs established in 7. Precision-guided therapy (PGT) was recommended by the ZERO multidisciplinary tumor board for 53 patients (78%), including 5 recommendations guided by HTS. PI3K/mTOR inhibitors and MEK inhibitors were the most recommended PGTs. 21 patients (31%), receiving 24 PGTs, were eligible for survival analysis. The clinical benefit rate (per RAPNO) was 52% for patients receiving PGT, with 5 patients exhibiting PR and 6 patients SD &amp;gt;6 months. Notably, the 5 PR included: a PR in a patient with BRAFV600E mutation to dabrafenib/trametinib, a near-CR in a patient with germline BRCA2 mutation to olaparib/durvalumab, a sustained PR in a patient with FGFR1 mutation to trametinib/bevacizumab and 2 patients with PIK3CA mutations who received PGT in the context of recent radiotherapy. Median overall survival of the PGT group was 21.2 months versus 11.8 months for the rest of the cohort (hazard ratio 0.67 [95%CI 0.39-1.1]). CONCLUSIONS These results, for the first time, highlight the potential clinical benefit of PGT in H3K27-altered DMG.

Effects of clinical covariates on serum miRNA expression among women without ovarian cancer.

Serum microRNAs (miRNAs) are potential biomarkers for ovarian cancer; however, many factors may influence miRNA expression. To understand potential confounders in miRNA analysis, we examined how sociodemographic factors and comorbidities, including known ovarian cancer risk factors, influence serum miRNA levels in women without ovarian cancer. Data from 1,576 women from the Mass General Brigham Biobank collected between 2012 and 2019, excluding subjects previously or subsequently diagnosed with ovarian cancer, were examined. Using a focused panel of 179 miRNA probes optimized for serum profiling, miRNA expression was measured by flow cytometry using the Abcam Fireplex® assay and correlated with subjects' electronic medical records. The study population broadly reflected the New England population. The median age of subjects was 49 years, 34% were current or prior smokers, 33% were obese (BMI >30kg/m2), 49% were postmenopausal, and 11% had undergone prior bilateral oophorectomy. Significant differences in miRNA expression were observed among ovarian risk factors such as age, obesity, menopause, BRCA1 or BRCA2 germline mutations or breast cancer in family history. Additionally, miRNA expression was significantly altered by prior bilateral oophorectomy, hypertension, and hypercholesterolemia. Other variables, such as smoking, parity, age at menarche, hormonal replacement therapy, oral contraception, breast, endometrial, or colon cancer, and diabetes were not associated with significant changes in the panel when corrected for multiple testing. Serum miRNA expression patterns are significantly affected by patient demographics, exposure history, and medical comorbidities. Understanding confounders in serum miRNA expression is important for refining clinical assays for cancer screening.

Neoadjuvant talazoparib in patients with germline BRCA1/2 mutation-positive, early-stage triple-negative breast cancer: exploration of tumor BRCA mutational status

BackgroundTalazoparib monotherapy in patients with germline BRCA-mutated, early-stage triple-negative breast cancer (TNBC) showed activity in the neoadjuvant setting in the phase II NEOTALA study (NCT03499353). These biomarker analyses further assessed the mutational landscape of the patients enrolled in the NEOTALA study.MethodsBaseline tumor tissue from the NEOTALA study was tested retrospectively using FoundationOne®CDx. To further hypothesis-driven correlative analyses, agnostic heat-map visualizations of the FoundationOne®CDx tumor dataset were used to assess overall mutational landscape and identify additional candidate predictive biomarkers of response.ResultsAll patients enrolled (N = 61) had TNBC. In the biomarker analysis population, 75.0% (39/52) and 25.0% (13/52) of patients exhibited BRCA1 and BRCA2 mutations, respectively. Strong concordance (97.8%) was observed between tumor BRCA and germline BRCA mutations, and 90.5% (38/42) of patients with tumor BRCA mutations evaluable for somatic-germline-zygosity were predicted to exhibit BRCA loss of heterozygosity (LOH). No patients had non-BRCA germline DNA damage response (DDR) gene variants with known/likely pathogenicity, based on a panel of 14 non-BRCA DDR genes. Ninety-eight percent of patients had TP53 mutations. Genomic LOH, assessed continuously or categorically, was not associated with response.ConclusionThe results from this exploratory biomarker analysis support the central role of BRCA and TP53 mutations in tumor pathobiology. Furthermore, these data support assessing germline BRCA mutational status for molecular eligibility for talazoparib in patients with TNBC.

Multiple targets, germline BRCA1 mutation and HRD in a lung cancer patient: Molecular considerations and treatment decision-making.

Several biomarkers are currently available to address targeted treatments in cancer patients, with lung malignancies representing one of the best examples. We report the case of a patient affected by advanced non-small cell lung cancer with an uncommon histology and a complex biology. The use of a large next-generation sequencing (NGS) NGS panel allowed us to identify an extremely rare BRAF mutation (V600Q), a MET amplification, a high tumor mutational burden, a germline pathogenetic BRCA1 mutation and a homologous recombination deficiency through RAD51 assay. The treatment decision was driven by the abundance of molecular information. This case highlights that an attentive and critical evaluation of molecular reports is key for the tailoring of treatment algorithms at the patient-level scale.

The prognostic and predictive value of homologous recombination deficiency status in patients with advanced stage epithelial ovarian carcinoma after first-line platinum-based chemotherapy.

Homologous recombination (HR) comprises series of interrelated pathways that repair double-stranded DNA breaks and inter-strand crosslinks. It provides support for DNA replication to recover stalled or broken replication forks. Compared with homologous recombination proficiency (HRP), cancers with homologous recombination deficiency (HRD) are more likely to undergo cell death when treated with DNA-damaging agents, such as platinum agents, and have better disease control. Patients diagnosed with stage III/IV ovarian cancer, early stages with recurrence, who received adjuvant chemotherapy after debulking surgery, and who also had known HR status were eligible. Forty-four patients were included, with 21 in the HRD group (including 8 with germline mutations) and 23 in the HRP group. The HRD group was composed predominantly of serous carcinoma (95.2%), while mucinous (n=3) and clear cell (n=1) cases were all found in the HRP group. Stage III/IV disease was 66.7% and 91.3% in HRD and HRP groups, respectively (p=0.064). Patients who were optimally debulked to no residual disease was 90.0% and 72.7% (p=0.243), respectively. Late line use of PARP inhibitors was 33.3% and 17.4% (p=0.303). Median PFS was 22.5 months (95% CI, 18.5 - 66.6) and 21.5 months (95% CI, 18.3-39.5) (p=0.49) in HRD and HRP respectively. Median platinum free interval (PFI) was 15.8 months (95% CI 12.4-60.4) and 15.9 months (95% CI 8.3-34.1) (p=0.24), respectively. Median OS was 88.2 months (95% CI 71.2-NA) and 49.7 months (95% CI 35.1-NA) (p=0.21). The PFS of the patients with germline BRCA mutations (n=5) was 54.3 months (95% CI 23.1-NA) and 21.5 months (95% CI 18.3-39.5) in the HRP group (p=0.095); the PFI difference was 47.7 months (95% CI 17.6-NA) in the BRCA mutation group, and 15.9 months (95% CI 12.4-60.4) in HRP, showing statistical significance (p=0.039); while the median OS was NA and 49.7 months (95% CI 35.1-NA) respectively (p=0.051). When adding two additional patients with somatic BRCA mutations to the germline BRCA mutation carriers, the median OS is NA (95% CI 73, NA) versus 49.7 months (95% CI 35.1, NA) for HRP (p=0.045). HRD status was not associated with longer PFS or PFI in advanced ovarian cancer who received first line adjuvant platinum-based chemotherapy. Its role as a prognostic marker for overall survival is suggested, particularly in the subgroup with germline and somatic BRCA mutations.

Radiogenomics of homologous recombination deficiency (HRD) in breast cancer: Radiomics-based image biomarker for HRD.

554 Background: Homologous recombination deficiency (HRD) in breast cancer is an actionable target, with treatment efficacy potentially linked to timely detection. Notably, BRCA1 and BRCA2 are key genes implicated in HRD, and their pathogenic germline mutations are crucial criteria for the use of poly (ADP-ribose) polymerase inhibitors (PARPi). Although germline BRCA1/2 mutations are detectable in only a small fraction (1-5%) of breast cancers, recent whole-genome sequencing (WGS) studies have revealed that up to 22% of breast cancers also exhibit HRD-like genomic characteristics, suggesting a broader potential for HRD-targeted therapy. This has spurred the development of genomic-feature-based HRD identification methods. However, the invasive and costly nature of these methods poses a challenge. This has prompted our investigation into non-invasive image biomarkers for HRD identification. Methods: Invasive breast cancer patients were recruited from March 2021 to August 2022. Eligibility criteria included availability of fresh-frozen tumor tissue for WGS and suitability for dynamic contrast-enhanced (DCE) MRI to facilitate radiomics analysis. The association between HRD and radiomic features as well as clinicopathologic factors was investigated through rigorous genomic and statistical analysis. Results: This study encompassed 145 patients aged 20 to 69 years, of whom 16.6% (24 out of 145) were genomically identified as HRD. All patients harboring pathogenic germline mutations in BRCA1 (n=3) or BRCA2 (n=2), along with concomitant somatic LOH, exhibited HRD. A comprehensive analysis of 214 radiomic features revealed that tumor sphericity, informational measure of correlation 1 (IMC1), size-zone non-uniformity normalized (SZNN), and small area emphasis (SAE) derived from subtracted early dynamic T1-weighted imaging were significantly correlated with HRD. Moreover, these radiomic features demonstrated substantial diagnostic value, as evidenced by their ROC-AUC and PR-AUC performance against baseline models: Sphericity (ROC: 0.62, p=0.055; PR: 0.22, p=0.053), SAE (ROC: 0.63, p=0.052; PR: 0.32, p=0.007), SZNN (ROC: 0.63, p=0.04; PR: 0.30, p=0.007), and IMC1 (ROC: 0.62, p=0.067; PR: 0.29, p=0.02). Additionally, our findings suggest that these radiomic features are more directly related to HRD than to the triple-negative phenotype, which is commonly linked to HRD. Conclusions: We found that four radiomic features from MRI have significant predictive value for identifying HRD in breast cancer. Given their fair predictability and immediate availability, these features are ideally suited for a screening approach, potentially identifying more patients eligible for targeted treatment. This finding represents a significant advancement in the fields of radiology and precision oncology, opening new avenues for patient-specific treatment strategies.

Sequential combination of sacituzumab govitecan and talazoparib in metastatic triple negative breast cancer (mTNBC): Results from a phase II study.

1102 Background: The antibody-drug conjugate (ADC) sacituzumab govitecan (SG) has demonstrated improvement in overall survival for patients with metastatic triple negative breast cancer (mTNBC). Despite great interest in enhancing efficacy of ADCs using combination therapy, there are no approved regimens. Preclinical data suggest that SG synergizes with Poly ADP-ribose polymerase inhibitors (PARPi) to induce DNA damage and cell death. Though the phase 1b study demonstrated intolerable myelosuppression with simultaneous dosing, tolerability was improved with sequential administration of SG and the PARPi talazoparib (Bardia AACR 2022). Here we report clinical outcomes from the phase II dose expansion cohort (NCT04039230). Methods: In a single-arm phase II study, adult patients with measurable mTNBC (per ASCO/CAP guidelines) were eligible. Starting dose was SG at 10mg/kg on days 1 and 8 with talazoparib 1mg on days 15-21. Growth factor (G-CSF) prophylaxis was required. The primary endpoint was the confirmed Objective Response Rate (ORR) calculated per RECIST v1.1 and secondary endpoints included progression-free survival (PFS) and overall survival (OS). The Clinical Benefit Rate (CBR) at 6 months was also measured. Results: From June 2021 to March 2023, 26 patients were enrolled. The median age was 54 (range, 35 to 81). Patients received a median of 2 prior therapy lines for metastatic disease (range, 0 to 7). 6/26 patients remain on treatment at time of data cutoff. Median PFS was 6.2 months (95% CI, 3.7 to 12.8), and median OS was 18.0 months (95% CI, 10.7 to not evaluable). The confirmed ORR was 30.1% (95% CI, 14 to 52) and the CBR at 6 months was 53.8% (95% CI, 33 to 73). Serious adverse events (AEs) were seen in 10 (38.5%) of patients; in 7 (26.9%) serious AEs were treatment related. The most common treatment related AEs were anemia (92.3%), neutropenia (88.5%), nausea (84.6%) fatigue (80.7%), and thrombocytopenia (65.3%). Grade ≥3 neutropenia and anemia were seen in 80.7% and 34.6% of cases, respectively. One or more dose reductions were required in 58.0% of patients. One patient with a germline BRCA mutation was treated for 625 days before disease progression. Updated biomarker and survival data will be presented at the meeting. Conclusions: In this single-arm phase II study, SG in combination with talazoparib was feasible and demonstrated preliminary evidence of efficacy. A randomized clinical trial is needed to determine if the SG-PARPi combination is superior to SG monotherapy. Clinical trial information: NCT04039230 .