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10 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
BRCA or PALB2-mutant pancreatic cancer is pancreatic cancer in someone who inherited a faulty copy of a gene that repairs broken DNA. These tumours respond better to platinum chemotherapy, and the POLO trial showed that the PARP inhibitor olaparib, taken after platinum has held the disease, delays its return; that made it the first targeted drug approved for a pancreatic cancer subgroup.
BRCA1, BRCA2 and PALB2 encode proteins of homologous recombination repair. Tumours that have lost both copies cannot repair double-strand DNA breaks accurately, which makes them sensitive to platinum drugs that create such breaks and to PARP inhibitors, which trap the repair enzyme PARP on DNA and are lethal to cells without homologous recombination (synthetic lethality). Germline carriers develop pancreatic cancer at a younger age and carry risks of breast, ovarian and prostate cancer for themselves and their relatives, so a diagnosis triggers cascade testing of the family and, for unaffected carriers, consideration of pancreatic surveillance in a research programme.
Retrospective series and the platinum-containing arms of trials showed that carriers live longer on FOLFIRINOX or gemcitabine plus cisplatin than on non-platinum regimens, and a randomised phase 2 found gemcitabine plus cisplatin effective as first line. POLO (2019) randomised germline BRCA carriers whose metastatic disease had not progressed on at least sixteen weeks of platinum chemotherapy to maintenance olaparib or placebo: olaparib roughly doubled progression-free survival without lengthening overall survival, and the FDA approved it in December 2019. Rucaparib produced similar maintenance activity in a phase 2 that included PALB2 carriers and somatic mutations, and niraparib with ipilimumab has shown promise as maintenance in a broader platinum-sensitive population.
| Setting | Approach | Guideline |
|---|---|---|
| Testing | Germline testing for BRCA1, BRCA2, PALB2 and other cancer genes for every patient with pancreatic cancer, with cascade testing of relatives and surveillance for unaffected carriers in a research setting. | not mapped |
| Metastatic, first line | Platinum-containing chemotherapy: modified FOLFIRINOX, NALIRIFOX or gemcitabine plus cisplatin, chosen by fitness. | not mapped |
| Maintenance | Olaparib after at least sixteen weeks of first-line platinum without progression in germline BRCA carriers (POLO); rucaparib for PALB2 and somatic alterations on phase 2 evidence; continued chemotherapy as the alternative. | not mapped |
| Resectable or borderline | Platinum-based neoadjuvant or adjuvant chemotherapy (modified FOLFIRINOX) rather than gemcitabine alone; adjuvant PARP inhibition only in trials. | not mapped |
| After progression on a PARP inhibitor | Non-platinum chemotherapy (gemcitabine plus nab-paclitaxel) or daraxonrasib after first-line chemotherapy; trials of PARP inhibitor combinations. | not mapped |