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Patient:

A 67-year-old woman from rural New South Wales.

Initial referral:

The patient was referred to the Precision Care MDT for review of her molecular report and recommendations regarding PARP inhibitor monotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC).

Clinical history:

• Diagnosed with de-novo metastatic pancreatic ductal adenocarcinoma in 2022, with metastases to liver and pelvis
• Initial treatment: Clinical trial with Gemcitabine, Nab-Paclitaxel +/- investigational agent (Sept-Dec 2022), resulting in progressive disease
• Second-line treatment: FOLFIRINOX (Jan-Nov 2023), resulting in partial response followed by progressive disease
• Enrolled in a Phase 1/2 trial in January 2024
• Found to have a germline BRCA2 mutation and referred to a hereditary cancer clinic

Molecular findings:

• FoundationOne CDx testing revealed:
  • Two different BRCA2 mutations (VAF 40% and 14%)
  • KRAS G12D mutation (VAF 39%)
  • RB1 and TP53 mutations
• Low tumour mutational burden (TMB) of 4.8 Mut/Mb

Our approach:

The MDT conducted a comprehensive review of the patient's clinical history, pathology, and molecular reports. Key considerations included:

1. The presence of a BRCA2 reversion mutation (VAF 14%) likely developed during platinum-based chemotherapy
2. The impact of this reversion mutation on potential PARP inhibitor efficacy
3. The presence of other targetable mutations, particularly KRAS G12D

Value-added insights:

1. Literature review: We noted that while BRCA2/HRD is usually a later driver of PDAC, in this case, it was likely an early driver of oncogenesis.
2. Mutation analysis: We identified that the BRCA2 reversion mutation might restore BRCA protein function, potentially leading to resistance to both platinum-based therapy and PARP inhibitors.
3. Alternative targets: We highlighted the KRAS G12D mutation as another potentially targetable pathway.

Recommendations:

Based on our integrated analysis, we provided a prioritised treatment hierarchy:

1. KRAS G12D targeted therapy
2. MTAP loss targeted therapy
3. BRCA2 (PARP inhibitor trials/self-funding)

We also recommended a bioinformatician review of the specific BRCA2 reversion mutations to confirm their impact on protein function.

Outcome:

Our recommendations provided the referring oncologist with:

1. A clear treatment hierarchy based on both molecular findings and the patient's treatment history
2. Insight into potential resistance mechanisms
3. Guidance on further molecular analysis to inform treatment decisions

This case shows how the Precision Care Initiative can provide personalised, cutting-edge treatment recommendations by combining clinical expertise with advanced molecular analysis.