Gain of ALK Gene Copy Number May Predict Lack of Benefit from Anti-EGFR Treatment in Patients with Advanced Colorectal Cancer and RAS-RAF-PI3KCA Wild-Type Status

Abstract

IntroductionAlthough cetuximab and panitumumab show an increased efficacy for patients with KRAS-NRAS-BRAF and PI3KCA wild-type metastatic colorectal cancer, primary resistance occurs in a relevant subset of molecularly enriched populations.Patients and MethodsWe evaluated the outcome of 68 patients with advanced colorectal cancer and RAS, BRAF and PI3KCA status according to ALK gene status (disomic vs. gain of ALK gene copy number – defined as mean of 3 to 5 fusion signals in ≥10% of cells). All consecutive patients received cetuximab and irinotecan or panitumumab alone for chemorefractory disease.ResultsNo ALK translocations or amplifications were detected. ALK gene copy number gain was found in 25 (37%) tumors. Response rate was significantly higher in patients with disomic ALK as compared to those with gain of gene copy number (70% vs. 32%; p = 0.0048). Similarly, progression-free survival was significantly different when comparing the two groups (6.7 vs. 5.3 months; p = 0.045). A trend was observed also for overall survival (18.5 vs. 15.6 months; p = 0.885).ConclusionGain of ALK gene copy number might represent a negative prognostic factor in mCRC and may have a role in resistance to anti-EGFR therapy.

Circulating Tumor Cells with Aberrant ALK Copy Number Predict Progression-Free Survival during Crizotinib Treatment in ALK-Rearranged Non–Small Cell Lung Cancer Patients

“…In tumor biopsies from ALK-rearranged patients, ALK-CNG is frequent but in most cases limited to three or four ALK-copies. The presence of ALK-CNG tumor cells was also associated with aggressive clinical outcome in several cancers such as neuroblastoma, breast, and colorectal cancer, with most ALK-CNG co-occurring with other gene aberrations such as MYCN, MET, or EGFR (36,(47)(48)(49)(50). Hyperploid tumor cells harboring a high number of ALK-copies are rarely found in tumor biopsies from ALK-rearranged patients but are a large contingent of CTCs.…”

Cost-effectiveness of RAS screening before monoclonal antibodies therapy in metastatic colorectal cancer based on FIRE3 Study

“…Although more precise genetic mutation testing will guarantee personalized treatment, which could protect portions of population from unnecessary toxicity and socio-sanitary costs, the substantial supernumerary testing and treatment costs impose a considerable health burden on patients as well as society 10 . Hence the cost-effectiveness of RAS screening before anti-EGFR therapy in mCRC is urgently needed.…”

ALK: a tyrosine kinase target for cancer therapy

“…However, there was no association of ALK amplification to either ALK protein expression or downstream phospho-STAT3 expression in these tumors. Copy-number gain of ALK was detected in 3.4% (26/756) (Bavi et al 2013) and 37% (25/68) (Pietrantonio et al 2014) of colorectal cancer patients. Copy-number increase does not correlate with protein expression in the above studies, but was associated with poor prognosis and may predict lack of benefit from anti-EGFR treatment in colorectal cancer patients.…”