BRCA1 Tumor Research Articles

Stat3 Tyrosine 705 and Serine 727 Phosphorylation Associate With Clinicopathological Characteristics and Distinct Tumor Cell Phenotypes in Triple-Negative Breast Cancer.

Signal transducer and activator of transcription 3 (Stat3) is responsible for many aspects of normal development and contributes to the development and progression of cancer through regulating epithelial cell identity and cancer stem cells. In breast cancer, Stat3 is associated with triple-negative breast cancers (TNBC) and its function has been related to the activation of p63, itself a marker of basal-like TNBC and a master regulator of stem cell activities. Stat3 activation is controlled by dual phosphorylation at tyrosine 705 (pTyr705) and serine 727 (pSer727), although it is unclear whether these have equivalent effects, and whether they are related or independent events. To address these issues, we investigated Stat3 phosphorylation at the two sites by immunohistochemistry in 173 patients with TNBC. Stat3 phosphorylation was assessed by automated quantitative measurements of digitized scanned images and classified into four categories based on histoscore. The results were analyzed for associations with multiple markers of tumor phenotype, proliferation, BRCA status, and clinicopathological characteristics. We show that the levels of pTyr705- and pSer727-Stat3 were independent in 34% of tumors. High pTyr705-Stat3 levels were associated with the luminal differentiation markers ERβ/AR and MUC1, whereas tumors with high levels of pSer727-Stat3 were more likely to be positive for the basal marker CK5/6, but were independent of p63 and were EGFR negative. Combined high pSer727- and low Tyr705-Stat3 phosphorylation associated with basal-like cancer. Although high Stat3 phosphorylation levels were associated with less aggressive tumor characteristics, they did not associate with improved survival, indicating that Stat3 phosphorylation is an unfavorable indicator for tumors with an otherwise good prognosis according to clinicopathological characteristics. These findings also show that pTyr705-Stat3 and pSer727-Stat3 associate with specific breast tumor phenotypes, implying that they exert distinct functional activities in breast cancer.

Physician behavior and perceptions around genetic biomarker test utilization for the management of newly diagnosed advanced ovarian cancer patients: US physician survey (223)

Physician behavior and perceptions around genetic biomarker test utilization for the management of newly diagnosed advanced ovarian cancer patients: US physician survey (223)

Characterization of the HER2 status in BRCA-mutated breast cancer: a single institutional series and systematic review with pooled analysis

BackgroundPathogenic variants (PVs) in BRCA1/2 genes account for ∼6% of breast and 20% of ovarian cancers. Most breast tumors developed by BRCA1 carriers are triple negative. BRCA2 tumors have similar rates of estrogen receptor positivity as sporadic controls but are less likely to be human epidermal growth factor receptor 2 (HER2)-positive. Prevalence of HER2 positivity among breast cancers (BCs) in BRCA1/2 mutation carriers is poorly and variably described, ranging from 0% to 10% and 0% to 13% in BRCA1 and BRCA2 carriers, respectively.Patients and methodsWe assessed the prevalence of HER2 positivity among a single institutional cohort of 398 BCs developed in carriers of BRCA1/2 PVs (240 BRCA1, 158 BRCA2). Subsequently, a systematic review of the literature and pooled analysis was carried out.ResultsIn our series we found a 7% HER2 positivity rate among all first BRCA1/2 BCs overall. In BRCA1 carriers, 5.4% of BCs were HER2-positive compared with 9.5% in BRCA2-mutated patients. Among bilateral BCs, HER2-positive cases were 15.2% in the BRCA1 group and 23.1% in the BRCA2 group. Notably, six BRCA1 and eight BRCA2 carriers showed discordant HER2 status between BC and bilateral BC (23.7%, 14/59). The systematic review included 21 083 BRCA1/2 patients from 73 eligible studies. The pooled rate of BRCAmut/HER2-positive BCs is 9.1% (95% confidence interval 7.3% to 11.2%). BRCA1 and BRCA2 when reported as separate data ranged from 0% to 33.3% (mean 8.3%) and from 0% to 86% (mean 10.3%), respectively.ConclusionsAs compared with sporadic cases, BCs occurring in BRCA1 and/or BRCA2 PVs carriers are less frequently HER2-positive. Prevalence of HER2 positivity in our series was consistent with pooled analysis and did not exceed 10%. Although not common, co-existence of BRCA mutations and HER2 overexpression and/or gene amplification should be acknowledged. More research is needed to better characterize this subgroup of patients who should not be excluded a priori from clinical trials of targeted therapy for BRCA1/2-driven cancers.

Management Strategies of Breast Cancer Patients with BRCA1 and BRCA2 Pathogenic Germline Variants.

Most of breast cancer cases are sporadic; however, 15–20% are associated with family history, and some are inherited. Among those, deleterious mutations in BRCA1 and BRCA2 tumor suppressor genes are the most commonly encountered pathogenic germline variants (PGVs). Given the availability and affordability of multi-gene panel sequencing technologies, testing for PGVs is commonly practiced. With our enhanced understanding of cancer genetics and specific molecular alterations, the better acceptance of risk-directed screening and prevention, and the recent introduction of novel targeted therapies, management of BRCA-positive breast cancers is taking a new direction, focusing more on risk-reducing interventions, including mastectomy and salpingo-oophorectomy, and incorporating special treatment regimens, including platinum-based chemotherapy, and the recently-introduced PARP (poly (ADP)-ribose polymerase) inhibitors. Given the recent advances in reproductive technology and molecular medicine, younger women with PGVs may have the option of embryo selection through preimplantation genetic testing and diagnosis, thus preventing the potential transmission of the implicated genes to the next generations. In this review, we cover the clinical implications of identifying a pathogenic germline mutation in BRCA1 and BRCA2 genes in breast cancer patients, and their relatives, across the continuum of care – from cancer prevention and early detection, through active treatment and up to survivorship issues.

A Systematic Pan-Cancer Analysis of YY1 Aberrations and their Relationship with Clinical Outcome, Tumor Microenvironment, and Therapeutic Targets.

Yin-Yang 1 (YY1) has a crucial function in the development of several malignancies, according to recent research. However, nothing is known about its aberrant expression and prognostic significance in human pan-cancer. We first explored the potential carcinogenic effect of YY1 in 33 cancers using the cancer genome atlas (TCGA) project and gene expression omnibus (GEO) datasets in this research. Then, we contained a variety of elements, for instance, gene expression, the state of survival, gene alterations, protein phosphorylation, immune infiltration, and related cellular pathways, and used a series of bioinformatics methods to investigate the underlying molecular mechanism of YY1 in the etiology or clinical prognosis of various malignancies. In most malignancies, YY1 was expressed at high levels, and the level of YY1 expression was statistically associated with the prognosis of tumor patients. The S118 site of YY1 implied higher phosphorylation expression in breast cancer, colon cancer, uterine corpus endometrial carcinoma (UCEC), and lung adenocarcinoma (LUAD) tumor tissues, but lower phosphorylation levels in ovarian cancer and clear cell carcinoma tumor tissues. For S247, higher phosphorylation levels were found in colon cancer, UCEC, and LUAD tumor tissue, and lower phosphorylation expression was found in clear cell carcinoma tumor tissue. In TCGA database, YY1 expression in BRCA, BRCA-LumA, BRCA-LumB, CESC, CHOL, COAD, ESCA, HNSC, HNSC-HPV-, KIRP, LGG, LIHC, and PAAD tumor tissues was a statistically significant positive connection of the estimated infiltration value of cancer-associated fibroblasts but a negative correlation in TGCT. In addition, the functional mechanism of YY1 also involves viral carcinogenesis and ribonucleic acid (RNA) metabolism related functions. Our first pan-cancer analysis offers a pretty comprehensive knowledge of YY1's oncogenic involvement in various cancers.

Abstract 812: High RAD51 gene expression is associated with aggressive biology and with poor survival in breast cancer

Abstract INTRODUCTION: Homologous recombination deficiency (HRD) is involved in breast cancer carcinogenesis, however, activation of DNA repair in cancer cells may promote its survival and progression. RAD51 plays an essential role in homologous recombination with BRCA2. Recently, RAD51 has been highlighted to play a role in resistance to DNA-damaging chemotherapy or PARP inhibitors. We hypothesized that RAD51 as a prognostic and predictive biomarker of drug sensitivity in breast cancer. MATERIALS AND METHODS: Total of 4500 primary breast cancer patients from three independent cohorts were examined. High and low expression of RAD51 were divided by median RNA expression. Response to treatments were assessed in total of 3000 patients across 11 independent cohorts of breast cancer patients that received neoadjuvant chemotherapy. RESULTS: RAD51 was upregulated in cancer compared to normal tissues in the TCGA cohort and was positively correlated with HRD. Cancer with high RAD51 group enriched DNA repair gene set in gene set enrichment analysis (GSEA) in all cohorts and had high expression of HRD-related genes including BRCA1 and BRCA2. Histological grade and Ki67 expression were positively correlated with RAD51, and all cancer proliferation gene sets from Hallmark (E2F target, G2M checkpoint, Myc Targets v1 and v2, and Mitotic Spindle) were strongly enriched in the high RAD51 expression breast cancer in all cohorts. In TCGA, tumor mutation burden and neoantigen were also higher in tumor with high RAD51 expression, but RAD51 expression was not elevated in BRCA1 or BRCA2 mutant tumors. Cytolytic activity score, a marker of cancer immunity, was elevated high RAD51 group in two cohorts, and the immune cell fraction calculated by the xCell algorithm showed increase in immune cell infiltration, including CD4 memory T cells, Th1 cells, M1 macrophages and activated dendritic cells, in all cohorts, suggesting a certain level of activation of cancer immunity in this RAD51 high breast cancer group. However, contrary to previous reports, RAD51 expression in breast cancer cell lines did not show any association between sensitivity to chemotherapy or PARP inhibitors. Neither for the breast cancer NAC cohort, RAD51 expression was not increased in the residual burden group, but conversely increase in RAD51expression was observed in pathological complete response group in some cohorts. Surprisingly, RAD51 was significantly associated with worse overall survival in all three large cohorts included in this analysis, and with worse disease-specific survival in two cohorts. CONCLUSIONS: RAD51 expression was significantly associated with worse survival, but did not with treatment-responsive, suggesting its usefulness as prognostic, but not predictive, biomarker. Citation Format: Rongrong Wu, Ankit Patel, Yoshihisa Tokumaru, Mariko Asaoka, Masanori Oshi, Li Yan, Takashi Ishikawa, Kazuaki Takabe. High RAD51 gene expression is associated with aggressive biology and with poor survival in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 812.

Abstract 507: Trop-2 expression in triple-negative breast cancer according to histological subtype: correlations with tumor infiltrating lymphocytes (TILs) and survival

Abstract Background: Trop-2 is a transmembrane calcium signal transducer highly expressed in multiple solid tumors including breast cancer. Limited data exist about associations between Trop-2 protein expression, clinicopathological characteristics and outcome in triple-negative breast cancers (TNBC). Given the approval of sacituzumab govitecan in unselected TNBC, its evaluation in other breast cancer settings and the emergence of other Trop-2 targeted antibody-drug conjugates, Trop-2 emerges as an important drug target in solid tumors. Methods: Trop-2-expression of patients with TNBC diagnosed between 2000-2017 at UZ Leuven was determined with IHC (ab227689, Abcam) (continuous and categorical variables, high 201-300, medium 100-200 and low <100 H-score). Associations of Trop-2-expression with age, BMI, germline BRCA status, tumor grade and size, histological subtype, lymphovascular invasion (LVI), presence of DCIS, nodal status, stromal TILs, androgen receptor (AR), standardized mitotic index, and outcome (invasive disease-free survival (iDFS), distant recurrence-free survival (D-RFi) and breast cancer-specific survival (BCSS)) were assessed. Associations with continuous variables were assessed by the Spearman correlation coefficient (ρ). Group differences were assessed by the Kruskal Wallis test for multiple groups or Mann-Whitney U test for two groups. Cox proportional hazards models were used to assess the association between Trop-2 expression and outcome. Results: Total of 658 patients with a median age at diagnosis of 53y (range 22-89y) were included, with median follow-up 9.6y. Low, medium and high Trop-2 expression was seen in 58.2%, 25.3% and 16.5% of cases. AR was positive in 25.5% of cases (10%-cutoff). Highest Trop-2 expression was observed in tumors with apocrine histology (median 180 score), and lowest expression in tumors with metaplastic histology (median 45 score) (p<.001). Higher Trop-2 expression was correlated with higher AR expression (10%-cutoff) (p=0.009), more presence of nodal involvement (p=0.016), associated DCIS (p=0.004) and LVI (p=0.006). Trop-2 expression was not associated with pathological complete response (pCR) observed in 22 of 64 patients treated with neoadjuvant chemotherapy (p=0.96). There was an iDFS events frequency of 199 out of 658 (30.2%). There was no correlation between Trop-2 expression and sTILs or outcome. Conclusion: In patients with TNBC in a large tertiary center, higher Trop-2 expression was correlated with apocrine histology, higher AR expression, more associated DCIS, more LVI and nodal involvement. There was no correlation between Trop-2 expression and sTILs or outcome. Citation Format: Hava Izci, Kevin Punie, Lise Waumans, Annouschka Laenen, Hans Wildiers, Freija Verdoodt, Christine Desmedt, Jan Ardui, Ann Smeets, Sileny Han, Ines Nevelsteen, Patrick Neven, Giuseppe Floris. Trop-2 expression in triple-negative breast cancer according to histological subtype: correlations with tumor infiltrating lymphocytes (TILs) and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 507.

Kinase Activity of PAR1b, Which Mediates Nuclear Translocation of the BRCA1 Tumor Suppressor, Is Potentiated by Nucleic Acid-Mediated PAR1b Multimerization.

PAR1b is a cytoplasmic serine/threonine kinase that controls cell polarity and cell–cell interaction by regulating microtubule stability while mediating cytoplasmic-to-nuclear translocation of BRCA1. PAR1b is also a cellular target of the CagA protein of Helicobacter pylori, which leads to chronic infection causatively associated with the development of gastric cancer. The CagA-PAR1b interaction inactivates the kinase activity of PAR1b and thereby dampens PAR1b-mediated BRCA1 phosphorylation, which reduces the level of nuclear BRCA1 and thereby leads to BRCAness and BRCAness-associated genome instability underlying gastric carcinogenesis. While PAR1b can multimerize within the cells, little is known about the mechanism and functional role of PAR1b multimerization. We found in the present study that PAR1b was multimerized in vitro by binding with nucleic acids (both single- and double-stranded DNA/RNA) via the spacer region in a manner independent of nucleic-acid sequences, which markedly potentiated the kinase activity of PAR1b. Consistent with these in vitro observations, cytoplasmic introduction of double-stranded DNA or expression of single-stranded RNA increased the PAR1b kinase activity in the cells. These findings indicate that the cytoplasmic DNA/RNA contribute to nuclear accumulation of BRCA1 by constitutively activating/potentiating cytoplasmic PAR1b kinase activity, which is subverted in gastric epithelial cells upon delivery of H. pylori CagA oncoprotein.

AGO-OVAR 28/ENGOT-ov57: Niraparib versus niraparib in combination with bevacizumab in patients with carboplatin-taxane based chemotherapy in advanced ovarian cancer—A multicenter, randomized, phase III trial.

TPS5612 Background: Standard of care chemotherapy in patients (pts) with advanced ovarian cancer (AOC) is the combination of carboplatin and paclitaxel. Data from the PRIMA trial has shown a significant benefit in pts by the addition of a maintenance treatment (MT) with niraparib irrespective of BRCA or HRD-status in high-grade ovarian cancers (OC). The PAOLA-1 trial evaluated MT in pts with AOC with the combination of olaparib and bevacizumab and has also shown a significant benefit compared to bevacizumab monotherapy. However, it is unclear if a PARP-inhibitor (PARPi) MT monotherapy is sufficient or if the addition of bevacizumab is needed. Therefore, we investigate, if the treatment strategy of carboplatin / paclitaxel / bevacizumab / PARPi is superior to the treatment of carboplatin / paclitaxel / PARPi in an all-comer population. Methods: AGO-OVAR 28/ ENGOT-ov57 (NCT05009082; EudraCT Number: 2021-001271-16) is an Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Study Group led, international, multicenter, randomized, prospective phase III trial within the ENGOT trial network. The trial population is composed of adult pts with newly diagnosed, advanced high-grade epithelial OC, primary peritoneal cancer or fallopian tube cancer FIGO III/IV (except FIGO IIIA2 without nodal involvement). All pts should have completed the first cycle of chemotherapy (carboplatin and paclitaxel) as part of Study Run-In-Period. Prior to day1 of cycle2, pts with a valid central tumor BRCA ( tBRCA) test result will be randomized 1:1 into either Arm1 and will receive 5 additional cycles of carboplatin and paclitaxel, q21d followed by niraparib for up to 3 years; or into Arm2 where pts will receive 5 additional cycles of carboplatin and paclitaxel plus bevacizumab, q21d followed by bevacizumab, q21d (for up to 1 year) and niraparib for up to 3 years. Patients who are scheduled for neoadjuvant chemotherapy and interval debulking surgery are also allowed to be included in the trial. The primary objective is progression free survival (PFS). Secondary objectives include but are not limited to: PFS according to tBRCA-status, overall survival, PFS2, safety and tolerability, and quality of life. The trial will start in Q1/2022 with First Patient First Visit expected in Q2/2022. It is planned to recruit 970 patients. Clinical trial information: NCT05009082.

Testing of newly diagnosed advanced high grade ovarian cancer (OC) patients with the Myriad Genetics MyChoice CDx Plus next generation sequencing-based in vitro diagnostic test emphasizes the need for public insurance coverage of genetic testing: Results of a national program by the Hellenic Society of Medical Oncology (HeSMO).

e18520 Background: Homologous Recombination deficiency (HRD) represents a distinct entity in OC. Clinical data suggest that treatment selection can be based on both BRCA1/2 mutations and bearing Genomic Instability Status (GIS). Testing for GIS is critical in order to expand patients’ pool for targeted treatment. Myriad my Choice, is currently the only FDA approved test that can detect HRD by assessing BRCA1/BRCA2 mutation and GIS status in OC tumor specimens using 3 biomarkers: loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions. To address this need, HeSMO has initiated a national program to provide access to myChoice to newly diagnosed patients with high grade stage III/IV OC. Methods: Patients with newly diagnosed stage III/IV high grade OC were eligible to participate in this program. The specific performance characteristics of myChoice CDx assay were determined on FFPE tumor samples by the evaluation of a range of representative tumor BRCA1 and BRCA2 sequence variants (e.g. single nucleotide variants, insertions or deletions and variants in homopolymers), Large Rearrangements (e.g. deletions and duplications affecting single and multiple exons) and a representative range of GIS. The overall results are composed of two major components: GIS Status (positive or negative) and tumor (t) BRCA1/2 Status (positive or negative). The combined results form the basis of the overall interpretation of the myChoice CDx Myriad HRD Status. Results: From December 2020 to January 2022, 454 patients from all over the country were tested within this program. 220 patients (48.46%) had a positive GIS report and 179 (39.43%) had a negative one. Among GIS positive cases, 122 patients were tBRCAwt (26.87%) 78 patients were tBRCA mutated (17.18%) and 10 patients had suspected deleterious BRCA1/2 mutations (2.20%). Inconclusive was the report in 38 specimens (8.37%) and myChoice Lab failed to complete the analysis in 15 cases (3.30%). Furthermore, mutations were also detected in a number of other genes, including but not limited to, ATM, BRIP1, PALB2, RAD51C, RAD51D, FANCL, CHEK2. Conclusions: In our series, 48.46% of the patients with high grade OC tested as BRCA1/2 and/or GIS positive, in accordance with published data, underlying the clinical need to implement GIS testing in OC patients’ molecular evaluation. Apart from the significant implications for treatment possibilities in an expanded patients’ population, these results are important for cancer prevention. We strongly believe that our results will strengthen our efforts for reimbursement of such testing in high grade OC patients, and will serve as a roadmap for the establishment of local HRD testing solutions.

BRCA1 haploinsufficiency promotes chromosomal amplification under Fenton reaction-based carcinogenesis through ferroptosis-resistance

Germline-mutation in BRCA1 tumor suppressor gene is an established risk for carcinogenesis not only in females but also in males. Deficiency in the repair of DNA double-strand breaks is hypothesized as a responsible mechanism for carcinogenesis. However, supporting data is insufficient both in the mutation spectra of cancers in the patients with BRCA1 germline-mutation and in murine knockout/knock-in models of Brca1 haploinsufficiency. Furthermore, information on the driving force toward carcinogenesis in BRCA1 mutation carriers is lacking. Here we applied Fenton reaction-based renal carcinogenesis to a rat heterozygously knockout model of BRCA1 haploinsufficiency (mutant [MUT] model; L63X/+). Rat MUT model revealed significant promotion of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA). Array-based comparative genome hybridization of the RCCs identified significant increase in chromosomal amplification, syntenic to those in breast cancers of BRCA1 mutation carriers, including c-Myc, in comparison to those in the wild-type. Subacute-phase analysis of the kidney after repeated Fe-NTA treatment in the MUT model revealed dysregulated iron metabolism with mitochondrial malfunction assessed by expression microarray and electron microscopy, leading to renal tubular proliferation with iron overload. In conclusion, we for the first time demonstrate that biallelic wild-type BRCA1 provides more robust protection for mitochondrial metabolism under iron-catalyzed oxidative stress, preventing the emergence of neoplastic cells with chromosomal amplification. Our results suggest that oxidative stress via excess iron is a major driving force for carcinogenesis in BRCA1 haploinsufficiency, which can be a target for cancer prevention and therapeutics.

Reflex BRCA1 and BRCA2 tumour genetic testing for high-grade serous ovarian cancer: streamlined for clinicians but what do patients think?

BackgroundReflex (automatic) BRCA1 and BRCA2 (BRCA1/2) genetic testing of tumour tissue is being completed for all newly diagnosed high-grade serous ovarian cancer (HGSOC) in the province of Ontario, Canada. The objective of this study was to measure the psychological impact of tumour genetic testing among individuals with a new diagnosis of HGSOC.MethodsParticipants had a new diagnosis of HGSOC and received reflex BRCA1/2 tumour genetic testing as a component of their care. Eligible individuals were recruited from two oncology centres in Toronto, Canada. One week after disclosure of tumour genetic test results, consenting participants were asked to complete a questionnaire that measured cancer-related distress, dispositional optimism, knowledge of hereditary breast/ovarian cancer, recall of tumour genetic test results, satisfaction, and the psychological impact of receiving tumour genetic test results. The Multidimensional Impact of Cancer Risk Assessment (MICRA) questionnaire was used to measure the psychological impact of tumour genetic testing.Results76 individuals completed the study survey; 13 said they did not receive their tumour test results. Of the remaining 63 participants, the average MICRA score was 26.8 (SD = 16.3). Higher total MICRA scores were seen among those with children (p = 0.02), who received treatment with primary surgery (p = 0.02), and had higher reported cancer-related distress (p < 0.001). Higher dispositional optimism (p < 0.001) and increasing age (p = 0.03) were associated with lower total MICRA scores. Most (83.5%) participants reported being satisfied/highly satisfied with having tumour testing completed; however, 40.8% could not accurately recall their tumor test results.ConclusionsThis study is the first to assess psychological outcomes following reflex BRCA1/2 tumour genetic testing in women newly diagnosed with HGSOC. Increased dispositional optimism provided a protective effect, while increased cancer-related distress increased the psychological impact of tumour genetic testing. Educational resources are needed to help increase patient understanding and recall of tumour results, particularly when tumour genetic testing includes analysis of genes that may have implications for hereditary cancer risk. Additional research is required to better understand the patient experience of reflex tumour genetic testing.

Aging accelerates while multiparity delays tumorigenesis in mouse models of high-grade serous carcinoma

ObjectivesThe “incessant ovulation” hypothesis links increased risk for tubo-ovarian high-grade serous carcinoma (HGSC) due to more ovulations and reduced risk conferred by pre-menopausal exposures like oral contraceptive use, multiparity, and breastfeeding. However, most women diagnosed with HGSC are postmenopausal, implying age is a major risk factor for HGSC. Our mouse model for HGSC, based on tamoxifen (TAM)-induced somatic inactivation of the Brca1, Trp53, Rb1, and Nf1 (BPRN) tumor suppressor genes in oviductal epithelium, recapitulates key genetic, histopathologic, and biological features of human HGSCs. We aimed to credential the model for future efforts to define biological and risk modification factors in HGSC pathogenesis. MethodsBPRN mice were treated with TAM to induce tumors at defined ages and parity status. ResultsBPRN mice aged 9-months prior to tumor induction had markedly shorter survival than 6–8 week old mice induced to form tumors (median 46.5 weeks versus 61.5 weeks, log-rank test P = 0.0006). No significant differences in cancer phenotypes were observed between multiparous versus nulliparous BPRN mice. However, using a modified tumor model with one wild-type Nf1 allele (BPRNfl/+), nulliparous mice had more advanced tumors than multiparous mice (Mantel-Haenszel Chi-square test of association, P = 0.01). ConclusionsOur findings show aging is associated with significantly shortened survival post tumor induction in the BRPN model and multiparity delays development and/or progression of HGSC in certain genetic contexts. The findings support relevance of our mouse model to gain mechanistic insights into how known factors exert their protective effects and to test novel approaches for HGSC prevention.

Management of BRCA Tumour Testing in an Integrated Molecular Tumour Board Multidisciplinary Model.

Tumour testing of the BRCA1/2 genes is routinely performed in patients with different cancer histological subtypes. To accurately identify patients with tumour-detected germline pathogenic variants (PVs) is a relevant issue currently under investigation. This study aims at evaluating the performance of the tumour-to-germline diagnostic flowchart model defined at our Institutional Molecular Tumour Board (MTB). Results from tumour BRCA sequencing of 641 consecutive unselected cancer patients were discussed during weekly MTB meetings with the early involvement of clinical geneticists for appropriate referral to genetic counselling. The overall tumour detection rate of BRCA1/2 PVs was 8.7% (56/641), ranging from 24.4% (31/127) in high-grade ovarian cancer to 3.9% (12/304) in tumours not associated with germline BRCA1/2 PVs. Thirty-seven patients with PVs (66%) were evaluated by a clinical geneticist, and in 24 of them (64.9%), germline testing confirmed the presence of the PV in blood. Nine of these patients (37.5%) were not eligible for germline testing according to the criteria in use at our institution. Cascade testing was subsequently performed on 18 relatives. The tumour-to-germline diagnostic pipeline, developed in the framework of our institutional MTB, compared with guideline-based germline testing following genetic counselling, proved to be effective in identifying a higher number of germline BRCA PVs carriers.

A commentary on the discrepancy between blood and tumour BRCA testing: An open question.

A commentary on the discrepancy between blood and tumour BRCA testing: An open question.

Tumor BRCA Testing in Epithelial Ovarian Cancers: Past and Future-Five-Years' Single-Institution Experience of 762 Consecutive Patients.

Simple SummaryTumor BRCA testing is crucial in the clinical management of women affected by epithelial ovarian cancer (EOC). In the present study, we aimed to report the results of five years of experience in tumor BRCA testing performed in a single-institution diagnostic setting. We profiled 762 consecutive EOC patients with a failure rate of less than 1% and less than two weeks of turnaround time, which is consistent with the clinical needs. We identified 23.4% of cases with pathogenic/likely pathogenic mutations, including 76% of patients affected by germline and 24% by somatic alterations. Here, we proposed a comprehensive and multidisciplinary clinical workflow that could be successfully followed for the identification of somatic as well as germline alterations, maximizing the benefit of BRCA testing both from a therapeutic and risk assessment perspective.The establishment of PARP inhibitors in the treatment of epithelial ovarian carcinoma (EOC) has prompt BRCA assessment at the time of diagnosis. We described our five years of experience of tumor BRCA testing, as part of a multidisciplinary workflow for the management of EOC patients. We used a BRCA next-generation sequencing (NGS) test for profiling formalin-fixed, paraffin-embedded (FFPE) EOCs of 762 consecutive patients, with a success rate of 99.7% and a median turnaround time of 12 days. We found 178 (23.4%) cases with pathogenic/likely pathogenic (P/LP) mutations, 74 (9.7%) cases with variants of uncertain significance and 508 (66.8%) wild type tumors. Among 174 patients without P/LP mutations and investigated with multiple-ligation probe-amplification analysis on peripheral blood, two (1.1%) were positive for large rearrangements. Patients with P/LP alterations and/or with positive family history were referred to genetic counselling. Comparing tumor and blood NGS test results of 256 patients, we obtained a tumor test negative predictive value of 100% and we defined 76% of P/LP alterations as germline and 24% as somatic variants. The proposed workflow may successfully identify EOC patients with BRCA1/2 alteration, guiding both therapeutic and risk assessment clinical decisions.

PTEN alterations in sporadic and BRCA1-associated triple negative breast carcinomas

The similarities between sporadic basal-like breast cancer (BLBC) and BRCA1-mutated breast tumours raise the possibility that deregulation of the same pathway may underlie these tumour types. The aim of this study was to determine if PTEN aberrations are characteristic of both BRCA1 tumours and sporadic TN breast carcinomas with low BRCA1 expression, and can thus be used to identify sporadic tumours potentially sensitive to PARP inhibitors. Twelve BRCA1 tumours, 19 non-BRCA familial breast tumours and 71 unselected TN breast carcinomas were screened for PTEN mutations and assessed for PTEN expression and BRCA1 mRNA expression. Loss of PTEN expression was observed in 67% of BRCA1 tumours and more specifically in 89% of TN BRCA1 tumours highlighting the link between PTEN loss and BLBC in the context of germline BRCA1 mutations. Regarding unselected TN tumours, 56% showed PTEN expression loss and 35% displayed low BRCA1 mRNA expression. Unlike familial breast cancers with low BRCA1 mRNA expression, no significant correlation was observed between the loss of PTEN expression and low BRCA1 mRNA expression in this unselected TN tumours panel. Our data suggest that, unlike the germinal context, PTEN and BRCA1 alterations in sporadic TN breast tumours are independent events.

Abstract OT2-24-02: ZEST: Randomized phase III study evaluating efficacy and safety of niraparib in patients with HER2-negative BRCA-mutated or triple-negative breast cancer with detectable circulating tumor DNA after definitive therapy

Abstract OT2-24-02: ZEST: Randomized phase III study evaluating efficacy and safety of niraparib in patients with HER2-negative BRCA-mutated or triple-negative breast cancer with detectable circulating tumor DNA after definitive therapy

Unique ER PR expression pattern in breast cancers with CHEK2 mutation: a hormone receptor and HER2 analysis based on germline cancer predisposition genes

PurposeEstrogen-receptor (ER) and progesterone-receptor (PR) expression levels in breast cancer, which have been principally compared via binomial descriptors, can vary widely across tumors. We sought to characterize ER and PR expression levels using semi-quantitative analyses of receptor staining in germline pathogenic variant (PV) carriers of cancer predisposition genes.MethodsWe conducted a retrospective chart review of patients who underwent germline genetic testing for cancer predisposition genes at a tertiary cancer center genetics clinic. We performed comparisons of semi-quantitative ER and PR percentage staining levels across carriers and non-carriers of cancer predisposition genes.ResultsBreast cancers from BRCA1 PV carriers expressed significantly lower ER (15.2% vs 78.2%, p < 0.001) and lower PR (6.8% vs 41.1%, p < 0.001) staining compared to non-PV carriers. Similarly, breast cancers of BRCA2 (66.7% vs 78.2%, p = 0.005) and TP53 (50.6% vs 78.2%, p = 0.015) PV tumors also displayed moderate decreases in ER staining. Conversely, CHEK2 tumors displayed higher ER (93.1% vs 78.2%, p = 0.005) and PR (72% vs 48.8%, p = 0.001) staining when compared to non-PV carriers. We observed a wide range of dispersion across the ER and PR staining levels of the carriers and noncarriers. ER and PR ranges of dispersion of CHEK2 tumors were uniquely narrower than all other groups.ConclusionThe findings of our study suggest that precise expression levels of ER and PR in breast cancers can vary widely. These differences are further augmented when comparing expression staining across PV and non-PV carriers, suggesting potentially unique tumorigenesis and progression pathways influenced by germline cancer predisposition genes.

Determinants of Response to Talazoparib in Patients with HER2-Negative, Germline BRCA1/2-Mutated Breast Cancer.

PARP inhibitors (PARPi) have demonstrated efficacy in tumors with germline breast cancer susceptibility genes (gBRCA) 1 and 2 mutations, but further factors influencing response to PARPi are poorly understood. Breast cancer tumor tissue from patients with gBRCA1/2 mutations from the phase III EMBRACA trial of the PARPi talazoparib versus chemotherapy was sequenced using FoundationOne CDx. In the evaluable intent-to-treat population, 96.1% (296/308) had ≥1 tumor BRCA (tBRCA) mutation and there was strong concordance (95.3%) between tBRCA and gBRCA mutational status. Genetic/genomic characteristics including BRCA loss of heterozygosity (LOH; identified in 82.6% of evaluable patients), DNA damage response (DDR) gene mutational burden, and tumor homologous recombination deficiency [assessed by genomic LOH (gLOH)] demonstrated no association with talazoparib efficacy. Overall, BRCA LOH status, DDR gene mutational burden, and gLOH were not associated with talazoparib efficacy; however, these conclusions are qualified by population heterogeneity and low patient numbers in some subgroups. Further investigation in larger patient populations is warranted.