Heterogeneity in the colorectal primary tumor and the synchronous resected liver metastases prior to and after treatment with an anti-EGFR monoclonal antibody

Daniela Adua, Francesca Di Fabio, Giorgio Ercolani, Michelangelo Fiorentino, Elisa Gruppioni, Annalisa Altimari, Fabiola Lorena Rojas Limpe, Nicola Normanno, Antonio Daniele Pinna, Carmine Pinto

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Abstract

Molecular heterogeneity between primary tumors (PTs) and synchronous resected liver metastasis in colorectal cancer (CRC) has potential relevance in treatment strategies. Next-generation sequencing (NGS) may be able to increase the chances of identifying multiple molecular driver alterations, calling for therapy. The aim of the present study was to evaluate mutations in PT and synchronous resected liver metastases for patients with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) exon 2 wild-type metastatic (m)CRC who underwent chemotherapy (CT) featuring an anti-epidermal growth factor receptor (EGFR) monoclonal antibody. Genomic analysis was performed on 54 lesions from 7 patients with mCRC. For each patient, a PT biopsy or a surgical specimen was obtained prior to CT, and the PT and all liver metastases resected following CT were analyzed. DNA libraries were generated using the Ion AmpliSeq Colon and Lung Cancer Panel, assessing the most frequent somatic mutations in 22 genes involved in colon tumorigenesis, and sequencing was performed on an Ion Personal Genome Machine system. A partial response was achieved in all the patients, with a median progression free survival time of 11 months (range, 3-21 months). All the patients were subjected to surgical liver metastasis resection. The median overall survival time was 31 months (range, 4-46 months). Molecular analysis of the genes correlated with the target therapy, suggesting significant intratumor heterogeneity, as revealed by the different mutational landscape of certain PTs and synchronous resected liver metastases following systemic therapy when compared with the PT prior to treatment. In particular, the loss and acquisition of mutations in KRAS, neuroblastoma RAS viral oncogene homolog (NRAS), tumor protein p53 (TP53), the p110α catalytic subunit of phosphoinositide 3-kinase (PIK3CA), F-box/WD repeat-containing protein 7 (FBXW7) and phosphatase and tensin homolog (PTEN) were observed. In addition, one patient developed a mucinous pattern following systemic CT. Taken together, the results of the present study demonstrated that intratumor heterogeneity is likely to affect the response to therapy, and to drive acquired resistance to targeted agents. The preliminary data also suggest a potential role for NGS in the evaluation of biological drug resistance, affecting future sequential treatment strategies.

Original languageEnglish
Pages (from-to)113-120
Number of pages8
JournalMolecular and Clinical Oncology
Volume7
Issue number1
DOIs
Publication statusPublished - Jul 2017

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Epidermal Growth Factor Receptor
Colorectal Neoplasms
Monoclonal Antibodies
Neoplasm Metastasis
Liver
Neoplasms
Drug Therapy
Oncogenes
Mutation
Therapeutics
Ions
1-Phosphatidylinositol 4-Kinase
Neuroblastoma
Gene Library
Phosphoric Monoester Hydrolases
Drug Resistance
Sarcoma
Colonic Neoplasms
Genes
Disease-Free Survival

Keywords

  • Journal Article

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Heterogeneity in the colorectal primary tumor and the synchronous resected liver metastases prior to and after treatment with an anti-EGFR monoclonal antibody. / Adua, Daniela; Di Fabio, Francesca; Ercolani, Giorgio; Fiorentino, Michelangelo; Gruppioni, Elisa; Altimari, Annalisa; Rojas Limpe, Fabiola Lorena; Normanno, Nicola; Pinna, Antonio Daniele; Pinto, Carmine.

In: Molecular and Clinical Oncology, Vol. 7, No. 1, 07.2017, p. 113-120.

Research output: Contribution to journalArticle

Adua, Daniela ; Di Fabio, Francesca ; Ercolani, Giorgio ; Fiorentino, Michelangelo ; Gruppioni, Elisa ; Altimari, Annalisa ; Rojas Limpe, Fabiola Lorena ; Normanno, Nicola ; Pinna, Antonio Daniele ; Pinto, Carmine. / Heterogeneity in the colorectal primary tumor and the synchronous resected liver metastases prior to and after treatment with an anti-EGFR monoclonal antibody. In: Molecular and Clinical Oncology. 2017 ; Vol. 7, No. 1. pp. 113-120.
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AU - Ercolani, Giorgio

AU - Fiorentino, Michelangelo

AU - Gruppioni, Elisa

AU - Altimari, Annalisa

AU - Rojas Limpe, Fabiola Lorena

AU - Normanno, Nicola

AU - Pinna, Antonio Daniele

AU - Pinto, Carmine

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AB - Molecular heterogeneity between primary tumors (PTs) and synchronous resected liver metastasis in colorectal cancer (CRC) has potential relevance in treatment strategies. Next-generation sequencing (NGS) may be able to increase the chances of identifying multiple molecular driver alterations, calling for therapy. The aim of the present study was to evaluate mutations in PT and synchronous resected liver metastases for patients with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) exon 2 wild-type metastatic (m)CRC who underwent chemotherapy (CT) featuring an anti-epidermal growth factor receptor (EGFR) monoclonal antibody. Genomic analysis was performed on 54 lesions from 7 patients with mCRC. For each patient, a PT biopsy or a surgical specimen was obtained prior to CT, and the PT and all liver metastases resected following CT were analyzed. DNA libraries were generated using the Ion AmpliSeq Colon and Lung Cancer Panel, assessing the most frequent somatic mutations in 22 genes involved in colon tumorigenesis, and sequencing was performed on an Ion Personal Genome Machine system. A partial response was achieved in all the patients, with a median progression free survival time of 11 months (range, 3-21 months). All the patients were subjected to surgical liver metastasis resection. The median overall survival time was 31 months (range, 4-46 months). Molecular analysis of the genes correlated with the target therapy, suggesting significant intratumor heterogeneity, as revealed by the different mutational landscape of certain PTs and synchronous resected liver metastases following systemic therapy when compared with the PT prior to treatment. In particular, the loss and acquisition of mutations in KRAS, neuroblastoma RAS viral oncogene homolog (NRAS), tumor protein p53 (TP53), the p110α catalytic subunit of phosphoinositide 3-kinase (PIK3CA), F-box/WD repeat-containing protein 7 (FBXW7) and phosphatase and tensin homolog (PTEN) were observed. In addition, one patient developed a mucinous pattern following systemic CT. Taken together, the results of the present study demonstrated that intratumor heterogeneity is likely to affect the response to therapy, and to drive acquired resistance to targeted agents. The preliminary data also suggest a potential role for NGS in the evaluation of biological drug resistance, affecting future sequential treatment strategies.

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