What are the actionable mutation targets in ovarian cancer?

Actionable Mutation Targets in Ovarian Cancer

BRCA1/2 mutations (germline and somatic) are the primary actionable targets in ovarian cancer, present in approximately 18-22% of high-grade serous cases, and should be tested at diagnosis in all patients with high-grade non-mucinous tubo-ovarian carcinoma to guide PARP inhibitor therapy. 1, 2

Primary Actionable Targets

BRCA1/2 Mutations - The Gold Standard

• Testing mandate: All patients with high-grade non-mucinous epithelial ovarian cancer require both germline and somatic BRCA1/2 testing at diagnosis, regardless of stage, family history, or clinical features 1, 2
• Prevalence: Germline BRCA1/2 mutations occur in 13-15% of high-grade serous ovarian cancers (HGSOC); somatic mutations add another 5-7% 1
• Therapeutic impact: BRCA1/2 pathogenic variants qualify for FDA-approved PARP inhibitors (olaparib, niraparib, rucaparib) in both upfront maintenance and recurrent settings, with significantly higher response rates 2
• Clinical benefit: In SOLO1, olaparib maintenance in BRCA-mutated newly diagnosed advanced ovarian cancer showed dramatic progression-free survival benefit (HR 0.31-0.44 across trials) 2

Homologous Recombination Deficiency (HRD) Testing

• Recommendation: Genomic instability testing is recommended specifically for BRCA wild-type, high-grade non-mucinous FIGO stage III-IV disease at diagnosis 1
• Caveat: The 2024 ESGO-ESMO consensus and 2020 ASCO guidelines diverge here—ASCO explicitly states no recommendation can be made for routine HRD testing due to low evidence quality, while ESGO-ESMO endorses it for stage III-IV BRCA wild-type cases 1, 2
• Clinical context: HRD-positive tumors (beyond BRCA mutations) showed benefit in PAOLA-1 (HR 0.33) and PRIMA (HR 0.50 in HRD/BRCA wild-type), but the assays lack standardization 2

Mismatch Repair Deficiency (dMMR)

• Testing indication: Somatic tumor testing for dMMR should be performed in clear cell, endometrioid, and mucinous ovarian cancers 2
• May consider: Testing for dMMR in other histologic subtypes 2
• Therapeutic relevance: dMMR qualifies for FDA-approved immunotherapy (pembrolizumab) in recurrent disease 2

Secondary and Emerging Targets

PIK3CA Mutations

• Prevalence: Found in 25% of ovarian cancers in Japanese cohorts, representing the most common actionable alteration after BRCA 3
• Histotype specificity: More frequent in non-serous histotypes (68.1% of non-serous tumors harbor actionable alterations vs. lower rates in serous) 3
• Therapeutic potential: PI3K/AKT pathway inhibitors are under investigation

KRAS Mutations

• Prevalence: 13.9% in ovarian cancers, particularly non-serous types 3
• Clinical note: Mutations tend to occur in mutually exclusive patterns with other actionable targets 3

Low-Grade Serous Ovarian Cancer (LGSOC) Specific Targets

• BRAF mutations: Including D594G and V600 variants identified in LGSOC 4
• MEK pathway: Trametinib and other MEK inhibitors show variable response 4
• Actionability: LGSOC shows markedly higher proportion of actionable alterations (36% vs. 7% in HGSOC) and may benefit from earlier molecular testing at first relapse 5

Rare but Actionable Targets

• EGFR mutations: Extremely rare (0.08% prevalence) but highly actionable when present, including exon 19 deletions, L858R, and T790M mutations responsive to osimertinib 6
• ERBB2 (HER2): 4.3% prevalence, targetable with HER2-directed therapies 3
• PTEN, CDK4, MSH2: Emerging targets with pathogenic mutations identified in specific populations 7

Critical Testing Algorithm

1. At diagnosis of high-grade non-mucinous ovarian cancer:

   • Germline BRCA1/2 testing (mandatory) 1, 2
   • If germline negative → somatic tumor BRCA1/2 testing (mandatory) 1, 2
   • Adequate tissue required: ≥30% tumor cells from treatment-naive surgical specimen or image-guided biopsy 1

2. For BRCA wild-type, stage III-IV disease:

   • HRD/genomic instability testing for first-line maintenance therapy decisions 1

3. For clear cell, endometrioid, mucinous histotypes:

   • Somatic dMMR testing 2

4. For LGSOC or refractory disease:

   • Consider comprehensive next-generation sequencing to identify rare actionable targets (EGFR, BRAF, PIK3CA) 6, 4, 5

Common Pitfalls

• Do not base clinical decisions on variants of uncertain significance (VUS)—wait for reclassification or use clinical features and family history instead 2
• Timing matters: In HGSOC, molecular tumor board referral is most valuable in recurrent/refractory settings, but rapid clinical deterioration often limits implementation 5
• Tissue adequacy: Cell blocks from peritoneal/pleural effusions can be used but must contain sufficient tumor cells 1
• Genetic counseling: Germline testing results have implications for first- and second-degree relatives (50% and 25% risk respectively for autosomal dominant BRCA mutations) and should involve genetic counselors 2