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19.09.2023 | Original Article

Clinical outcomes and response to chemotherapy in a cohort of pancreatic cancer patients with germline variants of unknown significance (VUS) in BRCA1 and BRCA2 genes

verfasst von: Anna Maria Militello, Giulia Orsi, Alessandro Cavaliere, Monica Niger, Antonio Avallone, Lisa Salvatore, Giampaolo Tortora, Ilario Giovanni Rapposelli, Guido Giordano, Silvia Noventa, Elisa Giommoni, Silvia Bozzarelli, Marina Macchini, Umberto Peretti, Letizia Procaccio, Alberto Puccini, Stefano Cascinu, Cristina Montagna, Michele Milella, Michele Reni

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 6/2023

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Abstract

Purpose

The clinical outcome and the efficacy of chemotherapy in pancreatic cancer patients with BRCA1/2 Variants of Unknown Significance (VUS) is unknown. We explored the effects of chemotherapy with or without Platinum in non metastatic and metastatic pancreatic cancer patients with BRCA1/2 VUS.

Methods

A retrospective analysis of non-metastatic or metastatic pancreatic cancer patients with gBRCA1/2 VUS treated in 13 Italian centers between November 2015 and December 2020 was performed. All patients were assessed for toxicity and RECIST 1.1 response. Metastatic patients were evaluated for survival outcome.

Results

30 pancreatic cancer patients with gBRCA1/2 VUS were considered: 20 were M+ and 10 were non-M+. Pl-CT was recommended to 16 patients: 10 M+ (6 FOLFIRINOX and 4 PAXG) and 6 non-M+ (3 FOLFIRINOX and 3 PAXG); 11 patients received Nabpaclitaxel-Gemcitabine (AG; 8 M+) and 3 patients (2 M+) were treated with Gemcitabine (G). The RECIST 1.1 response rate was 27% for AG and 44% for Pl-CT (22% for (m) FOLFIRINOX and 71% PAXG). 1 year Progression-Free Survival was 37.5% for patients treated with AG and 33% in the Pl-CT subgroup. Median Overall Survival (OS) was 23.5 months for patients treated with AG and 14 months for the Pl-CT subgroup. 1 Year and 2 Year OS were numerically better for AG (1 Year OS: 75% vs 60% and 2 Year OS: 50% and 20% in AG and Pl-CT subgroups, respectively) as well.

Conclusions

Pl-CT does not seem to be associated with a better outcome compared to AG chemotherapy in PDAC patients with BRCA 1/2 VUS.

Siegel RL et al (2021) Cancer statistics, 2021. Ca Cancer J Clin 71(1):7–33PubMedCrossRef

Wattenberg MM et al (2020) Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation. Br J Cancer 122(3):333–339PubMedCrossRef

Pokataev I et al (2020) Efficacy of platinum-based chemotherapy and prognosis of patients with pancreatic cancer with homologous recombination deficiency: comparative analysis of published clinical studies. ESMO open. 5(1):e000578PubMedPubMedCentralCrossRef

Rosen MN (2021) BRCA mutated pancreatic cancer: a change is coming. World J Gastroenterol 27(17):1943PubMedPubMedCentralCrossRef

Golan T et al (2014) Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer 111(6):1132–1138PubMedPubMedCentralCrossRef

Orsi G et al (2021) Chemotherapy toxicity and activity in patients with pancreatic ductal adenocarcinoma and germline BRCA1-2 pathogenic variants (gBRCA1-2pv): a multicenter survey. ESMO open 6(5):100238PubMedPubMedCentralCrossRef

Conroy T et al (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. New England J Med 364(19):1817–1825CrossRef

Conroy T et al (2018) FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. New England J Med 379(25):2395–2406CrossRef

Reni M et al (2018) Nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in metastatic pancreatic adenocarcinoma (PACT-19): a randomised phase 2 trial. Lancet Gastroenterol Hepatol 3(10):691–697PubMedCrossRef

10.

Reni M et al (2007) A randomized phase II trial of PEXG (cisplatin, epirubicin, capecitabine, gemcitabine) or PDXG (docetaxel) regimen in advanced pancreatic adenocarcinoma. J Clin Oncol 25:4628–4628CrossRef

11.

Hoff V, Daniel D et al (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. New England J Med 369(18):1691–1703CrossRef

12.

Golan T et al (2019) Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. New England J Med 381(4):317–327CrossRef

13.

Chen F, Roberts NJ, Klein AP (2017) Inherited pancreatic cancer. Chin Clin Oncol 6(6):58PubMedPubMedCentralCrossRef

14.

Golan T et al (2020) Geographic and ethnic heterogeneity of germline BRCA1 or BRCA2 mutation prevalence among patients with metastatic pancreatic cancer screened for entry into the POLO trial. J Clin Oncol 38(13):1442–1454PubMedCrossRef

15.

Peretti U et al (2021) Germinal BRCA1-2 pathogenic variants (gBRCA1-2pv) and pancreatic cancer: epidemiology of an Italian patient cohort. ESMO open 6(1):100032PubMedPubMedCentralCrossRef

16.

Eleonora LA et al (2021) Brca-mutant pancreatic ductal adenocarcinoma. Br J Cancer 125(10):1321–1332CrossRef

17.

Sharon E et al (2008) Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Human Mutat 29(11):1282–1291CrossRef

18.

Daly MB et al (2021) Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 2021, NCCN clinical practice guidelines in oncology. J National Comprehens Cancer Network 19(1):77–102CrossRef

19.

Eccles BK et al (2015) Understanding of BRCA VUS genetic results by breast cancer specialists. BMC Cancer 15(1):1–9CrossRef

20.

Richter Sue et al (2013) Variants of unknown significance in BRCA testing: impact on risk perception, worry, prevention and counseling. Ann Oncol 24:69–74CrossRef

21.

Oulas A et al (2019) Selecting variants of unknown significance through network-based gene-association significantly improves risk prediction for disease-control cohorts. Sci Rep 9(1):1–15CrossRef

22.

Richards S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the american college of medical genetics and genomics and the association for molecular pathology. Genet Med 17(5):405–423PubMedPubMedCentralCrossRef

23.

Landrum MJ et al (2014) ClinVar: public archive of relationships among sequence variation and human phenotype. Nucl Acids Res 42(D1):D980–D985PubMedCrossRef

24.

Spurdle AB et al (2012) ENIGMA—evidence-based network for the interpretation of germline mutant alleles: an international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes. Human Mutat 33(1):2–7CrossRef

25.

Freeman PJ et al (2018) VariantValidator: Accurate validation, mapping, and formatting of sequence variation descriptions. Human Mutat 39(1):61–68CrossRef

26.

Sonnhammer E, Eddy LL, Sean R, Durbin R (1997) a comprehensive database of protein domain families based on seed alignments. Proteins Struct Function Bioinform 28(3):405–420CrossRef

27.

Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clini Oncol 15(6):2403–2413CrossRef

28.

Spurdle AB et al (2012) Enigma—evidence-based network for the interpretation of germline mutant alleles: an international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes. Human Mutation 33(1):2–7PubMedCrossRef

29.

Guidugli L et al (2013) A classification model for brca2 dna binding domain missense variants based on homology-directed repair activitycharacterization of BRCA2 DNA binding domain mutations. Cancer Res 73(1):265–275PubMedCrossRef

30.

Guidugli L et al (2018) Assessment of the clinical relevance of BRCA2 missense variants by functional and computational approaches. Am J Human Gene 102(2):233–248CrossRef

31.

Caputo SM et al (2021) Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: a powerful approach. Am J Human Gene 108(10):1907–1923CrossRef

32.

Tempero M et al (2021) Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study. Ann Oncol 32(5):600–608PubMedCrossRef

33.

CutsemEric V et al (2020) Randomized phase III trial of pegvorhyaluronidase alfa with nab-paclitaxel plus gemcitabine for patients with hyaluronan-high metastatic pancreatic adenocarcinoma. J Clin Oncol 38(27):3185CrossRef

34.

BEKAII-SAAB T et al (2021) 1466P Napabucasin+ nab-paclitaxel with gemcitabine in patients (pts) with metastatic pancreatic adenocarcinoma (mPDAC): Results from the phase III CanStem111P study. Ann Oncol 32:S1084–S1085CrossRef

35.

Gill S et al (2016) PANCREOX: a randomized phase III study of fluorouracil/leucovorin with or without oxaliplatin for second-line advanced pancreatic cancer in patients who have received gemcitabine-based chemotherapy. J Clin Oncol 34(32):3914–3920PubMedCrossRef

36.

Oettle H et al (2014) Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol 32(23):2423–2429PubMedCrossRef

37.

Wang-Gillam A et al (2016) Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet 387(10018):545–557PubMedCrossRef

38.

Chiorean EG et al (2021) Randomized phase ii study of PARP inhibitor ABT-888 (Veliparib) with modified FOLFIRI versus FOLFIRI as second-line treatment of metastatic pancreatic cancer: SWOG S1513FOLFIRI with or without veliparib for pancreatic cancer. Clin Cancer Res 27(23):6314–6322PubMedPubMedCentralCrossRef

39.

Dines JN et al (2020) Systematic misclassification of missense variants in BRCA1 and BRCA2 “coldspots.” Gene Med 22(5):825–830CrossRef

40.

Hoffman-Andrews L (2017) The known unknown: the challenges of genetic variants of uncertain significance in clinical practice. J Law Biosci 4(3):648PubMedCrossRef

41.

Li MM et al (2017) Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the association for molecular pathology, american society of clinical oncology, and college of american pathologists. J Mol Diagnost 19(1):4–23CrossRef

42.

Federici G, Soddu S (2020) Variants of uncertain significance in the era of high-throughput genome sequencing: a lesson from breast and ovary cancers. J Exp Clin Cancer Res 39(1):1–12CrossRef

43.

Choi MC (2019) Clinical significance of variants of unknown significances in BRCA genes. J Gynecol Oncol. https://doi.org/10.3802/jgo.2019.30.e80CrossRefPubMedPubMedCentral

44.

Easton DF et al (2007) A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer–predisposition genes. Am J Human Gene 81(5):873–883CrossRef

45.

Lindor NM et al (2012) A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). Human Mutat 33(1):8–21CrossRef

46.

Parsons MT et al (2019) Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Human Mutat 40(9):1557–1578CrossRef

Titel: Clinical outcomes and response to chemotherapy in a cohort of pancreatic cancer patients with germline variants of unknown significance (VUS) in BRCA1 and BRCA2 genes
verfasst von: Anna Maria Militello
Giulia Orsi
Alessandro Cavaliere
Monica Niger
Antonio Avallone
Lisa Salvatore
Giampaolo Tortora
Ilario Giovanni Rapposelli
Guido Giordano
Silvia Noventa
Elisa Giommoni
Silvia Bozzarelli
Marina Macchini
Umberto Peretti
Letizia Procaccio
Alberto Puccini
Stefano Cascinu
Cristina Montagna
Michele Milella
Michele Reni
Publikationsdatum: 19.09.2023
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 6/2023
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-023-04585-w

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Clinical outcomes and response to chemotherapy in a cohort of pancreatic cancer patients with germline variants of unknown significance (VUS) in BRCA1 and BRCA2 genes