Abstract 451P
Background
About 40% of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy do not achieve favourable outcomes. Treatment failure results not only in a poorer prognosis but also in increased healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumour and assess their effect on anti-EGFR response.
Methods
Tumour (somatic) and blood (germline) DNA samples were obtained from two well-defined cohorts of mCRC patients: 38 sensitive (CR/PR at the 1st CT-scan or >6 months SD) versus 23 resistant (PD at the 1st CT-scan) to EGFR blockade. Genetic variant screening of 43 EGFR-related genes was performed by using targeted next-generation sequencing. Relevant clinical data was collected through chart review to assess genetic results.
Results
After genetic analyses, five resistant patients carrying a validated mutation of non-response in RAS/BRAF were excluded from the study. We found eight new potential somatic variants of non-response. Three of them were located in insulin-related genes (p.Ile668Asn and p.Glu1218Lys in IGF1R, p.Thr1156Met in IRS2). Another three variants were found in genes belonging to the LRIG family (p.Thr152Thr in LRIG1, p.Ser697Leu in LRIG2 and p.Val812Met in LRIG3). The remaining two variants were found in NRAS (p.Gly115Glufs*46) and PDGFRA (p.Thr301Thr). No somatic variants of good response were identified. Table: 451P
| Gene | Genetic variant | Sensitive patients (n= 38) | Resistant patients (n= 18) | P-value (Fisher’s test) |
| IGF1R | NM_001291858.1: c.2003T>A; p.Ile668Asn | 0 | 3 | 0.029 |
| NM_001291858.1: c.3652G>A; p.Glu1218Lys | 0 | 4 | 0.008 | |
| IRS2 | NM_003749.2: c.3467C>T; p.Thr1156Met | 0 | 3 | 0.029 |
| LRIG1 | NM_015541: c.456G>A; p.Thr152Thr | 0 | 4 | 0.008 |
| LRIG2 | NM_014813.2: c.2090C>T; p.Ser697Leu | 0 | 3 | 0.029 |
| LRIG3 | NM_001136051.2: c.2434G>A; p.Val812Met | 0 | 3 | 0.029 |
| NRAS | NM_002524.3: c.344del; p.Gly115Glufs*46 | 0 | 3 | 0.029 |
| PDGFRA | NM_001347828: c.903G>A; p.Thr301Thr | 0 | 3 | 0.029 |
Conclusions
This study shows that novel somatic genetic variants along the EGFR-triggered pathway could modulate the response to anti-EGFR drugs in mCRC patients and reveals the influence of insulin-related and LRIG genes on anti-EGFR efficacy. These findings can help in the future to characterize those patients resistant to anti-EGFR treatments despite harbouring RAS/BRAF wild-type tumours.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Hospital de la Santa Creu i Sant Pau.
Funding
Asociación Española Contra el Cáncer.
Disclosure
D. Páez: Advisory/Consultancy: Amgen; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: F. Hoffmann-La Roche Ltd. All other authors have declared no conflicts of interest.