1. Pooled Analysis of Clinical Outcome of Patients with Chemorefractory Metastatic Colorectal Cancer Treated within Phase I/II Clinical Studies Based on Individual Biomarkers of Susceptibility: A Single-Institution Experience
- Author
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Federica Pazzi, Sara Di Bella, Tiziana Cipani, Calogero Lauricella, Erica Bonazzina, Andrea Sartore-Bianchi, Valentina Gambi, Alessio Amatu, Giovanni Burrafato, Laura Palmeri, Angelo Vanzulli, Francesca Rusconi, Riccardo Ricotta, Andrea Cassingena, Giovanna Marrapese, Salvatore Siena, Silvio Veronese, Katia Bencardino, Laura Giannetta, Silvia Ghezzi, Michele Schirru, Mauro Truini, Alessandra Gambaro, C. Funaioli, Ilaria Schiavetto, Giulio Cerea, Giulia Carlo-Stella, Emanuele Valtorta, Emiliana Tarenzi, and Stefano Stabile
- Subjects
0301 basic medicine ,Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,Population ,Context (language use) ,medicine.disease_cause ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Pharmacology (medical) ,Original Research Article ,Neoplasm Metastasis ,education ,Aged ,Retrospective Studies ,Aged, 80 and over ,education.field_of_study ,business.industry ,Cancer ,Retrospective cohort study ,Middle Aged ,medicine.disease ,3. Good health ,Clinical trial ,030104 developmental biology ,Response Evaluation Criteria in Solid Tumors ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Female ,KRAS ,business ,Colorectal Neoplasms - Abstract
Patients with metastatic colorectal cancer (mCRC) refractory to standard therapies have a poor prognosis. In this setting, recruitment into clinical trials is warranted, and studies driven by selection according to individual tumor molecular characteristics are expected to provide added value. We retrospectively analyzed data from patients with mCRC refractory to or following failure of standard therapies who were enrolled into phase I/II clinical studies at the Niguarda Cancer Center based on the presence of a specific molecular profile expected to represent the target of susceptibility to the experimental drug(s). From June 2011 to May 2016, 2044 patients with mCRC underwent molecular screening. Eighty patients (3.9%) were enrolled in ad hoc studies; the median age was 60 years (range 36–86) and the median number of previous treatment lines was five (range 2–8). Molecular characteristics exploited within these studies were MGMT promoter hypermethylation (48.7%), HER2 amplification (28.8%), BRAF V600E mutation (20%), and novel gene fusions involving ALK or NTRK (2.5%). One patient (1%) had RECIST (Response Evaluation Criteria In Solid Tumors) complete response (CR), 13 patients (16.5%) experienced a partial response (PR), and 28 (35%) stable disease (SD). Median progression-free survival (PFS) was 2.8 months (range 2.63–3.83), with 24% of patients displaying PFS >5 months. Median growth modulation index (GMI) was 0.85 (range 0–15.61) and 32.5% of patients had GMI >1.33. KRAS exon 2 mutations were found in 38.5% of patients, and among the 78 patients with known KRAS status, those with wild-type tumors had longer PFS than those with mutated tumors (3.80 [95% CI 2.80–5.03] vs. 2.13 months [95% CI 1.77–2.87], respectively, p = 0.001). Median overall survival (OS) was 7.83 months (range 7.17–9.33) for all patients, and patients with KRAS wild-type tumors had longer OS than those with mutated tumors (7.83 [95% CI 7.33–10.80] vs. 7.18 months [95% CI 5.63–9.33], respectively, p = 0.06). This single-institution retrospective study indicates that in a heavily pretreated population approximately 4% of mCRC tumors display a potential actionable molecular context suitable for therapeutic intervention. Application of molecular selection is challenging but improves clinical outcome even in later lines of treatment.
- Published
- 2017