# BRCA or PALB2-mutant pancreatic ductal adenocarcinoma

Source: https://onco.cc/cancers/brca-palb2-pdac/  
OnCo record `brca-palb2-pdac` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

Resistance to PARP inhibitors arises through reversion mutations that restore the reading frame of BRCA, through loss of PARP trapping and through replication fork protection, and platinum resistance often precedes it. Trials are testing PARP inhibitors earlier and in combination with immunotherapy, ATR inhibitors and chemotherapy, and whether carriers with resectable disease should receive platinum-based neoadjuvant treatment or adjuvant PARP inhibition. ATM, CHEK2 and other repair gene variants are found in a further few percent of patients but respond less predictably to platinum and PARP inhibitors than BRCA and PALB2.

## Fields

- Kind: Cancer
- Last checked: 2026-09-18
- Also known as: BRCA-mutated pancreatic cancer; gBRCA pancreatic cancer; Homologous recombination deficient pancreatic cancer; PALB2-mutant pancreatic cancer
- Tags: subtype-page; gastrointestinal
- Group: gastrointestinal
- Burden: About 5 to 7 percent of pancreatic ductal adenocarcinomas arise in people carrying an inherited BRCA1, BRCA2 or PALB2 variant, BRCA2 most often, with higher rates in people of Ashkenazi Jewish descent; a further group has somatic alterations or other DNA repair gene defects such as ATM.
- Subtypes: Germline BRCA2-mutant PDAC (the commonest; POLO population); Germline BRCA1-mutant PDAC; Germline PALB2-mutant PDAC (rucaparib phase 2; olaparib label covers BRCA only); Somatic BRCA or PALB2-altered PDAC (PARP inhibitor benefit less certain); ATM, CHEK2 or other homologous recombination gene-altered PDAC (variable platinum sensitivity); Platinum-resistant BRCA-mutant PDAC with reversion mutations (PARP inhibitors ineffective)
- Biomarkers: Germline BRCA1, BRCA2 and PALB2 testing in every patient at diagnosis; Somatic homologous recombination gene alterations on tumour sequencing; Homologous recombination deficiency signatures (investigational in the pancreas); Response to at least sixteen weeks of platinum without progression (POLO eligibility); BRCA reversion mutations in plasma at progression on a PARP inhibitor; Family history and Ashkenazi Jewish ancestry (prior probability of a variant)

## Standard of care

- 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. ([Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [Germline BRCA mutation (gBRCA)](https://onco.cc/terms/gbrca-mutation/), [Germline vs somatic mutations](https://onco.cc/terms/germline-vs-somatic/), [High-risk pancreatic surveillance (CAPS / PRECEDE)](https://onco.cc/technologies/pancreatic-surveillance/))
- Metastatic, first line: Platinum-containing chemotherapy: modified FOLFIRINOX, NALIRIFOX or gemcitabine plus cisplatin, chosen by fitness. ([FOLFIRINOX / mFOLFIRINOX](https://onco.cc/drugs/folfirinox/), [NALIRIFOX (liposomal irinotecan + oxaliplatin + 5-FU/LV)](https://onco.cc/drugs/nalirifox/), [Gemcitabine + cisplatin](https://onco.cc/drugs/gemcitabine-cisplatin/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Platinum-sensitive / platinum-resistant](https://onco.cc/terms/platinum-sensitivity/))
- 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. ([Olaparib](https://onco.cc/drugs/olaparib/), [POLO](https://onco.cc/trials/polo/), [Rucaparib](https://onco.cc/drugs/rucaparib/), [PARP inhibitors](https://onco.cc/technologies/parp-inhibitor/))
- Resectable or borderline: Platinum-based neoadjuvant or adjuvant chemotherapy (modified FOLFIRINOX) rather than gemcitabine alone; adjuvant PARP inhibition only in trials. ([FOLFIRINOX / mFOLFIRINOX](https://onco.cc/drugs/folfirinox/), [PRODIGE 24 / CCTG PA6](https://onco.cc/trials/prodige-24/), [PREOPANC-1 / PREOPANC-2](https://onco.cc/trials/preopanc/), [Neoadjuvant / adjuvant / perioperative](https://onco.cc/terms/neoadjuvant-adjuvant/))
- After progression on a PARP inhibitor: Non-platinum chemotherapy (gemcitabine plus nab-paclitaxel) or daraxonrasib after first-line chemotherapy; trials of PARP inhibitor combinations. ([Gemcitabine + nab-paclitaxel](https://onco.cc/drugs/gemcitabine-nab-paclitaxel/), [Daraxonrasib](https://onco.cc/drugs/daraxonrasib/), [BRCA reversion mutations](https://onco.cc/terms/brca-reversion-mutations/))

## State of the art

- Olaparib maintenance after platinum (POLO) is the first approved targeted therapy for a pancreatic cancer subgroup.
- Universal germline testing at diagnosis is guideline standard and finds carriers who would be missed by family history.
- Platinum-based regimens are preferred at every stage for carriers.
- PARP inhibitor combinations with immunotherapy and ATR inhibitors and earlier use are in trials.

## Open problems

- Olaparib delays progression but has not lengthened overall survival, and the best duration of maintenance is unknown.
- Somatic and non-BRCA repair gene alterations respond unpredictably, and there is no validated homologous recombination deficiency test for the pancreas.
- Reversion mutations restore repair and defeat both platinum and PARP inhibitors.
- Whether unaffected carriers benefit from pancreatic surveillance is still being established.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/BRCA_mutation
- Wikipedia: https://en.wikipedia.org/wiki/BRCA_mutation
- NCCN Guidelines: Pancreatic Adenocarcinoma: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455

## Connected records

- cancers: [Borderline resectable pancreatic ductal adenocarcinoma](https://onco.cc/cancers/borderline-resectable-pdac/), [KRAS G12C-mutant pancreatic ductal adenocarcinoma](https://onco.cc/cancers/kras-g12c-pdac/), [KRAS wild-type pancreatic ductal adenocarcinoma](https://onco.cc/cancers/kras-wild-type-pdac/), [Metastatic pancreatic ductal adenocarcinoma](https://onco.cc/cancers/metastatic-pdac/), [Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma](https://onco.cc/cancers/msi-high-pdac/), [Pancreatic acinar cell carcinoma](https://onco.cc/cancers/pancreatic-acinar-cell-carcinoma/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Platinum-sensitive ovarian cancer](https://onco.cc/cancers/platinum-sensitive-ovarian-cancer/), [Resectable pancreatic ductal adenocarcinoma](https://onco.cc/cancers/resectable-pdac/)
- technologies: [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [High-risk pancreatic surveillance (CAPS / PRECEDE)](https://onco.cc/technologies/pancreatic-surveillance/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [PARP inhibitors](https://onco.cc/technologies/parp-inhibitor/)
- targets: [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/), [KRAS](https://onco.cc/targets/kras/)
- drugs: [Cisplatin](https://onco.cc/drugs/cisplatin/), [Daraxonrasib](https://onco.cc/drugs/daraxonrasib/), [FOLFIRINOX / mFOLFIRINOX](https://onco.cc/drugs/folfirinox/), [Gemcitabine + cisplatin](https://onco.cc/drugs/gemcitabine-cisplatin/), [Gemcitabine + nab-paclitaxel](https://onco.cc/drugs/gemcitabine-nab-paclitaxel/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [NALIRIFOX (liposomal irinotecan + oxaliplatin + 5-FU/LV)](https://onco.cc/drugs/nalirifox/), [Niraparib](https://onco.cc/drugs/niraparib/), [Olaparib](https://onco.cc/drugs/olaparib/), [Rucaparib](https://onco.cc/drugs/rucaparib/), [Talazoparib](https://onco.cc/drugs/talazoparib/)
- companies: [AstraZeneca](https://onco.cc/companies/astrazeneca/), [Merck & Co. (MSD)](https://onco.cc/companies/merck/), [Pfizer (incl. Seagen)](https://onco.cc/companies/pfizer/)
- pathways: [DNA damage response & homologous recombination](https://onco.cc/pathways/ddr/), [Double-strand break repair: HR versus end joining](https://onco.cc/pathways/homologous-recombination-repair/), [Pancreatic cancer (KEGG map)](https://onco.cc/pathways/pancreatic-cancer-signalling/), [Synthetic lethality: paired dependencies](https://onco.cc/pathways/synthetic-lethality-map/)
- terms: [BRCA reversion mutations](https://onco.cc/terms/brca-reversion-mutations/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Germline BRCA mutation (gBRCA)](https://onco.cc/terms/gbrca-mutation/), [Germline vs somatic mutations](https://onco.cc/terms/germline-vs-somatic/), [Homologous recombination deficiency (HRD)](https://onco.cc/terms/hrd/), [Neoadjuvant / adjuvant / perioperative](https://onco.cc/terms/neoadjuvant-adjuvant/), [Platinum-sensitive / platinum-resistant](https://onco.cc/terms/platinum-sensitivity/)
- trials: [POLO](https://onco.cc/trials/polo/), [PREOPANC-1 / PREOPANC-2](https://onco.cc/trials/preopanc/), [PRODIGE 24 / CCTG PA6](https://onco.cc/trials/prodige-24/), [Study of Daraxonrasib and Daraxonrasib + GnP as First-line Treatment in Patients With Metastatic Pancreatic Adenocarcinoma](https://onco.cc/trials/nct07491445/)
- people: [Bert Vogelstein](https://onco.cc/people/bert-vogelstein/), [Diane M. Simeone](https://onco.cc/people/diane-simeone/), [Eileen M. O'Reilly](https://onco.cc/people/eileen-oreilly/), [Susan M. Domchek](https://onco.cc/people/susan-domchek/), [Talia Golan](https://onco.cc/people/talia-golan/)
- ideas: [Automatic germline testing for every cancer type where it changes care](https://onco.cc/ideas/idea-prev-reflex-germline-testing/)

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