Mutations In BRCA1 Genes Research Articles

Interferon-ε is a tumour suppressor and restricts ovarian cancer.

High-grade serous ovarian cancers have low survival rates because of their late presentation with extensive peritoneal metastases and frequent chemoresistance1, and require new treatments guided by novel insights into pathogenesis. Here we describe the intrinsic tumour-suppressive activities of interferon-ε (IFNε). IFNε is constitutively expressed in epithelial cells of the fallopian tube, the cell of origin of high-grade serous ovarian cancers, and is then lost during development of these tumours. We characterize its anti-tumour activity in several preclinical models: ovarian cancer patient-derived xenografts, orthotopic and disseminated syngeneic models, and tumour cell lines with or without mutations in Trp53 and Brca genes. We use manipulation of the IFNε receptor IFNAR1 in different cell compartments, differential exposure status to IFNε and global measures of IFN signalling to show that the mechanism of the anti-tumour activity of IFNε involves direct action on tumour cells and, crucially, activation of anti-tumour immunity. IFNε activated anti-tumour T and natural killer cells and prevented the accumulation and activation of myeloid-derived suppressor cells and regulatory T cells. Thus, we demonstrate that IFNε is an intrinsic tumour suppressor in the female reproductive tract whose activities in models of established and advanced ovarian cancer, distinct from other type I IFNs, are compelling indications of potential new therapeutic approaches for ovarian cancer.

CT-based radiomics nomogram analysis for assessing BRCA mutation status in patients with high-grade serous ovarian cancer.

Radiomics nomogram analysis is widely preoperatively used to assess gene mutations in various tumors. To explore the value of computed tomography (CT)-based radiomics nomogram analysis for assessing BRCA gene mutation status of patients with high-grade serous ovarian cancer (HGSOC). In total, 96 patients with HGSOC were retrospectively screened and randomly divided into primary (n = 68) and validation cohorts (n = 28). The clinical model was constructed based on clinical features and CT morphological features using univariate and multivariate logistic analyses. Maximum-relevance and minimum-redundancy (mRMR) and least absolute shrinkage and selection operator (LASSO) were performed for feature dimensionality reduction and radiomics score was calculated. The nomogram model combining the clinical model and the radiomics score was constructed using multivariate logistic regression. Receiver operating characteristic (ROC) curves were generated to assess models' performance. The calibration analysis and decision curve analysis (DCA) were also performed. The clinical model consisted of CA125 level and supradiaphragmatic lymphadenopathy and yielded an area under the curve (AUC) of 0.69 (primary cohort) and 0.81 (validation cohort). The radiomics model was built with seven selected features and showed an AUC of 0.87 (primary cohort) and 0.81 (validation cohort). The nomogram finally showed the highest AUC of 0.89 (primary cohort) and 0.87 (validation cohort). The nomogram presented favorable calibrations in both the primary and validation cohorts. DCA further confirmed the clinical benefits of the constructed nomogram. CT-based radiomics nomogram provides a non-invasive method to discriminate BRCA gene mutation status of HGSOC and potentially helps develop precise medical strategies.

Recent Update of Targeted Therapy in Cholangiocarcinoma

Cholangiocarcinoma (CCA) is one of the cancers with the worst prognosis. Its incidence and mortality have increased in recent years, but treatment options are limited. Although various clinical trials have been conducted, there is no effective therapeutic agent yet. As molecular genetic profiling is progressing in CCA, the interest in targeted therapies is growing. To realize targeted therapy in practice, various clinical requirements must be met. A molecular biological test should be performed on a patient’s tissue or blood, a target should be determined using an appropriate analysis method, and there should be a targeted agent. Regarding CCA, genetic variation occupies an intermediate level. Accordingly, many new agents have been recently developed for molecular biological targets. The most common genetic aberrations show almost similar patterns in intrahepatic and extrahepatic CCA. However, HER2 gene amplification is more often observed in extrahepatic CCA, and FGFR2 fusion, IDH1 mutation, and RAS-RAF-MEK-ERK signaling system mutations are more frequently found in intrahepatic CCA. Phase 2 or 3 clinical trials are being conducted with zanidatamab for HER2 amplification, pemigatinib/infigratinib for FGFR fusion, ivosidenib for IDH1 mutation, and dabrafenib for BRAFV600E mutation. In addition, clinical trials for agents targeting the NTRK, BRCA, and ARID1A gene mutations are ongoing. These targeted therapies are expected to have a bright future as a new treatment for CCA.

Mutations of BRCA1, BRCA2, and PALB2 Genes in Breast Tumor Tissue: Relationship with the Effectiveness of Neoadjuvant Chemotherapy and Disease Prognosis.

The study included 66 patients with breast cancer. DNA copy number aberrations (CNA) were assessed by high-density CytoScanHD™ Array micro matrix analysis. Gene mutations were assessed by sequencing on the MiSeq™ Sequencing System using the Accel-Amplicon BRCA1, BRCA2, and PALB2 Panel. It has been established that the presence of a normal copy number of PALB2 is associated with a lack of response to chemotherapy in Taxotere-containing treatment regimens (p = 0.05). In addition, the presence of a PALB2 deletion is associated with 100% metastatic survival rates (log-rank test p = 0.04). As a result of sequencing, 25 mutations were found in the BRCA1 gene, 42 mutations in BRCA2, and 27 mutations in the PALB2 gene. The effect of mutations on the effectiveness of treatment is controversial, but an effect on the survival of patients with breast cancer has been shown. So, in the presence of pathogenic mutations in the BRCA2 gene, 100% metastatic survival is observed (log-rank test p = 0.05), as well as in the elimination of PALB2 mutations during treatment (log-rank test p = 0.07). Currently, there is little data on the effect of chromosomal aberrations and mutations in the BRCA1/2 and PALB2 genes on the effectiveness of treatment and prognosis of the disease. At the same time, the study of these genes has great potential for testing focused on a personalized approach to the treatment of patients with breast cancer.

Systemic Therapy for Metastatic Triple Negative Breast Cancer: Current Treatments and Future Directions.

Until recently, despite its heterogenous biology, metastatic triple negative breast cancer (TNBC) was treated as a single entity, with successive lines of palliative chemotherapy being the only systemic option. Significant gene expression studies have demonstrated the diversity of TNBC, but effective differential targeting of the four main (Basal-like 1 and 2, mesenchymal and luminal androgen receptor) molecular sub-types has largely eluded researchers. The introduction of immunotherapy, currently useful only for patients with PD-L1 positive cancers, led to the stratification of first-line therapy using this immunohistochemical biomarker. Germline BRCA gene mutations can also be targeted with PARP inhibitors in both the adjuvant and metastatic settings. In contrast, the benefit of the anti-Trop-2 antibody-drug conjugate (ADC) Sacituzumab govitecan (SG) does not appear confined to patients with tumours expressing high levels of Trop-2, leading to its potential utility for any patient with an estrogen receptor (ER)-negative, HER2-negative advanced breast cancer (ABC). Most recently, low levels of HER2 expression, detected in up to 60% of TNBC, predicts benefit from the potent HER2-directed antibody-drug conjugate trastuzumab deruxtecan (T-DXd), defining an additional treatment option for this sub-group. Regrettably, despite recent advances, the median survival of TNBC continues to lag far behind the approximately 5 years now expected for patients with ER-positive or HER2-positive breast cancers. We review the data supporting immunotherapy, ADCs, and targeted agents in subgroups of patients with TNBC, and current clinical trials that may pave the way to further advances in this challenging disease.

An overview of the research progress of BRCA gene mutations in breast cancer.

The breast cancer susceptibility gene (BRCA) is an important tumor suppressor gene, including BRCA1 and BRCA2, a biomarker that assesses the risk of breast cancer and influences a patient's individualized treatment options. BRCA1/2 mutation (BRCAm) increases the risk of breast cancer. However, breast-conserving surgery is still an option for BRCAm, and prophylactic mastectomy and nipple-sparing mastectomy may also reduce the risk of breast cancer. BRCAm is sensitive to Poly (ADP-ribose) polymerase inhibitor (PARPi) therapy due to specific types of DNA repair defects, and its combination with other DNA damage pathway inhibitors and endocrine therapy and immunotherapy are also used for the treatment of BRCAm breast cancer. The current treatment and research progress of BRCA1/2 mutant breast cancer in this review provides a basis for the individualized treatment of patients with this type of breast cancer.

A nonsense mutation in BRCA1 gene in a Vietnamese patient with breast cancer

Breast cancer is the most frequent female cancer, and it is increasing at an alarming rate. The typical symptom of breast cancer is breast lumps or swellings, though they can also develop close to the breast or under the arm. Breast cancer usually spreads to distant organs such as the bone, liver, lungs, and brain. Approximately 95% of breast cancer patients who arrive with the early-stage disease show no macroscopic signs of metastases. Although it is possible to reduce some breast cancer risks through prevention, the majority of patients in low-income countries are detected at a late stage. Because of this, even though current therapy is improving, early diagnosis is still crucial for improving the quality of treatment and the survival rate. Sex, age, family history, and an unhealthy lifestyle are some of the risk factors that may increase the chances of getting this disease. Familial or hereditary breast cancer accounts for 10% of breast cancers. Mutations in the BRCA1 and BRCA2 genes were responsible for 50% of all familial or hereditary breast cancer cases. In this research, mutations in a Vietnamese patient with familial breast cancer were analyzed using whole exome sequencing. As a result, 17 variants have been reported in the ClinVar database as “germline mutations” in familial breast cancer were detected. Of these, a heterozygous nonsense mutation c.5314C>T (p.R1772X) in the BRCA1 gene was identified as the genetic cause of this case. This mutation has been previously reported as pathogenic in the ClinVar database (ClinVar variation ID: 55480). Our results provide insight into the genetic causes of breast cancer as well as support the genetics diagnosis of familial breast cancer.

An integrated analysis of microRNAs regulating DNA damage response in triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) remains a clinical challenge due to its aggressive phenotype and limited treatment options for the patients. Many TNBC patients show an inherent defect in the DNA repair capacity primarily by acquiring germline mutations in BRCA1 and BRCA2 genes leading to Homologous Recombination Deficiency (HRD). Epigenetic modifications such as BRCA1 promoter methylation and miRNA expression targeting DNA repair pathway genes have contributed to the HRD phenotype in TNBC. Hence, we aimed to identify microRNAs that are associated with HRD status in the TCGA-BRCA project.Materials and methodsWe implemented a miRNA prediction strategy for identifying miRNAs targeting HR pathway genes using an in silico predicted and experimentally validated list from published literature for their association with genomic instability and factors affecting HRD. In silico analysis was performed to study miRNA expression patterns regulated by DNA methylation and TMB status in the TNBC patients from TCGA-BRCA project. Finally, we analysed selected miRNA expression with immune cell infiltration pattern in the TNBC patient cohort.ResultsOur study identified miRNAs associated with HRD, tumour mutation burden (TMB), and immune cell infiltration. Identified miRNA signatures were associated with the miR-17 ~ 92 cluster, miR-106b ~ 25 cluster, and miR-200b ~ 429 cluster. Pathway analysis of selected miRNAs suggested their association with altered immune cell infiltration in TNBC.ConclusionOur study identified 6 ‘HRD associated miRNAs’ such as miR-106b, miR-93, miR-17, miR-20a, miR-200b, and miR-429 as novel miRNA-based signatures associated with HR deficiency in TNBC.

Czech Women's Point of Views on Immediate Breast Reconstruction after Mastectomy due to BRCA Gene Mutation or Breast Cancer.

(1) Objective: Breast cancer is the most common cancer in women, and the incidence of the disease continues to increase. The issue of immediate breast reconstruction (IBR) in women with BRCA mutations and breast cancer is highly topical. This study is based on the long-term experience of our workplace with the diagnosis and treatment of breast cancer in women. We use the possibilities of oncoplastic surgery, including IBR. Our effort involves learning about women's awareness of IBR with a mastectomy at the same time. (2) Methods: The method of quantitative research of women's awareness using a structured anonymous questionnaire was chosen. Out of the total number of 84 respondents who already underwent IBR, 36.9% were due to BRCA mutations, and 63.1% were due to breast cancer. (3) Results: All of the respondents learned about the possibility of IBR before treatment or during treatment planning. The information was first obtained mainly from an oncologist. Women obtained the most information regarding IBR from a plastic surgeon. Before the mastectomy, all of the respondents already knew what IBR meant, as well as about the payment of IBR by the health insurance company. All of the respondents would choose the IBR option again. A total of 94.0% of women cited preservation of body integrity as a reason for undergoing IBR, and 88.1% of women knew about the possibility of performing IBR with their own tissues. (4) Conclusions: There are few specialized centers with a team of experts in reconstructive breast surgery in the Czech Republic, especially those that perform IBR. Research has shown that all of the patients were well informed about IBR, but the vast majority only learned about IBR before the surgical procedure was planned. All of the women wished to maintain body integrity. Our study results in the recommendations for patients and for healthcare management.

Implant-Based Breast Reconstruction after Risk-Reducing Mastectomy in BRCA Mutation Carriers: A Single-Center Retrospective Study.

Women with BRCA gene mutations have a higher lifetime risk of developing breast cancer. Furthermore, cancer is usually diagnosed at a younger age compared to the wild-type counterpart. Strategies for risk management include intensive surveillance or risk-reducing mastectomy. The latter provides a significant reduction of the risk of developing breast cancer, simultaneously ensuring a natural breast appearance due to the preservation of the skin envelope and the nipple-areola complex. Implant-based breast reconstruction is the most common technique after risk-reducing surgery and can be achieved with either a submuscular or a prepectoral approach, in one or multiple stages. This study analyzes the outcomes of the different reconstructive techniques through a retrospective review on 46 breasts of a consecutive, single-center case series. Data analysis was carried out with EpiInfo version 7.2. Results of this study show no significant differences in postoperative complications between two-stage tissue expander/implant reconstruction and direct-to-implant (DTI) reconstruction, with DTI having superior aesthetic outcomes, especially in the prepectoral subgroup. In our experience, the DTI prepectoral approach has proven to be a safe and less time-consuming alternative to the submuscular two-stage technique, providing a pleasant reconstructed breast and overcoming the drawbacks of subpectoral implant placement.

Alkylation of nucleobases by 2-chloro-N,N-diethylethanamine hydrochloride (CDEAH) sensitizes PARP1-deficient tumors.

Targeting BRCA1- and BRCA2-deficient tumors through synthetic lethality using poly(ADP-ribose) polymerase inhibitors (PARPi) has emerged as a successful strategy for cancer therapy. PARPi monotherapy has shown excellent efficacy and safety profiles in clinical practice but is limited by the need for tumor genome mutations in BRCA or other homologous recombination genes as well as the rapid emergence of resistance. In this study, we identified 2-chloro-N,N-diethylethanamine hydrochloride (CDEAH) as a small molecule that selectively kills PARP1- and xeroderma pigmentosum A-deficient cells. CDEAH is amonofunctional alkylating agent that preferentially alkylates guanine nucleobases, forming DNA adducts that can be removed from DNA by either a PARP1-dependent base excision repair or nucleotide excision repair. Treatment of PARP1-deficient cells leads to the formation of strand breaks, an accumulation of cells in S phase and activation of the DNA damage response. Furthermore, CDEAH selectively inhibits PARP1-deficient xenograft tumor growth compared to isogenic PARP1-proficient tumors. Collectively, we report the discovery of an alkylating agent inducing DNA damage that requires PARP1 activity for repair and acts synergistically with PARPi.

Combining next-generation hormonal therapy with PARP inhibition in metastatic castration-resistant prostate cancer

In a paradigm of precision oncology, elegant preclinical work showed that inhibition of poly(ADP-ribose) polymerase (PARP) proteins can exploit a deficiency of cancer cells to repair DNA double-strand breaks through homologous recombination repair (HRR), 1 Lord CJ Ashworth A PARP inhibitors: synthetic lethality in the clinic. Science. 2017; 355: 1152-1158 Crossref PubMed Scopus (1411) Google Scholar and the resulting synthetic lethality was first shown to be clinically effective in ovarian cancer carrying a germline deleterious mutation in BRCA1 or BRCA2, key HRR genes. 2 Banerjee S Moore KN Colombo N et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021; 22: 1721-1731 Summary Full Text Full Text PDF PubMed Scopus (92) Google Scholar For prostate cancer, the discovery of alterations in BRCA2 and other HRR-related genes in up to 20% of advanced disease 3 Robinson D Van Allen EM Wu YM et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015; 161: 1215-1228 Summary Full Text Full Text PDF PubMed Scopus (2077) Google Scholar led to the development of several biomarker-driven trials of PARP inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC) 4 Abida W Patnaik A Campbell D et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. 2020; 38: 3763-3772 Crossref PubMed Scopus (309) Google Scholar , 5 de Bono JS Mehra N Scagliotti GV et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 2021; 22: 1250-1264 Summary Full Text Full Text PDF PubMed Scopus (79) Google Scholar , 6 Hussain M Mateo J Fizazi K et al. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020; 383: 2345-2357 Crossref PubMed Scopus (289) Google Scholar , 7 Smith MR Scher HI Sandhu S et al. Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2022; 23: 362-373 Summary Full Text Full Text PDF PubMed Scopus (41) Google Scholar and to the regulatory approval of rucaparib and olaparib as monotherapy for the treatment of mCRPC harbouring mutations in BRCA2 and other HRR genes. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trialTalazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations. Full-Text PDF

Real world study on the effect of PARPi as maintenance therapy after first-line and second-line chemotherapy on platinum sensitivity in patients with recurrent high-grade serous epithelial ovarian cancer.

e17574 Background: This study investigated the effect of PARPi as maintenance therapy after 1st-line and 2nd-line chemotherapy on platinum sensitivity in patients with recurrent high-grade serous epithelial ovarian cancer (rHGSOC). Methods: 172 patients with rHGSOC at Zhejiang Cancer Hospital and Jiaxing Maternity and Child Health Care Hospital from Jan 2017 to Dec 2021were retrospectively analyzed. Patients who received PARPi as maintenance therapy after first-line chemotherapy were enrolled to the 1st-PARPi group (n=23), and subjects who did not receive PARPi maintenance therapy were enrolled to the 1st control group (n=105). Similarly, 2nd- PARPi group (had not use PARPi in first-line treatment n=30), 2nd-control group (n=89) were divided. To evaluate progression-free survival (PFS), the first progression to second progression (TTSP), the second progression to third progressio (TTTP), PFS between the second progression and the end of the second-line chemotherapy (PFSs), PFS between the third progression and the end of the third-line chemotherapy (PFSt) and to compare whether PARPi as maintenance therapy affects the platinum sensitivity of these patients. Results: PFSs in 1st-PARPi vs.1st-control group (median 5 vs. 11 m; p=0.0037). PFSt in 2nd-PARPi vs. 2nd-control group(median 4.5 vs. 9.0 m; p=0.0009). TTSP in 1st-PARPi vs. 1st-control group (median 11 vs. 16 m; p=0.0045). TTTP in 2nd-PARPi vs. 2nd-control group (median 10 vs. 15 m; p=0.0007). Among the 23 patients in 1st-PARPi group and 105 patients in 1st-control group, 9 and 99 patients were platinum sensitive while 14 and 6 patients were platinum resistant respectively (HR 14.46, 95% CI =4.07-51.53, P < 0.0001). Among the 30 patients in 2nd-PARPi group and 89 patients in 2nd-control group, 10 and 71 patients were platinum sensitive while and 20 and 18 patients were platinum resistant respectively (HR 4.37 95% CI=1.98-9.64, P < 0.0001). Age, stage, residual tumor after initial surgery treatment and the courses of platinum-based chemotherapy before PARPi,BRCA gene mutation were not the related factors affecting the platinum sensitivity of next line chemotherapy. There was no statistical difference in the effect of duration of PARPi on the platinum sensitivity of next line chemotherapy (duration of PARPi≥ 18 months vs. <18 months in 1st-PARPi group, HR 0.60, 95% CI=0.18-2.04, P=0.41; duration of PARPi≥ 12 months vs. <12 months in 2nd-PARPi group, HR 0.62, 95% CI=0.26-1.48, P=0.24, respectively). Conclusions: Patients with rHGSOC using PARPi affected the platinum sensitivity and were more likely to lead to platinum resistance no matter how long the during of PARPi were.This conclusion was consistent with the cross resistance between PARPi and platinum. Care should be taken when using PARPi after 1st-line and 2nd-line chemotherapy as maintenance therapy.

A population-based study of BRCA breast cancer incidence and prognosis in the Italian Emilia Romagna region: The MUTina study.

10616 Background: In Italy, about 3% of all breast cancer (BC) are related to BRCA1 and BRCA2 gene mutations. In the Emilia Romagna Region, a unique hub and spoke model was adopted for select and follow people at risk, starting from the Regional Screening Programs, General Practioners and specialists, covering all the area. This study was designed to uniformly identify and treat BRCA1/2 related BC. Characteristics and outcome of tumors detected by this protocol will be presented. Methods: In this multicenter-retrospective study, seven out of nine provinces collected data about BRCA-related BC identified in the Emilia-Romagna region. Patients and tumors characteristics, surgical information, treatment modalities for early (neoadjuvant or adjuvant therapies) and advanced disease, type of relapse (local/distant), second primary tumors occurrence, surgical preventive strategies (bilateral mastectomy, oophorectomy), gene testing data, disease free survival (DFS) and overall survival (OS) were registered. Comparisons between BRCA1 and BRCA2 tumors were performed. Results: Since 2000 to 2011, 284 BC were registered (171 BRCA1, 110 BRCA2 and 3 BRCA1 and BRCA2 mutated) with a median age at onset of 42 years. BRCA1-related tumors were mostly triple negative BC (TNBC) compared to BRCA2 ones. The diagnosis was at stage I in 52.3% of cases, being 59.7% BRCA1 and 39% BRCA2 (P = 0.0015). BRCA2 patients, compared to BRCA1, received more frequent up-front surgery (85% vs. 74.9%, P = 0.049) and less chemotherapy (34.1% vs 65.9%, P = 0.004). After a median 12-years follow-up period, 136 patients (47,9%) developed an ipsilateral/local or systemic recurrence or contralateral second BC. BRCA1 developed more local recurrences, compared to BRCA2 that had more distant relapses (P = 0.013). Median OS was not reached in the whole population, with 80.3% of patients alive at the analysis cut-off. Among the two populations, there was a benefit trend for BRCA1 patients (P = 0.071), mostly for those who received chemotherapy (P = 0.0036), contralateral mastectomy (P = 0.0001) and oophorectomy (P < 0.0001). Finally, 25.7% of patients developed a second tumor, excluding BC, mostly ovarian cancer. Conclusions: Although BRCA1-related BCs show more aggressive characteristics than BRCA2 BC, the early diagnosis due to our regional surveillance program, leads to a trend for better outcome, even if not statistically significant. The BRCA1 highest rate of recurrence reflects the tendency to local rather than distant relapse. Furthermore, the BRCA deficiency appears to be a predictor of chemosensitivity. Finally bilateral mastectomy and oophorectomy seem to be associated to better outcome. In conclusions, our data support the using of an intensive screening associated to maximal surgery and chemotherapy when BC arises in BRCA carriers, to overcome the unfavorable tumors characteristics of these patients.

Clinical and social importance of follow-up assessment of family members of patients with BRCA mutations.

10621 Background: The identification of BRCA1 and BRCA2 genes mutations are of paramount importance in the treatment and follow-up of hereditary cancer patients. When a pathogenic variant (PV) is identified in one of these genes, the surveillance for new primary tumors becomes individualized. When a pathogenic mutation is identified other family members may also be at high risk for developing tumors. Then the investigation should become familiar. Methods: This study reports the experience of a public oncogenetics service with the identification and follow-up of relatives of patients with BRCA mutations. Of the 1505 patients registered, 773 are probands, of which 71 had a mutation in one of the BRCA genes. A total of 503 family members were evaluated, with an average of 13 relatives per proband. Results: Of the 353 relatives with a BRCA1 mutation, 132 had the familial mutation, and only 18 had cancer diagnosis. The mean age of the evaluated family members was 37 years, lower than the mean age at diagnosis of the probands, which was approximately 41 years, two founder mutations in BRCA1 (NM_007300.4:c.3331_3334del and NM_007300.4:c.211A > G) were more recurrent among index cases, which is associated with the ancestral background of the local population. For the BRCA2 gene, 148 family members were evaluated, of which 77 had a mutation and 23 had a previous cancer diagnosis. The mean age of family members evaluated for BRCA2 mutation was 43 years, similar to the mean age at diagnosis of the proband: 41 years. The NM_000059.4:c.1389_1390del and NM_000059.4:c.7124T > G variants was the most frequent in BRCA2. Conclusions: This data reinforces the importance of genetic counseling and testing of family members when a pathogenic variant is identified in a cancer patient. It is clear that early initiation of surveillance protocols, with screening and prophylactic surgeries are very effective tools for those high risk patients, they just have to be early diagnosed with the PV to benefit from this strategies. In addition, this assessment helps in understanding the mutational profile of the population in order to improve the planning of services in oncogenetics.

Clinical assessment of HRD scoring in relation to PARPi response in terms of statistical guidance on reporting results for CDx tests evaluation.

e17597 Background: Homologous recombination deficiency (HRD) is a tumor characteristic that can be assessed via different biomarkers such as individual mutations in BRCA1 and BRCA2 genes, and/or other HRR genes and genomic instability. We assessed a combined HRD score in three measures; BRCAs mutations, HRR mutation (HRRm) status, and genomic instability scoring via a specific bioinformatic algorithm of the testing panel to establish clinical validation. Methods: We tested 157 ovarian cancer patients’ FFPE samples to define HRD score, BRCA1/2 mutation and other HRRm status, to camper the responses to PARP inhibitors. For the HRD scoring, all the samples that were previously tested with alternative HRD tests and the cases had an indication of PARPi also tested via HRDInfo (CE-IVD) Panel for clinical diagnostics in this study. The PPA, NPA and OPA have been measured according to the FDA regulations of overall agreement for a follow-on CDx to show clinical evidence. Results: Depending on the three levels of testing strategy, BRCA1-2 mutation status in relation to the clinical response for PARPi has the lowest positive percent agreement (PPA) with 63.41% while HRD score has the highest with 97.62% that is higher than the any alternative HRD tests. All the PPA, NPA and OPA measures showed in the Figure for BRCA1-2 status and Genomic Instability stand alone and all BRCA1-2 plus other HRR genes plus Genomic Instability Status (GIS) to define HRD scoring. Conclusions: Even though the testing rate of HRD tests are still low all around the world and limited to specific cancers, there is an increasing requirement for different types of cancers. However, most alternative HRD tests have high overall concordance but fail to reach FDA CDx test requirements. Thus, this study showing the clinical evidence in the treatment of PARPi response data together with high PPA, NPA and OPA measures of HRDInfo panel and its bioinformatics algorithm. [Table: see text]

Cost-effectiveness analyses of population-based multi-gene testing for the prevention of breast and ovarian cancer in the United States.

10596 Background: The current method of testing for BRCA gene mutations, which is based on family history, often fails to identify many carriers. With the advancement of next-generation sequencing technologies, which have significantly lowered the cost of genetic testing and sequencing, population-based testing has been proposed. We evaluated the cost-effectiveness of population-based multi-gene testing as a means of preventing breast and ovarian cancer. Methods: We developed a microsimulation model to assess the cost-effectiveness of multi-gene testing (BRCA1/BRCA2/PALB2) for all women aged 30-35 years compared to the current standard of care that is family history-based. We selected these genes for analyses as they are most prevalent high penetrance genes. We assumed a test uptake rate of 70%. Carriers of pathogenic variants who were not affected by cancer were offered interventions, such as MRI/mammography, chemoprevention, or risk-reducing mastectomy and risk-reducing salpingo-ophorectomy (RRSO), to reduce the risk of breast and ovarian cancer. We incorporated excess coronary heart disease (CHD) deaths from premenopausal RRSO. Our main outcome measure was the incremental cost-effectiveness ratio (ICER)(i.e., cost per-quality-adjusted life year (QALY) gained), with the commonly used societal willingness to pay of $100,000/QALY in the US as the C-E threshold. We ran 500 simulations on 1,000,000 women, employing a lifetime time horizon and payer perspective, and adjusted the cost to 2022 US dollar. We also used probabilistic sensitivity analyses to evaluate model uncertainty. Results: In the base case, population-based multi-gene testing is more cost-effective compared to family-history based testing, with an ICER of $41,306/QALY (95%CI $35,630-$48,441/QALY). This new testing method is able to prevent an additional 1,369 cases of breast cancer and 807 cases of ovarian cancer, but it will also result in 8 excess heart-disease deaths per million women. The probabilistic sensitivity analyses show that the probability that population-based multi-gene testing is cost-effective is 100% for all the simulations. When the cost of the test exceeds $1,100 population-based multi-gene testing becomes economically inefficient (ICER $10,0886/QALY). Conclusions: Population-based multi-gene testing is a more cost-effective option for the prevention of breast cancer and ovarian cancer when compared to current family-history-based testing methods.

The case for acceleration of prospective multi- stakeholder led community-based research in young Black women with triple negative breast cancer (TNBC).

1089 Background: Black women face a three- fold increase in TNBC BRCA1 gene mutations. In TNBC, there is a higher rate of recurrence and metastasis to other organs. Lower access to timely care and more advance stage at diagnosis contribute to poorer outcomes. Black women have the lowest survival rate at each stage of TNBC diagnosis compared to other demographic groups. Research Question: Over the past 10 years, what real world community interventions have been published regarding risk for and diagnosis with TNBC in Black or African American women? Methods: Using the following keywords: TNBC, diversity, health equity, young adults, Black, African American, authors conducted PUBMED and Google Scholar searches for years 2011 to 2022 to summarize publications on community-based interventions with Black or African American women at risk of or diagnosed with TNBC. Results: A validated publication assessment revealed 70 publications: 63 retrospective and 7 prospective studies. Prospective studies were categorized using the NASEM cancer continuum of care domains. The number of studies that addressed the domains included: risk=1, screening =1, diagnosis=3, treatment=2, survivorship=1 end of life=0, outcomes=1. No studies reported the following criteria: A co-creation approach with community-based participatory research principles; interventions led by patients and Black women who are at risk for TNBC; multi stakeholder interventions led by community leaders or patient organizations with long-standing trust of diverse populations; addressing and resolving social drivers of health inequities, mental health, palliative care services or implicit bias; or inclusion in clinical studies. Conclusions: It is critical to address the disproportionate impact of TNBC in partnership with Black women. To achieve equitable health outcomes, we advise public and private sector leaders to make more funding available to support community-engaged approaches in high prevalence geographic areas. 1) Provide CBPR training and opportunities for diverse investigators and patient- and community-based organizations. 2) Build capacity for social needs assessment and interventions. 3) Employ community-based implementation science focused on all care continuum domains including the gaps between domains. 4) Increase public awareness of health issues in Black women and address resistance, access and eligibility for participation in clinical research. 5) Offer RFPs to transform care through collaboration between researchers, providers, patient and community-based organizations, health departments, and payers; engaging clinical and lay navigators and community health workers; design solutions that address barriers; and development and implementation of policy with a focus on standardization, accountability, and enforceability.

Androgen receptor signaling mechanism in prostate cancer: resistance to antiandrogen therapy and association with DNA repair genes

Background. Metastatic castration-resistant prostate cancer remains a complex problem due to patients' previous treatments and limited selection of subsequent therapies. While 2nd generation antiandrogens are initially effective, resistance to them is not an exceptional event. Mechanisms depending on androgen receptor and independent of it have been described. A special focus is on mutations in DNA repair genes, particularly genes involved in homologous recombination repair (HRR) as a possible cause of somatic genetic abnormalities specifically in progressive metastatic disease. However, data on the effect of the HRR defect on the effectiveness of antiandrogen therapy for prostate cancer are very limited, which requires additional clinical studies.Aim. To evaluate the effect of clinical, morphological, molecular and genetic factors on the effectiveness of enzalutamide antiandrogen therapy in patients with prostate cancer and known mutations in DNA repair genes involved in HRR and mismatch repair.Materials and methods. The study was performed at the Clinical Oncological Dispensary No. 1 (Krasnodar). Retrospective analysis of clinical and morphological parameters of 54 patients with prostate cancer who received enzalutamide antiandrogen therapy and with known status of germ line and somatic mutations of HRR DNA repair genes (BRCA1, BRCA2, ATM, BARD, BRIP1, CDK12, CHEK1, CHEK2, PALB2, RAD51B, RAD51C, RAD54L, FANCL) and microsatellite instability in immunohistochemical determination of mismatch repair deficit was performed. Statistical analysis was performed using IBM SPSS Statistics v.22 software.Results and conclusion. In 17 of 54 patients, pathogenic germline and somatic mutations of HRR genes were detected: 7 mutations in BRCA2 gene, 4 - in CHEK2, 2 - in BRCA1, 2 - in CDK12, 1 - in BRIP1 and 1 - in ATM. It was shown that in the group of patients with metastatic castration-resistant prostate cancer, histological grade per the International Society of Urological Pathology (ISUP) G2 (total Gleason score 7 (3 + 4)) is significantly associated with the absence of HRR mutation, and grade G3 (total Gleason score 7 (4 + 3)) was associated with HRR mutations (р <0.05). Increase in prostate-specific antigen (PSA) level/biochemical progression 12-16 weeks after enzalutamide therapy start was significantly associated with metastatic castration-resistant prostate cancer without HRR mutations (р <0.05). In case of tumor response to enzalutamide therapy, decrease in PSA level did not depend on the age of disease onset, differentiation grade, primary advancement, previous docetaxel treatment, and presence of HRR mutation. Cox multivariate regression test showed that prescription of docetaxel before enzalutamide increased the risk of PSA-progression (hazard ratio (HR) 5.160; 95 % confidence interval (CI) 1.549-17.189; р = 0.008) and radiographic progression (HR 5.161; 95 % CI 1.550-17.187; р = 0.008). Progression risk decreased with increased level of PSA decrease 12-16 weeks after enzalutamide therapy start: for PSA decrease >30 % HR 0.150; 95 % CI 0.040-0.570; р = 0.005; for PSA decrease >50 % HR 0.039; 95 % CI 0.006-0.280; р = 0.001; for PSA decrease >90 % HR 0.116; 95 % CI 0.036-0.375; р = 0.000. Presence of HRR mutation, age <58 years, primary metastatic disease and poorly differentiated morphology did not affect duration without PSA-progression (p >0.05). Kaplan-Meier curves showed a trend towards increased time to development of castration resistance in the group of primary early cancer (Breslow р = 0.06; Tarone-Ware р = 0.062). Subgroup analysis showed that in the cohort of patients with castration-resistant prostate cancer (n = 48), absence of HRR mutation in patients who previously received docetaxel therapy increases time to PSA-progression compared to patients with mutations (log-rank р <0.05).

Cost-effectiveness analysis of olaparib treatment for metastatic castration-resistant prostate cancer with BRCA 1/2 mutations following a new hormonal agent in China

BackgroundThe poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, olaparib has been approved for the treatment of mCRPC in patients with BRCA1/2 mutations who have progressed following prior therapy that included a new hormonal agents. Patients with prostate cancer carrying BRCA gene mutations exhibit a more aggressive disease progression and poorer prognosis, posing challenges for the effectiveness of current treatment options. MethodsFrom the perspective of healthcare payers in China, a three-state partition survival model (progression-free survival, progressed disease and death) was constructed to conduct a cost-effectiveness analysis of olaparib versus enzalutamide for the approved indication. The efficacy and safety of olaparib and enzalutamide were obtained from PROfound trial. Cost were from pricing records and the literature. The model was simulated for 10 years with monthly cycles. Costs and health outcomes were discounted by 5%. Sensitivity analyses were conducted to evaluate the robustness of parameters on the results. ResultsIn the base-case analysis, the total cost of olaparib was ¥ 101,012, with a total of 1.1576 QALYs gained. The total cost of enzalutamide was ¥ 52,425, with a total of 0.5929 QALYs gained. Compared to enzalutamide, olaparib had an ICER of ¥ 86,043 per QALY, with an increase in total costs of ¥ 48,587 and an increase in QALYs of 0.5647. At a threshold of three times per capita GDP of China (¥ 257,094 in 2022), the probability of olaparib being cost-effective compared to enzalutamide was 99.0%. ConclusionFrom the healthcare payer perspective, olaparib is cost-effective compared to enzalutamide for the treatment of metastatic castration-resistant prostate cancer in patients with BRCA1/2 mutations who have progressed following prior therapy that included a new hormonal agent.