Marco Siano1, Vittoria Espeli2, Nicolas Mach3, Paolo Bossi4, Lisa Licitra5, Michele Ghielmini6, Milo Frattini7, Silvana Canevari8, Loris De Cecco9. 1. Cantonal Hospital St. Gallen, Dept. of Med. Oncology and Hematology, Rorschacherstrasse 95, CH-9007 St. Gallen, Switzerland. Electronic address: marco.siano@kssg.ch. 2. Oncology Institute of Southern Switzerland, San Giovanni Hospital, CH-6500 Bellinzona, Switzerland. Electronic address: vittoria.espeli@eoc.ch. 3. Oncology Centre, Clinical Research Unit DFDL, University Hospital, CH-1205 Geneva, Switzerland. Electronic address: nicolas.mach@hcuge.ch. 4. Fondazione IRCCS Istituto Nazionale dei Tumori, Head and Neck Medical Oncology Dept., Via Venezian 1, I-20133 Milan, Italy. Electronic address: paolo.bossi@istitutotumori.mi.it. 5. Fondazione IRCCS Istituto Nazionale dei Tumori, Head and Neck Medical Oncology Dept., Via Venezian 1, I-20133 Milan, Italy; State University of Milan, Via Festa del Perdono, 7, I-20122 Milano, Italy. Electronic address: lisa.licitra@istitutotumori.mi.it. 6. Oncology Institute of Southern Switzerland, San Giovanni Hospital, CH-6500 Bellinzona, Switzerland. Electronic address: michele.ghielmini@eoc.ch. 7. Institute of Pathology, Laboratory of Molecular Pathology, CH-6600 Locarno, Switzerland. Electronic address: milo.frattini@ti.ch. 8. Fondazione IRCCS Istituto Nazionale dei Tumori, Integrated Biology Platform, Department of Applied Research and Technology Development, Via Amadeo 42, I-20133 Milan, Italy. Electronic address: silvana.canevari@istitutotumori.mi.it. 9. Fondazione IRCCS Istituto Nazionale dei Tumori, Integrated Biology Platform, Department of Applied Research and Technology Development, Via Amadeo 42, I-20133 Milan, Italy. Electronic address: loris.dececco@istitutotumori.mi.it.
Abstract
OBJECTIVE: Platinum-based chemotherapy plus the anti-EGFR monoclonal antibody (mAb) cetuximab is used to treat recurrent/metastatic (RM) head-neck squamous cell carcinoma (HNSCC). Recently, we defined Cluster3 gene-expression signature as a potential predictor of favorable progression-free survival (PFS) in cetuximab-treated RM-HNSCC patients and predictor of partial metabolic FDG-PET response in an afatinib window-of-opportunity trial. Another anti-EGFR-mAb (panitumumab) was used as the treatment agent in RM-HNSCC patients in the phase II PANI01trial. PANI01 tumor samples were analyzed using functional genomics to explore response predictors to anti-EGFR therapy. MATERIALS AND METHODS: Whole-gene expression and real-time PCR analyses were applied to pre-treatment samples from 25 PANI01 patients. Three gene signatures (Cluster3 score, RAS onco-signature, microenvironment score) and seven selected miRNAs were separately analyzed for association with panitumumab efficacy. RESULTS: Cluster3 expression levels had a profile with a significant bimodal separation of samples (P = 3.08 E-13). Higher RAS activation, microenvironment score, and miRNA expression were associated with low-Cluster3 patients. The same biomarkers were separately associated with PFS. Patients with high-Cluster3 had significantly longer PFS than patients with low-Cluster3 (median PFS: 174 versus 51 days; log-rank P = 0.0021). ROC analysis demonstrated accuracy in predicting PFS (AUC = 0.877). CONCLUSIONS: Despite differences in clinical settings and anti-EGFR inhibitors used for treatment, response prediction by the Cluster3 signature and selected miRNAs was essentially the same. Translation into a useful clinical assay requires validation in a broader setting.
OBJECTIVE:Platinum-based chemotherapy plus the anti-EGFR monoclonal antibody (mAb) cetuximab is used to treat recurrent/metastatic (RM) head-neck squamous cell carcinoma (HNSCC). Recently, we defined Cluster3 gene-expression signature as a potential predictor of favorable progression-free survival (PFS) in cetuximab-treated RM-HNSCC patients and predictor of partial metabolic FDG-PET response in an afatinib window-of-opportunity trial. Another anti-EGFR-mAb (panitumumab) was used as the treatment agent in RM-HNSCC patients in the phase II PANI01trial. PANI01 tumor samples were analyzed using functional genomics to explore response predictors to anti-EGFR therapy. MATERIALS AND METHODS: Whole-gene expression and real-time PCR analyses were applied to pre-treatment samples from 25 PANI01 patients. Three gene signatures (Cluster3 score, RAS onco-signature, microenvironment score) and seven selected miRNAs were separately analyzed for association with panitumumab efficacy. RESULTS: Cluster3 expression levels had a profile with a significant bimodal separation of samples (P = 3.08 E-13). Higher RAS activation, microenvironment score, and miRNA expression were associated with low-Cluster3 patients. The same biomarkers were separately associated with PFS. Patients with high-Cluster3 had significantly longer PFS than patients with low-Cluster3 (median PFS: 174 versus 51 days; log-rank P = 0.0021). ROC analysis demonstrated accuracy in predicting PFS (AUC = 0.877). CONCLUSIONS: Despite differences in clinical settings and anti-EGFR inhibitors used for treatment, response prediction by the Cluster3 signature and selected miRNAs was essentially the same. Translation into a useful clinical assay requires validation in a broader setting.
Keywords:
Anti-EGFR; Gene expression signatures; Head and neck cancer; Hypoxia signature; Microenvironment score; Progression-free survival; Recurrent/metastatic; Second line treatment; miRNA
Authors: Chen Huang; Lijun Chen; Sara R Savage; Rodrigo Vargas Eguez; Yongchao Dou; Yize Li; Felipe da Veiga Leprevost; Eric J Jaehnig; Jonathan T Lei; Bo Wen; Michael Schnaubelt; Karsten Krug; Xiaoyu Song; Marcin Cieślik; Hui-Yin Chang; Matthew A Wyczalkowski; Kai Li; Antonio Colaprico; Qing Kay Li; David J Clark; Yingwei Hu; Liwei Cao; Jianbo Pan; Yuefan Wang; Kyung-Cho Cho; Zhiao Shi; Yuxing Liao; Wen Jiang; Meenakshi Anurag; Jiayi Ji; Seungyeul Yoo; Daniel Cui Zhou; Wen-Wei Liang; Michael Wendl; Pankaj Vats; Steven A Carr; D R Mani; Zhen Zhang; Jiang Qian; Xi S Chen; Alexander R Pico; Pei Wang; Arul M Chinnaiyan; Karen A Ketchum; Christopher R Kinsinger; Ana I Robles; Eunkyung An; Tara Hiltke; Mehdi Mesri; Mathangi Thiagarajan; Alissa M Weaver; Andrew G Sikora; Jan Lubiński; Małgorzata Wierzbicka; Maciej Wiznerowicz; Shankha Satpathy; Michael A Gillette; George Miles; Matthew J Ellis; Gilbert S Omenn; Henry Rodriguez; Emily S Boja; Saravana M Dhanasekaran; Li Ding; Alexey I Nesvizhskii; Adel K El-Naggar; Daniel W Chan; Hui Zhang; Bing Zhang Journal: Cancer Cell Date: 2021-01-07 Impact factor: 31.743