BACKGROUND: Chemotherapies have limited efficacy in pancreatic cancer (PC) and biliary tract cancer (BTC), underscoring the need for new regimens. Recently, tumor-agnostic approaches have been developed for some targeted therapies in advanced solid tumors; however, the frequency of alterations by clinical and genomic background is unclear in PC and BTC. METHODS: To assess the frequencies of druggable gene alterations and investigate new potential therapeutic targetable genomic alterations, advanced PC and BTC patients were tested with comprehensive genomic profiling at Foundation Medicine during the course of clinical care. RESULTS: A total of 16 913 PC patients and 3031 BTC patients were available for analyses, and frequencies of genomic alterations were stratified by age (≥40 years or <40 years), microsatellite instability status, tumor mutational burden status (high ≥10 or low <10 Muts/Mb), and select genomic alterations. Alterations in BRCA2, BRAF, ERBB2, CDK12, PIK3CA, FGFR2, EGFR, and other potential targets were seen across cohorts, with enrichment observed within particular subsets such as in PC patients lacking a KRAS mutation. In BTC patients, the rate of ERBB2 amplification was statistically significantly higher in the tumor mutational burden-high population (23.3% vs 13.7%). Interestingly, CDK12 rearrangement was observed in BTC patients with ERBB2 amplification tumors. In patients younger than 40 years, FGFR2 rearrangement (4%) was observed in PC: GATA6 amplification (11.1%) and rearrangement of BRAF (2.8%)FGFR2 (5.6%) was observed in BTC patients. CONCLUSIONS: We identified an appreciable frequency of immunotherapy biomarkers and targetable gene alterations in both PC and BTC, with notable frequencies in PC samples lacking KRAS mutations and children or adolescent and young adult populations, that should encourage comprehensive genomic profiling testing.
BACKGROUND: Chemotherapies have limited efficacy in pancreatic cancer (PC) and biliary tract cancer (BTC), underscoring the need for new regimens. Recently, tumor-agnostic approaches have been developed for some targeted therapies in advanced solid tumors; however, the frequency of alterations by clinical and genomic background is unclear in PC and BTC. METHODS: To assess the frequencies of druggable gene alterations and investigate new potential therapeutic targetable genomic alterations, advanced PC and BTC patients were tested with comprehensive genomic profiling at Foundation Medicine during the course of clinical care. RESULTS: A total of 16 913 PC patients and 3031 BTC patients were available for analyses, and frequencies of genomic alterations were stratified by age (≥40 years or <40 years), microsatellite instability status, tumor mutational burden status (high ≥10 or low <10 Muts/Mb), and select genomic alterations. Alterations in BRCA2, BRAF, ERBB2, CDK12, PIK3CA, FGFR2, EGFR, and other potential targets were seen across cohorts, with enrichment observed within particular subsets such as in PC patients lacking a KRAS mutation. In BTC patients, the rate of ERBB2 amplification was statistically significantly higher in the tumor mutational burden-high population (23.3% vs 13.7%). Interestingly, CDK12 rearrangement was observed in BTC patients with ERBB2 amplification tumors. In patients younger than 40 years, FGFR2 rearrangement (4%) was observed in PC: GATA6 amplification (11.1%) and rearrangement of BRAF (2.8%)FGFR2 (5.6%) was observed in BTC patients. CONCLUSIONS: We identified an appreciable frequency of immunotherapy biomarkers and targetable gene alterations in both PC and BTC, with notable frequencies in PC samples lacking KRAS mutations and children or adolescent and young adult populations, that should encourage comprehensive genomic profiling testing.
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Authors: H A Burris; M J Moore; J Andersen; M R Green; M L Rothenberg; M R Modiano; M C Cripps; R K Portenoy; A M Storniolo; P Tarassoff; R Nelson; F A Dorr; C D Stephens; D D Von Hoff Journal: J Clin Oncol Date: 1997-06 Impact factor: 44.544
Authors: Aurelien Marabelle; Dung T Le; Paolo A Ascierto; Anna Maria Di Giacomo; Ana De Jesus-Acosta; Jean-Pierre Delord; Ravit Geva; Maya Gottfried; Nicolas Penel; Aaron R Hansen; Sarina A Piha-Paul; Toshihiko Doi; Bo Gao; Hyun Cheol Chung; Jose Lopez-Martin; Yung-Jue Bang; Ronnie Shapira Frommer; Manisha Shah; Razi Ghori; Andrew K Joe; Scott K Pruitt; Luis A Diaz Journal: J Clin Oncol Date: 2019-11-04 Impact factor: 44.544
Authors: Talia Golan; Pascal Hammel; Michele Reni; Eric Van Cutsem; Teresa Macarulla; Michael J Hall; Joon-Oh Park; Daniel Hochhauser; Dirk Arnold; Do-Youn Oh; Anke Reinacher-Schick; Giampaolo Tortora; Hana Algül; Eileen M O'Reilly; David McGuinness; Karen Y Cui; Katia Schlienger; Gershon Y Locker; Hedy L Kindler Journal: N Engl J Med Date: 2019-06-02 Impact factor: 91.245
Authors: Zachary R Chalmers; Caitlin F Connelly; David Fabrizio; Laurie Gay; Siraj M Ali; Riley Ennis; Alexa Schrock; Brittany Campbell; Adam Shlien; Juliann Chmielecki; Franklin Huang; Yuting He; James Sun; Uri Tabori; Mark Kennedy; Daniel S Lieber; Steven Roels; Jared White; Geoffrey A Otto; Jeffrey S Ross; Levi Garraway; Vincent A Miller; Phillip J Stephens; Garrett M Frampton Journal: Genome Med Date: 2017-04-19 Impact factor: 11.117
Authors: Robert L Coleman; Amit M Oza; Domenica Lorusso; Carol Aghajanian; Ana Oaknin; Andrew Dean; Nicoletta Colombo; Johanne I Weberpals; Andrew Clamp; Giovanni Scambia; Alexandra Leary; Robert W Holloway; Margarita Amenedo Gancedo; Peter C Fong; Jeffrey C Goh; David M O'Malley; Deborah K Armstrong; Jesus Garcia-Donas; Elizabeth M Swisher; Anne Floquet; Gottfried E Konecny; Iain A McNeish; Clare L Scott; Terri Cameron; Lara Maloney; Jeff Isaacson; Sandra Goble; Caroline Grace; Thomas C Harding; Mitch Raponi; James Sun; Kevin K Lin; Heidi Giordano; Jonathan A Ledermann Journal: Lancet Date: 2017-09-12 Impact factor: 79.321