*2.2.2 EGFR gene copy number*

*Advances in the Molecular Understanding of Colorectal Cancer*

*2.2.1 Skin toxicity*

**2.2 Future predictive biomarkers for anti-EGFR therapy**

for anti-EGFR therapy efficacy in patients with mCRC.

Dermatological toxicities such as papulopustular rash (acneiform eruption), erythema, and skin fissures are common side effects of treatment with anti-EGFR antibodies, as EGFR is involved in the normal development and physiology of the epidermis [54]. Both undifferentiated and proliferating keratinocytes in the basal and suprabasal layers of the epidermis express EGFR, and keratinocytes depend on EGFR to regulate proliferation, differentiation, migration, and survival [55]. The emergence of skin toxicity has therefore been investigated as an on-target marker

Subset analyses of outcomes by skin toxicity severity suggest that improvements in outcome are associated with a higher grade of severity for patients treated with either panitumumab or cetuximab. For example, in the CRYSTAL trial of cetuximab as a first-line therapy, PFS was 11.3 months compared with 5.4 months in patients with G3 and G0-1 skin reactions, respectively [56]. Similarly, the randomized phase III EPIC study of cetuximab plus irinotecan *vs* irinotecan after fluoropyrimidine and oxaliplatin failure in patients with EGFR-expressing mCRC observed a median PFS of 15.6 months for patients who developed G3-4 rash compared to 5.8 months for those with no rash [57]. In the PRIME study of panitumumab plus FOLFOX4 (first line) and 20050181 study of panitumumab plus FOLFIRI (second line) the addition of a targeted agent even appeared detrimental for outcomes in patients with G0-1 skin toxicity as compared to the control arms [58, 59]. Better outcomes in patients with higher-grade skin toxicity were further noted for both arms in a randomized trial of cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer [60]. A meta-analysis by Petrelli *et al* of 14 studies including a total of 3833 patients, found that the occurrence of skin toxicity was a predictive factor for survival (HR 0.51; 95% CI 0.40–0.64) and progression (HR 0.58; 95% CI 0.49–0.68). However, 12 of the studies included patients with either *KRAS* wild-type or mutated

tumors, and data on skin toxicity by *KRAS* mutation status remains limited.

Analysis of skin toxicity in the randomized phase III ASPECCT study of panitumumab *vs* cetuximab in chemorefractory wild-type *KRAS* exon 2 mCRC observed improved outcomes in patients with higher grade of severity for both antibodies, although patients with higher-grade skin toxicity had longer median duration of treatment [61]. Two retrospective trial analyses (PRIME and AIO CRC-0104 [cetuximab with CAPOX or CAPIRI, first-line]) suggest that the relationship between skin toxicity and outcome may not only apply to patients with wild-type *RAS* tumors, but perhaps also to patients mutant *RAS* tumors [62, 63]. A recent meta-analysis of skin toxicity identified seven and five studies that reported information on PFS and OS stratified by *KRAS* mutation status, respectively [64]. Improved clinical outcome in the presence of higher grade severity was observed for both patients with wildtype *KRAS* tumors and those with mutant *KRAS* tumors (PFS for wild-type *KRAS*, HR = 0.60, 95% CI (0.51, 0.70); mutant *KRAS*, HR = 0.60, 95% CI (0.45, 0.80), OS for wild-type *KRAS*, HR = 0.54, 95% CI (0.46, 0.65), mutant *KRAS*, HR = 0.64, 95% CI (0.50, 0.81), P < 0.001]. However, only mCRC patients with wild-type *KRAS* tumors who suffered grade 2+ skin toxicity derived absolute benefit from anti-EGFR treatment additional to best BSC or chemotherapy (PFS HR = 0.58, 95% CI (0.41,

These data raise the question whether wild-type *RAS* patients receiving anti-EGFR therapy who do not develop skin toxicity should receive a dose escalation to induce skin toxicity or whether treatment should be discontinued. Further prospective data are needed to establish the clinical value of skin toxicity as a predictive biomarker.

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0.82), OS HR = 0.73, 95% CI (0.61, 0.88)).

*EGFR* is localized on chromosome 7p11.2 which exhibits DNA copy number gain in approximately 35% of colorectal cancers [65]. Based on this observation, *EGFR* gene copy number has been investigated as a predictive biomarker for anti-EGFR therapy in multiple *post hoc* analyses. Study results have been aggregated in three meta-analyses [66-68], which broadly concurred in identifying gain of *EGFR* gene copy number as associated with improved outcomes among patients receiving cetuximab or panitumumab treatment. This association was found to be retained in subgroup analyses for patients with *KRAS* wild-type tumors, with one metaanalysis suggesting that this difference was not present in patients with *KRAS* mutated tumors [69]. However, the methodologies and criteria used for scoring increased EGFR gene copy number were highly inconsistent across different studies, and more research is required to clarify the predictive potential of this biomarker.
