Letter to the Editor

BJC Open article

British Journal of Cancer (2014) 111, 2203–2204. doi:10.1038/bjc.2014.401 www.bjcancer.com
Published online 12 August 2014

Coexistence of KRAS mutation with mutant but not wild-type EGFR predicts response to tyrosine-kinase inhibitors in human lung cancer

A Choughule1,4, R Sharma1,2,4, V Trivedi1,2,4, A Thavamani1,2, V Noronha1, A Joshi1, S Desai3, P Chandrani2, P Sundaram2, S Utture1, N Jambhekar3, S Gupta1, J Aich2, K Prabhash1 and A Dutt2

  1. 1Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Center, Mumbai, India
  2. 2Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Center, Navi Mumbai, India
  3. 3Department of Pathology, Tata Memorial Hospital, Tata Memorial Center, Mumbai, India

Correspondence: Dr J Aich or Dr K Prabhash; or Dr A Dutt, E-mail: jyoti.aich@gmail.com or E-mail: kprabhash1@gmail.com or ; E-mail: adutt@actrec.gov.in

4These authors contributed equally to this work.

Sir,

EGFR and KRAS mutations occur mutually exclusively in NSCLC, suggesting functional redundancy (Kosaka et al, 2004; Pao et al, 2005; Shigematsu et al, 2005; Tam et al, 2006). However, they predict contrasting response rates to tyrosine-kinase inhibitors (TKIs) – while EGFR mutation predicts longer progression-free survival rate (Lynch et al, 2004; Mok et al, 2009; Fukuoka et al, 2011; Chougule et al, 2013), adverse prognosis is associated with patients harbouring KRAS mutations (Mao et al, 2010; Ihle et al, 2012). The recently reported co-occurrence of KRAS and EGFR activating mutations (Li et al, 2014) in 30 of 5125 patients raises questions about the relative values of EGFR and KRAS mutation status as predictors of outcome in NSCLC. This has obvious implications for routine KRAS testing in this disease, potentially precluding EGFR TKI therapy from some patients, similar to the current practice in colorectal cancer (Lievre et al, 2006).

EGFR mutations occur less frequently among Caucasians (10–15%) compared to East Asians (30–60%) (Lynch et al, 2004; Paez et al, 2004) in contrast to KRAS mutations for which the situation is opposite – Caucasians vs East Asians, 25–50% vs 5–15%, respectively (Mao et al, 2010; Roberts et al, 2010). We recently reported an intermediate frequency of EGFR mutations (23%) in a study involving 907 Indian NSCLC patients (Chougule et al, 2013). In a smaller study at our centre there was 74% response to TKI among patients with tumours having EGFR mutations compared to 5% in those with wild-type EGFR (Noronha et al, 2013). We performed directed sequencing of KRAS exons 2 and 3 in 86 patients from the same cohort and correlated its status with outcome after treatment with EGFR TKI (see Supplementary Table S1). There were 15 patients with KRAS G12C and 1 patient with KRAS G12V mutation for an overall mutation rate of 18.6%. Three of these 86 patients had coincident KRAS G12C and EGFR Exon-19 Del (E746-A750) mutations (Table 1), which were independently validated in each of the three samples by four orthogonal technologies (Sequenom Mass Array genotyping, Taqman Real Time PCR, Sanger Sequencing and SNaPShot PCR; see Supplementary Figure 1). All these three patients had partial response to EGFR TKI. However, only 1 of the remaining 13 patients with KRAS mutation had partial response and his tumour had wild-type EGFR with unknown copy number. This is consistent with previous studies: response to EGFR TKI in one of five patients harbouring KRAS mutation with unknown EGFR copy number or mutation status (Zhu et al, 2008); 1 response in 20 KRAS mutant patients who also harboured EGFR amplification but not EGFR mutation (Gumerlock et al, 2005); and response to gefitinib in three of five patients with coincident EGFR and KRAS mutations (Benesova et al, 2010). Furthermore, it has been shown that when KRAS and EGFR mutations are coincident in the same tumour, the genetic lesion in the latter is almost exclusively in exon-19, with virtually no occurrence of exon-21 abnormalities (Li et al, 2014). This was also true in all three cases in our series with coincident EGFR and KRAS mutations. Of note, mutations in exon-19 have been shown to predict a higher response to EGFR TKI than those in exon-21 (Mitsudomi et al, 2005).


In summary, these data suggest that NSCLC patients with KRAS mutations are unlikely to respond to EGFR TKI therapy in the absence of coincident EGFR alterations. Therefore additional KRAS molecular testing may not add predictive value in selecting patients for EGFR TKI therapy and cannot be routinely recommended.

Top

References

  1. Benesova L, Minarik M, Jancarikova D, Belsanova B, Pesek M (2010) Multiplicity of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC) patients treated with tyrosine kinase inhibitors. Anticancer Res 30(5): 1667–1671. | PubMed | ISI |
  2. Chougule A, Prabhash K, Noronha V, Joshi A, Thavamani A, Chandrani P, Upadhyay P, Utture S, Desai S, Jambhekar N, Dutt A (2013) Frequency of EGFR mutations in 907 lung adenocarcioma patients of Indian ethnicity. PLoS One 8(10): e76164. | Article | PubMed |
  3. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS (2011) Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 29(21): 2866–2874. | Article | PubMed | ISI | CAS |
  4. Gumerlock PH, Holland WS, Chen H, Franklin WA, Hirsch FR, Mack PC, Davies AM, McCoy J, West HJ, Gandara DR (2005) Mutational analysis of K-RAS and EGFR implicates KRAS as a resistance marker in the Southwest Oncology Group (SWOG) trial S0126 of bronchioalveolar carcinoma (BAC) patients (pts) treated with gefitinib. Proc Am Soc Clin Oncol 23(Suppl 623s): : abstr 7008.
  5. Ihle NT, Byers LA, Kim ES, Saintigny P, Lee JJ, Blumenschein GR, Tsao A, Liu S, Larsen JE, Wang J, Diao L, Coombes KR, Chen L, Zhang S, Abdelmelek MF, Tang X, Papadimitrakopoulou V, Minna JD, Lippman SM, Hong WK, Herbst RS, Wistuba II, Heymach JV, Powis G (2012) Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. J Natl Cancer Inst 104(3): 228–239. | Article | PubMed | ISI | CAS |
  6. Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T, Mitsudomi T (2004) Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res 64(24): 8919–8923. | Article | PubMed | ISI | CAS |
  7. Li S, Li L, Zhu Y, Huang C, Qin Y, Liu H, Ren-Heidenreich L, Shi B, Ren H, Chu X, Kang J, Wang W, Xu J, Tang K, Yang H, Zheng Y, He J, Yu G, Liang N (2014) Coexistence of EGFR with KRAS, or BRAF, or PIK3CA somatic mutations in lung cancer: a comprehensive mutation profiling from 5125 Chinese cohorts. Br J Cancer 110(11): 2812–2820. | Article | PubMed | ISI |
  8. Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Côté JF, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66(8): 3992–3995. | Article | PubMed | ISI | CAS |
  9. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350(21): 2129–2139. | Article | PubMed | ISI | CAS |
  10. Mao C, Qiu LX, Liao RY, Du FB, Ding H, Yang WC, Li J, Chen Q (2010) KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies. Lung Cancer 69(3): 272–278. | Article | PubMed | ISI |
  11. Mitsudomi T, Kosaka T, Endoh H, Horio Y, Hida T, Mori S, Li J, Chen Q (2005) Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol 23(11): 2513–2520. | Article | PubMed | ISI | CAS |
  12. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361(10): 947–957. | Article | PubMed | ISI | CAS |
  13. Noronha V, Prabhash K, Thavamani A, Chougule A, Purandare N, Joshi A, Sharma R, Desai S, Jambekar N, Dutt A, Mulherkar R (2013) EGFR mutations in Indian lung cancer patients: clinical correlation and outcome to EGFR targeted therapy. PLoS One 8(4): e61561. | Article | PubMed |
  14. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304(5676): 1497–1500. | Article | PubMed | ISI | CAS |
  15. Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M, Zakowski MF, Heelan RT, Kris MG, Varmus HE (2005) KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2(1): e17. | Article | PubMed | CAS |
  16. Roberts PJ, Stinchcombe TE, Der CJ, Socinski MA (2010) Personalized medicine in non-small-cell lung cancer: is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy? J Clin Oncol 28(31): 4769–4777. | Article | PubMed | ISI |
  17. Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, Fong KM, Lee H, Toyooka S, Shimizu N, Fujisawa T, Feng Z, Roth JA, Herz J, Minna JD, Gazdar AF (2005) Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97(5): 339–346. | Article | PubMed | ISI | CAS |
  18. Tam IY, Chung LP, Suen WS, Wang E, Wong MC, Ho KK, Lam WK, Chiu SW, Girard L, Minna JD, Gazdar AF, Wong MP (2006) Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features. Clin Cancer Res 12(5): 1647–1653. | Article | PubMed | ISI | CAS |
  19. Zhu CQ, da Cunha Santos G, Ding K, Sakurada A, Cutz JC, Liu N, Zhang T, Marrano P, Whitehead M, Squire JA, Kamel-Reid S, Seymour L, Shepherd FA, Tsao MS (2008) Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 26(26): 4268–4275. | Article | PubMed | ISI | CAS |

Supplementary Information accompanies this paper on British Journal of Cancer website

BJC Open article

This work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License.
To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/