Giovanni Randon1, Rossana Intini2, Chiara Cremolini3, Elena Elez4, Michael J Overman5, Jeeyun Lee6, Paolo Manca1, Francesca Bergamo2, Filippo Pagani1, Maria Antista1, Valentina Angerilli7, Francisco Javier Ros Montaña4, Daniele Lavacchi8, Alessandra Boccaccino9, Giovanni Fucà1, Silvia Brich10, Laura Cattaneo10, Matteo Fassan11, Filippo Pietrantonio12, Sara Lonardi2. 1. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumouri di Milano, Milano, Italy. 2. Department of Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy. 3. Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. 4. Vall D'Hebron University Hospital (HUVH) and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain. 5. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center. 6. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University, School of Medicine, South Korea. 7. Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy. 8. Medical Oncology Unit, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy. 9. Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. 10. Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Dei Tumouri di Milano, Milan, Italy. 11. Department of Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy; Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy. 12. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumouri di Milano, Milano, Italy. Electronic address: filippo.pietrantonio@istitutotumori.mi.it.
Abstract
AIM: To unveil genomic and immunohistochemical expression profiles associated with primary resistance to EGFR/BRAF targeted therapy in patients with BRAF-mutated and microsatellite stable (MSS) metastatic colorectal cancer. EXPERIMENTAL DESIGN: In this multicenter case-control study on patients treated with EGFR/BRAF ± MEK blockade, we compared a primary resistance cohort (N = 20; RECISTv1.1 PD/SD, and progression-free survival [PFS] <16 weeks) versus a sensitive one (N = 19; RECISTv1.1 PR/CR, and PFS ≥16 weeks) in terms of clinical and genomic/expression data by means of comprehensive genomic profiling, tumour mutational burden (TMB), BRAF-mutant transcriptional subtypes (BM) classification and PTEN expression. RESULTS: Left-sided tumours (28% of the total) were enriched in the sensitive versus resistant cohort (53% versus 10%, P = 0.010). Genomic alterations in the PIK3CA/MTOR pathway, BM1 status and PTEN loss were similarly distributed among patients with resistant and sensitive tumours. Amplification of CCND1-3 genes were found only in patients with primary resistance (20% versus 0%, P = 0.106). TMB and prevalence of intermediate TMB (TMB-I 6-20 mutations/Mb) were higher in the resistant versus sensitive cohort (median TMB: 6 [IQR, 3-7.29] versus 3 [IQR, 1.26-3.5]; P = 0.013; TMB-I/H: 60% versus 11%; P = 0.001). Patients with TMB-I had shorter PFS (3.3 versus 5.9 months; HR = 2.19, 95%CI, 1.07-4.47, P = 0.031) and overall survival (6.3 versus 10.5 months; HR = 2.22, 95%CI, 1.02-4.81, P = 0.044). CONCLUSION: Despite the small sample size, the association of a relatively higher TMB with limited benefit from EGFR/BRAF blockade in patients with MSS and BRAF-mutated mCRC deserves prospective validation.
AIM: To unveil genomic and immunohistochemical expression profiles associated with primary resistance to EGFR/BRAF targeted therapy in patients with BRAF-mutated and microsatellite stable (MSS) metastatic colorectal cancer. EXPERIMENTAL DESIGN: In this multicenter case-control study on patients treated with EGFR/BRAF ± MEK blockade, we compared a primary resistance cohort (N = 20; RECISTv1.1 PD/SD, and progression-free survival [PFS] <16 weeks) versus a sensitive one (N = 19; RECISTv1.1 PR/CR, and PFS ≥16 weeks) in terms of clinical and genomic/expression data by means of comprehensive genomic profiling, tumour mutational burden (TMB), BRAF-mutant transcriptional subtypes (BM) classification and PTEN expression. RESULTS: Left-sided tumours (28% of the total) were enriched in the sensitive versus resistant cohort (53% versus 10%, P = 0.010). Genomic alterations in the PIK3CA/MTOR pathway, BM1 status and PTEN loss were similarly distributed among patients with resistant and sensitive tumours. Amplification of CCND1-3 genes were found only in patients with primary resistance (20% versus 0%, P = 0.106). TMB and prevalence of intermediate TMB (TMB-I 6-20 mutations/Mb) were higher in the resistant versus sensitive cohort (median TMB: 6 [IQR, 3-7.29] versus 3 [IQR, 1.26-3.5]; P = 0.013; TMB-I/H: 60% versus 11%; P = 0.001). Patients with TMB-I had shorter PFS (3.3 versus 5.9 months; HR = 2.19, 95%CI, 1.07-4.47, P = 0.031) and overall survival (6.3 versus 10.5 months; HR = 2.22, 95%CI, 1.02-4.81, P = 0.044). CONCLUSION: Despite the small sample size, the association of a relatively higher TMB with limited benefit from EGFR/BRAF blockade in patients with MSS and BRAF-mutated mCRC deserves prospective validation.
Authors: Elena Elez; Javier Ros; Jose Fernández; Guillermo Villacampa; Ana Belén Moreno-Cárdenas; Carlota Arenillas; Kinga Bernatowicz; Raquel Comas; Shanshan Li; David Philip Kodack; Roberta Fasani; Ariadna Garcia; Javier Gonzalo-Ruiz; Alejandro Piris-Gimenez; Paolo Nuciforo; Grainne Kerr; Rossana Intini; Aldo Montagna; Marco Maria Germani; Giovanni Randon; Ana Vivancos; Ron Smits; Diana Graus; Raquel Perez-Lopez; Chiara Cremolini; Sara Lonardi; Filippo Pietrantonio; Rodrigo Dienstmann; Josep Tabernero; Rodrigo A Toledo Journal: Nat Med Date: 2022-09-12 Impact factor: 87.241