BRCA or PALB2-mutant pancreatic ductal adenocarcinoma
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.
Overview
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.
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.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowBleeding or bruising
Bleeding that will not stop, black or bloody stools, or unexplained bruising when platelets are expected to be low.
- Emergency services nowBlood clot
A swollen painful calf, or sudden breathlessness with chest pain; venous thromboembolism including pulmonary embolism is a labelled warning.
- Emergency services nowFainting or palpitations
Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
- Check before combiningFood and drink: Olaparib
Avoid grapefruit and Seville oranges.
- Check before combiningKidneys: Cisplatin
Dose reduce or avoid for CrCl below 60 (carboplatin is the alternative).
- Check before combiningKidneys: Olaparib
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
Anatomy and lymph node drainage
- Pancreatic head (most PDAC)
- Body and tail
- Ampulla
- Islets (pancreatic NET)
- Intrahepatic ducts
- Perihilar (Klatskin)
- Distal bile duct
- Gallbladder
- Nodes: peripancreatic
- Nodes: hepatic hilar
- Nodes: coeliac and superior mesenteric
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.
- Pancreatic head (most PDAC)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)
- Body and tail
- Ampulla
- Islets (pancreatic NET)
- Intrahepatic ducts
- Perihilar (Klatskin)
- Distal bile duct
- Gallbladder
- peripancreatic
- hepatic hilar
- coeliac and superior mesenteric
Same organ: 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, 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
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.
- High-risk pancreatic surveillance (CAPS / PRECEDE)Established
- Liquid biopsy (ctDNA)Standard of care
Nothing recorded yet.
Nothing recorded yet.
Also on OnCo: Symptoms and red flags · Early detection roadmap.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
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.
Subtypes & biomarkers
top- 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)
- 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)
How often this target appears
- 1994BRCA1 identified; BRCA2 follows in 1995 and is linked to pancreatic cancer risk
- 2005PARP inhibition shown to kill BRCA-deficient cells (synthetic lethality)
- 2014Retrospective series show BRCA carriers with pancreatic cancer live longer on platinum chemotherapy
- 2018ASCO and NCCN recommend germline testing for every patient with pancreatic cancer
- 2019POLO: olaparib maintenance delays progression in germline BRCA carriers; FDA approval in December
- 2021Rucaparib maintenance phase 2 extends the approach to PALB2 and somatic alterations
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 10 changes by month →- 2026-09-18This recordBRCA or PALB2-mutant pancreatic ductal adenocarcinomaFacts on this page last checked
When this page itself was last checked or edited.
- 2022Trial resultPREOPANC-1 / PREOPANC-2PREOPANC-1 / PREOPANC-2 reported
PREOPANC-1 5-year OS 20.
- 2021MilestoneRucaparibRucaparib maintenance phase 2 extends the approach to PALB2 and somatic alterations
A milestone in how this cancer is treated.
- 2019Trial resultPOLOPOLO reported
PFS HR 0.
- 2019MilestonePOLOPOLO: olaparib maintenance delays progression in germline BRCA carriers; FDA approval in December
A milestone in how this cancer is treated.
- 2018Trial resultPRODIGE 24 / CCTG PA6PRODIGE 24 / CCTG PA6 reported
OS 54.
What is in development for BRCA or PALB2-mutant pancreatic ductal adenocarcinoma, drawn from the whole corpus: 3 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Trials under way · 1
- Study of Daraxonrasib and Daraxonrasib + GnP as First-line Treatment in Patients With Metastatic Pancreatic Adenocarcinoma · phase 3 · Revolution Medicines, Inc.
Trials reported · 1
- POLO · phase 3 · 2019 · mixed
Ideas not yet in a trial · 1
Open problems and what is being done
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.
and how the field plans to fix it →What is being done about thisResistance to treatmentAvailable now- Liquid biopsy (ctDNA)Standard of care
- TalazoparibApproved
In trialsNothing recorded yet.
Ideas and roadmapsNothing recorded yet.
Background: Drug resistance (primary and acquired). Also on OnCo: Resistance atlas · Lines of therapy.
Whether unaffected carriers benefit from pancreatic surveillance is still being established.
Trials
topTrials recruiting now
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.
Landmark trials
Expert centres
topExpert centres
London · cancer center | United Kingdom | none recorded | 0 | 1,026 | 17,745 | #7 | |
Amsterdam · cancer center | Netherlands | none recorded | 0 | 1,451 | 25,873 | #45 | |
Paris · consortium | France | none recorded | 1 | not matched | - | - | |
Philadelphia · cancer center | United States | 0 | 3,148 | 54,267 | - | ||
Beijing · hospital | China | none recorded | 0 | 1,784 | 18,230 | - | |
L'Hospitalet de Llobregat · cancer center | Spain | 0 | 988 | 14,310 | - | ||
Naples · cancer center | Italy | none recorded | 0 | 961 | 15,028 | - | |
Philadelphia, PA · cancer center | United States | 0 | 755 | 12,225 | - | ||
| Israel | none recorded | 0 | 715 | 9,094 | - | ||
Guangzhou · hospital | China | none recorded | 0 | 704 | 7,832 | - | |
Philadelphia, PA · hospital | United States | none recorded | 0 | 695 | 9,931 | - | |
| United Kingdom | none recorded | 0 | 693 | 7,168 | - | ||
Nagaizumi, Shizuoka · cancer center | Japan | none recorded | 0 | 657 | 3,545 | - | |
London · research institute | United Kingdom | none recorded | 0 | 641 | 10,459 | none recorded | - |
Helsinki · cancer center | Finland | none recorded | 0 | 558 | 5,920 | - |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with BRCA or PALB2-mutant pancreatic ductal adenocarcinoma but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about BRCA or PALB2-mutant pancreatic ductal adenocarcinoma
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example Germline BRCA1, BRCA2 and PALB2 testing in every patient at diagnosis, Somatic homologous recombination gene alterations on tumour sequencing, Homologous recombination deficiency signatures, Response to at least sixteen weeks of platinum without progression, BRCA reversion mutations in plasma at progression on a PARP inhibitor), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include Germline BRCA2-mutant PDAC, Germline BRCA1-mutant PDAC, Germline PALB2-mutant PDAC.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Testing
- For my situation (testing), which of the standard options do you recommend and why?Why: Guideline options include: 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.
Metastatic, first line
- For my situation (metastatic, first line), which of the standard options do you recommend and why?Why: Guideline options include: Platinum-containing chemotherapy: modified FOLFIRINOX, NALIRIFOX or gemcitabine plus cisplatin, chosen by fitness.
- Am I a candidate for FOLFIRINOX / mFOLFIRINOX, NALIRIFOX (liposomal irinotecan + oxaliplatin + 5-FU/LV), Gemcitabine + cisplatin or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Maintenance
- For my situation (maintenance), which of the standard options do you recommend and why?Why: Guideline options include: 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.
- Am I a candidate for Olaparib, Rucaparib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of POLO apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Resectable or borderline
- For my situation (resectable or borderline), which of the standard options do you recommend and why?Why: Guideline options include: Platinum-based neoadjuvant or adjuvant chemotherapy (modified FOLFIRINOX) rather than gemcitabine alone; adjuvant PARP inhibition only in trials.
- Am I a candidate for FOLFIRINOX / mFOLFIRINOX, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of PRODIGE 24 / CCTG PA6 and PREOPANC-1 / PREOPANC-2 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
After progression on a PARP inhibitor
- For my situation (after progression on a parp inhibitor), which of the standard options do you recommend and why?Why: Guideline options include: Non-platinum chemotherapy (gemcitabine plus nab-paclitaxel) or daraxonrasib after first-line chemotherapy; trials of PARP inhibitor combinations.
- Am I a candidate for Gemcitabine + nab-paclitaxel, Daraxonrasib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Any stage
- Are there clinical trials I could join, for example of Rucaparib, Niraparib, Talazoparib, Ipilimumab?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “Olaparib delays progression but has not lengthened overall survival, and the best duration of maintenance is unknown”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Somatic and non-BRCA repair gene alterations respond unpredictably, and there is no validated homologous recombination deficiency test for the pancreas”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
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.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
9targets
4drugs
11companies
8pathways
4terms
7trials
4ideas
1people
5Latest papers
topQuery 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.
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