539P - Tumor heterogeneity and efficacy of first-line cetuximab + FOLFIRI in KRAS mutant metastatic colorectal cancer (mCRC) patients (pts) of the CAPRI G...

Date 29 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Biomarkers
Colon Cancer
Rectal Cancer
Presenter Nicola Normanno
Citation Annals of Oncology (2014) 25 (suppl_4): iv167-iv209. 10.1093/annonc/mdu333
Authors N. Normanno1, A.M. Rachiglio2, M. Lambiase2, E. Martinelli3, F. Fenizia2, C. Esposito2, C. Roma2, T. Troiani4, F. Tatangelo5, G. Botti5, D. Rizzi6, E. Maiello7, G. Colucci6, F. Ciardiello3
  • 1Dept. Biologia Cellulare E Bioterapie, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, 80131 - Napoli/IT
  • 2Laboratory Of Pharmacogenomics, Centro di Ricerche Oncologiche di Mercogliano (CROM), Mercogliano/IT
  • 3Dipt. Di Internistica Clinica E Sperimentale, AOU Seconda Università degli Studi di Napoli (AOU-SUN), 80131 - Napoli/IT
  • 4Dip. Medico Chirurgico Di Internistica, Azienda Ospedaliera Universitaria Policlinico Federico II-AOU Federico II, 80131 - Napoli/IT
  • 5Dept. Anatomia Patologica, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, 80131 - Napoli/IT
  • 6Goim, Gruppo Oncologico dell'Italia Meridionale, Bari/IT
  • 7Oncology Dept., IRCCS Casa Sollievo della Sofferenza, 71013 - San Giovanni Rotondo/IT

Abstract

Aim

Cetuximab treatment in mCRC is restricted to pts with KRAS and NRAS wt tumors. Recent data suggest that low levels of KRAS mutant alleles might confer resistance to anti-EGFR therapies.

Methods

In the CAPRI GOIM trial, KRAS exon 2 wt mCRC pts received first line cetuximab plus FOLFIRI. Primary endpoint was progression-free survival (PFS). Tumor samples were assessed by next generation sequencing (NGS) with the Ion AmpliSeq™ Lung and Colon Cancer Panel that covers over 500 mutations in hot spot regions of 22 genes. The allelic frequency of mutant KRAS, NRAS, BRAF and PIK3CA was normalized for the neoplastic cell content and multiplied by 2 to obtain the Heterogeneity Score (HS), which corresponds to the fraction of neoplastic cells carrying a specific mutation.

Results

NGS analysis was performed in 182 cases. Forty-five cases (24.7%) had mutations in KRAS, 24 (13.2%) in PIK3CA, 15 (8.2%) in BRAF, and 13 (7.1%) in NRAS. KRAS and NRAS mutations were mutually exclusive, whereas PIK3CA and BRAF mutations were detected in RAS mutant tumors. The KRAS HS ranged between 12 and 260, indicating a wide heterogeneity of KRAS mutant alleles content in CRC. However, the KRAS HS mean value of 90,93 and median value of 84,44 suggested that in most CRC the majority of neoplastic cells carry a mutant KRAS allele. Similar findings were observed for NRAS (HS range 35,5-146,67; mean 102,77; median 117,14). In contrast, in BRAF (HS range 17,14-120; mean 54,82; median 54,29) and PIK3CA (HS range 14,29-120; mean 54,82; median 54,29) mutant cases only a fraction of neoplastic cells seem to carry the mutant allele. The RR was 70% in KRAS mutant pts with an HS < 40 (low KRAS; n.10) and 45,7% in KRAS HS > 40 pts (high KRAS; n.35); mPFS were 7,97 and 8,37 months for low KRAS and high KRAS subgroups, respectively. Importantly, 7/10 low KRAS tumors had additional mutations in PIK3CA (n.6), TP53 (n.4), BRAF (n.2), ERBB2 (n.1), FGFR3 (n.1), and/or FBXW7 (n.1).

Conclusions

Pts carrying low levels of mutant KRAS alleles showed a mPFS similar to pts with high KRAS mutant allele frequency. However, this phenomenon could be due to the complex mutational profile of CRC rather than to the KRAS mutational status.

Disclosure

N. Normanno: Advisory Boards: Merck Serono, Amgen; F. Ciardiello: Advisory Boards: Roche, Merck Serono, Astellas, Bayer. All other authors have declared no conflicts of interest.