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Clinical Trial
. 2011 May;22(5):1078-1087.
doi: 10.1093/annonc/mdq588. Epub 2010 Nov 3.

Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study

L Licitra  1 , R Mesia  2 , F Rivera  3 , É Remenár  4 , R Hitt  5 , J Erfán  6 , S Rottey  7 , A Kawecki  8 , D Zabolotnyy  9 , M Benasso  10 , S Störkel  11 , S Senger  12 , C Stroh  13 , J B Vermorken  14
Affiliations
Clinical Trial

Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study

L Licitra et al. Ann Oncol. 2011 May.

Abstract

Background: The phase III EXTREME study demonstrated that combining cetuximab with platinum/5-fluorouracil (5-FU) significantly improved overall survival in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) compared with platinum/5-FU alone. The aim of this investigation was to evaluate elevated tumor EGFR gene copy number as a predictive biomarker in EXTREME study patients.

Patients and methods: Dual-color FISH was used to determine absolute and relative EGFR copy number. Models of differing stringencies were used to score and investigate whether increased copy number was predictive for the activity of cetuximab plus platinum/5-FU.

Results: Tumors from 312 of 442 patients (71%) were evaluable by FISH and met the criteria for statistical analysis. A moderate increase in EGFR copy number was common, with high-level amplification of the gene occurring in a small fraction of tumors (∼11%). Considering each of the models tested, no association of EGFR copy number with overall survival, progression-free survival or best overall response was found for patients treated with cetuximab plus platinum/5-FU.

Conclusion: Tumor EGFR copy number is not a predictive biomarker for the efficacy of cetuximab plus platinum/5-FU as first-line therapy for patients with R/M SCCHN.

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Figures

Figure 1.
Figure 1.
Representative FISH analyses showing tumors comprising cells with (A) normal gene copy number (two signals for each probe per cell); (B) high-level EGFR gene amplification, as demonstrated by the presence of large EGFR signal clusters; (C) low/moderate-level gene amplification, as demonstrated by the presence of small EGFR signal clusters; (D) polysomy, as demonstrated by >2 EGFR/CEN-7 signals per cell; (E) heterogeneity for EGFR copy number, with only a subpopulation showing high-level gene amplification and (F) heterogeneity for EGFR copy number, with certain cells showing polysomy and others, normal copy numbers.
Figure 2.
Figure 2.
Scatter and box plots did not demonstrate an association between FISH score and (A) overall survival time, (B) progression-free survival (PFS) time or (C) best overall response, for patients in either study arm, when EGFR copy number was analyzed according to enrichment models A–E, as indicated. The upper and lower boundaries of each box plot represent the 25th and 75th percentile and the horizontal lines within the box represent the median values. The bars extend to the last observation not defined as an extreme value (represented by + symbols) or to the minimum/maximum values if an extreme value was not identified. CR, complete response; CT, chemotherapy; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.
Figure 2.
Figure 2.
Scatter and box plots did not demonstrate an association between FISH score and (A) overall survival time, (B) progression-free survival (PFS) time or (C) best overall response, for patients in either study arm, when EGFR copy number was analyzed according to enrichment models A–E, as indicated. The upper and lower boundaries of each box plot represent the 25th and 75th percentile and the horizontal lines within the box represent the median values. The bars extend to the last observation not defined as an extreme value (represented by + symbols) or to the minimum/maximum values if an extreme value was not identified. CR, complete response; CT, chemotherapy; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.
Figure 2.
Figure 2.
Scatter and box plots did not demonstrate an association between FISH score and (A) overall survival time, (B) progression-free survival (PFS) time or (C) best overall response, for patients in either study arm, when EGFR copy number was analyzed according to enrichment models A–E, as indicated. The upper and lower boundaries of each box plot represent the 25th and 75th percentile and the horizontal lines within the box represent the median values. The bars extend to the last observation not defined as an extreme value (represented by + symbols) or to the minimum/maximum values if an extreme value was not identified. CR, complete response; CT, chemotherapy; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.
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References

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