Location of Primary Tumor and Benefit From Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies in Patients With <i>RAS</i> and <i>BRAF</i> Wild-Type Metastatic Colorectal Cancer

Moretto, Roberto; Cremolini, Chiara; Rossini, Daniele; Pietrantonio, Filippo; Battaglin, Francesca; Mennitto, Alessia; Bergamo, Francesca; Loupakis, Fotios; Marmorino, Federica; Berenato, Rosa; Marsico, Valentina Angela; Caporale, Marta; Antoniotti, Carlotta; Masi, Gianluca; Salvatore, Lisa; Borelli, Beatrice; Fontanini, Gabriella; Lonardi, Sara; Braud, Filippo de; Falcone, Alfredo

doi:10.1634/theoncologist.2016-0084

Cited by 100 publications

(77 citation statements)

References 19 publications

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“…The Role of Primary Tumor Sidedness: A growing body of data has shown that the location of the primary tumor can be both prognostic and predictive of response to EGFR inhibitors in metastatic CRC. [118][119][120][121][122][123][124][125] For example, outcomes of 75 patients with metastatic CRC treated with cetuximab, panitumumab, or cetuximab/irinotecan in first-line or subsequent lines of therapy at 3 Italian centers were analyzed based on sidedness of the primary tumor. 119 No responses were seen in the patients with rightsided primary tumors, compared with a response rate of 41% in those with left-sided primaries (P=.003).…”

Section: Cetuximab and Panitumumabmentioning

confidence: 99%

“…118,119,121,122 The panel believes that primary tumor sidedness is a surrogate for the nonrandom distribution of molecular subtypes across the colon and that the ongoing analysis of tumor specimens from the study will enable a better understanding of the biologic explanation of the observed difference in response to EGFR inhibitors. Until that time, only patients whose primary tumors originated on the left side of the colon (splenic flexure to rectum) should be offered cetuximab or panitumumab in the first-line treatment of metastatic disease.…”

Section: Cetuximab and Panitumumabmentioning

confidence: 99%

“…Until that time, only patients whose primary tumors originated on the left side of the colon (splenic flexure to rectum) should be offered cetuximab or panitumumab in the first-line treatment of metastatic disease. Evidence also suggests that sidedness is predictive of response to EGFR inhibitors in subsequent lines of therapy, 118,119,122 but the panel awaits more definitive studies. Until such data are available, all patients with RAS wild-type tumors can be considered for panitumumab or cetuximab in subsequent lines of therapy if neither was previously given.…”

Section: Cetuximab and Panitumumabmentioning

confidence: 99%

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Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology

Benson¹,

Venook²,

Cederquist³

et al. 2017

J Natl Compr Canc Netw

738

515

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OverviewColorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. In 2016, an estimated 95,270 new cases of colon cancer and approximately 39,220 cases of rectal cancer will occur. During the same year, an estimated 49,190 people will die of colon and rectal cancer combined. AbstractThis portion of the NCCN Guidelines for Colon Cancer focuses on the use of systemic therapy in metastatic disease. Considerations for treatment selection among 32 different monotherapies and combination regimens in up to 7 lines of therapy have included treatment history, extent of disease, goals of treatment, the efficacy and toxicity profiles of the regimens, KRAS/NRAS mutational status, and patient comorbidities and preferences. Location of the primary tumor, the BRAF mutation status, and tumor microsatellite stability should also be considered in treatment decisions. J Natl Compr Canc Netw 2017;15(3): 370-398 NCCN Categories of Evidence and ConsensusCategory 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. These guidelines are also available on the Internet. For the latest update, visit NCCN.org.

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Section: Cetuximab and Panitumumabmentioning

confidence: 99%

Section: Cetuximab and Panitumumabmentioning

confidence: 99%

Section: Cetuximab and Panitumumabmentioning

confidence: 99%

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Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology

Benson¹,

Venook²,

Cederquist³

et al. 2017

J Natl Compr Canc Netw

738

515

View full text Add to dashboard Cite

show abstract

“…The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology clearly declare that the therapeutic sensitivity of molecular targeted drugs differs for tumors in different locations. Treatment with EGFR inhibitors, such as cetuximab, panitumumab, or irinotecan can significantly prolong the survival of patients with left-sided colon cancer [12]. For RAS wild-type colon cancer, left-sided tumors had longer overall survival than rightsided tumors treated with bevacizumab.…”

Section: Introductionmentioning

confidence: 99%

Distinguishable Prognostic Signatures of Left- and Right-Sided Colon Cancer: a Study Based on Sequencing Data

Liang

Zeng

Qin

et al. 2018

Cell Physiol Biochem

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Key WordsLeft-and right-sided • Colon cancer • Prognosis • TCGA Abstract Background/Aims: Left-and right-sided colon cancers are considered to be two different diseases and have altered outcomes. However, specific molecules to predict the prognosis of left-and right-sided colon cancers are currently lacking. Methods: Expression profiling of colon cancer were downloaded from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) of left-and right-sided colon cancers were compared by DESeq analysis. The prognostic values of DEGs were assessed by univariate and multivariate Cox regression. Prognostic index models of two side colon cancers were conducted with prognostic values genes, respectively. Interaction of DEGs was then analyzed by the protein-protein interaction (PPI). Different biology function of two sides of colon cancer was assessed by Gene Set Enrichment Analysis (GSEA). Results: A total of 167 DEGs were identified between left-and right-sided colon cancers based on TCGA data. Using univariate COX regression analysis, five genes (PHACTR3, CKMT2, CYP2W1, ERFE, HOXC4) were related to overall survival in left-sided, and eight distinguishable genes (EREG, ERFE, HOXC6, SLC22A31, TFF1, GFI1, ZG16, RASL10B) in right-sided. Further, left-sided prognostic model was established with PHACTR3 and CKMT2 (HR=2.040; 95%CI=1.004-4.145; P=0.049). Distinguishable prognostic signature for right-sided colon cancer was established based on EREG, ERFE, GFI1, and RASL10B (HR=3.530; 95%CI: 1.934-6.444; P<0.001) in multivariate analysis. PPI analysis of 167 DEGs showed that CCL5, GNG4, GNLY, GZMH, DRD2, and FASLG genes were at the core of interaction network. In GSEA function analysis, four pathways, including antigen processing and presentation, natural killer cell mediated cytotoxicity, intestinal immune network for Iga production, and type I diabetes mellitus, were significantly enriched in the DEGs of the right-sided colon cancer. Conclusions: This study constructs a panel of potential prognostic model of left-and right-sided colon cancers, respectively. We also provide molecular biological alterations between left-and rightsided colon cancers.

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“…In October 2016, results of a robust meta-analysis 3 confirmed previous evidence of a significantly worse patient prognosis associated with right-sided tumours (located up to the proximal two-thirds of the transverse colon) versus left-sided tumours (located within the distal third of the transverse colon or beyond), independent of disease stage -thus demonstrating the importance of including primary tumour location as a stratification factor in clinical trial design. With regard to predicting patient benefit from targeted agents, although findings indicate that no interaction exists between 'sidedness' and the efficacy of anti-VEGF therapy with bevacizumab 4 , the location of the primary tumour does seem to affect sensitivity to anti-EGFRantibodies 5,6 . In this respect, subgroup analyses of six international, randomized, controlled trials in large cohorts of patients with RAS-wild-type mCRC were also reported in October 2016 , and the results showed clear differences in the efficacy of anti-EGFR therapy in patients with left-sided and rightsided primary tumours (Supplementary information S1 (table)).…”

mentioning

confidence: 99%