C Cremolini1, F Morano2, R Moretto1, R Berenato2, E Tamborini3, F Perrone3, D Rossini1, A Gloghini3, A Busico3, G Zucchelli1, C Baratelli4, E Tamburini5, M Tampellini6, E Sensi7, G Fucà2, C Volpi3, M Milione3, M Di Maio4, G Fontanini7, F De Braud2,8, A Falcone1, F Pietrantonio2. 1. Unit of Medical Oncology 2, Department of Translational Research and New Technologies in Medicine and Surgery, Azienda Ospedaliera-Universitaria Pisana, University of Pisa, Pisa. 2. Medical Oncology Department, IRCCS Istituto Nazionale dei Tumori, Milan. 3. Laboratory of Experimental Molecular Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. 4. Department of Oncology, University of Turin - Ordine Mauriziano Hospital, Turin. 5. Department of Oncology, Ospedale Infermi, Rimini. 6. Department of Oncology, Ospedale San Luigi, Orbassano. 7. Department of Surgical, Medical, Molecular Pathology and Critical Care, Università di Pisa, Pisa. 8. Department of Oncology and Hematoncology, University Of Milan, Milan, IRCCS Fondazione Istituto Nazionale dei Tumori, Milan, Italy.
Abstract
BACKGROUND: Refining the selection of metastatic colorectal cancer patients candidates for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies beyond RAS and BRAF testing is a challenge of precision oncology. Several uncommon genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than EGFR or downstream signalling pathways, have been suggested by preclinical and retrospective studies. PATIENTS AND METHODS: We conducted this multicentre, prospective, case-control study to demonstrate the negative predictive impact of a panel of rare genomic alterations [PRESSING (PRimary rESiStance IN RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-eGfr monoclonal antibodies) panel], including HER2/MET amplifications, ALK/ROS1/NTRK1-3/RET fusions and PIK3CA mutations. Hypothesizing a prevalence of candidate alterations of 15% and 0% in resistant and sensitive RAS and BRAF wild-type patients, respectively, with two-sided α and β errors of 0.05 and 0.20, 47 patients per group were needed. RESULTS: Forty-seven patients per group were included. PRESSING panel alterations were significantly more frequent in resistant (24 out of 47, 51.1%) than in sensitive (1 out of 47, 2.1%) patients (P < 0.001) and in right- (12 out of 29, 41.4%) than left-sided (13 out of 65, 20.0%) tumours (P = 0.03). The predictive accuracy of PRESSING panel and sidedness was 75.3% and 70.2%, respectively. Among hyper-selected patients, right-sidedness was still associated with resistance (P = 0.002). The predictive accuracy of the combined evaluation of PRESSING panel and sidedness was 80.4%. As a secondary analysis, 8 (17.0%) resistant and 0 sensitive patients showed microsatellite instability (P < 0.001). CONCLUSION: The investigated panel of genomic alterations allows refining the selection of RAS and BRAF wild-type metastatic colorectal cancer patients candidates for anti-EGFRs, partially explaining and further corroborating the predictive ability of primary tumour sidedness.
BACKGROUND: Refining the selection of metastatic colorectal cancer patients candidates for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies beyond RAS and BRAF testing is a challenge of precision oncology. Several uncommon genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than EGFR or downstream signalling pathways, have been suggested by preclinical and retrospective studies. PATIENTS AND METHODS: We conducted this multicentre, prospective, case-control study to demonstrate the negative predictive impact of a panel of rare genomic alterations [PRESSING (PRimary rESiStance IN RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-eGfr monoclonal antibodies) panel], including HER2/MET amplifications, ALK/ROS1/NTRK1-3/RET fusions and PIK3CA mutations. Hypothesizing a prevalence of candidate alterations of 15% and 0% in resistant and sensitive RAS and BRAF wild-type patients, respectively, with two-sided α and β errors of 0.05 and 0.20, 47 patients per group were needed. RESULTS: Forty-seven patients per group were included. PRESSING panel alterations were significantly more frequent in resistant (24 out of 47, 51.1%) than in sensitive (1 out of 47, 2.1%) patients (P < 0.001) and in right- (12 out of 29, 41.4%) than left-sided (13 out of 65, 20.0%) tumours (P = 0.03). The predictive accuracy of PRESSING panel and sidedness was 75.3% and 70.2%, respectively. Among hyper-selected patients, right-sidedness was still associated with resistance (P = 0.002). The predictive accuracy of the combined evaluation of PRESSING panel and sidedness was 80.4%. As a secondary analysis, 8 (17.0%) resistant and 0 sensitive patients showed microsatellite instability (P < 0.001). CONCLUSION: The investigated panel of genomic alterations allows refining the selection of RAS and BRAF wild-type metastatic colorectal cancer patients candidates for anti-EGFRs, partially explaining and further corroborating the predictive ability of primary tumour sidedness.
Authors: Aziz Zaanan; Julie Henriques; Romain Cohen; David Sefrioui; Camille Evrard; Christelle de la Fouchardiere; Thierry Lecomte; Thomas Aparicio; Magali Svrcek; Julien Taieb; Thierry André; Dewi Vernerey; David Tougeron Journal: J Natl Cancer Inst Date: 2021-04-06 Impact factor: 13.506
Authors: Aziz Zaanan; Qian Shi; Julien Taieb; Steven R Alberts; Jeffrey P Meyers; Thomas C Smyrk; Catherine Julie; Ayman Zawadi; Josep Tabernero; Enrico Mini; Richard M Goldberg; Gunnar Folprecht; Jean Luc Van Laethem; Karine Le Malicot; Daniel J Sargent; Pierre Laurent-Puig; Frank A Sinicrope Journal: JCO Precis Oncol Date: 2020-02-26
Authors: Giovanni Randon; Rona Yaeger; Jaclyn F Hechtman; Paolo Manca; Giovanni Fucà; Henry Walch; Jeeyun Lee; Elena Élez; Jenny Seligmann; Benedetta Mussolin; Filippo Pagani; Marco Maria Germani; Margherita Ambrosini; Daniele Rossini; Margherita Ratti; Francesc Salvà; Susan D Richman; Henry Wood; Gouri Nanjangud; Annunziata Gloghini; Massimo Milione; Alberto Bardelli; Filippo de Braud; Federica Morano; Chiara Cremolini; Filippo Pietrantonio Journal: J Natl Cancer Inst Date: 2021-11-02 Impact factor: 13.506