BRCA1 negative

Where existing NGS data for cancer susceptibility genes is stored to diagnostic standard in UK laboratories, this study suggests it is cost-effective to analyse, report and clinically manage patients and relatives by extended analysis to an 8-gene panel compared to the historical genetic testing.

BRCA1 and BRCA2 methylation was significant and correlated with decreased survival in patients with operable pancreatic cancer. A larger cohort of patients is required to further explore the potential of these findings as well as to investigate whether BRCA1/2 methylation in plasma could serve as a potential prognostic biomarker in pancreatic cancer.

Also in this series, STIC is associated with an abnormal p53 pattern in fallopian tubes of high-grade EOCs. In summary, TP53 aberrations are the most frequent and early molecular events in EOC carcinogenesis independently from BRCA mutation status.

P1/2, N=37, Active, not recruiting, Kari Wisinski | Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2023 --> Mar 2024

Our findings show the utility of the BRCA1/ID4 ratio in predicting neoadjuvant therapy response, which needs further evaluation in larger cohorts with long-term outcomes.

Women with MS have lower all-cause survival after breast cancer diagnosis than women without MS. Hence it is important to identify any risk factors or therapies that might be associated with increased risk of cancer.

The completion of multigene panel testing did not lead to a significant increase in MICRA or CWS scores. Key limitations of this study include a small sample size and an all Caucasian population.

Although this study did not meet its primary endpoint, there were 2 TNBC patients without a gBRCA1/2 mutation who achieved a partial response to this non-chemotherapy regimen. Future biomarker testing may help elucidate these findings and possible predictors of response.

In immunocytochemical analysis, tumor cells were positive for calretinin, podoplanin, epithelial membrane antigen, and methylthioadenosine phosphorylase; tumor cells were negative for BRCA1-associated protein 1, CD68, and desmin. The intracytoplasmic vacuoles were positive for adipophilin expression.

Our data show that abemaciclib and pembrolizumab were quickly implemented into routine care. Olaparib is used for pts with BRCA1/2 mutated tumors, but only few BRCA1/2 tests were documented so far. Future analysis will show whether BRCA1/2 testing increases, now that olaparib has been approved.

Figure: Figure 1a/1b Liver core biopsy H&E 20X objective, blue arrows revealing clusters of pleomorphic tumor cells. 1c: Liver Core biopsy with CK7 immunohistochemical stain 10X objective, a blue arrow indicating presence of tumor cells 1d: cross-sectional imaging of MRI abdomen/pelvis with and without contrast demonstrating normal signal and morphology, no suspicious lesions are seen.

P1/2, N=37, Active, not recruiting, Kari Wisinski | Recruiting --> Active, not recruiting

Clinical trial results demonstrate the pronounced clinical benefits of pembrolizumab combined with chemotherapy for high-risk, early-stage TNBC and adjuvant olaparib for high-risk, early-stage HER2-negative BRCA1/2-mutated breast cancer.

We interrogated the sensitivity to olaparib vs. carboplatin of 8 TNBC Patient-Derived Xenografts (PDX) models. These results were consistent with observations in cell lines showing a significant increase of RAD51-foci in olaparib-resistant subclones compared with sensitive parental cells, suggesting HR restoration in these models. Our results thus support the notion that the actual HRD status of BRCA1-Me TNBC, especially if previously exposed to chemotherapy, may be questioned and should be verified using the BRCA1- and RAD51-foci assay.

The examination of signaling genes in patients who met the established criteria for hereditary breast cancer but were negative for BRCA1/2 pathogenic variants provided additional information for approximately 8% of the families. The results of the present study suggest that NGS is a powerful tool for investigating the underlying genetic causes of occurrence and progression of breast cancer.

In younger BRCA1/BRCA2/PALB2-negative women, the aggregated burden of PGVs in breast cancer risk genes was associated with the increased risk of CBC and was inversely proportional to the age at onset.

Attitudes and subjective norms were predictors of intention to communicate updated genetic information to at-risk biological relatives, and predictors may vary by degree of relationship.

P1/2, N=37, Recruiting, Kari Wisinski | N=54 --> 37 | Trial completion date: Dec 2023 --> Jun 2023 | Trial primary completion date: Dec 2022 --> Jun 2023

The genes identified by exomiser (phenotype score >0.75) are associated with various biological processes such as DNA integrity maintenance, transcription regulation, cell cycle regulation, and apoptosis. Our findings provide novel and prevalent gene variants associated with the HBOC condition in the West Indian population which could be further studied for early diagnosis and better prognosis of HBOC.

Under the employed selection criteria, detection rate of mutation was low (1.74%). Most of family member of breast cancer with unknown BRCA ness was negative under criteria. If BRCA mutation screening for BrCa/OvCa families could be necessary, further larger scaled studies for useful criteria should be investigated.

Both mBRCA1 and mBRCA2 carriers are characterized by higher RS results that stem from a distinct gene expression profile of most genes in the RS assay. Single Gene Expression and Gene Group Scores vs the Commercial Use DB

For germline BRCA1-mutated breast cancer, TP53 R175H was unanimously the most frequent mutation among the three germline cohorts. Our study provides lists of potential shared neoantigens among BRCA1-related breast cancer, which may be used in developing off-the-shelf neoantigen-based vaccines.

Germline analysis of actionable genes revealed 4 patients carrier of pathogenic germline variants respectively of RAD51C (2 patients), RAD51D, and PALB2. Molecular profiling of EOCs using our custom NGS panel has enabled the detection of both somatic and germline variants, allowing the selection of patients suitable for targeted therapies, and the identification of high-risk OC families that can benefit from genetic counseling and testing.

A total of 46 matched cases and controls were analyzed. Median age was 50 with a range of 28-74. Of the cases, 18 had a BRCA1 PV and 28 had a BRCA2 PV.

P2, N=111, Terminated, National Cancer Institute (NCI) | Completed --> Terminated; Eli Lilly prematurely terminated the study.

The detection of more BRCA1/2 mutations in patients of ovarian cancer is important for efforts to provide targeted therapy. No

Our cohort showed an important incidence of deleterious and suspected deleterious BRCA1 and BRCA2 mutations, suggesting that genetic testing should be discussed and offered to patients with high-risk features. Many high-risk patients tested negative for BRCA1 and BRCA2 mutations, therefore future studies should aim to test for mutations in other breast cancer susceptibility genes (eg, CHEK2, PALB2, and BRIP1). Running culturally sensitive genetic research in a country with limited resources is a challenging exercise and highlights the urgent need for guiding regulations. We recommend establishing a clinical cancer genetics programme, through which unaffected family members would benefit from early breast cancer screening and appropriate risk-reduction measures.

In conclusion, four (4.8%) early-onset breast cancer patients fulfilling the HBOC and LFL syndromes presented TP53 pathogenic variants, confirming the relevance of genetic tests in this group of patients. In contrast to other Brazilian regions, TP53 p.R337H variant appeared with low prevalence.

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.

The safety run-in indicated that this combination is safe and well tolerated with mostly grade 1-2 AEs. This combination therapy has moved into the phase II trial, with 2 cohorts. Cohort A includes BRCA-wildtype patients with TNBC and cohort 2 includes those with a BRCA mutation and HER2-negative disease.

SMARCB1 alterations can be associated with schwannomatosis, along with several malignancies, and radiation increases the risk for lifetime malignancy. This case highlights the importance of full genetic work up for pediatric patients, particularly in the setting of radiation treatment.

P1/2, N=54, Recruiting, Kari Wisinski | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2021 --> Dec 2022

TP53 germline mutation screening detects a clinically meaningful risk of early onset BC from this ethnicity and should be considered in all early onset BC regardless of the family history of cancer, especially in young patients that are negative for BRCA mutations.

Providing a multi-gene panel testing to BRCA1/2-wt BC/OC/PC patients with a strong personal and/or family history of cancer could significantly increase the detection rates of germline PVs/LPVs in other cancer predisposition genes beyond BRCA1/2. The use of a multi-gene panel testing could improve the inherited cancer risk estimation and clinical management of patients and unaffected family members.

In particular, we analyzed the clinical trials results leading to approvals and their update (when available), according to setting (localized and locally advanced or metastatic) and clinical features (hormone receptor positive, HER2 positive, triple negative, BRCA 1/2 mutation). The aim of this paper is to describe the clinical benefit obtained with the new indications.

A comprehensive histological examination considering architectural patterns and their heterogeneity can help in prognostication of HGSOCs.

Supports for this type of effort may include coordinators and genetic counseling assistants and an available database with patients' contact information and prior genetic test results. Updated testing allows women more information about their risk and may expand the value of genetic counseling.

P2, N=111, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Mar 2022 --> Aug 2021

Treatment reveals a higher degree of cytotoxicity than cisplatin against both cell lines. However, the expression level of the BRCA1 protein is dramatically reduced after treatment with the combined inhibitors, compared with the untreated controls. This observation highlights the cellular responses of triple-negative BRCA1 proficient breast cancer MDA-MB-231 cells to RAPTA-EA1 through BRCA1 inhibition and provides insights into alternative treatments for breast cancer.

P1/2, N=54, Recruiting, Kari Wisinski | Trial completion date: May 2022 --> Dec 2022 | Trial primary completion date: May 2021 --> Dec 2021

CIN-high is a prognostic factor correlated with shorter DFS and was independent with the germline BRCA1 mutation pattern. Higher CIN values were significantly correlated with TP53 copy loss in breast cancer patients with germline BRCA1 mutation. Our results revealed a reliable molecular parameter for distinguishing patients with poor prognosis from the BRCA1-mutated breast cancer patients.

Further studies need to specify this effect. Potential use of PAF-AH as a biomarker for predicting the disease risk of BRCA1 mutation carriers and for the prognosis of patients with BRCA1-negative ovarian cancer should be explored.