Negative hyper-selection of metastatic colorectal cancer patients for anti-EGFR monoclo na l antibodies: the PRESSING case-control study

Abstract

Background

Refining the selection of metastatic colorectal cancer (mCRC) patients candidates for anti-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 signaling pathways, have been suggested by preclinical and retrospective studies.

Patients and methods

We conducted this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of rare genomic alterations (PRESSING panel), including HER2/MET amplifications, ALK/ROS1/NTRK1-3/RET fusions, and HER2/PI3K/PTEN/AKT1 mutations. Hypothesizing a prevalence of candidate alterations of 15% and 0% in resistant and sensitive RAS and BRAF wild-type patients, respectively, with 2-sided alpha- and beta-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 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 mCRC patients candidates for anti-EGFRs, partially explaining and further corroborating the predictive ability of primary tumour sidedness.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2huqgBc