News - HRD + BRCA1 mutation

Niraparib in Tumors Metastatic to the CNS (clinicaltrials.gov)

P2, N=20, Recruiting, Massachusetts General Hospital | Trial completion date: Dec 2026 --> Jun 2027 | Trial primary completion date: Dec 2024 --> Dec 2025

7 days ago

Trial completion date • Trial primary completion date • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BAP1 (BRCA1 Associated Protein 1) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD50 (RAD50 Double Strand Break Repair Protein) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • RAD54L (DNA Repair And Recombination Protein RAD54) • XRCC2 (X-Ray Repair Cross Complementing 2) • RAD54B (RAD54 Homolog B) • XRCC3 (X-Ray Repair Cross Complementing 3)

BRCA1 mutation • HRD • ATM mutation • PALB2 mutation • BAP1 mutation • BRIP1 mutation • HRD + BRCA1 mutation • RAD51C mutation • RAD51D mutation • RAD50 mutation • RAD51B mutation • BARD1 mutation • MRE11A mutation • RAD54L mutation • NBN mutation • HRD signature

Zejula (niraparib)

10d

Can Morphology and Immune Infiltration Predict the Homologous Recombination Deficiency Status in Newly Diagnosed High-Grade Serous Ovarian Carcinoma? (PubMed, Arch Pathol Lab Med)

The combination of these 3 criteria showed high specificity (0.99; 95% CI, 0.97-0.99) but low sensitivity (0.07; 95% CI, 0.04-0.10). The morphology of HGSOC correlates with HRD status and BRCA status but cannot substitute for molecular analysis in daily practice.

10 days ago

Journal • BRCA Biomarker

BRCA1 (Breast cancer 1, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)

BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA mutation

Myriad myChoice® CDx Plus

20d

BRCA loss of function including BRCA1 DNA-methylation, but not BRCA-unrelated homologous recombination deficiency, is associated with platinum hypersensitivity in high-grade ovarian cancer. (PubMed, Clin Epigenetics)

In HGOC BRCA mutational status together with BRCA1-methylation exhibit the best predictive power for favorable clinical outcome and thus high sensitivity to platinum-based therapy, whereas BRCA-unrelated HRD positivity was not associated with improved platinum sensitivity.

20 days ago

Journal • BRCA Biomarker • PARP Biomarker • Epigenetic controller

BRCA1 (Breast cancer 1, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)

BRCA1 mutation • HRD • BRCA wild-type • HRD + BRCA1 mutation • BRCA mutation • BRCA1 expression

21d

Poly (ADP-Ribose) Polymerase Inhibitor Olaparib-Resistant BRCA1-Mutant Ovarian Cancer Cells Demonstrate Differential Sensitivity to PARP Inhibitor Rechallenge. (PubMed, Cells)

UWB-OlaJR exhibits varying sensitivity to PARPis, showing cross-resistance to veliparib and talazoparib, and sensitivity with increased cytotoxicity to niraparib and rucaparib. Moreover, S1 nuclease fiber assay shows that niraparib and rucaparib induce greater DNA single-strand gaps than other PARPis, leading to increased DNA damage and cell death. Our study provides novel insights into differential PARPi sensitivity in olaparib-resistant BRCA-mutant OvCa, which requires further investigation of inter-agent differences in large prospective studies.

21 days ago

Journal • BRCA Biomarker • PARP Biomarker

BRCA1 (Breast cancer 1, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)

BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA mutation

Lynparza (olaparib) • Talzenna (talazoparib) • Zejula (niraparib) • Rubraca (rucaparib) • veliparib (ABT-888)

27d

Olaparib monotherapy in advanced triple-negative breast cancer patients with homologous recombination deficiency and without germline mutations in BRCA1/2: The NOBROLA phase 2 study. (PubMed, Breast)

The observed results could prompt further investigation.

27 days ago

Clinical • P2 data • Journal • BRCA Biomarker • PARP Biomarker • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency)

BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation

Lynparza (olaparib)

27d

Discovery of Pyrazolo[1,5,4-de]quinoxalin-2(3H)-one Derivatives as Highly Potent and Selective PARP1 Inhibitors. (PubMed, J Med Chem)

30 achieved tumor regression in the BRCA1-mutated MDA-MB-436 xenograft model and showed synergistic efficacy in combination with carboplatin in the SUM149PT xenograft model. In the rat hematological toxicity study, 30 exhibited minimal impact on hematological parameters at 25 mg/kg, while AZD5305 at 1 mg/kg caused 56.5% reduction of reticulocyte. Taken together, we discovered compound 30 with a therapeutic index superior to that of PARP1 inhibitors AZD5305 and AZD9574 in the preclinical setting.

27 days ago

Journal • BRCA Biomarker • PARP Biomarker

BRCA1 (Breast cancer 1, early onset) • HRD (Homologous Recombination Deficiency) • PARP2 (Poly(ADP-Ribose) Polymerase 2)

BRCA1 mutation • HRD • HRD + BRCA1 mutation

carboplatin • saruparib (AZD5305) • AZD9574

A Comprehensive Genomic Profiling Solution That Integrates BRCA1/2 Mutational Status and Genomic Instability to Characterize Homologous Recombination Deficiency (AMP 2024)

We developed a novel method to determine genomic instability for characterizing the consequences of HRD using OCA Plus, which was developed using 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.

1 month ago

BRCA Biomarker

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency)

BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation

Oncomine™ Comprehensive Assay Plus

2ms

Prevalence of actionable genomic alterations (GA) and predictive value of tumor mutational burden (TMB) for immune checkpoint inhibitor (ICI) effectiveness in HR(+)HER2(-) metastatic breast cancer (MBC) (SABCS 2024)

Background: Pembrolizumab, an anti-PD1 antibody ICI is an FDA-approved option for patients with HR(+)HER2(-) MBC who have exhausted standard of care options and have high TMB (≥10 mut/mb, FoundationOne®CDx)... About 70% of TBx harbor at least one GA with established clinical utility. Pts with TMB10+ vs. TMB<10 had more favorable PFS and rwOS on ICI.

2 months ago

Checkpoint inhibition • Tumor mutational burden • BRCA Biomarker • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker • Metastases

HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • PTEN (Phosphatase and tensin homolog) • HRD (Homologous Recombination Deficiency) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • PALB2 (Partner and localizer of BRCA2) • NTRK (Neurotrophic receptor tyrosine kinase)

BRCA2 mutation • BRCA1 mutation • TMB-H • MSI-H/dMMR • PIK3CA mutation • HRD • PALB2 mutation • HRD + BRCA1 mutation • AKT1 mutation • HRD signature • BRCA1 fusion

FoundationOne® CDx

Keytruda (pembrolizumab)

2ms

Pan-cancer Analysis of Homologous Recombination Deficiency in Cell Lines. (PubMed, Cancer Res Commun)

We found that in cell lines, HRD was associated with sensitivity to PARP inhibition in breast cancer, but not at a pan-cancer level. By generating large-scale, pan-cancer datasets on HRD predictions in cell lines, we aim to facilitate efforts to improve our understanding of HRD and its utility as a biomarker.

2 months ago

Preclinical • Journal • BRCA Biomarker • PARP Biomarker • Pan tumor

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • HRD (Homologous Recombination Deficiency)

BRCA2 mutation • BRCA1 mutation • HRD • BRCA wild-type • HRD + BRCA1 mutation

2ms

The discrepancy of somatic BRCA1/2 pathogenic variants from two different platforms in epithelial ovarian, fallopian tube, and peritoneal cancer. (PubMed, Sci Rep)

In the case of the strong implication of BRCA PV/LPV with a negative result with one genetic test, different platforms could be considered in limited cases. Careful interpretation and further studies for the cross-validation of gene analysis platforms are needed.

2 months ago

Journal • BRCA Biomarker • PARP Biomarker

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)

BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA1 mutation + BRCA2 mutation

2ms

The association of the chemotherapy response score and homologous recombination deficiency in patients undergoing interval tumor reductive surgery following neoadjuvant chemotherapy. (PubMed, Int J Gynecol Cancer)

A positive response to chemotherapy at the time of interval tumor reductive surgery defined by the chemotherapy response score was associated with homologous recombination status and the likelihood of achieving a complete gross resection.

2 months ago

Journal • BRCA Biomarker • Surgery

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency)

BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation

2ms

Exploring Molecular Drivers of PARPi Resistance in BRCA1-Deficient Ovarian Cancer: The Role of LY6E and Immunomodulation. (PubMed, Int J Mol Sci)

Overall, our study provides novel insights into the molecular determinants of PARPi resistance and highlights LY6E as a promising prognostic biomarker in the management of HRD ovarian cancer. Future studies are needed to fully elucidate the molecular mechanisms underlying the role of LY6E in PARPi resistance.

2 months ago

Journal • BRCA Biomarker • PARP Biomarker • IO biomarker • Immunomodulating

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • RAD21 (RAD21 Cohesin Complex Component) • LY6E (Lymphocyte Antigen 6 Family Member E)

BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA1 expression

4ms

LUNG-MAP Sub-Study: Rucaparib in Treating Patients With Genomic LOH High and/or Deleterious BRCA1/2 Mutation Stage IV or Recurrent Non-small Cell Lung Cancer (A Lung-MAP Treatment Trial) (clinicaltrials.gov)

P2, N=64, Active, not recruiting, SWOG Cancer Research Network | Trial completion date: Jul 2024 --> Jan 2025

4 months ago

Trial completion date • Metastases

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)

BRAF V600E • BRCA2 mutation • BRCA1 mutation • EGFR mutation • BRAF V600 • EGFR T790M • HRD • ALK fusion • ROS1 fusion • HRD + BRCA1 mutation

Rubraca (rucaparib)

6ms

Cytology-based HRD testing and BRCA mutational profiling in a set of ovarian cancer patients (ECP 2024)

Our data supports considering ascitic cytology samples suitable for HRD testing and BRCA1 and BRCA2 mutation analysis. Further studies are needed to validate the practice of using ascitic cytology as a diagnostic specimen for HRD testing when tissue is not accessible, as it could prove crucial to provide ovarian cancer patients with essential information in an early stage of the diagnostic process.

6 months ago

Clinical • PARP Biomarker • BRCA Biomarker • Cytology

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)

BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA1 mutation + BRCA2 mutation • BRCA mutation

Myriad myChoice® CDx Plus • SOPHiA DDM HRD Solution

8ms

PARP inhibitors suppress tumours via centrosome error-induced senescence independent of DNA damage response. (PubMed, EBioMedicine)

Our findings uncover an alternative mechanism by which PARP inhibitors efficiently suppress tumours, thereby pointing to a potential new therapeutic strategy for centrosome error-related tumours.

8 months ago

Journal • BRCA Biomarker • PARP Biomarker

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • PARP2 (Poly(ADP-Ribose) Polymerase 2)

BRCA1 mutation • HRD • HRD + BRCA1 mutation

9ms

S1513: FOLFIRI or Modified FOLFIRI and Veliparib as Second Line Therapy in Treating Patients With Metastatic Pancreatic Cancer (clinicaltrials.gov)

P2, N=123, Active, not recruiting, National Cancer Institute (NCI)

9 months ago

Trial completion date • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CEACAM5 (CEA Cell Adhesion Molecule 5)

BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA1 mutation + BRCA2 mutation

irinotecan • veliparib (ABT-888) • leucovorin calcium • fluorouracil topical

9ms

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.

9 months ago

Review • Journal • BRCA Biomarker • PARP Biomarker

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)

BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA mutation

9ms

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.

9 months ago

Journal • BRCA Biomarker

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)

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

10ms

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.

10 months ago

PARP Biomarker • BRCA Biomarker • Pan tumor

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)

BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation

MSK-IMPACT

10ms

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.

10 months ago

BRCA Biomarker • Circulating tumor DNA

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)

BRCA2 mutation • BRCA1 mutation • HER-2 amplification • PIK3CA mutation • HRD • ATM mutation • CDK12 mutation • HRD + BRCA1 mutation • ATM mutation + CDK12 mutation

Guardant360® CDx

10ms

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.

10 months ago

PARP Biomarker • BRCA Biomarker

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)

BRCA2 mutation • BRCA1 mutation • EGFR mutation • EGFR exon 19 deletion • HRD • ARID1A mutation • EGFR E746_A750del • HRD + BRCA1 mutation • RAD50 mutation • EGFR E746

Guardant360® CDx

Lynparza (olaparib) • Tagrisso (osimertinib)

10ms

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.

10 months ago

Checkpoint inhibition • Tumor mutational burden • PD(L)-1 Biomarker • PARP Biomarker • BRCA Biomarker • IO biomarker • Metastases

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)

PD-L1 expression • BRCA2 mutation • BRCA1 mutation • TMB-H • HRD • PD-L1 negative • BRCA wild-type • HRD + BRCA1 mutation • BRCA mutation

PD-L1 IHC 22C3 pharmDx

11ms

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.

11 months ago

Journal • BRCA Biomarker

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)

TP53 mutation • BRCA1 mutation • HRD • BRCA wild-type • BRIP1 mutation • HRD + BRCA1 mutation • BRCA mutation • HRD signature

11ms

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.

11 months ago

BRCA Biomarker

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)

BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA mutation

OncoScan™ CNV Assay

11ms

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.

11 months ago

Clinical • PARP Biomarker • BRCA Biomarker

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)

BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA mutation

Myriad myChoice® CDx

Lynparza (olaparib)

11ms

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.

11 months ago

Journal • FDA event • BRCA Biomarker • BRCA Companion diagnostic • Companion diagnostic • Discordant

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)

BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation

TruSight Oncology 500 Assay • Myriad myChoice® CDx Plus • TruSight Oncology 500 HRD Assay

11ms

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.

11 months ago

Review • Journal • BRCA Biomarker • PD(L)-1 Biomarker • IO biomarker

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 )

TP53 mutation • BRCA2 mutation • BRCA1 mutation • HRD • POLE mutation • HRD + BRCA1 mutation • TP53 expression • PGR expression

Herceptin (trastuzumab)

11ms

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.

11 months ago

Journal • Next-generation sequencing • BRCA Biomarker • PARP Biomarker

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)

TP53 mutation • BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA mutation

12ms

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.

12 months ago

Journal • Biomarker testings • PARP Biomarker • BRCA Biomarker • IO biomarker • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency)

BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA1 mutation + BRCA2 mutation

FoundationOne® CDx

12ms

DIDO: Niraparib and Dostarlimab in HRD Solid Tumors (clinicaltrials.gov)

P2, N=30, Recruiting, West Cancer Center | Not yet recruiting --> Recruiting

12 months ago

Enrollment open • Combination therapy • Metastases

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)

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

Zejula (niraparib) • Jemperli (dostarlimab-gxly)

1year

P2, N=64, Active, not recruiting, SWOG Cancer Research Network | Trial completion date: Jan 2024 --> May 2024

1 year ago

Trial completion date

BRAF V600E • BRCA2 mutation • BRCA1 mutation • EGFR mutation • BRAF V600 • EGFR T790M • HRD • ALK fusion • ROS1 fusion • HRD + BRCA1 mutation

Rubraca (rucaparib)

1year

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.

1 year ago

BRCA Biomarker

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))

KRAS mutation • BRCA1 mutation • HRD • ATM mutation • ARID1A mutation • PALB2 mutation • CDK12 mutation • BAP1 mutation • CHEK2 mutation • HRD + BRCA1 mutation • BRCA mutation • NBN mutation

FoundationOne® CDx

1year

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.

1 year ago

Journal • PD(L)-1 Biomarker • PARP Biomarker • BRCA Biomarker • IO biomarker

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)

PD-L1 expression • BRCA2 mutation • BRCA1 mutation • PD-L1 overexpression • HRD • PALB2 mutation • BRIP1 mutation • HRD + BRCA1 mutation • BARD1 mutation

Prosigna™ Breast Cancer Prognostic Gene Signature Assay

1year

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.

1 year ago

Journal • BRCA Biomarker • PARP Biomarker • Metastases

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)

BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA1 mutation + BRCA2 mutation • BRCA mutation

Lynparza (olaparib) • ceralasertib (AZD6738)

1year

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.

1 year ago

Journal • BRCA Biomarker • PARP Biomarker • Pan tumor

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)

BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • PARP1 mutation

1year

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

1 year ago

Phase classification • Trial primary completion date • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)

BRCA2 mutation • BRCA1 mutation • HRD • PALB2 mutation • HRD + BRCA1 mutation

Rubraca (rucaparib) • leucovorin calcium • Onivyde (nanoliposomal irinotecan) • fluorouracil topical

1year

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.

1 year ago

Journal • Real-world evidence • BRCA Biomarker • PARP Biomarker • Real-world effectiveness • Real-world

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)

BRCA2 mutation • BRCA1 mutation • HER-2 negative • HRD • PALB2 mutation • HRD + BRCA1 mutation • HRD signature

1year

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.

1 year ago

Journal • BRCA Biomarker • PARP Biomarker • IO biomarker

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)

BRCA1 mutation • HRD • BRCA wild-type • HRD + BRCA1 mutation

1year

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

1 year ago

Trial completion • Trial completion date • Metastases

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)

HER-2 positive • BRCA2 mutation • BRCA1 mutation • HR positive • HER-2 negative • HRD • BRCA wild-type • HRD + BRCA1 mutation • HR positive + HER-2 negative

Zejula (niraparib)

1year

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.

1 year ago

Review • Journal • BRCA Biomarker • PARP Biomarker • IO biomarker

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency)

BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation • BRCA1 mutation + BRCA2 mutation

1year

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.

1 year ago

Clinical • BRCA Biomarker • PARP Biomarker

TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency)

BRCA2 mutation • BRCA1 mutation • HRD • HRD + BRCA1 mutation

1year

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.

1 year ago

BRCA Biomarker

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) • BRCA (Breast cancer early onset) • CDH1 (Cadherin 1) • 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)

ER positive • BRCA1 mutation • HRD • PALB2 mutation • HRD + BRCA1 mutation • RAD51C mutation • PMS2 mutation • RAD51 mutation