543P - P16(INK4A) gene hypermethylation and KRAS mutation are independent predictors of FOLFIRI and cetuximab chemotherapy in patients with metastatic colo...

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Colon and Rectal Cancer
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Se Hyun Kim
Authors S.H. Kim1, K.H. Park2, S.J. Shin1, K.Y. Lee3, T.I. Kim1, N.K. Kim3, S.Y. Rha1, J.K. Roh1, J.B. Ahn4
  • 1Internal Medicine, Yonsei University College of Medicine, Seoul/KR
  • 2Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul/KR
  • 3Surgery, Yonsei University College of Medicine, Seoul/KR
  • 4Department Of Medical Oncology, Yonsei University College of Medicine, Seoul/KR



P16 (INK4a) inhibits cyclin dependent kinases (CDKs) and plays various roles in cancer and senescence. P16 aberrancy is frequently detected in various cancers and may contribute to multidrug resistance. Hypermethylation of CpG island of p16 occurs in a significant proportion in colorectal cancer (CRC) and also is one of the CpG island methylator phenotype (CIMP) markers.

Patients and method

We analyzed tumor samples from 49 patients with metastatic colorectal cancer (mCRC) who were treated with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) and cetuximab (1st line 22 pts, 2nd line 27 pts). Pyrosequencing was used to identify KRAS mutation and hypermethylation of 6 CpG island loci (p16, p14, MINT1, MINT2, MINT31, hMLH1) in DNA extracted from formalin-fixed paraffin-embedded specimens. To analyze the relation between methylation status of CIMP markers including p16 and clinical outcome, logistic regression and Cox regression were performed.


Hypermethylation of p16 gene was detected in 14 of 49 patients (28.6%) and was significantly associated with KRAS mutation (Fisher's exact, P = 0.01) and CIMP+ (Fisher's exact, P = 0.002). Patients with p16 unmethylated tumors had significant longer time to progression (TTP, median 9.0 vs 3.5 months; log-rank, P = 0.001) and overall survival (OS, median 44.9 vs 16.4 months; log-rank, P = 0.008) than those with p16 methylated tumors. KRAS mutation was also associated with shortened TTP (median 8.9 vs 4.4 months; HR = 3.1, P = 0.008) and OS (median 44.9 vs 16.1 months; HR = 5.2, P < 0.0001). Patients with both KRAS and p16 aberrancy (n = 6) had markedly shortened TTP (median 2.8 months) compared with those with either KRAS or p16 aberrancy (n = 11; median 8.6 months, P = 0.021) or those with neither of them (n = 32; median 9.0 months, P <0.0001). Although a trend toward shorter TTP and OS was seen in CIMP + , this was not statistically significant. In multivariate analysis, KRAS mutation and p16 methylation were independently associated with shorter TTP (KRAS mutation HR = 2.58, P = 0.04; p16 methylation HR = 2.98, P = 0.02).


Promoter CpG island hypermethylation of p16 was predictive of clinical outcome in mCRC patients treated with cetuximab and FOLFIRI, irrespective of KRAS mutation.


All authors have declared no conflicts of interest.