4878 - Next-generation sequencing (NGS) in metastatic colorectal cancer (mCRC): novel mutated genes and their effect on response to therapy (Alliance)

Background

CALGB (Alliance)/SWOG 80405 was a randomized phase III trial that found no difference in overall survival (OS) in first-line mCRC Patients (pts) treated with bevacizumab (Bev) or cetuximab (Cet) combined with the same chemotherapy. By applying NGS to tumour DNA collected from pts in the trial, we aimed to discover novel mutated genes associated with differential response to therapy with the biologics and prognosis.

Methods

Primary tumour DNA from 520 pts was profiled for somatic gene mutations. Mutations in 426 genes were determined by NGS (FoundationOne). OS was the primary endpoint, both as a time-to-event and a categorical (<20 or ≥ 20 months) variable. Cox proportional hazard models (hazard ratio, HR) and logistic regression (odds ratio, OR) were used, respectively, adjusted by MSI status, BRAF V600E, all RAS mutations, arm, gender, and age. Interactions between mutated genes and treatment (Bev versus Cet) on OS were tested.

Results

In Bev-treated pts, tumours with mutated IGF1 (6%) conferred worse OS than WT tumours (HR 2.8 [1.5-5.2], p = 0.0009), and tumours with mutated KDR (11%) conferred worse OS than WT tumours (OR 4.4 [1.6-12.3], p = 0.004). In Cet-treated pts, tumours with mutated FANCD2 (6%) conferred worse OS than WT tumours (HR 2.7 [1.4-5.3], p = 0.004), and tumours with mutated APC (74%) conferred better OS than WT tumours (OR 0.3 [0.1-0.6], p = 0.0009). RNF43-mutated tumours (12%) and SMARCA4-mutated tumours (6%) conferred worse OS in Cet-treated pts than Bev-treated pts (interaction p-value 0.002 and 0.0009, respectively). In all patients in the study, FANCI-mutated tumours (4%) conferred worse OS than WT tumours (HR 2.0 [1.2-3.3], p = 0.005; OR 5.0 [1.9-14.8], p = 0.002). The full set of NGS results will be presented, including the mutational map of tumour location.

Conclusions

To our knowledge, this is the largest and most comprehensive NGS analysis of somatic DNA mutations in tumours from mCRC pts treated with standard of care therapy. It provides novel gene candidates affecting response to Bev and Cet, each combined with chemotherapy, as well as mutated genes affecting the prognosis of patients. If validated in other phase III studies, these results may be used to guide treatment decisions in pts with mCRC.

Clinical trial identification

NCT00265850.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

U10CA180821, U10CA180882, U10CA180888 and U10CA180830 (SWOG); Genentech, Eli Lilly & Co., Pfizer, Sanofi.

Disclosure

X. Qu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech. M. Bertagnolli: Research grant / Funding (self): BMS; Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): Roche; Research grant / Funding (self): Sanofi; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Genentech. A. Venook: Research grant / Funding (self), travel: Genentech; Research grant / Funding (self): BMS; Travel / Accommodation / Expenses: Roche. O. Kabbarah: Full / Part-time employment: Genentech; Shareholder / Stockholder / Stock options: Roche. H.J. Lenz: Honoraria (self): Roche; Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.