Reply to ‘Cetuximab-related skin toxicity and efficacy: do we understand the mechanisms?’ by Evesque et al.

We read with great interest the letter ‘Cetuximab-related skin toxicity and efficacy: do we understand the mechanisms?’ by Evesque et al.1Evesque L. Francois E. Milano G. Cetuximab-related skin toxicity and efficacy: do we understand the mechanisms?.Ann Oncol. 2020; 31: 964-965Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar in reply to our previously published article.2Holch J.W. Held S. Stintzing S. et al.Relation of cetuximab-induced skin toxicity and early tumor shrinkage in metastatic colorectal cancer patients: results of the randomized phase 3 trial FIRE-3 (AIO KRK0306).Ann Oncol. 2020; 31: 72-78Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar We thank the authors for complementing our own work with biological and pharmacological hypotheses which might link cetuximab-induced skin toxicity (Cet-ST) to outcomes in patients with metastatic colorectal cancer (mCRC). In our article, we focused on the detailed characterization of the empirically well-investigated impact of Cet-ST on patient survival. Here, we evaluated the prognostic and predictive relevance considering also early tumor shrinkage (ETS), another on-treatment surrogate for clinical outcome in patients with mCRC. We intentionally decided against the presentation of hypotheses regarding underlying biological mechanisms, as they are all based on preliminary data and an adequate exploration would have exceeded the framework of our paper. This is illustrated by the example of polymorphisms in the intron 1 of the EGFR gene (epithelial growth factor receptor). According to Evesque and co-workers, different polymorphisms are supposed to impact on treatment efficacy of anti-EGFR-directed therapies. Here, the authors reference publications recording back to 2004 and 2008.3Amador M.L. Oppenheimer D. Perea S. et al.An epidermal growth factor receptor intron 1 polymorphism mediates response to epidermal growth factor receptor inhibitors.Cancer Res. 2004; 64: 9139-9143Crossref PubMed Scopus (233) Google Scholar,4Graziano F. Ruzzo A. Loupakis F. et al.Pharmacogenetic profiling for cetuximab plus irinotecan therapy in patients with refractory advanced colorectal cancer.J Clin Oncol. 2008; 26: 1427-1434Crossref PubMed Scopus (109) Google Scholar In fact, conflicting results from a prospective clinical trial were published subsequently and should be discussed.5Loupakis F. Antoniotti C. Cremolini C. et al.Prospective study of EGFR intron 1 (CA)n repeats variants as predictors of benefit from cetuximab and irinotecan in chemo-refractory metastatic colorectal cancer (mCRC) patients.Pharmacogenomics J. 2014; 14: 322-327Crossref PubMed Scopus (9) Google Scholar We thank the authors for raising the important issue regarding an obvious imbalance in BRAF mutation status between Cet-ST subgroups, as displayed in Table 1 of our paper.2Holch J.W. Held S. Stintzing S. et al.Relation of cetuximab-induced skin toxicity and early tumor shrinkage in metastatic colorectal cancer patients: results of the randomized phase 3 trial FIRE-3 (AIO KRK0306).Ann Oncol. 2020; 31: 72-78Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Because of the limited number of patients with activating BRAF mutations, we refrained from integrating this parameter into the multivariate analysis (Figure 12Holch J.W. Held S. Stintzing S. et al.Relation of cetuximab-induced skin toxicity and early tumor shrinkage in metastatic colorectal cancer patients: results of the randomized phase 3 trial FIRE-3 (AIO KRK0306).Ann Oncol. 2020; 31: 72-78Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar). However, we performed a sensitivity analysis that is displayed in Supplementary Figure S4.2Holch J.W. Held S. Stintzing S. et al.Relation of cetuximab-induced skin toxicity and early tumor shrinkage in metastatic colorectal cancer patients: results of the randomized phase 3 trial FIRE-3 (AIO KRK0306).Ann Oncol. 2020; 31: 72-78Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Here, we evaluated the impact of ETS, Cet-ST and other parameters on overall survival in patients with no mutations in RAS and BRAF proto-oncogenes. This analysis yielded essentially comparable results regarding the evaluation of RAS-wild-type patients as displayed in Figure 1.2Holch J.W. Held S. Stintzing S. et al.Relation of cetuximab-induced skin toxicity and early tumor shrinkage in metastatic colorectal cancer patients: results of the randomized phase 3 trial FIRE-3 (AIO KRK0306).Ann Oncol. 2020; 31: 72-78Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Taken together, we agree with our colleagues that a better molecular understanding regarding the impact of Cet-ST on patient outcomes is important and should be addressed in further investigations. In principle, this also applies to another biomarker for mCRC—primary tumor sidedness—which is already established in routine clinical practice without precise understanding of the underlying molecular mechanism.6Holch J.W. Ricard I. Stintzing S. et al.The relevance of primary tumour location in patients with metastatic colorectal cancer: a meta-analysis of first-line clinical trials.Eur J Cancer. 2017; 70: 87-98Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar Hence, we do not see a marked limitation in our conclusion that Cet-ST and ETS may serve as biomarkers for optimized patient management on the basis of previously published and our own data. Consequently, a prospective evaluation of these parameters should go hand in hand with further investigations deciphering their molecular basis. None declared.