Causality and functional relevance of BRCA1 and BRCA2 pathogenic variants in non-high-grade serous ovarian carcinomas.

The identification of causal BRCA1/2 pathogenic variants (PVs) in epithelial ovarian carcinoma (EOC) aids the selection of patients for genetic counselling and treatment decision-making. Current recommendations therefore stress sequencing of all EOCs, regardless of histotype. Although it is recognised that BRCA1/2 PVs cluster in high-grade serous ovarian carcinomas (HGSOC), this view is largely unsubstantiated by detailed analysis. Here, we aimed to analyse the results of BRCA1/2 tumour sequencing in a centrally revised, consecutive, prospective series including all EOC histotypes. Sequencing of n = 946 EOCs revealed BRCA1/2 PVs in 125 samples (13%), only eight of which were found in non-HGSOC histotypes. Specifically, BRCA1/2 PVs were identified in high-grade endometrioid (3/20; 15%), low-grade endometrioid (1/40; 2.5%), low-grade serous (3/67; 4.5%), and clear cell (1/64; 1.6%) EOCs. No PVs were identified in any mucinous ovarian carcinomas tested. By re-evaluation and using loss of heterozygosity and homologous recombination deficiency analyses, we then assessed: (1) whether the eight 'anomalous' cases were potentially histologically misclassified and (2) whether the identified variants were likely causal in carcinogenesis. The first 'anomalous' non-HGSOC with a BRCA1/2 PV proved to be a misdiagnosed HGSOC. Next, germline BRCA2 variants, found in two p53-abnormal high-grade endometrioid tumours, showed substantial evidence supporting causality. One additional, likely causal variant, found in a p53-wildtype low-grade serous ovarian carcinoma, was of somatic origin. The remaining cases showed retention of the BRCA1/2 wildtype allele, suggestive of non-causal secondary passenger variants. We conclude that likely causal BRCA1/2 variants are present in high-grade endometrioid tumours but are absent from the other EOC histotypes tested. Although the findings require validation, these results seem to justify a transition from universal to histotype-directed sequencing. Furthermore, in-depth functional analysis of tumours harbouring BRCA1/2 variants combined with detailed revision of cancer histotypes can serve as a model in other BRCA1/2-related cancers. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Exploration of poly (ADP-ribose) polymerase inhibitor resistance in the treatment of BRCA1/2-mutated cancer.

Breast cancer susceptibility 1/2 (BRCA1/2) genes play a crucial role in DNA damage repair, yet mutations in these genes increase the susceptibility to tumorigenesis. Exploiting the synthetic lethality mechanism between BRCA1/2 mutations and poly(ADP-ribose) polymerase (PARP) inhibition has led to the development and clinical approval of PARP inhibitor (PARPi), representing a milestone in targeted therapy for BRCA1/2 mutant tumors. This approach has paved the way for leveraging synthetic lethality in tumor treatment strategies. Despite the initial success of PARPis, resistance to these agents diminishes their efficacy in BRCA1/2-mutant tumors. Investigations into PARPi resistance have identified replication fork stability and homologous recombination repair as key factors sensitive to PARPis. Additionally, studies suggest that replication gaps may also confer sensitivity to PARPis. Moreover, emerging evidence indicates a correlation between PARPi resistance and cisplatin resistance, suggesting a potential overlap in the mechanisms underlying resistance to both agents. Given these findings, it is imperative to explore the interplay between replication gaps and PARPi resistance, particularly in the context of platinum resistance. Understanding the impact of replication gaps on PARPi resistance may offer insights into novel therapeutic strategies to overcome resistance mechanisms and enhance the efficacy of targeted therapies in BRCA1/2-mutant tumors.

Prevalence and Reclassification of Genetic Variants in South African Populations with Breast Cancer.

Concurrent testing of numerous genes for hereditary breast cancer (BC) is available but can result in management difficulties. We evaluated use of an expanded BC gene panel in women of diverse South African ancestries and assessed use of African genomic data to reclassify variants of uncertain significance (VUS). A total of 331 women of White, Black African, or Mixed Ancestry with BC had a 9-gene panel test, with an additional 75 genes tested in those without a pathogenic/likely pathogenic (P/LP) variant. The proportion of VUS reclassified using ClinGen gene-specific allele frequency (AF) thresholds or an AF > 0.001 in nonguidelines genes in African genomic data was determined. The 9-gene panel identified 58 P/LP variants, but only two of the P/LP variants detected using the 75-gene panel were in confirmed BC genes, resulting in a total of 60 (18.1%) in all participants. P/LP variant prevalence was similar across ancestry groups, but VUS prevalence was higher in Black African and Mixed Ancestry than in White participants. In total, 611 VUS were detected, representing 324 distinct variants. 10.8% (9/83) of VUS met ClinGen AF thresholds in genomic data while 10.8% (26/240) in nonguideline genes had an AF > 0.001. Overall, 27.0% of VUS occurrences could potentially be reclassified using African genomic data. Thus, expanding the gene panel yielded few clinically actionable variants but many VUS, particularly in participants of Black African and Mixed Ancestry. However, use of African genomic data has the potential to reclassify a significant proportion of VUS.

BRCA1/2 reversion mutations in a pan-cancer cohort.

Tumor sensitivity to platinum (Pt)-based chemotherapy and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors is increased by homologous recombination deficiency-causing mutations; in particular, reversion mutations cause drug resistance by restoring protein function. Treatment response is predicted by breast cancer susceptibility gene 1/2 (BRCA1/2) mutations; however, BRCA1/2 reversion mutations have not been comprehensively studied in pan-cancer cohorts. We aimed to characterize BRCA1/2 reversion mutations in a large pan-cancer cohort of Japanese patients by retrospectively analyzing sequencing data for BRCA1/2 pathogenic/likely pathogenic mutations in 3738 patients with 32 cancer types. We identified somatic mutations in tumors or circulating cell-free DNA that could restore the ORF of adverse alleles, including reversion mutations. We identified 12 (0.32%) patients with somatic BRCA1 (n = 3) and BRCA2 (n = 9) reversion mutations in breast (n = 4), ovarian/fallopian tube/peritoneal (n = 4), pancreatic (n = 2), prostate (n = 1), and gallbladder (n = 1) cancers. We identified 21 reversion events-BRCA1 (n = 3), BRCA2 (n = 18)-including eight pure deletions, one single-nucleotide variant, six multinucleotide variants, and six deletion-insertions. Seven (33.3%) reversion deletions showed a microhomology length greater than 1 bp, suggesting microhomology-mediated end-join repair. Disease course data were obtained for all patients with reversion events: four patients acquired mutations after PARP-inhibitor treatment failure, two showed somatic reversion mutations after disease progression, following Pt-based treatment, five showed mutations after both treatments, one patient with pancreatic cancer and BRCA1 reversion mutations had no history of either treatment. Although reversion mutations commonly occur in BRCA-associated cancers, our findings suggest that reversion mutations due to Pt-chemotherapy might be correlated with BRCA1/2-mediated tumorigenesis even in non-BRCA-associated histologies.

Benign polymorphisms in the BRCA genes with linkage disequilibrium is associated with cancer characteristics.

Germline pathogenic mutation of the BRCA gene increases the prevalence of breast cancer. Reports on the benign variants of BRCA genes are limited. However, the definition of these variants might be altered with the accumulation of clinical evidence. Therefore, in the present study, we focused on benign single nucleotide polymorphisms (SNPs) of BRCA genes. Linkage disequilibrium was calculated from whole genome sequencing of the BRCA genes obtained from 500 healthy controls and 49 breast cancer patients. Sanger sequencing was used to confirm the mutation. The linkage disequilibrium was noted for seven and three SNPs in the BRCA1 and BRCA2 genes, respectively. Breast cancer with BRCA1/2 linkage disequilibrium was not correlated with a personal history of benign diseases or family history of cancer. Nevertheless, breast cancer with BRCA1 linkage disequilibrium was correlated with high tumor-infiltrating lymphocytes and positive extensive intraductal components. The patients with BRCA1 linkage disequilibrium tended to have worse disease-specific survival. Cancers with BRCA2 linkage disequilibrium are associated with a lower ratio of grade III cancer. Moreover, patients with BRCA2 linkage disequilibrium tended to have better overall survival. In conclusion, linkage disequilibrium from benign SNPs of the BRCA genes potentially affects cancer characteristics.

BRCA1/2 mutations and outcomes among Middle Eastern patients with early-onset breast cancer in Oman.

BACKGROUND: High prevalence of early-onset breast cancer (EOBC) has been reported in Middle Eastern populations. For example, in Oman more than 50% of patients with breast cancer (BC) are under age 45 at diagnosis. Causes for this high incidence are unknown. Germline BRCA gene mutations have been associated with EOBC, however, prevalence of these mutations and how they relate to EOBC in Oman has not been assessed. PATIENTS AND METHODS: Clinical data were collected for patients with BC treated at Royal Hospital, Oman between 2010 and 2022. Germline BRCA1/2 gene mutations were identified using sequencing and MLPA. Correlation and Kaplan-Meier survival analyses were performed to test relationships among clinico-pathological features, gene mutations, and outcomes. RESULTS: Total of 1336 Middle Eastern patients with BC were included; 611 were aged <45 at diagnosis (45.7%). No significant correlation was found between BRCA1/2 mutation status and EOBC (P = .229), and the majority of EOBC cases had no family history of BC. EOBC tumors did, however, differ in clinicopathological features; EOBCs were significantly larger (P < .0001), of higher grade (P < .0001), and included more HER2-enriched, and triple negative subtypes (P = .018) compared with later onset cases. Accordingly, survival analyses revealed that EOBC had significantly worse disease-free survival (P = .002). BRCA gene variants showed a distinct range of mutations including, in BRCA2, 3 previously unreported mutations and 4 potential founder recurrent mutations. CONCLUSION: Our findings showed that germline BRCA1/2 mutations were not over-represented in EOBC cases in Oman, and therefore are unlikely to be responsible for high EOBC rates.

Cardiovascular disease risk after breast cancer treatment in patients with a BRCA1/2 pathogenic variant.

PURPOSE: Breast cancer (BC) treatment can induce adverse events, such as cardiovascular disease (CVD). Defective DNA repair, as in carriers of BRCA1/2 pathogenic variants (BRCA1/2pv), may contribute to CVD risk. We aimed to study if female BRCA1/2pv carriers are more sensitive to develop CVD after BC treatment than BC patients without a known BRCA1/2pv. METHODS: In a hospital-based cohort of 17,300 female BC patients, we identified 509 BRCA1/2pv carriers. Cardiovascular morbidity and mortality were assessed through hospital charts and general practitioner questionnaires. We performed Cox regression analyses comparing BRCA1/2pv carriers with all other BC patients, adjusting for age, radiotherapy regimen, chemotherapy regimen, and smoking status. RESULTS: Median follow-up time since BC treatment was 14 years. In total, 1108 women experienced ischemic heart disease (IHD), of whom 20 (1.8%) were BRCA1/2pv carriers. Heart failure (HF) was diagnosed in 638 women, of whom 10 (1.6%) were BRCA1/2pv carriers. BRCA1/2pv carriership was associated with a slight not statistically significant increase of IHD (adjHR 1.51, 95%CI 0.93; 2.42), but not with risk of HF (adjHR 0.86, 95%CI 0.44; 1.69). The association between radiotherapy and IHD risk was not significantly different between BRCA1/2pv carriers [HR 2.30 (95%CI 0.79; 6.66)] and other BC patients (HR 1.50, 95%CI 1.30; 1.73). Associations between anthracycline-based chemotherapy and HF risk also did not differ between carriers and other BC patients (HRs of 4.02 (95%CI 1.02; 15.77) and 2.31 (95%CI 1.77; 3.01), respectively). CONCLUSIONS: In BRCA1/2pv BC patients, we found no evidence for a higher risk of BC treatment-related CVD than in other BC patients.

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

INTRODUCTION: Homologous 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 METHODS: The 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. RESULTS: Cancer 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. CONCLUSIONS: In 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.

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer.

BACKGROUND: The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. METHODS: HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan-Meier method was utilised to analyse progression-free survival (PFS). RESULTS: This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5-22.1) versus 9.2 months (95% CI: 7.5-13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4-18.2) versus 22.2 months (95% CI: 18.3-NA)]. Conversely, positive PD-L1 expression on immune cells was associated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9-NA) versus 8.3 months (95% CI: 6.7-13.8)]. CONCLUSIONS: HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. TRIAL REGISTRATION: NCT03534453. Registered at May 23, 2018.

Surgical Decision Making in Genetically High-Risk Women: Quantifying Postoperative Complications and Long-Term Risks of Supplemental Surgery After Risk-Reducing Mastectomy.

BACKGROUND: Risk-reducing mastectomy (RRM) helps prevent breast cancer in high-risk women but also carries a risk of unanticipated supplemental surgeries. We sought to determine the likelihood of supplemental surgeries following RRM. METHODS: We performed a retrospective cohort study of female patients with a confirmed germline pathogenic variant (GPV) in a breast cancer susceptibility gene (BRCA1/2, PALB2 and others) who underwent bilateral or contralateral RRM at our institution between 2006 and 2022. Supplemental surgeries were defined as any operation requiring general or local anesthesia performed outside of the initially planned procedure(s). The Kaplan-Meier method was used to estimate the 5-years cumulative incidence of supplemental surgery. RESULTS: Of 560 GPV carriers, RRMs were performed in 258 (46.1%) women. The median age of the cohort was 44 years (interquartile range 37-52 years), with 33 (12.8%) patients undergoing RRM without reconstruction and 225 (87.2%) undergoing RRM with reconstruction. Following surgery, 34 patients (13.2%) developed early (< 30 days) postoperative complications, including infection, hematoma, seroma, loss of the nipple areola complex, flap necrosis, implant exposure and/or prosthesis removal. At a median follow-up of 3.8 years, 94 (36.4%) GPV carriers underwent at least one reoperation. Participants who experienced an early postoperative complication had the highest rate of reoperation (85.3% vs. 29.0%; p < 0.001) and a significantly higher likelihood of multiple additional surgical interventions (41.2% vs. 10.7%; p < 0.001). The 5-years rate of supplemental surgery was 39.2% [95% confidence interval (CI) 32.7-46.5] in the overall cohort and 31.5% (95% CI 24.9-39.3) in patients without an early postoperative complication. CONCLUSIONS: Unanticipated supplemental surgeries occur in 40% of GPV carriers following RRM and in nearly one-third of patients without early postoperative complications.

Synergistic antitumor effect of liposomal-based formulations of olaparib and topotecan in primary epithelial ovarian cancer cells.

BACKGROUND: Olaparib is a PARP inhibitor inducing synthetic lethality in tumors with deficient homologous recombination (HRD) caused by BRCA1/2 mutations. The FDA has approved monotherapy for first-line platinum-sensitive, recurrent high-grade epithelial ovarian cancer. Combination therapy alongside DNA-damaging therapeutics is a promising solution to overcome the limited efficacy in patients with HRD. The present study was designed to develop topotecan- and olaparib-loaded liposomes (TLL and OLL) and assess the effectiveness of their combination in patient-derived ovarian cancer samples. METHODS: We used HEOC, four clear-cell tumors (EOC 1-4), malignant ascites, and an OCI-E1p endometrioid primary ovarian cancer cell line and performed NGS analysis of BRCA1/2 mutation status. Antiproliferative activity was determined with the MTT assay. The Chou-Talalay algorithm was used to investigate the in vitro pharmacodynamic interactions of TLLs and OLLs. RESULTS: The OLL showed significantly higher efficacy in all ovarian cancer types with wild-type BRCA1/2 than a conventional formulation, suggesting potential for increased in vivo efficacy. The TLL revealed substantially higher toxicity to EOC 1, EOC 3, ascites and lower toxicity to HEOC than the standard formulation, suggesting better therapeutic efficacy and safety profile. The combination of studied compounds showed a higher reduction in cell viability than drugs used individually, demonstrating a synergistic antitumor effect at most of the selected concentrations. CONCLUSIONS: The concentration-dependent response of different ovarian cancer cell types to combination therapy confirms the need for in vitro optimization to maximize drug cytotoxicity. The OLL and TLL combination is a promising formulation for further animal studies, especially for eliminating epithelial ovarian cancer with wild-type BRCA1/2.

Germline Mutations in 32 Cancer Susceptibility Genes by Next-Generation Sequencing among Breast Cancer Patients.

INTRODUCTION: BRCA1/2 germline mutations are the most well-known genetic determinants for breast cancer. However, the distribution of germline mutations in non-BRCA1/2 cancer susceptibility genes in Chinese breast cancer patients is unclear. The association between clinical characteristics and germline mutations remains to be explored. METHODS: Consecutive breast cancer patients from Peking University People's Hospital were enrolled. Clinical characteristics were collected, and next-generation sequencing was performed using blood samples of participants to identify pathogenic/likely pathogenic (P/LP) germline mutations in 32 cancer susceptibility genes including homologous recombination repair (HRR) genes. RESULTS: A total of 885 breast cancer patients underwent the detection of germline mutations. 107 P/LP germline mutations of 17 genes were identified in 116 breast cancer patients including 79 (8.9%) in BRCA1/2 and 40 (4.5%) in 15 non-BRCA1/2 genes. PALB2 was the most frequently mutated gene other than BRCA1/2 but still relatively rare (1.1%). There were 38 novel P/LP germline variants detected. P/LP germline mutations in BRCA1/2 were significantly associated with onset age (p < 0.001), the family history of breast/ovarian cancer (p = 0.010), and molecular subtype (p < 0.001), while being correlated with onset age (p < 0.001), site of breast tumor (p = 0.028), and molecular subtype (p < 0.001) in HRR genes. CONCLUSIONS: The multiple-gene panel prominently increased the detection rate of P/LP germline mutations in 32 cancer susceptibility genes compared to BRCA1/2 alone. Onset younger than or equal to 45 years of age, bilateral and triple-negative breast cancer patients may be more likely to be recommended for detecting P/LP germline mutations in HRR genes.

Pathogenic germline variants in non-BRCA1/2 homologous recombination genes in ovarian cancer: Analysis of tumor phenotype and survival.

OBJECTIVE: To define molecular features of ovarian cancer (OC) with germline pathogenic variants (PVs) in non-BRCA homologous recombination (HR) genes and analyze survival compared to BRCA1/2 and wildtype (WT) OC. METHODS: We included patients with OC undergoing tumor-normal sequencing (MSK-IMPACT) from 07/01/2015-12/31/2020, including germline assessment of BRCA1/2 and other HR genes ATM, BARD1, BRIP1, FANCA, FANCC, NBN, PALB2, RAD50, RAD51B, RAD51C, and RAD51D. Biallelic inactivation was assessed within tumors. Progression-free (PFS) and overall survival (OS) were calculated from pathologic diagnosis using the Kaplan-Meier method with left truncation. Whole-exome sequencing (WES) was performed in a subset. RESULTS: Of 882 patients with OC, 56 (6.3%) had germline PVs in non-BRCA HR genes; 95 (11%) had BRCA1-associated OC (58 germline, 37 somatic); and 59 (6.7%) had BRCA2-associated OC (40 germline, 19 somatic). High rates of biallelic alterations were observed among germline PVs in BRIP1 (11/13), PALB2 (3/4), RAD51B (3/4), RAD51C (3/4), and RAD51D (8/10). In cases with WES (27/35), there was higher tumor mutational burden (TMB; median 2.5 [1.1-6.0] vs. 1.2 mut/Mb [0.6-2.6]) and enrichment of HR-deficient (HRD) mutational signatures in tumors associated with germline PALB2 and RAD51B/C/D compared with BRIP1 PVs (p < 0.01). Other features of HRD, including telomeric-allelic imbalance (TAI) and large-scale state transitions (LSTs), were similar. Although there was heterogeneity in PFS/OS by gene group, only BRCA1/2-associated OC had improved survival compared to WT OC (p < 0.01). CONCLUSIONS: OCs associated with germline PVs in non-BRCA HR genes represent a heterogenous group, with PALB2 and RAD51B/C/D associated with an HRD phenotype.

Does serous tubal intraepithelial carcinoma (STIC) metastasize? The clonal relationship between STIC and subsequent high-grade serous carcinoma in BRCA1/2 mutation carriers several years after risk-reducing salpingo-oophorectomy.

OBJECTIVE: The majority of high-grade serous carcinomas (HGSC) of the ovary, fallopian tube, and peritoneum arise from the precursor lesion called serous tubal intraepithelial carcinoma (STIC). It has been postulated that cells from STICs exfoliate into the peritoneal cavity and give rise to peritoneal HGSC several years later. While co-existent STICs and HGSCs have been reported to share similarities in their mutational profiles, clonal relationship between temporally distant STICs and HGSCs have been infrequently studied and the natural history of STICs remains poorly understood. METHODS: We performed focused searches in two national databases from the Netherlands and identified a series of BRCA1/2 germline pathogenic variant (GPV) carriers (n = 7) who had STIC, and no detectable invasive carcinoma, at the time of their risk-reducing salpingo-oophorectomy (RRSO), and later developed peritoneal HGSC. The clonal relationship between these STICs and HGSCs was investigated by comparing their genetic mutational profile by performing next-generation targeted sequencing. RESULTS: Identical pathogenic mutations and loss of heterozygosity of TP53 were identified in the STICs and HGSCs of five of the seven patients (71%), confirming the clonal relationship of the lesions. Median interval for developing HGSC after RRSO was 59 months (range: 24-118 months). CONCLUSION: Our results indicate that cells from STIC can shed into the peritoneal cavity and give rise to HGSC after long lag periods in BRCA1/2 GPV carriers, and argues in favor of the hypothesis that STIC lesions may metastasize.

Origin of Residual Tumor Masses in BRCA1/2-Driven Ovarian Carcinomas Treated by Neoadjuvant Chemotherapy: Selection of Preexisting BRCA1/2-Proficient Tumor Cells but Not the Gain of Second ORF-Restoring Mutation.

INTRODUCTION: Tubo-ovarian carcinomas (OCs) are highly sensitive to platinum-based neoadjuvant chemotherapy (NACT) but almost never demonstrate complete pathologic response. METHODS: We analyzed paired primary and residual tumor tissues from 30 patients with hereditary BRCA1/2-driven OCs (BRCA1: 17; BRCA2: 13), who were treated by carboplatin/paclitaxel NACT (median number of cycles: 3, range: 3-6). BRCA1/2 and TP53 genes were analyzed by the next-generation sequencing. The ratio between TP53 mutation-specific versus wild-type reads was considered to monitor the proportion of tumor and non-tumor cells in the tissue sample, and the ratio between BRCA1/2-mutated and wild-type reads was used to estimate the presence of cells with the loss or retention of heterozygosity (LOH or ROH, respectively). RESULTS: All 30 OCs had BRCA1/2 LOH in primary tumor and carried somatic TP53 mutation. Twenty-eight OCs had sufficient tumor cell cellularity in the post-NACT tissue to evaluate the ratio between mutated and wild-type BRCA1/2 alleles. Five (18%) out of 28 informative tumor pairs showed transition from LOH to ROH during NACT presumably affecting all or the vast majority of residual tumor cells. There were no signals of the emergence of a second open reading frame-restoring BRCA1/2 mutation. CONCLUSION: Chemonaive BRCA1/2-driven carcinomas may contain a fraction of tumor cells with preserved BRCA1/2 heterozygosity. NACT can cause a selection of pre-existing BRCA1/2-proficient tumor cells, without gaining secondary reversal BRCA1/2 mutations.

Assessing the acceptability and appropriateness of a psychoeducational graphic novel about inherited cancer risk designed for men.

Men with germline pathogenic variants in BRCA1 or BRCA2 genes are at an increased lifetime risk for developing breast cancer, prostate cancer, and pancreatic cancer. Men report that managing clinical care is challenging because they are under-informed about their cancer risks. As the demand for genetic testing has increased, so too has the need to relay accurate and relatable genetic health information. This research developed and assessed the acceptability and appropriateness of a psychoeducational graphic novel designed for men to improve their cancer risk knowledge, manage their cancer-related uncertainty, and increase their intent to disclose their BRCA1/2 risks to family members and healthcare providers. Through purposive and snowball sampling, men (n = 20) and certified genetic counselors (CGCs; n = 15) participated in semi-structured interviews assessing the acceptability and appropriateness of the graphic novel. Interviews were audio-recorded, transcribed, and thematically analyzed. Both reported that the graphic novel confirmed risk information provided helpful resources, included relatable storylines, and had a unique visual appeal. Some men remained unsure about how to perform recommended screenings and how to talk to family members, particularly children, about BRCA1/2 test results after assessing the graphic novel. CGCs also discussed the helpfulness of the graphic novel for their practice. Given that this psychoeducational graphic novel was appealing to men and CGCs, it shows promise as an acceptable approach that may assist men in managing their cancer risks and communicating their genetic risk information to family members and healthcare providers.

The Manchester Scoring System for predicting BRCA1/2 mutations underperforms in Arabic Omani breast cancer patients.

Risk assessment models that are applied to assess the lifetime risk of cancer and pathogenic variant risk are more commonly used in Western populations. Using these models, without validation, for non-Western populations has been questioned. This study aimed to evaluate the use and consistency of the Manchester Scoring System as a risk assessment model for the Omani population. A retrospective, file-based analysis was performed on breast cancer patients seen in a genomics department over a two-year period. Personal cancer history and family history were used to analyze the Manchester scores of 409 breast and/or cancer patients. The results show that, overall, the Manchester scores were low. If this risk assessment model had been used to determine eligibility for a priori service and genetic testing decisions, 12 BRCA pathogenic cases would have been missed. At this time, the Manchester Scoring System does not seem to be the best risk assessment model for use in the Omani population, unless the eligibility threshold of ≥6 is used, which could provide a better sensitivity for the Omani population. We propose using concepts of the Manchester Scoring model to create a scoring system that is more suitable for the Omani and Arabic population.

A pilot randomized controlled study to determine the effectiveness of video educational tool in BRCA1/2 pre-test counseling for Japanese breast cancer patients.

BRCA1/2 genetic testing has become clinically important in breast cancer care, but increasing demand may put a burden on the shortage of healthcare professionals. We performed a single-center, pilot randomized controlled study to assess the effectiveness of employing a video educational tool that included standard pre-test genetic counseling elements related to BRCA1/2. Patients with operable breast cancer who met the criteria for genetic testing based on age, sex, subtype, and family history were recruited. Sixty consenting participants were randomized 1:1 and placed in groups that received either traditional face-to-face pre-test counseling or video-viewing and face-to-face decisional support. To assess decisional conflict in the participants, surveys based on the Decisional Conflict Scale (DCS) were administered two times, once immediately after intervention and again 2-4 weeks later. The time taken for counseling and confirmation of whether the participants had undergone testing were also recorded. The difference in the total DCS scores between the two groups was not significantly different for either of the survey periods, and there was no significant difference in the number of participants who underwent testing (23/30 [76.7%] vs. 26/30 [86.7%]; p = 0.51). However, the "effective decision" subscale score was significantly higher in the video group 2-4 weeks after counseling (31.01 ± 16.82 vs. 21.43 ± 16.09; p = 0.04 [mean ± SD]). The time taken for counseling was significantly shorter in the video group (8.00 ± 4.5 vs. 27.00 ± 7.61 min; p < 0.001 [median ± SD]). Our findings indicate the potential benefit of the video educational tool for providing BRCA1/2-related information. These tools may also enable healthcare professionals to spend more time supporting psychological issues. Notably, after some time, patients may question whether their decision was appropriate. Therefore, it is necessary to identify those in conflict and provide them with proper support.

DDX11 loss causes replication stress and pharmacologically exploitable DNA repair defects.

DDX11 encodes an iron-sulfur cluster DNA helicase required for development, mutated, and overexpressed in cancers. Here, we show that loss of DDX11 causes replication stress and sensitizes cancer cells to DNA damaging agents, including poly ADP ribose polymerase (PARP) inhibitors and platinum drugs. We find that DDX11 helicase activity prevents chemotherapy drug hypersensitivity and accumulation of DNA damage. Mechanistically, DDX11 acts downstream of 53BP1 to mediate homology-directed repair and RAD51 focus formation in manners nonredundant with BRCA1 and BRCA2. As a result, DDX11 down-regulation aggravates the chemotherapeutic sensitivity of BRCA1/2-mutated cancers and resensitizes chemotherapy drug-resistant BRCA1/2-mutated cancer cells that regained homologous recombination proficiency. The results further indicate that DDX11 facilitates recombination repair by assisting double strand break resection and the loading of both RPA and RAD51 on single-stranded DNA substrates. We propose DDX11 as a potential target in cancers by creating pharmacologically exploitable DNA repair vulnerabilities.

Fear of cancer recurrence in breast cancer survivors carrying a BRCA1 or 2 genetic mutation : a cross-sectional study.

BACKGROUND: Fear of cancer recurrence (FCR) affects virtually all patients who have been treated for cancer, to varying degrees. Breast cancer survivors who carry a BRCA1 or BRCA2 gene mutation are at high risk of cancer recurrence. No study has yet assessed FCR specifically in this population. OBJECTIVES: This cross-sectional study, conducted in women who were treated for breast cancer and carrying a BRCA1/2 mutation, aimed to: (1) assess the mean level of FCR and estimate the proportion of patients with clinical levels of FCR; (2) examine the relationships between FCR and selected psychological variables (e.g., avoidance, intolerance to uncertainty) and quality of life; (3) explore whether FCR levels vary as a function of the past preventive treatment received; and (4) to assess the associations between FCR and the presence of decisional conflict or regret regarding the various preventive options. METHOD: Participants were recruited through an e-mail sent to an oncogenetic network mailing list (Réseau ROSE). Participants were asked to complete a battery of questionnaires online assessing FCR and other psychological and quality of life variables. RESULTS: A total of 89 women completed the survey. Most participants had undergone a preventive mastectomy (62.9%) and a preventive salpingo-oophorectomy (75.3%) at the time of the study. The mean Fear of Cancer Recurrence Inventory-severity score was 16.8, which exceeds the clinical cut-off score of 13, and 70.8% of the participants showed a clinical level of FCR. FCR was significantly associated with higher levels of anxiety and depression, and higher avoidance and intolerance of uncertainty, but not with quality of life. No significant difference was observed on the total FCR score between women who had received preventive surgery (mastectomy and/or salpingo-oophorectomy) and those considering it, and those not considering it. The association was significant between higher FRC scores and greater decisional conflicts and regrets about choosing to undergo preventive surgery. CONCLUSION: These data suggest that FCR is a significant problem for breast cancer survivors carrying a BRCA1/2 genetic mutation, even after undergoing a prophylactic surgery. This highlights the importance of providing these women with specific psychological intervention focusing on FCR.