Germline or somatic BRCA — does PARP work for both?

Yes. PARP inhibitor approvals cover both germline and somatic BRCA1/2 mutations in ovarian maintenance. Tumor testing detects both; germline testing distinguishes hereditary from sporadic for genetic-counseling purposes (Lynch-style implications for family members).

What is HRD positivity and how does it expand PARP eligibility?

HRD = homologous recombination deficiency. The Myriad MyChoice CDx scores genomic instability (LOH, telomeric allelic imbalance, large-scale state transitions) — a GIS ≥42 plus BRCA wild-type is HRD-positive. Olaparib + bevacizumab is approved for HRD-positive (PAOLA-1), and niraparib is approved across all HRD strata (PRIMA).

What's the MDS/AML risk on PARP inhibitors?

Roughly 1-2% over multiyear maintenance, higher with longer cumulative exposure. The risk is real and requires informed consent; the overall survival benefit in ovarian maintenance still favors PARP use for the indicated populations.

Variant cheat sheet · ovarian cancer

BRCA1 / BRCA2 mutations in ovarian cancer

Free clinical reference. Educational use only — not a substitute for professional medical advice.

TL;DR

BRCA1 or BRCA2 mutations (germline or somatic) in high-grade serous ovarian cancer are AMP/ASCO/CAP Tier I-A for PARP inhibitor maintenance (olaparib, niraparib, rucaparib) after platinum response. HRD-positive (BRCA wild-type but HRD-positive by Myriad MyChoice CDx or other validated assay) extends eligibility for olaparib + bevacizumab (PAOLA-1) and niraparib (PRIMA).

Biology

BRCA1 and BRCA2 are essential proteins in homologous recombination DNA double-strand break repair. Loss-of-function variants leave tumors dependent on alternative, error-prone repair pathways. PARP inhibitors block single-strand break repair, leading to synthetic-lethal accumulation of double-strand breaks the BRCA-deficient cell cannot fix. The HRD-positive phenotype (genomic instability) captures BRCA-like vulnerability beyond BRCA1/2 mutations themselves.

Epidemiology

BRCA1 or BRCA2 germline mutations occur in ~15-20% of high-grade serous ovarian cancers (HGSOC). Somatic mutations add another ~5-7%. HRD-positive (including BRCA-mutant) expands eligibility to ~50% of HGSOC. Genetic counseling and germline testing are standard at diagnosis.

Detection

Germline testing: standard at HGSOC diagnosis (genetic counseling required).
Somatic NGS on tumor tissue: FoundationOne CDx, Caris MI Profile, Tempus xT, Myriad MyChoice CDx.
HRD assays: Myriad MyChoice CDx (GIS score ≥42), FoundationOne CDx HRD signature.
Reflex testing pathway: tumor first, then germline confirmation for pathogenic findings.

FDA-approved targeted therapies

Drug	Indication	Line	Tier
Olaparib	BRCA1/2-mutant ovarian maintenance after platinum response (SOLO-1 / SOLO-2)	1L maintenance / recurrent	I-A
Olaparib + bevacizumab	HRD-positive ovarian maintenance (PAOLA-1)	1L maintenance	I-A
Niraparib	Ovarian maintenance (PRIMA, NOVA) — broader population including HRD-positive	1L maintenance / recurrent	I-A
Rucaparib	BRCA-mutant recurrent ovarian (ARIEL3)	Recurrent maintenance	I-A

Tier = AMP/ASCO/CAP 2017 (Li MM et al., J Mol Diagn 2017). Drug names link to openFDA labels where available. Synthetic data; consult primary sources before treatment.

Resistance pathways

BRCA reversion mutations: secondary mutations that restore the BRCA reading frame, recapitulating HR competency.
Loss of 53BP1 or shieldin complex (rescues HR).
Drug efflux upregulation.
Re-biopsy at progression is informative; plasma ctDNA can detect reversion mutations.

Pharmacogenomics

PARP inhibitors carry hematologic toxicity (anemia, neutropenia, thrombocytopenia) and rare but serious risk of MDS / AML. No CPIC-level germline pharmacogenomic guidance mandates testing before PARP initiation; clinical CBC monitoring is the standard safeguard.

Frequently asked questions

Germline or somatic BRCA — does PARP work for both?: Yes. PARP inhibitor approvals cover both germline and somatic BRCA1/2 mutations in ovarian maintenance. Tumor testing detects both; germline testing distinguishes hereditary from sporadic for genetic-counseling purposes (Lynch-style implications for family members).
What is HRD positivity and how does it expand PARP eligibility?: HRD = homologous recombination deficiency. The Myriad MyChoice CDx scores genomic instability (LOH, telomeric allelic imbalance, large-scale state transitions) — a GIS ≥42 plus BRCA wild-type is HRD-positive. Olaparib + bevacizumab is approved for HRD-positive (PAOLA-1), and niraparib is approved across all HRD strata (PRIMA).
What's the MDS/AML risk on PARP inhibitors?: Roughly 1-2% over multiyear maintenance, higher with longer cumulative exposure. The risk is real and requires informed consent; the overall survival benefit in ovarian maintenance still favors PARP use for the indicated populations.