Predictive value of epidermal growth factor receptor expression for first-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: Analysis of data from the EXTREME and CRYSTAL studies

Licitra, Lisa; Störkel, Stephan; Kerr, Keith M.; Cutsem, Éric Van; Pirker, Robert; Hirsch, Fred R.; Vermorken, Jan B.; Heydebreck, Anja von; Esser, Regina; Çelik, I.; Ciardiello, Fortunato

doi:10.1016/j.ejca.2012.11.018

Cited by 147 publications

(89 citation statements)

References 21 publications

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“…To our knowledge, this is the first study of RM-HNSCC that specifically investigates sensitivity to cetuximab/platinum-based therapy by gene expression and biology behind. After many years of unsuccessful research for biomarker identification and in-depth analysis of EGFR (25,26), our data suggest that a whole-transcriptome approach followed by in silico validation, a thorough functional genomics and drug-sensitivity estimate could uncover the biology behind responsiveness to cetuximab/platinum in RM-HNSCC patients, opening the way to the definition of a cetuximab-based treatment-sensitivity predictor.…”

Section: Discussionmentioning

confidence: 99%

Functional Genomics Uncover the Biology behind the Responsiveness of Head and Neck Squamous Cell Cancer Patients to Cetuximab

Bossi

Bergamini

Siano

et al. 2016

Clinical Cancer Research

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Purpose: To identify the tumor portrait of the minority of head and neck squamous cell carcinoma (HNSCC) patients with recurrent-metastatic (RM) disease who upon treatment with platinum-based chemotherapy plus cetuximab present a long-lasting response.Experimental Design: The gene expression of pretreatment samples from 40 HNSCC-RM patients, divided in two groups [14 long-progression-free survival (PFS) and 26 short-PFS (median ¼ 19 and 3 months, respectively)], was associated with PFS and was challenged against a dataset from metastatic colon cancer patients treated with cetuximab. For biologic analysis, we performed functional and subtype association using gene set enrichment analysis, associated biology across all currently available HNSCC signatures, and inferred drug sensitivity using data from the Cancer Genomic Project.Results: The identified genomic profile exhibited a significant predictive value that was essentially confirmed in the single publicly available dataset of cetuximab-treated patients. The main divergence between long-and short-PFS groups was based on developmental/differentiation status. The long-PFS patients are characterized by basal subtype traits such as strong EGFR signaling phenotype and hypoxic differentiation, further validated by the significantly higher association with the hypoxia metagene. The short-PFS patients presented a strong activation of RAS signaling confirmed in an in vitro model of two isogenic HNSCC cell lines sensitive or resistant to cetuximab. The predicted drug sensitivity for all four EGFR inhibitors was higher in long-versus short-PFS patients (P range: <0.0022-1eÀ07).Conclusions: Our data uncover the biology behind response to platinum-based chemotherapy plus cetuximab in RM-HNSCC cancer and may have translational implications improving treatment selection.

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Section: Discussionmentioning

confidence: 99%

Functional Genomics Uncover the Biology behind the Responsiveness of Head and Neck Squamous Cell Cancer Patients to Cetuximab

Bossi

Bergamini

Siano

et al. 2016

Clinical Cancer Research

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“…18,19), in Kras wild-type metastatic colorectal cancer (mCRC; ref. 20) as well as in NSCLC (21) patients. In an intention-to-treat analysis in NSCLC (Flex trial), tumor cell expression of EGFR (<40% vs. !40%) was not identified as a prognostic factor in relation to survival in the overall analysis (22).…”

Section: Introductionmentioning

confidence: 99%

PIK3CA Pathway Mutations Predictive of Poor Response Following Standard Radiochemotherapy ± Cetuximab in Cervical Cancer Patients

Rochefordière

Kamal

Floquet

et al. 2015

Clinical Cancer Research

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Purpose: EGFR is frequently overexpressed in cervical cancer, suggesting EGFR blockade as a promising treatment approach. Cetuximab, an anti EGFR antibody, used conjointly with radiochemotherapy, was feasible in first-line treatment of cervix carcinoma limited to the pelvis.Experimental Design: This randomized phase II trial enrolled 78 FIGO stage IB2-IIIB cervical cancer patients to either cisplatinbased radiochemotherapy alone (arm B, n ¼ 38) or conjointly with a 6-week course of weekly cetuximab (arm A, n ¼ 40). Brachytherapy was given to the pelvic mass. Primary endpoint was disease-free survival (DFS) at 2 years. EGFR expression and targeted sequencing were performed in 54 of 78 patients.Results: Cetuximab over a 6-week period did not improve DFS at 24 months. At 31 months median follow-up, DFS was not significantly different (P ¼ 0.18). Complete response at 4 to 6 months was strongly predictive for excellent DFS (log-rank test; P < 0.001). PIK3CA, KRAS, and STK11 mutations were observed in 22%, 4%, and 2% of patients, respectively. No tumor with a PI3K pathway mutation showed complete response (0/8 in arm A and 0/6 in arm B), whereas 14 of 52 (27%) tumors without mutations did (P ¼ 0.021). PI3K pathway-mutated tumors showed a trend toward poorer DFS (P ¼ 0.06) following cetuximab (8/22) as compared with those following standard treatment only (6/18).Conclusions: Similar to patients with head and neck cancer, patients with cervical cancer showed no gain in DFS at 2 years following a combined treatment of cetuximab with radiochemotherapy. Although treatment tolerance and compliance were satisfactory, it remains to be demonstrated whether maintenance therapy with cetuximab could be beneficial in selected patient groups.

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“…However, it has been published that detecting tumor p16-expression by immunohistochemistry can be a surrogate marker with 100 % sensitivity and 80 % specificity [9]. The growth factor receptor EGFR is known to be overexpressed in 80-90 % of HNSCCs, and to be associated with poor survival, nevertheless it cannot be used as a predictor of response rate to cetuximab therapy [10].…”

Section: Introductionmentioning

confidence: 99%

Correlations Between Prognosis and Regional Biomarker Profiles in Head and Neck Squamous Cell Carcinomas

Szentkúti

Dános

Brauswetter³

et al. 2014

Pathol. Oncol. Res.

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Head and neck squamous cell carcinomas (HNSC C) show diverse clinicopathological features and are mostly linked with poor outcome. In this study, we tested if the expression of tumor growth, cell cycle and basement membrane anchorage related biomarkers allow prognostic and clinicopathological stratification of HNSCC. Archived HNSCC samples from 226 patients included into tissue microarrays (TMA) were tested using immunohistochemistry. Histopathological evaluation and the analysis of immunostaining for EGFR, Ki67, p53, p16 ink4 and Collagen XVII proteins were carried out in digital whole slides. Statistical evaluation was carried out using Pearson's Chi-square test and Kaplan-Meier survival analysis. In the tested cohort, hypopharyngeal cancers had the least favorable, and glottic cancers had the most favorable prognosis. High Ki67 positive tumor cell fractions were associated with significantly worse prognosis and elevated rate of lymph node metastasis. Both Ki67 and EGFR expression correlated significantly with the tumor localization. Ki67 index was the highest in the hypopharyngeal region and it proved to be the lowest in the glottic region. EGFR expression was the highest in the oral cavity and the lowest in the glottic region. The survival rate of patients with p16 ink4

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Predictive value of epidermal growth factor receptor expression for first-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: Analysis of data from the EXTREME and CRYSTAL studies

Cited by 147 publications

References 21 publications

Functional Genomics Uncover the Biology behind the Responsiveness of Head and Neck Squamous Cell Cancer Patients to Cetuximab

Functional Genomics Uncover the Biology behind the Responsiveness of Head and Neck Squamous Cell Cancer Patients to Cetuximab

PIK3CA Pathway Mutations Predictive of Poor Response Following Standard Radiochemotherapy ± Cetuximab in Cervical Cancer Patients

Correlations Between Prognosis and Regional Biomarker Profiles in Head and Neck Squamous Cell Carcinomas

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