Loading
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.
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.
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.
Most pancreatic cancers arise in the head next to the bile duct, which is why jaundice is the presenting sign; bile duct cancers are named by where along the tree they sit.
Same organ: Glucagonoma, VIPoma, Somatostatinoma, Pancreatic ductal adenocarcinoma, Biliary tract cancer (cholangiocarcinoma), Intrahepatic cholangiocarcinoma, Extrahepatic cholangiocarcinoma (perihilar and distal), Biliary tract cancer (all types), Neuroendocrine tumours, Pancreatic neuroendocrine tumours, Grade 3 well-differentiated neuroendocrine tumour, Extrapulmonary neuroendocrine carcinoma, Gallbladder cancer, Gallbladder adenocarcinoma, Papillary carcinoma of the gallbladder, Mucinous carcinoma of the gallbladder, Adenosquamous and squamous carcinoma of the gallbladder, Neuroendocrine carcinoma of the gallbladder, Incidental gallbladder cancer (found after cholecystectomy), Carcinoma in situ and dysplasia of the gallbladder, Cystic duct carcinoma, Ampullary cancer (ampulla of Vater), Resectable pancreatic ductal adenocarcinoma, Borderline resectable pancreatic ductal adenocarcinoma, Locally advanced unresectable pancreatic ductal adenocarcinoma, Metastatic pancreatic ductal adenocarcinoma, KRAS G12C-mutant pancreatic ductal adenocarcinoma, KRAS wild-type pancreatic ductal adenocarcinoma, Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma, Pancreatic acinar cell carcinoma, Intraductal papillary mucinous neoplasm and other pancreatic cystic precursors, Pancreatoblastoma, Adenosquamous carcinoma of the pancreas, Colloid (mucinous non-cystic) carcinoma of the pancreas, Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells, Invasive carcinoma arising in an intraductal papillary mucinous neoplasm (IPMN-associated carcinoma), Mucinous cystic neoplasm of the pancreas with associated invasive carcinoma (MCN-associated carcinoma), Solid pseudopapillary neoplasm of the pancreas
Nothing recorded yet.
Also on OnCo: Symptoms and red flags · Early detection roadmap.
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.
Platinum-containing chemotherapy: modified FOLFIRINOX, NALIRIFOX or gemcitabine plus cisplatin, chosen by fitness.
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.
Platinum-based neoadjuvant or adjuvant chemotherapy (modified FOLFIRINOX) rather than gemcitabine alone; adjuvant PARP inhibition only in trials.
Non-platinum chemotherapy (gemcitabine plus nab-paclitaxel) or daraxonrasib after first-line chemotherapy; trials of PARP inhibitor combinations.
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Olaparib maintenance remains a standard option because of its progression-free benefit, tolerability and long-term survivors, but patients should know that it has not been shown to extend average survival.
It is the evidence that PALB2 and somatic BRCA2 belong in the PARP inhibitor conversation even though the olaparib label stops at germline BRCA.
It defines who a homologous recombination result should send to platinum: core-gene and biallelic carriers, germline or somatic, rather than any repair-gene variant.
Gemcitabine plus cisplatin is a validated platinum doublet for BRCA or PALB2 carriers, and the trial explains why PARP inhibitors are used as maintenance after platinum rather than concurrently with it.
A germline result is not the whole story: without loss of the second allele the tumour may not be repair-deficient, which is why tumour sequencing and, in trials, HRD signatures are read alongside.
Germline testing for every pancreatic cancer patient, platinum first line for BRCA carriers, and olaparib maintenance for those who respond are all downstream of POLO.
Family history misses most carriers, so the NCCN and ASCO guidelines moved to testing every patient; each carrier found is a family that can be offered surveillance and a patient who may be eligible for platinum and PARP inhibition.
The broad-panel figure: one patient in five carries something inheritable, and about one in fifteen carries something treatable.
Query for this cancer: (TITLE:"BRCA or PALB2-mutant pancreatic ductal adenocarcinoma" OR ABSTRACT:"BRCA or PALB2-mutant pancreatic ductal adenocarcinoma" OR TITLE:"BRCA-mutated pancreatic cancer" OR ABSTRACT:"BRCA-mutated pancreatic cancer" OR TITLE:"gBRCA pancreatic cancer" OR ABSTRACT:"gBRCA pancreatic cancer" OR TITLE:"Homologous recombination deficient pancreatic cancer" OR ABSTRACT:"Homologous recombination deficient pancreatic cancer" OR TITLE:"PALB2-mutant pancreatic cancer" OR ABSTRACT:"PALB2-mutant pancreatic cancer") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about BRCA or PALB2-mutant pancreatic ductal adenocarcinoma, not a curated reading list.
The targets of this cancer's medicines and the ones linked to it directly.
Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
A swollen painful calf, or sudden breathlessness with chest pain; venous thromboembolism including pulmonary embolism is a labelled warning.
Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
Avoid grapefruit and Seville oranges.
Dose reduce or avoid for CrCl below 60 (carboplatin is the alternative).
200 mg twice daily for CrCl 31-50.
See all on the product pages:CisplatinDaraxonrasibFOLFIRINOX / mFOLFIRINOXGemcitabine + cisplatinGemcitabine + nab-paclitaxelNALIRIFOX (liposomal irinotecan + oxaliplatin + 5-FU/LV)OlaparibRucaparib·Printable cards in the navigator
Newly diagnosed? Read the first 60 days with BRCA or PALB2-mutant pancreatic ductal adenocarcinoma, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record.
Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked.