Clinical utility of BRCA and ATM mutation status in circulating tumour DNA for treatment selection in advanced pancreatic cancer.
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
28 Aug 2024
28 Aug 2024
Historique:
received:
27
12
2023
accepted:
20
08
2024
revised:
10
08
2024
medline:
31
8
2024
pubmed:
31
8
2024
entrez:
28
8
2024
Statut:
aheadofprint
Résumé
Identification of homologous recombination deficiency (HRD) remains a challenge in advanced pancreatic cancer (APC). We investigated the utility of circulating tumour DNA (ctDNA) profiling in the assessment of BRCA1/2 and ATM mutation status and treatment selection in APC. We analysed clinical and ctDNA data of 702 patients with APC enroled in GOZILA, a ctDNA profiling study using Guardant360. Inactivating BRCA1/2 and ATM mutations were detected in 4.8% (putative germline, 3.7%) and 4.4% (putative germline, 0.9%) of patients, respectively. Objective response (63.2% vs. 16.2%) and PFS (HR 0.55, 95% CI 0.32-0.93) on platinum-containing chemotherapy were significantly better in patients with putative germline BRCA1/2 (gBRCA) mutation than those without. In contrast, putative gBRCA mutation had no impact on the efficacy of gemcitabine plus nab-paclitaxel. In 2 patients treated with platinum-containing therapy, putative BRCA2 reversion mutations were detected. Three of seven patients with somatic BRCA mutations responded to platinum-containing therapy, while only one of four with putative germline ATM mutations did. One-third of somatic ATM mutations were in genomic loci associated with clonal haematopoiesis. Comprehensive ctDNA profiling provides clinically relevant information regarding HRD status. It can be a practical, convenient option for HRD screening in APC.
Sections du résumé
BACKGROUND
BACKGROUND
Identification of homologous recombination deficiency (HRD) remains a challenge in advanced pancreatic cancer (APC). We investigated the utility of circulating tumour DNA (ctDNA) profiling in the assessment of BRCA1/2 and ATM mutation status and treatment selection in APC.
METHODS
METHODS
We analysed clinical and ctDNA data of 702 patients with APC enroled in GOZILA, a ctDNA profiling study using Guardant360.
RESULTS
RESULTS
Inactivating BRCA1/2 and ATM mutations were detected in 4.8% (putative germline, 3.7%) and 4.4% (putative germline, 0.9%) of patients, respectively. Objective response (63.2% vs. 16.2%) and PFS (HR 0.55, 95% CI 0.32-0.93) on platinum-containing chemotherapy were significantly better in patients with putative germline BRCA1/2 (gBRCA) mutation than those without. In contrast, putative gBRCA mutation had no impact on the efficacy of gemcitabine plus nab-paclitaxel. In 2 patients treated with platinum-containing therapy, putative BRCA2 reversion mutations were detected. Three of seven patients with somatic BRCA mutations responded to platinum-containing therapy, while only one of four with putative germline ATM mutations did. One-third of somatic ATM mutations were in genomic loci associated with clonal haematopoiesis.
CONCLUSION
CONCLUSIONS
Comprehensive ctDNA profiling provides clinically relevant information regarding HRD status. It can be a practical, convenient option for HRD screening in APC.
Identifiants
pubmed: 39198618
doi: 10.1038/s41416-024-02834-0
pii: 10.1038/s41416-024-02834-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Nature Limited.
Références
Casolino R, Paiella S, Azzolina D, Beer PA, Corbo V, Lorenzoni G, et al. Homologous recombination deficiency in pancreatic cancer: a systematic review and prevalence meta-analysis. J Clin Oncol. 2021;39:2617–31.
doi: 10.1200/JCO.20.03238
pubmed: 34197182
pmcid: 8331063
Lowery MA, Kelsen DP, Stadler ZK, Yu KH, Janjigian YY, Ludwig E, et al. An emerging entity: pancreatic adenocarcinoma associated with a known BRCA mutation: clinical descriptors, treatment implications, and future directions. Oncologist. 2011;16:1397–402.
doi: 10.1634/theoncologist.2011-0185
pubmed: 21934105
pmcid: 3228075
Golan T, Kanji ZS, Epelbaum R, Devaud N, Dagan E, Holter S, et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer. 2014;111:1132–8.
doi: 10.1038/bjc.2014.418
pubmed: 25072261
pmcid: 4453851
Rebelatto TF, Falavigna M, Pozzari M, Spada F, Cella CA, Laffi A, et al. Should platinum-based chemotherapy be preferred for germline Breast Cancer genes (BRCA) 1 and 2-mutated pancreatic ductal adenocarcinoma (PDAC) patients? A systematic review and meta-analysis. Cancer Treat Rev. 2019;80:101895.
doi: 10.1016/j.ctrv.2019.101895
pubmed: 31542591
Orsi G, Di Marco M, Cavaliere A, Niger M, Bozzarelli S, Giordano G, et al. Chemotherapy toxicity and activity in patients with pancreatic ductal adenocarcinoma and germline BRCA1-2 pathogenic variants (gBRCA1-2pv): a multicenter survey. ESMO Open. 2021;6:100238.
doi: 10.1016/j.esmoop.2021.100238
pubmed: 34392104
pmcid: 8371213
Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N. Engl J Med. 2019;381:317–27.
doi: 10.1056/NEJMoa1903387
pubmed: 31157963
pmcid: 6810605
Pishvaian MJ, Blais EM, Brody JR, Rahib L, Lyons E, De Arbeloa P, et al. Outcomes in patients with pancreatic adenocarcinoma with genetic mutations in DNA damage response pathways: results from the Know Your Tumor program. JCO Precis Oncol. 2019;3:1–10. https://doi.org/10.1200/PO.19.00115 .
Park W, Chen J, Chou JF, Varghese AM, Yu KH, Wong W, et al. Genomic methods identify homologous recombination deficiency in pancreas adenocarcinoma and optimize treatment selection. Clin Cancer Res. 2020;26:3239–47.
doi: 10.1158/1078-0432.CCR-20-0418
pubmed: 32444418
pmcid: 7380542
Golan T, O’Kane GM, Denroche RE, Raitses-Gurevich M, Grant RC, Holter S, et al. Genomic features and classification of homologous recombination deficient pancreatic ductal adenocarcinoma. Gastroenterology. 2021;160:2119–32.
doi: 10.1053/j.gastro.2021.01.220
pubmed: 33524400
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Pancreatic Adenocarcinoma. version 1.2022. February 24, 2022. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
Navina S, McGrath K, Chennat J, Singh V, Pal T, Zeh H, et al. Adequacy assessment of endoscopic ultrasound-guided, fine-needle aspirations of pancreatic masses for theranostic studies: optimization of current practices is warranted. Arch Pathol Lab Med. 2014;138:923–8.
doi: 10.5858/arpa.2013-0335-OA
pubmed: 24978918
Rothwell DG, Ayub M, Cook N, Thistlethwaite F, Carter L, Dean E, et al. Utility of ctDNA to support patient selection for early phase clinical trials: the TARGET study. Nat Med. 2019;25:738–43.
doi: 10.1038/s41591-019-0380-z
pubmed: 31011204
Nakamura Y, Taniguchi H, Ikeda M, Bando H, Kato K, Morizane C, et al. Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies. Nat Med. 2020;26:1859–64.
doi: 10.1038/s41591-020-1063-5
pubmed: 33020649
Vidula N, Rich TA, Sartor O, Yen J, Hardin A, Nance T, et al. Routine plasma-based genotyping to comprehensively detect germline, somatic, and reversion BRCA mutations among patients with advanced solid tumors. Clin Cancer Res. 2020;26:2546–55.
doi: 10.1158/1078-0432.CCR-19-2933
pubmed: 32034076
Slavin TP, Banks KC, Chudova D, Oxnard GR, Odegaard JI, Nagy RJ, et al. Identification of incidental germline mutations in patients with advanced solid tumors who underwent cell-free circulating tumor DNA sequencing. J Clin Oncol. 2018;36:JCO1800328.
doi: 10.1200/JCO.18.00328
pubmed: 30339520
Hu Y, Alden RS, Odegaard JI, Fairclough SR, Chen R, Heng J, et al. Discrimination of germline EGFR T790M mutations in plasma cell-free DNA allows study of prevalence across 31,414 cancer patients. Clin Cancer Res. 2017;23:7351–9.
doi: 10.1158/1078-0432.CCR-17-1745
pubmed: 28947568
pmcid: 5712272
Nakamura Y, Fujisawa T, Taniguchi H, Bando H, Okamoto W, Tsuchihara K, et al. SCRUM-Japan GI-SCREEN and MONSTAR-SCREEN: path to the realization of biomarker-guided precision oncology in advanced solid tumors. Cancer Sci. 2021;112:4425–32.
doi: 10.1111/cas.15132
pubmed: 34510657
pmcid: 8586659
Umemoto K, Sunakawa Y, Ueno M, Furukawa M, Mizuno N, Sudo K, et al. Clinical significance of circulating-tumour DNA analysis by metastatic sites in pancreatic cancer. Br J Cancer. 2023;128:1603–8.
doi: 10.1038/s41416-023-02189-y
pubmed: 36782009
pmcid: 10070329
Okusaka T, Nakamura M, Yoshida M, Kitano M, Ito Y, Mizuno N, et al. Clinical Practice Guidelines for Pancreatic Cancer 2022 from the Japan Pancreas Society: a synopsis. Int J Clin Oncol. 2023;28:493–511.
doi: 10.1007/s10147-023-02317-x
pubmed: 36920680
pmcid: 10066137
Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48:452–8.
doi: 10.1038/bmt.2012.244
Momozawa Y, Sasai R, Usui Y, Shiraishi K, Iwasaki Y, Taniyama Y, et al. Expansion of cancer risk profile for BRCA1 and BRCA2 pathogenic variants. JAMA Oncol. 2022;8:871–78.
doi: 10.1001/jamaoncol.2022.0476
pubmed: 35420638
pmcid: 9011177
Bolton KL, Ptashkin RN, Gao T, Braunstein L, Devlin SM, Kelly D, et al. Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nat Genet. 2020;52:1219–26.
doi: 10.1038/s41588-020-00710-0
pubmed: 33106634
pmcid: 7891089
Slavin TP, Coffee B, Bernhisel R, Logan J, Cox HC, Marcucci G, et al. Prevalence and characteristics of likely-somatic variants in cancer susceptibility genes among individuals who had hereditary pan-cancer panel testing. Cancer Genet. 2019;235–236:31–8.
Xu E, Su K, Zhou Y, Gong L, Xuan Y, Liao M, et al. Comprehensive landscape and interference of clonal haematopoiesis mutations for liquid biopsy: a Chinese pan-cancer cohort. J Cell Mol Med. 2021;25:10279–90.
doi: 10.1111/jcmm.16966
pubmed: 34658138
pmcid: 8572768
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.
doi: 10.1158/2159-8290.CD-12-0095
pubmed: 22588877
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.
doi: 10.1126/scisignal.2004088
pubmed: 23550210
pmcid: 4160307
Tate JG, Bamford S, Jubb HC, Sondka Z, Beare DM, Bindal N, et al. COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res. 2019;47:D941–D947.
doi: 10.1093/nar/gky1015
pubmed: 30371878
Stossel C, Raitses-Gurevich M, Atias D, Beller T, Glick Gorman Y, Halperin S, et al. Spectrum of response to platinum and PARP inhibitors in germline BRCA-Associated pancreatic cancer in the clinical and preclinical setting. Cancer Discov. 2023;13:1826–43.
doi: 10.1158/2159-8290.CD-22-0412
pubmed: 37449843
pmcid: 10401074
Abrams TA, Meyer G, Meyerhardt JA, Wolpin BM, Schrag D, Fuchs CS. Patterns of chemotherapy use in a U.S.-based cohort of patients with metastatic pancreatic cancer. Oncologist. 2017;22:925–33.
doi: 10.1634/theoncologist.2016-0447
pubmed: 28476943
pmcid: 5553956
Suzuki T, Kawai S, Ueno M, Lin Y, Kikuchi S. Treatment patterns in pancreatic cancer patients based on a hospital claims database in Japan. Jpn J Clin Oncol. 2021;51:228–34.
Jonsson P, Bandlamudi C, Cheng ML, Srinivasan P, Chavan SS, Friedman ND, et al. Tumour lineage shapes BRCA-mediated phenotypes. Nature. 2019;571:576–9.
doi: 10.1038/s41586-019-1382-1
pubmed: 31292550
pmcid: 7048239
Konstantinopoulos PA, Norquist B, Lacchetti C, Armstrong D, Grisham RN, Goodfellow PJ, et al. Germline and somatic tumor testing in epithelial ovarian cancer: ASCO guideline. J Clin Oncol. 2020;38:1222–45.
doi: 10.1200/JCO.19.02960
pubmed: 31986064
Abida W, Patnaik A, Campbell D, Shapiro J, Bryce AH, McDermott R, et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. 2020;38:3763–72.
doi: 10.1200/JCO.20.01035
pubmed: 32795228
pmcid: 7655021
Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518:495–501.
doi: 10.1038/nature14169
pubmed: 25719666
pmcid: 4523082
Shroff RT, Hendifar A, McWilliams RR, Geva R, Epelbaum R, Rolfe L, et al. Rucaparib monotherapy in patients with pancreatic cancer and a known deleterious BRCA mutation. JCO Precis Oncol. 2018;2:PO.17.00316. https://doi.org/10.1200/PO.17.00316 .
Lin KK, Harrell MI, Oza AM, Oaknin A, Ray-Coquard I, Tinker AV, et al. BRCA reversion mutations in circulating tumor DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma. Cancer Discov. 2019;9:210–9.
doi: 10.1158/2159-8290.CD-18-0715
pubmed: 30425037
Pettitt SJ, Frankum JR, Punta M, Lise S, Alexander J, Chen Y, et al. Clinical BRCA1/2 reversion analysis identifies hotspot mutations and predicted neoantigens associated with therapy resistance. Cancer Discov. 2020;10:1475–88.
doi: 10.1158/2159-8290.CD-19-1485
pubmed: 32699032
pmcid: 7611203
Brown TJ, Yablonovitch A, Till JE, Yen J, Kiedrowski LA, Hood R, et al. The clinical implications of reversions in patients with advanced pancreatic cancer and pathogenic variants in BRCA1, BRCA2, or PALB2 after progression on Rucaparib. Clin Cancer Res. 2023;29:5207–16.
doi: 10.1158/1078-0432.CCR-23-1467
pubmed: 37486343
pmcid: 10806928
Jensen K, Konnick EQ, Schweizer MT, Sokolova AO, Grivas P, Cheng HH, et al. Association of clonal hematopoiesis in DNA repair genes with prostate cancer plasma cell-free DNA testing interference. JAMA Oncol. 2021;7:107–10.
doi: 10.1001/jamaoncol.2020.5161
pubmed: 33151258