Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next-generation sequencing: findings from the CAPRI-GOIM trial

Ciardiello, Fortunato; Normanno, Nicola; Maiello, Evaristo; Martinelli, Erika; Troiani, Teresa; Pisconti, Salvatore; Giuliani, Francesco; Barone, Carlo; Cartenì, Giacomo; Rachiglio, Anna Maria; Montesarchio, Vincenzo; Tonini, Giuseppe; Rizzi, Daniele; Cinieri, Saverio; Bordonaro, Roberto; Febbraro, Antonio; Vita, F. De; Orditura, Michele; Fenizia, Francesca; Lambiase, Matilde; Rinaldi, Antonio; Tatangelo, Fabiana; Botti, Gerardo; Colucci, Giuseppe

doi:10.1093/annonc/mdu230

Cited by 112 publications

(115 citation statements)

References 16 publications

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“…One possibility is cancer intrinsic genetic heterogeneity, which could be more prominent in the metastatic setting (28,29). Heterogeneous genetic alterations in genes involved in the EGFR pathways have been hypothesized to play a role in resistance to anti-EGFR drugs in colorectal cancer, including activating mutations in KRAS, NRAS, B-RAF, and PIK3CA, and loss of expression of PTEN (13). The overall scenario is complicated by presence of additional genetic mechanisms able to activate the RAS pathway in the absence of molecular alterations affecting RAS or its immediate downstream effectors (30)(31)(32)(33)(34)(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

“…Molecular heterogeneity also plays an important role in the context of resistance, by limiting the success of therapies against a single target. Colorectal cancer patients can harbor different gene mutations in distinct tumor lesions, or even within different regions of the same lesion (13). All these alterations could converge on activation of the RAS-MEK-ERK pathway (9,10,14,15).…”

Section: Introductionmentioning

confidence: 99%

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Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab

Napolitano

Martini

Rinaldi³

et al. 2015

Clinical Cancer Research

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Purpose: In colorectal cancer, the activation of the intracellular RAS-RAF and PIK3CA-AKT pathways has been implicated in the resistance to anti-EGFR mAbs. We have investigated the role of regorafenib, an oral multikinase inhibitor, in combination with cetuximab, an anti-EGFR mAb, to overcome anti-EGFR resistance.Experimental Design: We have tested, in vitro and in vivo, the effects of regorafenib in a panel of human colorectal cancer cell lines with a KRAS mutation (SW480, SW620, HCT116, LOVO, and HCT15) or with a BRAF mutation (HT29), as models of intrinsic resistance to cetuximab treatment, and in two human colorectal cancer cell lines (GEO and SW48) that are cetuximabsensitive, as well as in their derived cells with acquired resistance to cetuximab (GEO-CR and SW48-CR).Results: Treatment with regorafenib determined a dose-dependent growth inhibition in all colorectal cancer cell lines. The combined treatment with cetuximab and regorafenib induced synergistic antiproliferative and apoptotic effects in cetuximabresistant cell lines by blocking MAPK and AKT pathways. Nude mice were injected s.c. with HCT116, HCT15, GEO-CR, and SW48-CR cells. The combined treatment caused significant tumor growth inhibition. Synergistic antitumor activity of regorafenib plus cetuximab was also observed in an orthotopic colorectal cancer model of HCT116 cells. In particular, the combined treatment induced a significant tumor growth inhibition in the primary tumor site (cecum) and completely prevented metastasis formation.Conclusions: The combined treatment with cetuximab and regorafenib could be a strategy to overcome resistance to anti-EGFR therapies in metastatic colorectal cancer patients. Clin Cancer Res; 21(13); 2975-83. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab

Napolitano

Martini

Rinaldi³

et al. 2015

Clinical Cancer Research

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“…Clinical trials have provided evidence that these mutations are negative predictors of response to anti-EGFR therapy [83][84][85][86][87][88]. BRAF is an immediate downstream molecule of RAS.…”

Section: Extended Ras and Braf Mutational Analysis For Metastatic Crcmentioning

confidence: 99%

Current applications of molecular pathology in colorectal carcinoma

2017

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Molecular pathology is playing an increasingly important role in the treatment and overall management of patients with colorectal carcinoma. Three distinct genetic pathways have been identified that play a role in carcinogenesis: the chromosomal instability pathway, the microsatellite instability pathway, and the CpG island methylator phenotype pathway. Certain genetic mutations, some of which overlap with the aforementioned pathways, can also indicate that a carcinoma patient has a genetic predisposition syndrome, such as familial adenomatous polyposis, Lynch syndrome, and hamartomatous polyposis syndromes. A variety of advanced methods, including next-generation sequencing, are available to test for these and other mutations, such as targetable mutations that may allow tailoring of a treatment regimen to a patient's specific cancer (e.g., KRAS and BRAF mutations). The possible future role of testing circulating tumor cells is also addressed. New mutations and syndromes continue to be discovered, ensuring that our knowledge of colorectal carcinoma and our ability to treat it will advance in the future.

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“…Furthermore, the higher sensitivity of NGS may permit the identification of mutations in RAS not identified by the standard Sanger sequencing technique, as highlighted by the analysis conducted in a subpopulation of the CAPRI-GOIM multicenter study (13,14). In this regard, it was also suggested that low levels of KRAS mutations could justify an intrinsic resistance mechanism to anti-EGFR mAbs (15,16).…”

Section: Introductionmentioning

confidence: 99%

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

Adua

Fabio

Ercolani

et al. 2017

Molecular and Clinical Oncology

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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.

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Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next-generation sequencing: findings from the CAPRI-GOIM trial

Abstract: This study demonstrates that NGS analysis in mCRC is feasible, reveals high level of intra and intertumor heterogeneity, and identifies patients that might benefit of FOLFIRI plus cetuximab treatment.

Cited by 112 publications

References 16 publications

Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab

Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab

Current applications of molecular pathology in colorectal carcinoma

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

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