Pharmacogenomic and pharmacoproteomic studies of cetuximab in metastatic colorectal cancer: biomarker analysis of a phase I dose-escalation study.

PURPOSE: This study assessed biomarkers for cetuximab efficacy in tissue samples collected during a phase I dose-escalation study exploring every second week administration of cetuximab as first-line therapy in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Sixty-two patients received cetuximab monotherapy for 6 weeks, followed by cetuximab plus infusional fluorouracil, leucovorin, and irinotecan until disease progression. Patients in the control arm received cetuximab as a 400 mg/m(2) initial dose then 250 mg/m(2) per week; patients in the dose-escalation arms received 400 to 700 mg/m(2) every second week. Tumor and skin biopsies were taken for immunohistochemical and microarray expression analyses (tumor only) at baseline and week 4. Plasma was collected for proteomic analysis at baseline and week 4. KRAS tumor mutation status was assessed. RESULTS: In subsets of paired skin samples from 35 patients, cetuximab treatment was associated with substantial downregulation of phospho(p)-EGFR, p-MAPK and proliferation and substantial upregulation of p27(Kip1) and p-STAT3 levels. No marked difference in these effects was noted for different schedules of administration and dose levels. In the cetuximab monotherapy phase, responses were seen only in patients whose tumors were wild-type for KRAS (eight of 29 v zero of 19 for KRAS mutant tumors; P = .015). Progression-free survival was longer for patients with KRAS wild-type compared with KRAS mutant tumors (log-rank P = .048). Genomics/proteomics analyses (42 and 45 patients, respectively) identified candidate biomarkers associated with response. CONCLUSION: Biomarker analysis supported the functional equivalence of weekly and every second week administration of cetuximab and provided further confirmation that patients with KRAS wild-type mCRC were those most likely to benefit from cetuximab treatment.

Retrospective analysis of surgical resection after induction chemotherapy for patients with T4b squamous cell head and neck cancer.

BACKGROUND: Standard treatment of patients with T4b squamous cell head and neck cancer (T4b-SCHNC) is concomitant chemo-radiotherapy (CT-RT). Recent Phase III trials with Taxane containing induction chemotherapy (IC) suggest that IC could also play a role in this setting. The value of resecting the residual mass after IC and before RT is not yet clear in this context. METHODS: We present the results of a retrospective analysis. RESULTS: Between 1984 and 2001, 113 patients (patients) with T4b-SCHNC were treated at our institution with IC. Four patients dead during IC and 57 patients achieved a complete or a >90% partial response at primary and proceeded to definitive RT (or concomitant CT/RT). Surgical resection was reconsidered after IC and before RT in the other 52 patients. Surgery was performed in 13 of them: in 7 patients resection was R1, all of them had loco-regional progression (2 also developed systemic metastases) and median OS after surgery was 21 months, with no patient alive at 48 months. In the other 6 patients a R0 resection was performed: 3 of these patients had loco-regional relapses (1 also developed systemic metastases) and the other 3 patients remain alive and disease free 56, 62 and 72 months after surgery. Considering the 52 patients that achieved less than a 90% partial response at primary with IC, overall survival was equivalent when no Resection or an R1 resection was performed after IC (5 year OS 8 vs. 0%, lrk, p=0.74), but a statistically significant improvement in OS was observed when an R0 resection was obtained (5 years OS 50%, lrk, p=0.02). CONCLUSIONS: R0 resections after IC and before RT could indicate an improvement in OS in patients with T4b-SCHNC that obtain less than a 90% PR at primary after IC. We consider that this approach deserves further research in prospective clinical trials.