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BIOMARKER:

HRD + BRCA1 mutation

i
Other names: BRCA1, BRCC1, PPP1R53, RNF53, Breast cancer 1, early onset, HRD, Homologous Recombination Deficiency
Entrez ID:
22h
Predictive Value and Therapeutic Significance of Somatic BRCA Mutation in Solid Tumors. (PubMed, Biomedicines)
Although the related literature is often controversial, recently published case reports and/or randomized studies demonstrated the effectiveness of PARPi in treating patients with somatic BRCA mutations. The aim of this review is to summarize the predictive role of somatic BRCA mutations and to provide further assistance for clinicians with the identification of patients who could potentially benefit from PARPi.
Review • Journal • BRCA Biomarker • PARP Biomarker
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
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BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA mutation
1d
Targeted and shallow whole genome sequencing identifies therapeutic opportunities in p53abn endometrial cancers. (PubMed, Clin Cancer Res)
sWGS and targeted sequencing identified therapeutic opportunities in 75% of p53abn EC patients. Further research is needed to determine the efficacy of treatments targeting these identified pathways within p53abn ECs.
Journal • BRCA Biomarker
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HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • HRD (Homologous Recombination Deficiency) • CCNE1 (Cyclin E1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • PPP2R1A (Protein Phosphatase 2 Scaffold Subunit Aalpha)
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TP53 mutation • BRCA2 mutation • BRCA1 mutation • HER-2 overexpression • HER-2 amplification • PIK3CA mutation • HER-2 mutation • HRD • MYC amplification • CCNE1 amplification • HRD + BRCA1 mutation • HRD signature
23d
Pan-cancer analysis identifies signatures of HRD-positivity in germline BRCA1/2 mutated non-BRCA associated cancers (AACR 2024)
Using a robust measure to detect HRD scars from MSK-IMPACT panel data, we demonstrate evidence for BRCA-mediated tumorigenesis in an expanded spectrum of cancers with potential therapeutic relevance.
BRCA Biomarker • PARP Biomarker • Pan tumor
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation
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MSK-IMPACT
23d
Genomic landscape of circulating tumor DNA in cervical cancer in Asia: NCCH1905/A-TRAIN trial (AACR 2024)
Comprehensive genomic profiling using liquid biopsy can rapidly identify potential candidates for targeted therapy in cervical cancer patients, regardless of histopathology. Clinical studies of precision medicines in Asia are encouraged for such patients.
BRCA Biomarker • Circulating tumor DNA
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HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • STK11 (Serine/threonine kinase 11) • HRD (Homologous Recombination Deficiency) • ARID1A (AT-rich interaction domain 1A) • NOTCH1 (Notch 1) • CDK12 (Cyclin dependent kinase 12)
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BRCA2 mutation • BRCA1 mutation • HER-2 amplification • PIK3CA mutation • HRD • ATM mutation • CDK12 mutation • HRD + BRCA1 mutation • ATM mutation + CDK12 mutation
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Guardant360® CDx
23d
Landscape of HRD aberration in EGFR mutated lung cancer and the role of PARP-inhibitor in EGFR mutated lung cancer with HRD aberration (AACR 2024)
We also present a case demonstrating a favorable response to the dual therapy of olaparib and osimertinib in NSCLC harboring EGFR, RAD50, and ARID1A mutations that progressed on osimertinib. There were 2298 patients in the NSCLC cohort (MSKCC database). HRD aberrations are uncommon in EGFR mutated lung cancer patients. Further investigation on the role of PARP inhibitor in EGFR mutated lung cancer is warranted.
BRCA Biomarker • PARP Biomarker
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EGFR (Epidermal growth factor receptor) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • ARID1A (AT-rich interaction domain 1A) • RAD50 (RAD50 Double Strand Break Repair Protein)
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BRCA2 mutation • BRCA1 mutation • EGFR mutation • EGFR exon 19 deletion • HRD • ARID1A mutation • EGFR E746_A750del • HRD + BRCA1 mutation • RAD50 mutation • EGFR E746
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Guardant360® CDx
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Lynparza (olaparib) • Tagrisso (osimertinib)
1m
Predictive Biomarkers for Immune Checkpoint Inhibitor (ICI) and Poly (ADP-Ribose) Polymerase (PARP) Inhibitor (PARPi) in Advanced Stage Breast Carcinoma (USCAP 2024)
Our study failed to show significant associations between PD-L1 IHC and HRD parameters. TMB score was positively associated with LOH-high, but not HRR gene mutation. Independently evaluating these markers needs to be considered to select patients for targeting therapies.
Checkpoint inhibition • Tumor mutational burden • PD(L)-1 Biomarker • PARP Biomarker • BRCA Biomarker • IO biomarker • Metastases
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PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
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PD-L1 expression • BRCA2 mutation • BRCA1 mutation • TMB-H • HRD • PD-L1 negative • BRCA wild-type • HRD + BRCA1 mutation • BRCA mutation
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PD-L1 IHC 22C3 pharmDx
2ms
Natural history of germline BRCA1 mutated and BRCA wild-type triple-negative breast cancer. (PubMed, Cancer Res Commun)
Circulating tumour DNA (ctDNA) recapitulated most tissue-derived stem-clonal and subclonal mutations while detecting some additional subclonal mutations. RNA-Seq revealed a stable basal-like pattern, with most highly expressed variants belonging to stem clone.
Journal • BRCA Biomarker
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BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • HRD (Homologous Recombination Deficiency) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • BRCA (Breast cancer early onset) • CSF3R (Colony Stimulating Factor 3 Receptor) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • ARID2 (AT-Rich Interaction Domain 2)
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TP53 mutation • BRCA1 mutation • HRD • BRCA wild-type • BRIP1 mutation • HRD + BRCA1 mutation • BRCA mutation • HRD signature
2ms
Changes in HRD status during treatment for ovarian high-grade serous carcinoma (SGO 2024)
This study demonstrates that cases identified as having HRD based on tumor tissue analysis prior to chemotherapy can be identified as not having HRD when tumor tissue collected at the time of IDS is examined. When testing for HRD, it should be recognized that this may change during the course of treatment.
BRCA Biomarker
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA mutation
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OncoScan™ CNV Assay
2ms
Clinical and molecular determinants of response to maintenance olaparib for primary and recurrent epithelial ovarian carcinoma (SGO 2024)
The incidence of ST response to maintenance olaparib is high and appears to be modulated by maintenance sequence (primary vs recurrent therapy). Response to most recent chemotherapy could be incorporated into prospective data as a surrogate for predicting response to PARP inhibitors. Efforts to increase utilization of PARP inhibitor therapy in the primary maintenance setting are warranted.
Clinical • PARP Biomarker • BRCA Biomarker
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA mutation
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Myriad myChoice® CDx
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Lynparza (olaparib)
2ms
Concordance between an FDA-approved companion diagnostic and an alternative assay kit for assessing homologous recombination deficiency in ovarian cancer. (PubMed, Gynecol Oncol)
Comparison between the Illumina and Myriad assays showed that overall HRD status, the individual components of BRCA analysis, and HRD GIS detection results were highly concordant (>93%), suggesting the TSO 500 HRD assay will approach the analytical accuracy of the FDA-approved Myriad assay.
Journal • FDA event • BRCA Biomarker • BRCA Companion diagnostic • Companion diagnostic • Discordant
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation
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TruSight Oncology 500 Assay • Myriad myChoice® CDx Plus • TruSight Oncology 500 HRD Assay
3ms
Predictive and prognostic biomarkers in female genital tract tumours: an update highlighting their clinical relevance and practical issues. (PubMed, Pathology)
HER2 testing by immunohistochemistry and in situ hybridisation is applicable to endometrial serous carcinomas to assess trastuzumab eligibility...Awareness of the variety and pitfalls of expression patterns for p16 and p53 in vulvar carcinomas is crucial for accurate designation. It is hoped that collaborative efforts in standardising and optimising biomarker testing for gynaecological tumours will contribute to evidence-based therapeutic decisions.
Review • Journal • BRCA Biomarker • PD(L)-1 Biomarker • IO biomarker
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HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • PGR (Progesterone receptor) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • HRD (Homologous Recombination Deficiency) • POLE (DNA Polymerase Epsilon) • FOLR1 ( Folate receptor alpha )
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TP53 mutation • BRCA2 mutation • BRCA1 mutation • HRD • POLE mutation • HRD + BRCA1 mutation • TP53 expression • PGR expression
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Herceptin (trastuzumab)
3ms
A novel targeted NGS panel identifies numerous homologous recombination deficiency (HRD)-associated gene mutations in addition to known BRCA mutations. (PubMed, Diagn Pathol)
Taken together, the present study proves the feasibility of a new HRD gene panel with reliable panel performance and offers the possibility to easily screen for resistance mutations acquired over treatment time.Mutations in HR-associated genes, besides BRCA1/2, might represent promising potential targets for synthetic lethality approaches. Thus, a substantial number of patients may benefit from expanding the scope of therapeutic agents like PARPi.
Journal • Next-generation sequencing • BRCA Biomarker • PARP Biomarker
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TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
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TP53 mutation • BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA mutation
3ms
Biomarker Testing Journey Among Patients with Advanced Solid Tumors and Treatment Patterns by Homologous Recombination Repair Status: A Clinico-Genomic Database Study. (PubMed, Adv Ther)
The majority of patients from this real-world dataset underwent FoundationOneCDx testing after initiation of first-line treatment. Testing appeared to influence treatment patterns, with a higher proportion of patients with BRCAm, HRRm, and HRD-positive disease receiving PARP inhibitors.
Journal • Biomarker testing • PARP Biomarker • BRCA Biomarker • IO biomarker • Metastases
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA1 mutation + BRCA2 mutation
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FoundationOne® CDx
3ms
DIDO: Niraparib and Dostarlimab in HRD Solid Tumors (clinicaltrials.gov)
P2, N=30, Recruiting, West Cancer Center | Not yet recruiting --> Recruiting
Enrollment open • Combination therapy • Metastases
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • RAD54L (DNA Repair And Recombination Protein RAD54) • FANCL (FA Complementation Group L) • PPP2R2A (Protein Phosphatase 2, Regulatory Subunit B, Alpha) • FANCI (FA Complementation Group I)
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BRCA1 mutation • HRD • ATM mutation • PALB2 mutation • CHEK2 mutation • BRIP1 mutation • HRD + BRCA1 mutation • RAD51C mutation • RAD51D mutation • RAD51B mutation • BARD1 mutation • RAD54L mutation • FANCI mutation • RAD51 mutation
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Zejula (niraparib) • Jemperli (dostarlimab-gxly)
4ms
Trial completion date
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EGFR (Epidermal growth factor receptor) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset) • CD4 (CD4 Molecule)
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BRAF V600E • BRCA2 mutation • BRCA1 mutation • EGFR mutation • BRAF V600 • EGFR T790M • HRD • ALK fusion • ROS1 fusion • HRD + BRCA1 mutation
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Rubraca (rucaparib)
4ms
Survival impact of homologous recombination deficiency in veterans with cholangiocarcinoma including mutual exclusivity with pathogenic KRAS and TP53. (ASCO-GI 2024)
Across a diverse integrated healthcare system of Veterans, mutations associated with HRD were found to be common, however, not prognostic in OS across a diverse patient population of CCA. Further work is needed to clarify exposure to platinum containing chemotherapy. TP53 MT CCA remains a critical unmet need that drives worsened outcomes including here in patients with mutations in HRD.
BRCA Biomarker
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • ARID1A (AT-rich interaction domain 1A) • BAP1 (BRCA1 Associated Protein 1) • PALB2 (Partner and localizer of BRCA2) • CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin))
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KRAS mutation • BRCA1 mutation • HRD • ATM mutation • ARID1A mutation • PALB2 mutation • CDK12 mutation • BAP1 mutation • CHEK2 mutation • HRD + BRCA1 mutation • BRCA mutation • NBN mutation
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FoundationOne® CDx
4ms
Homologous Recombination Deficiency Across Subtypes of Primary Breast Cancer. (PubMed, JCO Precis Oncol)
P2; The prevalence of HRD in non-TNBC suggests that therapy targeting HRD should be evaluated in a wider breast cancer patient population. Strict HRD criteria should be implemented to increase diagnostic precision with respect to functional HRD.
Journal • PD(L)-1 Biomarker • PARP Biomarker • BRCA Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • RAD51 (RAD51 Homolog A) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • BARD1 (BRCA1 Associated RING Domain 1)
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PD-L1 expression • BRCA2 mutation • BRCA1 mutation • PD-L1 overexpression • HRD • PALB2 mutation • BRIP1 mutation • HRD + BRCA1 mutation • BARD1 mutation
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Prosigna™ Breast Cancer Prognostic Gene Signature Assay
4ms
Olaparib and celarasertib (AZD6738) in patients with triple negative advanced breast cancer: results from Cohort E of the plasmaMATCH trial (CRUK/15/010). (PubMed, Clin Cancer Res)
Responses were observed in patients without germline or somatic BRCA1/2 mutations, including patients with mutations in other homologous recombination repair genes and tumours with functional homologous recombination deficiency by RAD51 foci. Conclusion The response rate to olaparib and ceralasertib did not meet pre-specified criteria for activity in the overall evaluable population, but responses were observed in patients who would not be expected to respond to Olaparib monotherapy.
Journal • BRCA Biomarker • PARP Biomarker • Metastases
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset) • RAD51 (RAD51 Homolog A)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA1 mutation + BRCA2 mutation • BRCA mutation
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Lynparza (olaparib) • ceralasertib (AZD6738)
4ms
BRCA1/2 reversion mutations in a pan-cancer cohort. (PubMed, Cancer Sci)
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.
Journal • BRCA Biomarker • PARP Biomarker • Pan tumor
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • PARP1 mutation
4ms
Liposomal Irinotecan, Fluorouracil, Leucovorin Calcium, and Rucaparib in Treating Patients With Metastatic Pancreatic, Colorectal, Gastroesophageal, or Biliary Cancer (clinicaltrials.gov)
P1/2, N=18, Active, not recruiting, Academic and Community Cancer Research United | Phase classification: P2 --> P1/2 | Trial primary completion date: Jan 2020 --> Feb 2024
Phase classification • Trial primary completion date • Metastases
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
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BRCA2 mutation • BRCA1 mutation • HRD • PALB2 mutation • HRD + BRCA1 mutation
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Rubraca (rucaparib) • leucovorin calcium • Onivyde (nanoliposomal irinotecan) • fluorouracil topical
4ms
Homologous Recombination Deficiency Landscape of Breast Cancers and Real-World Effectiveness of Poly ADP-Ribose Polymerase Inhibitors in Patients With Somatic BRCA1/2, Germline PALB2, or Homologous Recombination Deficiency Signature. (PubMed, JCO Precis Oncol)
Patients with sBRCA and gPALB2 derive similar benefit from PARPi as those with gBRCA alterations. In combination, HRDsig+, sBRCA, and gPALB2 represent an additional 19% of mBC that can potentially benefit from PARPi. Randomized trials exploring a more inclusive biomarker such as HRDsig are warranted.
Journal • Real-world evidence • BRCA Biomarker • PARP Biomarker • Real-world effectiveness • Real-world
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HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • BRCA (Breast cancer early onset)
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BRCA2 mutation • BRCA1 mutation • HER-2 negative • HRD • PALB2 mutation • HRD + BRCA1 mutation • HRD signature
4ms
Association Between Homologous Recombination Repair Biomarkers and Survival in Patients With Solid Tumors. (PubMed, JCO Precis Oncol)
This large, real-world study found no association between OS and either BRCA or HRR status but identified a possible linkage between HRD positivity and shorter median OS in patients with advanced solid tumors who did not receive PARPi or immunotherapy.
Journal • BRCA Biomarker • PARP Biomarker • IO biomarker
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
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BRCA1 mutation • HRD • BRCA wild-type • HRD + BRCA1 mutation
4ms
Niraparib Plus Aromatase Inhibitors for Luminal-like(HER2-,ER+) and gBRCA or HDR+ Metastatic Breast Cancer (LUZERN) (clinicaltrials.gov)
P2, N=14, Completed, MedSIR | Terminated --> Completed | Trial completion date: Dec 2022 --> Nov 2023
Trial completion • Trial completion date • Metastases
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset) • RAD51 (RAD51 Homolog A)
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HER-2 positive • BRCA2 mutation • BRCA1 mutation • HR positive • HER-2 negative • HRD • BRCA wild-type • HRD + BRCA1 mutation • HR positive + HER-2 negative
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Zejula (niraparib)
4ms
Detection and therapeutic implications of homologous recombination repair deficiency in pancreatic cancer: a narrative review. (PubMed, J Gastrointest Oncol)
Consistently detecting clinically significant the HRD status in PDAC has remained challenging with current commercially available platforms. Multiple novel HRD-targeted therapies for PDAC are currently in development and clinical trials, offering new opportunities for these patients.
Review • Journal • BRCA Biomarker • PARP Biomarker • IO biomarker
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA1 mutation + BRCA2 mutation
5ms
Exploring homologous recombination deficiency in pediatric high-grade gliomas (SNO 2023)
Overall, our study suggests that HRD exists in a fraction of pHGG samples, but is driven by inactivation of genes other than BRCA1/2, resulting in a different set of genomic scars compared to those in BCs. Functional analysis of sensitivity to PARP inhibitor and related DNA damage inhibitors is ongoing to evaluate potential therapeutic relevance of these genomic scars.
Clinical • BRCA Biomarker • PARP Biomarker
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TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation
5ms
Enhanced Cancer Cell Proliferation and Aggressive Phenotype Counterbalance in Breast Cancer with High BRCA1 Gene Expression (SABCS 2023)
Contrary to our initial hypothesis, we did not find any significant association between BRCA1 gene expression and survival outcomes in breast cancer patients. Based on the results of our study, we speculate that the interplay between enhanced cancer cell proliferation and aggressive tumor characteristics may counterbalance the effect of high BRCA1 expression in breast cancer.
BRCA Biomarker
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CD8 (cluster of differentiation 8) • TGFB1 (Transforming Growth Factor Beta 1)
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BRCA1 mutation • HER-2 negative • HRD • HRD + BRCA1 mutation • BRCA1 expression • BRCA2 expression
5ms
The MAGIC study: Universal whole genome tumour and germline sequencing of newly diagnosed breast cancer identifies a high proportion of ER+ BRCA-like tumours (SABCS 2023)
Tumour sequencing identified three times as many cases that might be eligible for HR repair defect targeted therapy than germline testing alone (16% versus 5.2%). Unlike a previous study (Ann Oncol., 2019 30:1071-1079), the majority of the BRCA-like BCs were ER+ with no evidence of a VUS in a known HBC gene suggesting these are driven by novel germline or somatic mutations in genes involved in DNA HR repair.
BRCA Biomarker
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ER (Estrogen receptor) • TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • STK11 (Serine/threonine kinase 11) • HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2) • CDH1 (Cadherin 1) • BRCA (Breast cancer early onset) • CHEK2 (Checkpoint kinase 2) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1)
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ER positive • BRCA1 mutation • HRD • PALB2 mutation • HRD + BRCA1 mutation • RAD51C mutation • PMS2 mutation • RAD51 mutation
5ms
Impact of PARP Inhibitor and Platinum Therapy on Clonal Hematopoiesis (ASH 2023)
Patients were treated with a variety of PARPi including Olaparib (n=48), Talazoparib (n=33), Rucaparib (n = 13) and Niraparib (n = 6.) Of the 418 patients, 45 individuals harbored an HRD germline mutation...The percentage of Trp53 R172H cells in the blood was measured by flow cytometry at baseline (6 weeks after transplantation) and after treatment with vehicle alone, Talazoparib or Olaparib daily, or cisplatin weekly, for 4 weeks...Indeed, our data suggest the opposite, with the fitness advantage of DDR gene-mutated HSPCs lost in cells with a heterozygous Brca1-mutations. These data suggest that PARPi therapy may have less of an impact on leukemia risk compared to carboplatin and in fact may show synergistic effects with HRD in blocking the competitive advantage of DDR CH during genotoxic stress.
BRCA Biomarker • PARP Biomarker
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2) • CHEK2 (Checkpoint kinase 2) • PPM1D (Protein Phosphatase Mg2+/Mn2+ Dependent 1D)
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TP53 mutation • BRCA1 mutation • HRD • CHEK2 mutation • HRD + BRCA1 mutation • TP53 R172H
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Lynparza (olaparib) • cisplatin • carboplatin • Talzenna (talazoparib) • Zejula (niraparib) • Rubraca (rucaparib)
5ms
RECURRENCE-FREE SURVIVAL AND OVERALL SURVIVAL IN EARLY- STAGE OVARIAN CANCER CONSIDERING HOMOLOGOUS RECOMBINATION DEFICIENCY(HRD) STATUS (IGCS 2023)
A total of 456 stage I/II patients were included. 22/456 (4.8%) had a germline or somatic BRCA1 mutation 46/456 (10.0%) had a BRCA2 mutation; These 68/456(14.9%) patients comprised the HRD group. The remaining cases were confirmed homologous recombination proficient (HRP, 388/ 456, 85.1%).
Clinical • BRCA Biomarker
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA mutation
6ms
A BRCA2 germline mutation and high expression of immune checkpoints in a TNBC patient. (PubMed, Cell Death Discov)
Altogether, these findings support an unveiled link between BRCA2 inactivation, HR deficiency and increased expression of immune checkpoints in TNBC. This clinical case highlights the importance of screening TNBC patients for genetic mutations and TMB biomarkers in order to predict the potential efficacy of immunotherapy.
Journal • Tumor mutational burden • BRCA Biomarker • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • PD-1 (Programmed cell death 1) • BAP1 (BRCA1 Associated Protein 1) • CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) • PD-L2 (Programmed Cell Death 1 Ligand 2) • EPHA3 (EPH receptor A3)
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TP53 mutation • BRCA2 mutation • BRCA1 mutation • TMB-H • HRD • BAP1 mutation • HRD + BRCA1 mutation • EPHA3 mutation • HRD signature
6ms
RediScore: Prospective validation of a pipeline for homologous recombination deficiency analysis. (PubMed, Oncol Lett)
"GIS was positive in 40% of the BRCA1/2-negative cases. The RediScore bioinformatics algorithm developed for GIS calculation in combination with NGS BRCA1/2 analysis is a viable and effective approach for HRD calculation in patients with ovarian cancer, offering a positive prediction for PARP inhibitor responsiveness in 55% of the patients."
Journal
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
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HRD • HRD + BRCA1 mutation • BRCA mutation
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Myriad myChoice® CDx • OncoScan™ CNV Assay • Oncomine™ BRCA Research Assay
6ms
Exploring homologous recombination deficiency threshold for predicting response to PARP inhibitor in prostate cancer (ESMO Asia 2023)
Conclusions HRD positive, defined as GIS score >9, may be an appropriate threshold to predict the likelihood of response to PARPi in prostate cancer. Prospective, and large sample clinical trials will be needed to confirm our findings.
BRCA Biomarker • PARP Biomarker
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA1 promoter methylation • High HRD score
6ms
Prevalence of homologous recombination deficiency in ovarian, primary peritoneal, and/or fallopian tube cancer: Results from the international HALO study (ESMO Asia 2023)
Conclusions This pioneering real-world study reports HRD prevalence in a large cohort of pts, ranging from 52.0% - 58.5% across the three study regions. Our results highlight the unmet need for capturing biomarker testing data and the utility of different HRD testing kits in real-world in resource-limited settings to inform treatment decisions.
BRCA Biomarker
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation
6ms
Genomic analysis of advanced breast cancer tumors from talazoparib-treated gBRCA1/2mut carriers in the ABRAZO study. (PubMed, NPJ Breast Cancer)
BRCA1- or BRCA2-mutated tumors show comparable clinical benefit within cohorts. While low patient numbers preclude correlations between HRD and efficacy, germline BRCA1/2 mutation detection from tumor-only sequencing shows high sensitivity and non-BRCA genetic/genomic events do not appear to influence talazoparib sensitivity in the ABRAZO trial.ClinicalTrials.gov identifier: NCT02034916.
Journal • BRCA Biomarker • PARP Biomarker • Metastases
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TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
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TP53 mutation • BRCA2 mutation • BRCA1 mutation • PIK3CA mutation • HRD • HRD + BRCA1 mutation
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Talzenna (talazoparib)
6ms
Homologous Recombination Abnormalities Associated With BRCA1/2 Mutations as Predicted by Machine Learning of Targeted Next-Generation Sequencing Data. (PubMed, Breast Cancer (Auckl))
These data demonstrate that CNA when combined with ML can reliably predict the presence of BRCA1/2 level HRD with high specificity. Using BRCA1/2 mutant cases as gold standard, this ML can be used to predict HRD in cancers with mutations in other HRR genes as well as in WT tumors.
Journal • Next-generation sequencing • BRCA Biomarker • Machine learning
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation
6ms
Chlorambucil in Metastatic PDAC Patients Bearing a Germ Line DNA Defects Repair Mutations (SALE Trial) (clinicaltrials.gov)
P2, N=20, Active, not recruiting, Michele Reni | Recruiting --> Active, not recruiting | N=30 --> 20 | Trial primary completion date: Jun 2021 --> Jan 2023
Enrollment closed • Enrollment change • Trial primary completion date • Metastases
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation
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Leukeran (chlorambucil)
6ms
BRCA1/2 Mutation Frequency In Early And Advanced Ovarian Cancer Patients. (ESGO 2023)
There were no differences of the frequencies of BRCA1 (p=0.7) or BRCA 2 (p=1.0) mutations at the DNA-BS between early and advanced stage OC.Conclusion BRCA1/2 frequency differences between patients with early and advanced stage OC are due to histological disparities. There are no hints that tumor biology defined by BRCA is different between early and advanced high-grade OC.
Clinical • BRCA Biomarker • PARP Biomarker • Metastases
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA mutation
7ms
Ovarian High-grade Serous Carcinoma with Transitional-like (SET) Morphology: A Homologous Recombination-deficient Tumor. (PubMed, Hum Pathol)
"Our results show that the majority of HGSCs with SET features are homologous recombination deficient tumors independently of the BRCA status and highlight the importance of the homologous recombination repair tumor testing especially in BRCA wild-type tumors. Recognition of transitional cell variant of HGSCs may help to identify patients most likely to benefit from PARP inhibitors."
Journal
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • CHEK2 (Checkpoint kinase 2) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • RAD54L (DNA Repair And Recombination Protein RAD54) • FANCL (FA Complementation Group L) • PPP2R2A (Protein Phosphatase 2, Regulatory Subunit B, Alpha)
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BRCA2 mutation • BRCA1 mutation • HRD • ATM mutation • PALB2 mutation • BRCA wild-type • CDK12 mutation • BRIP1 mutation • HRD + BRCA1 mutation • RAD51C mutation • RAD51D mutation • RAD51B mutation • BARD1 mutation • CHEK1 mutation • RAD54L mutation • CHEK1 expression
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Myriad myChoice® CDx Plus • SOPHiA DDM HRD Solution
7ms
Development of a novel metric to measure genomic instability using unbalanced copy number changes with fast comprehensive genomic profiling (ECP 2023)
Conclusion We devised a novel method to determine genomic instability for characterizing consequence of HRD using OCA Plus, which was developed for fast CGP of cancer FFPE samples to aid research into precision oncology. By combining genomic instability assessment with DNA repair pathway analysis such as mutations in BRCA1/2 and other genes in HRR pathway, OCA Plus will support research into the mechanisms underlying HRD.
BRCA Biomarker
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA mutation
8ms
An integrated analysis of microRNAs regulating DNA damage response in triple-negative breast cancer. (PubMed, Breast Cancer)
Our study identified 6 'HRD associated miRNAs' such as miR-106b, miR-93, miR-17, miR-20a, miR-200b, and miR-429 as novel miRNA-based signatures associated with HR deficiency in TNBC.
Journal • Tumor mutational burden • BRCA Biomarker
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TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset) • MIR200B (MicroRNA 200b) • MIR429 (MicroRNA 429) • MIR17 (MicroRNA 17) • MIR106B (MicroRNA 106b) • MIR20A (MicroRNA 20a) • MIR93 (MicroRNA 93)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA1 mutation + BRCA2 mutation
8ms
Mechanisms of PARP-Inhibitor-Resistance in BRCA-Mutated Breast Cancer and New Therapeutic Approaches. (PubMed, Cancers (Basel))
Several molecular mechanisms have been identified as causing PARP-inhibitor-resistance. In this review, we focus on the molecular mechanisms underlying the PARP-inhibitor-resistance in BRCA-mutated breast cancer and summarize potential therapeutic strategies to overcome the resistance mechanisms.
Review • Journal • BRCA Biomarker • PARP Biomarker
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
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BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA mutation
8ms
HRD status of patients with early stage non-small cell lung cancer (ESMO 2023)
Preliminary functional experiments in HRP (HR proficient, n=5) and HRD (n=4) PDX and organoids (n=3 and n=3 for HRD and HRP respectively) indicate that HRD tumors present low RAD51 foci count (p=0.03 after damage induction) and favorable response to Olaparib and CDDP. Conclusions These data suggest that homologous recombination may be deficient in a substantial proportion of early-stage NSCLC patients, supporting the potential use of PARPi in HRD patients in the adjuvant or maintenance setting.
Clinical • PARP Biomarker • BRCA Biomarker
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TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • RAD50 (RAD50 Double Strand Break Repair Protein) • CHEK1 (Checkpoint kinase 1)
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BRCA2 mutation • BRCA1 mutation • HRD • ATM mutation • PALB2 mutation • CHEK2 mutation • HRD + BRCA1 mutation • RAD50 mutation • CHEK1 mutation • CHEK1 expression
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AmoyDx® HRD Focus Panel
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Lynparza (olaparib)