European Archives of Oto-Rhino-Laryngology

, Volume 276, Issue 2, pp 541–550 | Cite as

Benefit of cetuximab addition to a platinum–fluorouracil-based chemotherapy according to KRAS-LCS6 variant in an unselected population of recurrent and/or metastatic head and neck cancers

  • Vianney BastitEmail author
  • Nicolas Bon-Mardion
  • Jean-Michel Picquenot
  • Vinciane Rainville
  • Cristian Moldovan
  • Arnaud François
  • Agnès Loeb
  • Sébastien Thureau
  • Dorel Manu
  • Fabrice Jardin
  • Jean-Paul Marie
  • Fréderic Di Fiore
  • Florian Clatot
Head & Neck



To evaluate the benefit of cetuximab (Cx) addition to platinum-based and 5-fluorouracil chemotherapy (PFU) in unselected recurrent and/or metastatic head and neck cancer patients (R/MHNC) according to KRAS-LCS6 variant status.


All patients who received at least two PFU ± Cx cycles from 2004 to 2014 were retrospectively included into to two distinct study periods according to Cx implementation: patients treated by PFU alone before 2009 and those treated by PFU + Cx from 2009. Primary objective was to evaluate the progression-free survival (PFS) between the two groups. Secondary objectives were to analyze the overall survival (OS) between the two groups and the prognostic impact of KRAS-LCS6 variant. Factors associated with survival were determined by a Cox multivariate analysis including age, WHO performance status (PS), type of treatment, KRAS-LCS6 variant, Charlson’s score and p16 status.


Overall, 134 patients were included: 59 (44%) in PFU group and 75 (56%) in PFU + Cx group. Baseline characteristics were well balanced including 30% of patients with 2–3 PS. Median PFS was significantly improved in PFU + Cx group compared to PFU group (6.1 vs 4.4 months, respectively, HR 0.68, p = 0.02) and with a trend for better OS. A KRAS-LCS6 variant was found in 27 (25%) of samples without prognostic impact neither in whole population nor according to treatment. In multivariate analysis, addition of Cx to PFU was the only factor significantly associated with a better PFS (p = 0.01, HR 0.6).


Our results suggest that PFU + Cx combination may be effective in unselected population of R/MHNC regardless the KRAS-LCS6 variant status.


Recurrent and/or metastatic head and neck cancers Cetuximab Unselected population KRAS-LCS6 Rs61764370 Prognosis 



The authors are grateful to Dr. M Bubenheim for his help in statistics and to Dr. T. Ducastelle for his help in collecting histological samples.


This is an academic research. Funding was provided by the Department of Medical Oncology of the Centre Henri Becquerel.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

405_2018_5235_MOESM1_ESM.docx (23 kb)
Supplementary material 1 (DOCX 22 KB)


  1. 1.
    Rettig EM, D’Souza G (2015) Epidemiology of head and neck cancer. Surg Oncol Clin 24:379–396. CrossRefGoogle Scholar
  2. 2.
    Pignon J-P, Maître A le, Maillard E, Bourhis J (2009) Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 92:4–14. CrossRefPubMedGoogle Scholar
  3. 3.
    Marur S, Forastiere AA (2008) Head and neck cancer: changing epidemiology, diagnosis, and treatment. Mayo Clin Proc 83:489–501. CrossRefPubMedGoogle Scholar
  4. 4.
    Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer H-R, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116–1127. CrossRefPubMedGoogle Scholar
  5. 5.
    Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, Kish JA, McClure S, VonFeldt E, Williamson SK (1992) Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 10:1245–1251CrossRefPubMedGoogle Scholar
  6. 6.
    Feldman R, Gatalica Z, Knezetic J, Reddy S, Nathan C-A, Javadi N, Teknos T (2016) Molecular profiling of head and neck squamous cell carcinoma. Head Neck 38:E1625–E1638. CrossRefPubMedGoogle Scholar
  7. 7.
    Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK (2010) Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 11:21–28. CrossRefPubMedGoogle Scholar
  8. 8.
    van der Linden N, Buter J, Pescott CP, Lalisang RI, de Boer JP, de Graeff A, van Herpen CML, Baatenburg de Jong RJ, Uyl-de Groot CA (2016) Treatments and costs for recurrent and/or metastatic squamous cell carcinoma of the head and neck in the Netherlands. Eur Arch Otorhinolaryngol 273:455–464. CrossRefPubMedGoogle Scholar
  9. 9.
    Chung CH, Lee JW, Slebos RJ, Howard JD, Perez J, Kang H, Fertig EJ, Considine M, Gilbert J, Murphy BA, Nallur S, Paranjape T, Jordan RC, Garcia J, Burtness B, Forastiere AA, Weidhaas JB (2014) A 3′-UTR KRAS-variant is associated with cisplatin resistance in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol 25:2230–2236. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Chin LJ, Ratner E, Leng S, Zhai R, Nallur S, Babar I, Muller R-U, Straka E, Su L, Burki EA, Crowell RE, Patel R, Kulkarni T, Homer R, Zelterman D, Kidd KK, Zhu Y, Christiani DC, Belinsky SA, Slack FJ, Weidhaas JB (2008) A SNP in a let-7 microRNA complementary site in the KRAS 3′UTR increases non-small cell lung cancer risk. Cancer Res 68:8535–8540. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    De Ruyck K, Duprez F, Ferdinande L, Mbah C, Rios-Velazquez E, Hoebers F, Praet M, Deron P, Bonte K, Speel E-J, Libbrecht L, De Neve W, Lambin P, Thierens H (2014) A let-7 microRNA polymorphism in the KRAS 3′-UTR is prognostic in oropharyngeal cancer. Cancer Epidemiol 38:591–598. CrossRefPubMedGoogle Scholar
  12. 12.
    Christensen BC, Moyer BJ, Avissar M, Ouellet LG, Plaza SL, McClean MD, Marsit CJ, Kelsey KT (2009) A let-7 microRNA-binding site polymorphism in the KRAS 3′ UTR is associated with reduced survival in oral cancers. Carcinogenesis 30:1003–1007. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Weidhaas JB, Harris J, Schaue D, Chen AM, Chin R, Axelrod R, El-Naggar AK, Singh AK, Galloway TJ, Raben D, Wang D, Matthiesen C, Avizonis VN, Manon RR, Yumen O, Nguyen-Tan PF, Trotti A, Skinner H, Zhang Q, Ferris RL, Sidransky D, Chung CH (2017) The KRAS-variant and cetuximab response in head and neck squamous cell cancer: a secondary analysis of a randomized clinical trial. JAMA Oncol 3:483–491. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Lynggaard CD, Therkildsen MH, Kristensen CA, Specht L (2015) The EXTREME regimen for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): treatment outcome in a single institution cohort. Acta Oncol 54:1071–1075. CrossRefPubMedGoogle Scholar
  15. 15.
    de Mello RA, Gerós S, Alves MP, Moreira F, Avezedo I, Dinis J (2014) Cetuximab plus platinum-based chemotherapy in head and neck squamous cell carcinoma: a retrospective study in a single comprehensive European cancer institution. PloS One 9:e86697. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Chang PM-H, Hsieh Y-Y, Chen M-H, Tzeng C-H, Chu P-Y, Chang S-Y, Chen P-M, Yang M-H (2010) Cetuximab-based therapy in recurrent/metastatic head and neck squamous cell carcinoma: experience from an area in which betel nut chewing is popular. J Chin Med Assoc 73:292–299. CrossRefPubMedGoogle Scholar
  17. 17.
    Yoshino T, Hasegawa Y, Takahashi S, Monden N, Homma A, Okami K, Onozawa Y, Fujii M, Taguchi T, Blas B de, Beier F, Tahara M (2013) Platinum-based chemotherapy plus cetuximab for the first-line treatment of Japanese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: results of a phase II trial. Jpn J Clin Oncol 43:524–531. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Soulières D, Aguilar JL, Chen E, Misiukiewicz K, Ernst S, Lee HJ, Bryant K, He S, Obasaju CK, Chang S-C, Chin S, Adkins D (2016) Cetuximab plus platinum-based chemotherapy in head and neck squamous cell carcinoma: a randomized, double-blind safety study comparing cetuximab produced from two manufacturing processes using the EXTREME study regimen. BMC Cancer 16:.
  19. 19.
    Herbst RS, Arquette M, Shin DM, Dicke K, Vokes EE, Azarnia N, Hong WK, Kies MS (2005) Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol 23:5578–5587. CrossRefPubMedGoogle Scholar
  20. 20.
    Ying H-Q, Wang F, He B-S, Pan Y-Q, Gao T-Y, Xu Y-Q, Li R, Deng Q-W, Sun H-L, Wang S-K (2014) The involvement of Kras gene 3′-UTR polymorphisms in risk of cancer and influence on patient response to anti-EGFR therapy in metastatic colorectal cancer: a meta-analysis. OncoTargets Ther 7:1487–1496. Google Scholar
  21. 21.
    Zhang S-Y, Shi J (2016) rs61764370 polymorphism of Kras and risk of cancer in Caucasian population: a meta-analysis. J Cancer Res Ther 12:699. CrossRefPubMedGoogle Scholar
  22. 22.
    Smits KM, Paranjape T, Nallur S, Wouters KAD, Weijenberg MP, Schouten LJ, van den Brandt PA, Bosman FT, Weidhaas JB, van Engeland M (2011) A let-7 microRNA SNP in the KRAS 3′UTR is prognostic in early-stage colorectal cancer. Clin Cancer Res 17:7723–7731. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Graziano F, Canestrari E, Loupakis F, Ruzzo A, Galluccio N, Santini D, Rocchi M, Vincenzi B, Salvatore L, Cremolini C, Spoto C, Catalano V, D’Emidio S, Giordani P, Tonini G, Falcone A, Magnani M (2010) Genetic modulation of the Let-7 microRNA binding to KRAS 3′-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab-irinotecan. Pharmacogenom J 10:458–464. CrossRefGoogle Scholar
  24. 24.
    Hollestelle A, Van Der Baan FH, Berchuck A, Johnatty SE, Aben KK, Agnarsson BA, Aittomäki K, Alducci E, Andrulis IL, Anton-Culver H, others (2016) No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer. Gynecol Oncol 141:386–401CrossRefPubMedGoogle Scholar
  25. 25.
    Paranjape T, Heneghan H, Lindner R, Keane FK, Hoffman A, Hollestelle A, Dorairaj J, Geyda K, Pelletier C, Nallur S, Martens JW, Hooning MJ, Kerin M, Zelterman D, Zhu Y, Tuck D, Harris L, Miller N, Slack F, Weidhaas J (2011) A 3′-untranslated region KRAS variant and triple-negative breast cancer: a case-control and genetic analysis. Lancet Oncol 12:377–386. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Crowley EH, Arena S, Lamba S, Di Nicolantonio F, Bardelli A (2014) Targeted knock-in of the polymorphism rs61764370 does not affect KRAS expression but reduces let-7 levels. Hum Mutat 35:208–214. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Vianney Bastit
    • 1
    • 2
    • 9
    Email author
  • Nicolas Bon-Mardion
    • 2
  • Jean-Michel Picquenot
    • 3
    • 4
  • Vinciane Rainville
    • 4
  • Cristian Moldovan
    • 5
  • Arnaud François
    • 6
  • Agnès Loeb
    • 7
  • Sébastien Thureau
    • 8
  • Dorel Manu
    • 1
  • Fabrice Jardin
    • 4
  • Jean-Paul Marie
    • 2
  • Fréderic Di Fiore
    • 4
    • 5
  • Florian Clatot
    • 4
    • 5
  1. 1.Department of Head and Neck SurgeryHenri Becquerel CentreRouenFrance
  2. 2.Department of Head and Neck SurgeryRouen University HospitalRouenFrance
  3. 3.Department of BiopathologyHenri Becquerel CentreRouenFrance
  4. 4.IRON Group, Normandy Centre for Genomic and Personalized Medicine, Rouen University Hospital, UNIROUEN, Inserm U1245, rue de GermontNormandie UniversitéRouenFrance
  5. 5.Department of Medical OncologyHenri Becquerel CentreRouenFrance
  6. 6.Department of BiopathologyRouen University HospitalRouenFrance
  7. 7.Department of Biomedical InformaticsHenri Becquerel CentreRouenFrance
  8. 8.Department of Radiation therapyHenri Becquerel CentreRouenFrance
  9. 9.Department of ENT and Head and Neck SurgeryCentre François BaclesseCaenFrance

Personalised recommendations