TPS3159 Background: Molecular targeted agents (MTA) resulted in breakthroughs in selected niches. It is often assumed that tumor regression is consecutive to an oncogenic de-addiction effect. An emerging hypothesis suggests that genomic instability may be associated with poor response to MTA. Indeed, the accumulation of defects in multiple oncogenes or tumor suppressor genes may result in the activation of multiple oncogenic pathways. These multiple signaling would mechanically result in a limitation of the oncogenic de-addiction process. Another hypothesis, suggests that tumor heterogeneity could also be associated with poor outcome under MTA. Such heterogeneity could also result from the genomic instability, and be appraised by bioinformatic and functional approaches. In this study, we thought to investigate whether molecular profiles reflecting a low level of genomic alterations in genes causally implicated in oncogenesis could be associated with an exceptional response (ER) to MTA. Methods: This is an exploratory, multicenter, multicohort, prospective trial conducted in 264 adult patients, with advanced breast, lung, colorectal, ovarian, kidney cancers and melanoma, having presented an ER to an approved MTA. ER is defined using the definition chosen by the NCI which combines the three criteria: - complete or partial response, - lasting > 6 months, - and not expected in > 10% of the patients in this drug – organ situation. The primary objective is to assess whether ER can be associated with a low level of genomic instability in the tumor. Low genomic instability is defined by the presence of less than the 5th quantile of genomic alterations (mutations, amplifications, deletions) to be expected in the given tumor type as per TCGA database. For each tumor type, the null hypothesis H0: π = 0.05 will be tested, against the one-sided alternative hypothesis π > 0.05. For each of the 6 cohorts, a sample size of 44 patients is necessary to achieve 80% power at π = 15 with a one-sided level 5% test. Patients presenting an ER will be identified retrospectively, in a nationwide manner, then monthly reviewed and validated for inclusion by a panel of pathology experts. As of February 2019, 75 patients have been included. The identification of molecular traits associated with ER might serve the development of predictive classifiers for precision medicine. This study also represents a unique opportunity to better understand cancer biology. Clinical trial information: NCT02701907.
Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy
