BRCA1 Mutation Research Articles

Prevalence of homologous recombination biomarkers in multiple tumor types: an observational study.

Aim: To determine the prevalence of deleterious mutations in BRCA1 and BRCA2 and in 13 genes involved in homologous recombination repair (HRR), the prevalence of genomic loss of heterozygosity and the allelic and hereditary status of BRCA1, BRCA2 and other HRR gene mutations in multiple solid tumor types.Patients & methods: This was a retrospective observational study of patients with an advanced/metastatic diagnosis in one of 15 solid tumor types, who were identified in a real-world clinico-genomic database.Results: Tumor tissue samples from 9457 patients were analyzed, among which 4.7% had known or suspected deleterious BRCA1/2 mutations. The prevalence (range) of mutations in HRR genes was 13.6% (2.4%-26.0%) and genomic loss of heterozygosity ≥16% was 20.6% (2.6-34.4%) across all tumor types.Conclusion: The prevalence of mutations varied significantly depending on the type of tumor.

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

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 A Cochrane literature search will be carried out to identify all the published and unpublished articles available in English from 2010 till date across various electronic databases including PubMed, Psych Info, SCI, Cochrane Central, Embase, Scopus, IND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

MRNA-specific readthrough of nonsense codons by antisense oligonucleotides (R-ASOs).

Nonsense mutations account for >10% of human genetic disorders, including cystic fibrosis, Alagille syndrome, and Duchenne muscular dystrophy. A nonsense mutation results in the expression of a truncated protein, and therapeutic strategies aim to restore full-length protein expression. Most strategies under development, including small-molecule aminoglycosides, suppressor tRNAs, or the targeted degradation of termination factors, lack mRNA target selectivity and may poorly differentiate between nonsense and normal stop codons, resulting in off-target translation errors. Here, we demonstrate that antisense oligonucleotides can stimulate readthrough of disease-causing nonsense codons, resulting in high yields of full-length protein in mammalian cellular lysate. Readthrough efficiency depends on the sequence context near the stop codon and on the precise targeting position of an oligonucleotide, whose interaction with mRNA inhibits peptide release to promote readthrough. Readthrough-inducing antisense oligonucleotides (R-ASOs) enhance the potency of non-specific readthrough agents, including aminoglycoside G418 and suppressor tRNA, enabling a path toward target-specific readthrough of nonsense mutations in CFTR, JAG1, DMD, BRCA1 and other mutant genes. Finally, through systematic chemical engineering, we identify heavily modified fully functional R-ASO variants, enabling future therapeutic development.

Occult residual ovarian tissue at the time of minimally invasive risk reducing surgery in women with BRCA mutations

ObjectiveTo describe extension of ovarian tissue beyond visible and National Comprehensive Cancer Network recommended margins among patients with BRCA mutations undergoing minimally invasive risk-reducing salpingo-oophorectomy. MethodsA prospective study of patients with BRCA mutations who underwent minimally invasive risk-reducing bilateral salpingo-oophorectomy was conducted. Patient enrollment occurred between October 2021 and 2023. Tissue specimens were analyzed according to the Sectioning and Extensively Examining the Fimbriated End protocol. ResultsTwenty women with BRCA mutations were prospectively enrolled. All patients underwent minimally invasive surgery with 70% undergoing concurrent hysterectomy (n = 14). Approximately half of these procedures were performed with robotic assistance (n = 9, 45%). One patient was admitted overnight (5%); the other nineteen were discharged on the day of surgery (95%). One patient experienced a major complication and required readmission (5%). Extension of ovarian tissue beyond the visible ovary was noted on pathologic examination of six specimens (30%). In one patient this was observed on the left (17%), in three on the right (50%), and in two bilateral extension (33%) was noted. The distance ovarian stroma extended microscopically beyond the visible ovary was between 2 and 14 mm, with a median of 5 mm. Among patients with microscopic extension of ovarian tissue, the majority (n = 5, 83%) had a BRCA2 mutation. ConclusionIn women with BRCA mutations undergoing risk-reducing minimally invasive surgery, approximately one third had microscopic extension of ovarian stroma beyond the visible ovary. Current guidelines which recommend resection of at least 20 mm of tissue beyond the visible ovary are likely adequate in this population.

Double Heterozygosity for Germline Mutations in Chinese Breast Cancer Patients.

Double pathogenic mutations occurring in an individual are considered a rare event. The introduction of a multiple-gene panel at Hong Kong Hereditary Breast Cancer Family Registry has allowed the identification of pathogenic variants in multiple genes, providing more information on clinical management and surveillance to the proband and their family members. Breast cancer patients who are double heterozygous (DH) for different hereditary breast and ovarian cancer syndrome (HBCO)-related genes were identified from a cohort of 3649 Chinese patients. Nine patients (0.25%) were observed to have germline DH mutations in ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MSH6, PALB2, and TP53. Three probands were diagnosed with unilateral breast cancer, two patients were diagnosed with bilateral breast cancer, and four patients had multiple primary cancers. The median age for breast cancer diagnosis was an early age of 36 years. Chinese DH carriers did not show worse phenotypes or have a significantly downhill clinical presentation. However, seven out of nine (77.8%) of our DH carriers harbored a BRCA1 mutation, and four of them (44.4%) developed bilateral breast cancer, suggesting Chinese DH individuals may have a higher chance of having bilateral breast cancer than other populations (p = 0.0237).

BRCAness, DNA gaps, and gain and loss of PARP inhibitor-induced synthetic lethality.

Mutations in the tumor-suppressor genes BRCA1 and BRCA2 resulting in BRCA1/2 deficiency are frequently identified in breast, ovarian, prostate, pancreatic, and other cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cancer cells by inducing synthetic lethality, providing an effective biomarker-guided strategy for targeted cancer therapy. However, a substantial fraction of cancer patients carrying BRCA1/2 mutations do not respond to PARPis, and most patients develop resistance to PARPis over time, highlighting a major obstacle to PARPi therapy in the clinic. Recent studies have revealed that changes of specific functional defects of BRCA1/2-deficient cells, particularly their defects in suppressing and protecting single-stranded DNA gaps, contribute to the gain or loss of PARPi-induced synthetic lethality. These findings not only shed light on the mechanism of action of PARPis, but also lead to revised models that explain how PARPis selectively kill BRCA-deficient cancer cells. Furthermore, new mechanistic principles of PARPi sensitivity and resistance have emerged from these studies, generating potentially useful guidelines for predicting the PARPi response and design therapies for overcoming PARPi resistance. In this Review, we will discuss these recent studies and put them in context with the classic views of PARPi-induced synthetic lethality, aiming to stimulate the development of new therapeutic strategies to overcome PARPi resistance and improve PARPi therapy.

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

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

Demographics and Clinical Decision Making in Patients with Germline Moderate Penetrance Non-BRCA Mutations in Breast Cancer Related Genes.

Management of pathogenic variants in high penetrance genes related to breast cancer (BC), such as BRCA1 and BRCA2, are well established. However, moderate penetrance mutations are understudied. We aim to compare risk reduction decision-making patterns in patients with a moderate penetrance BC-related genetic mutations, without a prior BC diagnosis. Female patients aged ≥ 18 years who tested positive for a BRCA1/2, high penetrance, or moderate penetrance mutation related to BC between 1996 and 2023 without a concurrent or prior BC diagnosis were retrospectively identified from a single academic center's database. Groups were stratified by mutation type: BRCA1/2 mutations (BRCA1, BRCA2), high penetrance mutations (HPM; CDH1, PALB2, PTEN, STK11, TP53), or moderate penetrance mutations (MPM; ATM, BARD1, CHEK2, NF1, RAD51C, RAD51D). Demographics and clinical outcomes were compared. A total of 528 patients met the inclusion criteria, with 66% (n = 350) having a BRCA1/2 mutation, 8% (n = 44) having HPM, and 25% (n = 134) having MPM; the median follow-up was 56.0 months. In our cohort, 20.9% of patients with BRCA mutations, 9.1% with HPM, and 7.5% with MPM chose to undergo risk-reducing mastectomies (RRM). Within the moderate penetrance cohort, patients who chose to undergo RRM were younger at the time of genetic testing (39.4 vs. 47.5 years, p = 0.03) and had a higher number of family members with BC (2 vs. 1, p = 0.05). Our findings provide insights into the demographic characteristics and family history of patients with moderate penetrance mutations and those who pursue risk-reducing surgery.

Is the Homologous Recombination Repair Mutation Defined by a 15-Gene Panel Associated with the Prognosis of Epithelial Ovarian Cancer?

There is no consensus regarding the specific genes included in the homologous recombination repair (HRR) gene panel for identifying the HRR deficiency (HRD) status and predicting the prognosis of epithelial ovarian cancer (EOC) patients. We aimed to explore a 15-gene panel involving the HRR pathway as a predictive prognostic indicator in Chinese patients newly diagnosed with EOC. We reviewed the previously published reports about different HRR gene panels and prespecified the 15-gene panel. The genetic testing results in a 15-gene panel from 308 EOC patients diagnosed between 2014 and 2022 from six centers were collected. The association of clinicopathologic characteristics, the use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) and progression-free survival (PFS) with 15-gene panel HRR mutations (HRRm) status was assessed. 43.2% (133/308) of patients were determined to carry 144 deleterious HRRm, among which68.1% (98/144) were germline mutations and 32.8% (101/308) were BRCA1/2gene lethal mutations. The hazard ratio (HR) (95% confidence interval, CI) for PFS (HRRmvHRR wild type, HRRwt) using the 15-gene panel HRRm was 0.42 (0.28-0.64) at all stages and 0.42 (0.27-0.65) at stages IIIC-IV. However, a prognostic difference was observed only between the BRCA mutation group and the HRRwt group, not between the non-BRCA HRRm group and the HRRwt group. For the subgroups of patients not using PARPis, the HR (95% CI) was 0.41 (0.24-0.68) at stages IIIC-IV. This study provides evidence that 15-gene panel HRRm can predict the prognosis of EOC, of these only the BRCA1/2 mutations, not non-BRCA HRRm, contribute to prognosis prediction. Among patients without PARPis, the HRRm group presented a better PFS. This is the first study of this kind in the Chinese population.

Unique immune characteristics and differential anti-PD-1-mediated reinvigoration potential of CD8+ TILs based on BRCA1/2 mutation status in epithelial ovarian cancers

BackgroundWe aimed to investigate the distinct immunological characteristics of the tumor immune microenvironment in epithelial ovarian cancer (EOC) according to BRCA1/2 mutations status and differential PD-1 expression levels.MethodsTumor-infiltrating lymphocytes (TILs)...

O-061 Ovarian cancer and fertility - current understanding

Abstract Introduction Ovarian cancer is a significant health concern worldwide and is the leading cause of death from gynecologic malignancies. While fertility preservation is essential for many young women diagnosed with cancer, concerns have been raised regarding the potential impact of fertility treatments on the risk of ovarian cancer development. 1. Ovarian Cancer Risk Factors Ovarian cancer is a multifactorial disease with various risk factors contributing to its development. A woman has a risk of 1 in 78 of having ovarian cancer in her life time, risk factors include: • Age: Ovarian cancer risk increases with age, with the highest incidence observed in women over 50 years old. About 12.1% of Ovarian Cancer patients are younger than 44 years old. • Family History: Women with a family history of ovarian or breast cancer, especially first-degree relatives, have an increased risk. • BRCA Mutations: Inherited mutations in BRCA1 and BRCA2 genes significantly elevate the risk of ovarian cancer. • Reproductive Factors: Factors such as nulliparity, early menarche, late menopause, and infertility have been associated with an increased risk of ovarian cancer. 2. Fertility Treatments and Ovarian Cancer Risk Understanding the mechanisms underlying ovarian cancer development is crucial for assessing the potential impact of fertility treatments : • Ovulation Hypothesis: The repeated ovulation theory suggests that each ovulatory cycle increases the risk of DNA damage to ovarian epithelial cells, potentially leading to cancer development. The use of fertility drugs to stimulate ovulation, such as clomiphene citrate and gonadotropins, has been studied , the early studies suggested a potential increased risk, more recent evidence has been conflicting, with some studies reporting no association. • In Vitro Fertilization (IVF): Several large-scale studies have investigated the relationship between IVF and ovarian cancer risk found no significant increase in ovarian cancer risk . • Hormonal Influence: Fertility drugs alter hormonal levels, particularly estrogen and progesterone, which may influence ovarian cancer risk. • Selection Bias: Some studies have suggested that the ovarian cancer risk may be confounded by underlying infertility factors rather than the treatments themselves. 3. Clinical Implications and Recommendations • Individual Risk Assessment: Clinicians should assess each patient's individual risk factors for ovarian cancer, including age, family history, and reproductive history, before initiating fertility treatments. • Informed Consent: Patients should be provided with comprehensive information regarding the potential risks and benefits of fertility treatments • Regular Surveillance: Women undergoing fertility treatments should receive regular gynecologic screenings and follow-up care to monitor for any signs or symptoms of ovarian cancer. • Shared Decision Making: Shared decision making between patients and healthcare providers is essential to ensure that treatment decisions align with patients' preferences and values. 4. Fertility Preservation Options • Most therapeutic options for Ovarian Cancer cause infertility, either by premature ovarian failure caused by cytotoxic agents in chemotherapy or surgical approaches that include unilateral or bilateral oophorectomy • In ovarian cancer patients, Oocyte cryopreservation is still the best option and the only one established along with embryo cryopreservation. Fertility preservation surgery can be suggested depending on histology, stage of disease and pre-existing ovarian reserve. • Ovarian tissue cryopreservation will not be an option as long as the risk of reseeding cancer cells is not fully eliminated. 5. Future Directions Advancements in molecular biology and genetics may shed light on the underlying mechanisms of ovarian cancer development and its potential association with fertility treatments. The artificial ovary and in vitro maturation of oocytes is a very attractive option in these patients, but further milestones have to be achieved

P-536 Preimplantation Genetic Testing for hereditary breast and ovarian cancer syndrome due to BRCA pathogenic variant : the parisian center experience

Abstract Study question What are the outcomes of Preimplantation genetic testing for monogenic disease (PGT-M) for BRCA pathogenic variants? Summary answer Among couples entering a PGT-M program for BRCA pathogenic variants, 23.5% achieved a live-birth. What is known already BRCA pathogenic variants are associated with an oncologic predisposition with variable penetrance and are accessible to screening and preventive procedures to avoid or early detect the development of cancer. Transmission of BRCAmutations to offspring poses a significant reproductive concern for BRCA mutation carriers. PGT-M offers a solution to prevent this mutation transmission. Despite reproductive challenges related to BRCA status, there are no existing international guidelines for applying PGT-M in these situations. In France, authorization for BRCA related PGT-M is case-specific, considering the personal and familial severity of the disease and submitted to a multidisciplinary prenatal diagnosis center (CPDPN). Study design, size, duration This retrospective observational study, is a single-center analysis of 46 requests for PGT-M related to BRCA pathogenic variants at our PGT center from January 2015 to December 2022. Participants/materials, setting, methods Forty-six couples asked for PGT-M for BRCA pathogenic variant carried by one of the partner. The present study involves the examination of data encompassing referrals, decisions as well as clinical outcomes associated with PGT-M. Main results and the role of chance Forty-six requests for PGT-M due to the risk of hereditary predisposition to breast and ovarian cancer have been received: 36 for a pathogenic variant in the BRCA1 gene and 10 for BRCA2. Nine couples ultimately did not proceed and dropped out. Eight requests were declined, either due to the refusal of the multidisciplinary prenatal diagnosis center (CPDPN) based on family history (n = 4) or alteration of ovarian reserve (n = 4), the 2 latter requests are still under investigation. In total, requests from 27 couples (55%) were considered eligible and feasible. Among them, 17 (63%) underwent at least one PGT-M cycles (5 dropped out before the beginning and 5 are still pending). Overall, 33 ovarian stimulation cycles for in vitro fertilization were initiated, resulting in the retrieval of 192 mature oocytes and the formation of 145 embryos. Of these, 97 were biopsied, and 38 did not carried the BRCA pathogenic variant. A total of 21 fresh or frozen embryo transfers were performed and 8 pregnancies were achieved, leading to 4 deliveries and 5 live births (23.5% of couples who started a PGT-M cycle). Limitations, reasons for caution In the absence of established guidelines, there is variability in information regarding PGT-M among oncogeneticists. Thus, only selected carriers of BRCA pathogenic variants are addressed to our PGT centers. Additionally, women participating in a fresh PGT cycle were selected on several criteria including ovarian reserve parameters. Wider implications of the findings PGT-M provides a viable alternative for couples seeking to prevent the transmission of BRCA mutations. To increase the PGT-M cumulative live birth rate, the transfer of male embryos carrying the variant, assumed to have lower tumor risks, should be considered and discussed with patients. Trial registration number Not applicable

Germline BRCA1 Mutation inSquamous Cell Carcinoma of Oesophagus: Driver versus Passenger Mutation

We report a rare case of 62-year-old South Asian women who visited the Molecular Pathology and Genomics Department for hereditary germline cancer genetic testing after being diagnosed with oesophageal cancer, reported as invasive keratinizing squamous cell carcinoma metastasized to the lymph nodes. Her personal history revealed that she was diagnosed with triple-negative breast cancer five years before oesophageal cancer. Germline cancer testing showed pathogenic variants in BRCA1 gene c.68_69delAG, which proved it a hereditary breast and ovarian cancer syndrome. She was started on PARP inhibitors but developed some secondary respiratory failure and succumbed to death. Less than 10 cases have been reported in the literature of the association of germline BRCA1 and Squamous cell Carcinoma – the esophagus. The article focuses on the probable pathogenesis of BRCA1 mutation with non-classic malignancies and the response of Poly adenosine diphosphate ribose polymerase inhibitors (PARP) inhibitors in such a scenario. We report an unusual manifestation of the BRCA1 gene with second primary oesophageal squamous cell cancer occurring five years later to triple-negative breast cancer.

Should Only Patients with BRCA Mutation Be Treated with a Combination of an Androgen Receptor Pathway Inhibitor and a PARP Inhibitor for Metastatic Castration-resistant Prostate Cancer? The Answer Is No

Patients who benefit the most from combinations of an androgen receptor pathway inhibitor and a PARP inhibitor are those with a BRCA mutation, but there are certainly patients without BRCA mutations who will benefit from this treatment strategy.

Increased Synthetic Cytotoxicity of Combinatorial Chemoradiation Therapy in Homologous Recombination Deficient Tumors

BackgroundHomologous recombination deficient (HRD) tumors are exquisitely sensitive to platinum-based chemotherapy and when combined with RT, leads to improved overall survival in multiple cancer types. Whether a subset of tumors with distinct molecular characteristics demonstrate increased benefit from cisplatin and RT (c-RT) is unclear. We hypothesized that HRD tumors, whether associated with BRCA mutations or genomic scars of HRD, exhibit exquisite sensitivity to c-RT, and that HRD may be a significant driver of c-RT benefit. MethodsSensitivity to c-RT was examined using isogenic and sporadic breast cancer cell lines. HRD was assessed using four assays: RT-induced Rad51 foci, a DR-GFP reporter assay, a genomic scar (large scale state transitions, LST), and clonogenic survival assays (CSA). Whole genome sequencing of 4 breast tumors from a phase 2 clinical trial of neoadjuvant c-RT in triple negative breast cancer (TNBC) was performed and defined HRD utilizing HRDetect. ResultsBRCA1/2 deficient cell lines displayed functional HRD based on the Rad51 functional assay, with c-RT to RT or cisplatin interaction ratios (IR) of 1.11 and 26.84 for the BRCA1 isogenic pair at 2uM Cisplatin and 6Gy, respectively. The highest LST lines demonstrated HRD and synthetic cytotoxicity to c-RT with IR at 2Gy and Cisplatin 20uM of 7.50, and the lowest LST line with IR of 0.65. Of 4 evaluable patients on the Phase 2 trial, one achieved pathologic complete response (pCR) with corresponding HRD based on multiple genomic scar scores including HRDetect and LST scores, compared with patients without pCR. ConclusionsHRD breast cancers, whether identified by BRCA1/2 mutation status, functional tests or mutational signatures, appear to be significantly more sensitive to c-RT compared to isogenic controls or tumors without HRD mutational signature. HRD tumors may be exquisitely sensitive to c-RT and warrants further clinical investigation to guide a precision oncology approach.

PARP Inhibitor Addition to Androgen Receptor Pathway Inhibitors in Metastatic Castration-resistant Prostate Cancer Should Be Limited to BRCA Mutation Carriers

For patients with metastatic castration-resistant prostate cancer whose tumors harbor BRCA1/2 alterations, the potential benefits of combining a PARP inhibitor and an androgen receptor pathway inhibitor for first-line treatment outweigh the potential side effects. Further research is required to identify patients without detectable BRCA1/2 defects who would benefit from this approach.

1137 Case Report: Bilateral Nipple Sparing Mastectomy for BRCA2 Mutation Patients with Unusual Presentation of Nipple Raynaud's Phenomenon

1137 Case Report: Bilateral Nipple Sparing Mastectomy for BRCA2 Mutation Patients with Unusual Presentation of Nipple Raynaud's Phenomenon

ADP-ribosylome analysis reveals homogeneous DNA-damage-induced serine ADP-ribosylation across wild-type and BRCA-mutant breast cancer cell lines

ADP-ribosylation (ADPr) signaling plays a crucial role in DNA damage response. Inhibitors against the main enzyme catalyzing ADPr after DNA damage, poly(ADP-ribose) polymerase 1 (PARP1), are used to treat patients with breast cancer harboring BRCA1/2 mutations. However, resistance to PARP inhibitors (PARPi) is a major obstacle in treating patients. To understand the role of ADPr in PARPi sensitivity, we use liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze ADPr in six breast cancer cell lines exhibiting different PARPi sensitivities. We identify 1,632 sites on 777 proteins across all cell lines, primarily on serine residues, with site-specific overlap of targeted residues across DNA-damage-related proteins across all cell lines, demonstrating high conservation of serine ADPr-signaling networks upon DNA damage. Furthermore, we observe site-specific differences in ADPr intensities in PARPi-sensitive BRCA mutants and unique ADPr sites in PARPi-resistant BRCA-mutant HCC1937 cells, which have low poly(ADP-ribose) glycohydrolase (PARG) levels and longer ADPr chains on PARP1.

BRCA Testing for Patients Treated in Italy: A National Survey of Breast Centers Associated with Senonetwork.

Breast units (BUs) provide breast cancer (BC) care, including prevention, treatment, and genetic assessment. Genetic research has highlighted BRCA1/2 mutations as key hereditary BC risk factors. BRCA testing is crucial for personalized treatment and prevention strategies. However, the integration of BRCA testing in Italian BUs faces multiple challenges. This study, by Senonetwork Italia, aimed to evaluate genetic testing practices and identify obstacles within Italian BUs. Senonetwork Italia conducted a 16-question web-based survey involving 153 BUs. The survey assessed aspects of BRCA testing, including timing, urgency, counseling, patient selection, and multi-gene panels. Of the 153 BUs, 109 (71.2%) responded. Testing before surgery was performed by 70.6% of centers, with urgent cases acknowledged by 87.2%. Most centers (56.0%) arranged urgent pre-test counseling within a week. BRCA mutation status influenced treatment decisions in 99.1% of cases. Multi-gene panels were used by 33.0% of centers for all genetic counseling cases, while 56.0% followed standard referral criteria. The main challenges included cost, reimbursement, and reporting timelines. This survey highlights significant variations in BRCA testing practices across Italian BUs and identifies key logistical and financial challenges. There is a need for standardized practices of genetic testing to ensure personalized and effective BC management in Italy.

Participation in a High-Risk Program Is Associated with a Diagnosis of Earlier-Stage Disease Among Women at Increased Risk for Breast Cancer Development.

High-risk programs provide recommendations for surveillance/risk reduction for women at elevated risk for breast cancer development. This study evaluated the impact of high-risk surveillance program participation on clinicopathologic breast cancer features at the time of diagnosis. Women followed in the authors' high-risk program (high-risk cohort [HRC]) with a diagnosis of breast cancer from January 2015 to June 2021 were identified and compared with the general population of women undergoing breast cancer surgery at Memorial Sloan Kettering Cancer Center (MSK; general cohort [GC]) during the same period. Patient and tumor factors were collected. Clinicopathologic features were compared between the two cohorts and in a subset of women with a family history of known BRCA mutation. The study compared 255 women in the HRC with 9342 women in the GC. The HRC patients were slightly older and more likely to be white and have family history than the GC patients. The HRC patients also were more likely to present with DCIS (41 % vs 23 %; p < 0.001), to have smaller invasive tumors (pT1: 100 % vs 77 %; p < 0.001), and to be pN0 (95 % vs 81 %; p < 0.001). The HRC patients had more invasive triple-negative tumors (p = 0.01) and underwent less axillary surgery (p < 0.001), systemic therapy (p < 0.001), and radiotherapy (p = 0.002). Among those with a known BRCA mutation, significantly more women in the HRC underwent screening mammography (75 % vs 40 %; p < 0.001) or magnetic resonance imaging (MRI: 82 % vs 9.9 %; p < 0.001) in the 12 months before diagnosis. Women followed in a high-risk screening program have disease diagnosed at an earlier stage and therefore require less-intensive breast cancer treatment than women presenting to a cancer center at the time of diagnosis. Identification of high-risk women and implementation of increased surveillance protocols are vital to improving outcomes.