BRCA1 deletion

Single-cell analyses confirmed deletion rate differences in gBRCA1/2 vs. non-carrier tumors as well as cells engineered to harbor gBRCA1/2 . The centrality of deletion-associated chromosomal instability to tumorigenesis shapes interpretation of the somatic evolution of non-malignant tissue and guides strategies for precision prevention and early detection.

The spectrum of pathogenic variants in the BRCA1/2 genes in La Rioja is similar to that in other Spanish regions, with some unique characteristics. The pathogenic c.6024dupG variant in the BRCA2 gene was detected in a large number of families and could have a founding effect in the Ebro riverside areas in the regions of La Rioja and Navarra.

Our study aims to systematically evaluate how Chr13q deletion impacts the progression of PC and its susceptibility to treatment. We anticipate that our study will establish a solid foundation of knowledge that can be used to identify aggressive primary PC and the related risk of progressing to lethal CRPC. This will help develop more effective treatments for patients with aggressive and lethal PC, particularly those with Chr13q..

The patient received docetaxel chemotherapy and pelvic radiotherapy. In a literature review, this case demonstrated the longest duration of effectiveness with olaparib alone without platinum-based chemotherapy. Additionally, the occurrence of relatively rare, fatal brain metastases in prostate cancer after a long period of CR suggests the necessity of regular brain imaging examinations.

Background : The PREDIX HER2 trial (n=202) compared neoadjuvant docetaxel, trastuzumab, and pertuzumab (DHP) vs. trastuzumab emtansine (T-DM1) in HER2-positive breast cancer, resulting in similar pathologic complete response (pCR) rates. Conclusion : Using multiomics analysis in a randomized trial, we show that T-DM1 and standard dual HER2 blockade harbor strikingly distinctive biomarkers of response. Further validation in prospective biomarker-driven studies, integrated multimodal predictive models and studies with novel antibody-drug conjugates are warranted.

This tumor thus warrants careful consideration. Accurate diagnosis can greatly improve early diagnosis and treatment of these tumors.

These observations map the prevalence of candidate drivers of resistance across time in a clinical setting, information with implications for clinical management and trial design in HRD breast cancers.

P2; N=15 --> 0 | Recruiting --> Withdrawn

Of the 42 pts with a treatment recommendation, 23 pts (56%) have received an on-label treatment, 19 with a PARP inhibitor and 4 with pembrolizumab... In this prospective study, 38% of pts with mCRPC were identified to have variants with an on-label treatment recommendation, highlighting the value of comprehensive testing to identify a relatively high number of these pts. In pts with both cfDNA and tissue testing, cfDNA alone detected 68% of these pts, emphasizing the value of cfDNA as a complement or alternative to tissue testing. Repeat cfDNA testing in a cohort of pts detected a new on-label variant in almost half of the pts tested, emphasizing the potential value of serial testing with tumor progression.

Furthermore, the founder effect of c.1918C>T (BRCA1) and c.8251_8254del (ATM) was verified in the Murcian population, whereas exon 2 deletion (BRCA2) was proven to be a Spanish founder mutation. Our algorithm enabled us to prioritize potentially pathogenic VUS that required further testing to determine their clinical significance and potential role in HBOC.

Two pts each had homozygous deletions in ATM, BRCA2 and CHEK2; another had FGFR2 fusion (FGFR2-KIAA1598). Conclusions Comprehensive ctDNA NGS can identify ESR1 mutations along with co-alterations that may inform therapeutic decisions for patients with ABC in AME.

We identified genomic alterations (TP53 mutations, FOXA1 and AR amplification, RB1 and BRCA2 deletions) from primary prostate tumors that are predictive of wide-spread metastases and poor outcomes.

We identified genomic alterations (TP53 mutations, FOXA1 and AR amplification, RB1 and BRCA2 deletions) from primary prostate tumors that are predictive of wide-spread metastases and poor outcomes.

Notably, CRISPR/Cas9-mediated deletion of Tspan8 or Thrsp prevents Brca2 HR- luminal cell expansion. Our findings indicate that Brca2 cells activate a transcriptional response after replication stress that preferentially favours outgrowth of HR- luminal cells through the expression of interferon-responsive and mammary alveolar genes.

From 71 patients with HGCS, we performed targeted germline and tumor sequencing and provided a comprehensive analysis of these 557 genes. We identified germline and somatic genetic alterations including somatic copy number alterations and analyzed their associations with relapse-free and overall survival. This single-site long-term follow-up study provides additional information on genetic alterations related to occurrence and outcome of HGSC. Our findings suggest that targeted treatments based on both variant and SCNA profile potentially could improve relapse-free and overall survival.

P2, N=150, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2022 --> Dec 2025

The present data provide an evident contribution of BRCA1 and BRCA2 mutation in patients of breast and ovarian cancer. One limitation of this study is the low number of patients who underwent TNBC testing.

Moreover, we find that 53BP1 loss is the prevalent resistance mechanism in HR-proficient BRCA1-deficient tumors, whereas resistance in BRCA2-deficient tumors is mainly induced by PARG loss. Furthermore, combined multi-omics analysis identifies additional genes and pathways potentially involved in modulating PARPi response.

A mutation in the BRCA1/2 genes was confirmed in 50% of the examined patients. In the study, we focused on the identification of mutated BRCA genes by a commercially available Sophia DDM™ system to identify a pathogenic or probable pathogenic variant in a cohort of patients with HGSOC in the Slovak population, which could result in better management and stratification of the individual.

gBRCA2-related prostate tumours are enriched for aggressive genomic features, such as BRCA2-RB1 co-deletion and MYC amplification. The presence or absence of these events modify the outcomes of gBRCA2 carriers.

Our work demonstrates the value of identifying HRD for therapeutic targeting by PARPi and platinum in individuals with the aggressive rare malignancy, uLMS and suggests that individuals with HRD uLMS should be included in trials of PARP1-specific PARPi.

We identified genomic alterations (TP53 mutations, FOXA1 and AR amplification, RB1 and BRCA2 deletions) from primary prostate tumors that are predictive of wide-spread metastases and poor outcomes.

P2; Not yet recruiting --> Recruiting | Initiation date: Feb 2023 --> Oct 2022

In this study, we demonstrated the prevalence of pathogenic germline LGRs beyond breast and ovarian cancer. The profiles of these pathogenic or likely-pathogenic alterations will fuel further investigations and highlight new understanding of LGRs across multiple cancer types.

We identified genomic alterations (TP53 mutations, FOXA1/AR amplification, RB1/BRCA2 deletion) from primary prostate carcinomas that are predictive of wide-spread metastases and poor outcome.

Of the 8 patients, 4 patients with BRCA2 CN less than 0.8 had an OR to the PARP inhibitor olaparib, while the other 4 patients with BRCA2 CN greater than 0.8 did not have an OR to olaparib... Our findings show that estimating CN decrease in BRCA2 using NGS can predict the prognosis of localized PC. Furthermore, our results may provide new insight into the utility of assessing both CN and AI of BRCA2 to accurately predict response to PARP inhibitors in mCRPC patients with BRCA2 alterations.

Our results suggest that a decrease in BRCA2 CN may be used as a biomarker for predicting recurrence after surgery in localized PC. Early screening for somatic alterations in BRCA2 using NGS may help to broadly predict the risk of PC progression.

Liquid biopsy profiling of PARPi-resistance breast cancer patients indicates that many patients develop multiple reversion mutations, and that alterations in the 53BP1-Shieldin pathway are present but less frequent. The co-occurrence of 53BP1-Shieldin pathway mutations and reversion mutations suggests parallel mechanisms of resistance can operate in the same patient.

RNA-based methods used were concordant with AI-based methods of TLS and sTIL detection. Our CNN-based method of identifying immune structures in the TME with morphological features on H&E WSIs may automate traditional pathology workflows with additional validation.

The choice of chemotherapeutic treatment regimens involving gemcitabine and FOLFIRINOX is currently solely based on the patient's performance status, but, ideally, it should be based on the tumors' individual biology...In summary, both patient-derived cell lines show distinct molecular phenotypes reflecting their individual tumor biology, with a unique clinical annotation of the respective patients. These preclinical ex vivo models can be further explored for potential new treatment strategies and might help in developing personalized (targeted) therapy regimens.

Our results suggest that a decrease in BRCA2 CN may be used as a biomarker for predicting recurrence after surgery in localized PC. Early screening for somatic alterations in BRCA2 using NGS may help to broadly predict the risk of PC progression.

This is the first study to reveal the BRCA1/2 LGR profile of a Chinese pan-cancer cohort by using an NGS-based assay. Two breast and ovarian cancer patients harboring NGS-determined BRCA1/2 LGR benefited from PARPi, indicating that NGS-based detection of BRCA1/2 LGR has the potential to guide PARPi treatment.

There were no women with TP53 or PALB2 germline alterations. Genetic analysis of non-selected HGSOC patients is an efficient tool for the identification of ethnicity-specific BRCA1/2 pathogenic variants.

Our study provides first insight into BC genetic landscape by the use of NGS in the under-represented East African Tanzanian populations. Our findings support the importance of genetic risk factors in BC etiology in Tanzania and showed a relatively high overall prevalence (6%) of germline BRCA1/2 pathogenic variants in BC patients. Therefore, our results indicate that BRCA1/2 pathogenic variants may well contribute to BC incidence in Tanzania. Thus, the identification of frequent variants in BRCA1/2 genes will enable implementation of rapid, inexpensive population-specific BRCA1/2 genetic testing, particularly for triple-negative BC patients known for their high prevalence in Tanzania. This will, in turn, greatly contributes to provide effective therapeutic strategies.

P2, N=15, Not yet recruiting, Dana-Farber Cancer Institute

In general, in our population ovarian cancer associated to BRCA mutation has worse prognosis than sporadic ovarian cancer (BRCA negative). In the other hand, the cases with the large deletion in exons 9-12 in BRCA1 gene has almost the double risk of primary resistance to platinum treatment versus any other pathogenic variant.

Ultrasensitive liquid biopsy enables detection of pathogenic BRCA1/2 alterations in plasma cfDNA of lung adenocarcinomas, despite low VAFs. Retrospective analysis suggests a difference in cfDNA mutational profiles in BRCA1/2 mutants, warranting further investigation on the role of BRCA1/2, HRD, and correlation with ICI treatment response in lung adenocarcinoma.

Of the 42 BRCA-negative cases, 4 (9.5%) carried a PV in a cancer susceptibility gene. The negative results obtained with MLPA in cases negative for BRCA and the extended genetic panel suggest that large deletions of BRCA are not a relevant cause of cancer susceptibility in this cohort. Otherwise, whole exome sequencing of 22 cases negatives for the previous genetic test showed pathogenic or probably PV in genes with no current evidence of association with breast and ovarian cancer.

Our study presents the cost effectiveness of the gene panel approach. We suggest that gene panels should be the first-tier genetic testing for hereditary breast cancer and MLPA analysis of BRCA1/2 genes should be investigated as a complementary method of NGS analysis.

However, higher risk levels, epithelioid histology, and KITex11-del retained prognostic independence. Conclusively, IHC is a useful surrogate of laborious IF in the combined assessment of 53BP1 and γ-H2AX to identify potential DDR-defective GISTs, which were frequently aberrated by HetDels and a harbinger of progression.

Consistent with TCGA results, OV and BRCA showed higher frequencies of 17q and 13q deletion compared to other cancer types. To conclude, we identified a correlation between cross-cancer difference in arm-level and focal chromosome aneuploidy affecting BRCA1/2 and BRCA-associated cancer risk, and how chromosome aneuploid may give rise to tissue-specific risks of cancer remain to be investigated.

The Resolution HRD assay offers highly sensitive, specific, and robust test results, and meets analytical requirements for clinical applications. It is intended as a companion diagnostic to niraparib in combination with abiraterone acetate plus prednisone (AAP) for the treatment of mCRPC patients.