Effect of Tumor Sidedness and Molecular Alterations on Outcomes in Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer

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In a study reported in the Journal of Clinical Oncology, Morano et al assessed prognostic/predictive role of tumor sidedness and presence of uncommon molecular alterations in anti-EGFR treatment primary resistance in patients with RAS/BRAF wild-type metastatic colorectal cancer.

Study Details

The prespecified retrospective analysis included 199 patients with RAS/BRAF wild-type disease who received panitumumab plus fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (FOLFOX-4) induction followed by maintenance with panitumumab with or without 5-FU/LV in the phase II Valentino trial.

Patient samples were investigated for molecular alterations using a PRESSING panel (PRESSING = primary resistance in RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibodies). The PRESSING panel included the following:

  • Immunohistochemistry (IHC) and in situ hybridization for HER2/MET amplification
  • IHC with or without RNA sequencing for ALK/ROS1/NTRKs/RET fusions
  • Next-generation sequencing for HER2/PIK3CAex.20/PTEN/AKT1 and RAS mutations with low mutant allele fraction
  • Multiplex polymerase chain reaction for microsatellite instability.

Patients were considered PRESSING-positive if they had any of the alterations, and PRESSING-negative if all were absent. PRESSING status and sidedness were correlated with overall response rate, progression-free survival, and overall survival in the study population and by treatment arm.

Outcomes by Sidedness and PRESSING Status

Overall, 85.4% of tumors were left-sided and 14.6% were right-sided. PRESSING-negative tumors were found in 75.4% of patients and PRESSING-positive tumors in 24.6%.

At a median follow-up of 26 months, poorer outcomes were observed for right- vs left-sided tumors in overall response rate (55.2% vs 74.1%; P = .037), median progression-free survival (8.4 vs 11.5 months; P = .026), and 2-year overall survival (50.2% vs 65.1%; P = .062). Poorer outcomes were also observed for PRESSING-positive vs PRESSING-negative tumors in overall response rate (59.2% vs 75.3%; P = .030), median progression-free survival (7.7 vs 12.1 months; P < .001), and 2-year overall survival (48.1% vs 68.1%; P = .021).


  • Right-sided and PRESSING-positive tumors were associated with poorer outcomes among patients receiving panitumumab plus FOLFOX-4 induction followed by maintenance with panitumumab with or without 5-FU/LV.
  • Outcomes in these tumor subgroups were particularly poor in patients receiving maintenance with panitumumab alone.

The progression-free survival benefit observed in the trial with the addition of 5-FU/LV to panitumumab maintenance was independent of tumor sidedness (P = .293 for interaction) and PRESSING status (P = .127 for interaction). Poorer outcomes were observed among patients receiving panitumumab alone as maintenance therapy who had right-sided tumors (median progression-free survival = 7.7 months, 2-year overall survival = 38.5%) or PRESSING-positive tumors (median progression-free survival = 7.4 months, 2-year overall survival = 47.0%).

The investigators concluded, “The combined assessment of sidedness and molecular alterations of anti-EGFR primary resistance identified a consistent proportion of patients with RAS/BRAF–[wild-type] [metastatic] colorectal cancer who had inferior benefit from initial anti-EGFR–based regimens, particularly after maintenance with single-agent anti-EGFRs.”

Filippo Pietrantonio, MD, of the Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, is the corresponding author for the Journal of Clinical Oncology article.

Disclosures: The study was supported by Amgen. For full disclosures of the study authors, visit

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