Primary Tumor Location Implications on Biological Therapy in Metastatic Colorectal Cancer

Oncology & Hematology Review, 2017;13(1):30–3 DOI:


Anti-epidermal growth factor receptors (anti-EGFRs) have been clinically proven to improve overall survival (OS) when combined with chemotherapy in the settings of extended RAS wild-type metastatic colorectal cancers. In addition, randomized phase III studies have confirmed the superiority of anti-EGFR therapy over bevacizumab in the front-line treatment of extended RAS wild-type metastatic colorectal cancer when it comes to response rate, and in select studies, OS. Recent updates from these clinical trials project convincing evidence that tumor sidedness is yet another predictive marker for response to anti-EGFR therapy. While left colonic RAS wild-type metastatic colorectal cancers derive major clinical benefit from anti-EGFR versus bevacizumab therapy, bevacizumab appears to have clear advantage in RAS wild-type metastatic right-sided tumors. In this review, we summarize recent reports from key clinical trials and their impact on day-to-day clinical practice.
Keywords: Sidedness, colorectal cancer, epidermal growth factor, metastatic disease, cetuximab, panitumumab, bevacizumab, chemotherapy
Disclosure: Marwan Fakih has nothing to declare in relation to this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. No funding was received for the publication of this article.

Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole and have given final approval for the version to be published.

Received: February 20, 2017 Accepted April 07, 2017
Correspondence: Marwan Fakih, City of Hope Comprehensive Cancer Center, 1500 E Duarte Rd, Duarte, CA 91010, US. E:
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.

Several studies have shown a survival advantage with the addition of anti-epidermal growth factor receptor (anti-EGFR) therapy to chemotherapy in molecularly selected patients with advanced colorectal cancer. The Panitumumab Randomized trial in combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy (PRIME) clinical trial investigated the addition of panitumumab to folinic acid, fluorouracil, and oxaliplatin (FOLFOX) in patients with KRAS exon-2 wild-type metastatic colorectal cancer.1 The addition of panitumumab to chemotherapy improved overall survival (OS) by 17% and translated in a statistically significant increase in median OS from 19.7 to 23.9 months.1Further analysis confirmed a lack of benefit from panitumumab in exon-3 and exon-4 KRAS mutations and exon 2, 3, and 4 NRAS mutations, therefore limiting panitumumab recommendations to extended RAS wild-type metastatic colorectal cancer. In this subgroup of patients, panitumumab improved the OS by 22%, extending the median OS from 20.2 to 26.0 months.2 Similar findings have been reported in the Cetuximab combined with iRinotecan in first-line therapY for metastatic colorectal cancer (CRYSTAL) trial, a randomized phase III clinical trial comparing folinic acid, fluorouracil, and irinotecan (FOLFIRI) to FOLFIRI plus cetuximab in the first-line treatment of KRAS wild-type metastatic colorectal cancer. The addition of cetuximab to FOLFIRI improved OS by 20% and was associated with a significant improvement in median survival from 20.0 to 23.5 months.3 Further analysis confirmed a lack of benefit from non-exon 2 KRAS and exons 2, 3, and 4 NRAS mutations. The addition of cetuximab to FOLFIRI in RAS wild-type metastatic colorectal cancer improved OS by 31%.4 These studies, and other supporting evidence from second-line (and beyond) clinical trials support the benefit from anti- EGFR therapy in extended RAS wild-type colorectal cancer.5 Additional evidence suggests that BRAF mutations, in addition to their poor prognostication, are also associated with lack of clinical benefit from anti-EGFR therapy.6 Recent studies, however, suggest that in addition to RAS and BRAF status, tumor sidedness has a considerable impact on metastatic colorectal cancer outcome, specifically with anti-EGFR therapy. In this review, we review pertinent literature on right and left colon cancer and its impact on anti-EGFR therapy recommendations in patients with advanced colorectal cancer.

Biological differences between right and left colon
The right and left colons are embryologically distinct. The right colon is derived from the midgut and consists of the cecum, ascending colon, and the proximal two-thirds of the transverse colon. The left colon is derived from the hindgut and extends from the end of the transverse colon cancer to the rectum.7 Indeed, the biological differences between the right and the left colon have been shown to exist at the molecular level—as confirmed by extensive gene expression studies on colonic tissue from human embryos and adults.8 Therefore, it is not surprising that distinct molecular differences have been seen between right and left colorectal cancers across different genomic data sets. Missaglia etal. reported on the biology of colorectal cancers from the PETACC-3 and the TCGA data sets.9 Right colonic tumors were more likely to be microsatellite instable (MSI) or MSI-like, associated with a RAS or a BRAF signature, have a serrated pathway, and to have a JAK-STAT gene signature. Left colonic tumors were more likely to be associated with WNT and MYC pathways activation, to have beta catenin activation, and to be associated with EGFR and HER2 upregulation. Even upon limiting the analysis to patients with microsatellite stability (MSS), KRAS wild-type, and BRAF wild-type tumors, left colonic tumors were associated with EGFR upregulation, which was lacking in right colonic tumors. These major variations between left and right colonic cancers, particularly at the EGFR expression and activation level, provide support to the subsequent clinical data that suggest a lack of anti-EGFR activity in right colonic tumors, irrespective of RAS status. It is likely that left colonic tumors, in contrast to right colonic tumors, are dependent on an overactive EGFR-pathway, making them more susceptible to EGFR blockade as a therapeutic strategy.

Prognostic implications of right and left colon cancers
Several studies have shown that the OS of colorectal cancer patients is negatively impacted by right sidedness. However, considerable debate remains around the interaction between tumor location and stage vis-à-vis OS. Both Weiss et al., and Meguid et al. reported on sidedness and outcome based on analyses of the Surveillance, Epidemiology, and End Results (SEER) data base.10,11 Both studies showed a worse outcome in patients with right colonic tumors, particularly those with stage III disease. Other populationbased studies reported on the OS of stage I–III colon cancers and generated conflicting results as to the impact of sidedness on outcome.12–14 Recent analysis of prospective clinical trials sheds additional light on the impact of sidedness in earlier stage disease, specifically in stage III colon cancer. The PETACC-3 clinical trial randomized 3,045 patients with stage III disease to receive fluorouracil (5-FU) and leucovorin (LV) versus FOLFIRI in the adjuvant setting. No difference in OS was noted between the two treatment arms. Patients with right colon tumors had similar rates of relapse as patients with left colon. However, once a patient relapsed, the OS was clearly impacted by sidedness, with an inferior outcome being noted in rightsided cancers.9 Similarly, a combined analysis of two randomized phase III clinical trials (Vioxx in Colorectal Cancer Therapy [VICTOR] and Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer [QUASAR-2]) failed to show a difference in relapse free survival (RFS) between right and left colons while confirming a significantly worse outcome in survival postrelapse in right versus left colon cancers.15 The above studies suggest that the impact of sidedness on outcome is more relevant following the development of metastatic disease, reflecting a possible difference in biology and response to therapy following the development of distant metastases. Such hypothesis is clearly supported by a recent meta-analysis of first-line metastatic disease clinical trials which showed a consistent and significant worsening in OS in metastatic colorectal cancer originating in the right colon.16 Since the poor OS in metastatic right colon cancer has been reported in studies that precede the use of anti-EGFR therapy, one cannot attribute the divergence in outcome to a difference in anti-EGFR response alone.

Anti-epidermal growth factor recepter therapy and sidedness
There is mounting clinical evidence that anti-EGFR response can be predicted by tumor sidedness in patients with RAS wild-type metastatic

1. Douillard JY, Siena S, Cassidy J, et al., Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study, J Clin Oncol, 2010;28:4697–705.
2. Douillard JY, Oliner KS, Siena S, et al., Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer, N Engl J Med, 2013;369:1023–34.
3. Van Cutsem E, Kohne CH, Lang I, et al., Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status, J Clin Oncol, 2011;29:2011–9.
4. Van Cutsem E, Lenz HJ, Kohne CH, et al., Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer, J Clin Oncol, 2015;33:692–700.
5. Peeters M, Oliner KS, Price TJ, et al., Analysis of KRAS/NRAS mutations in a phase III study of Panitumumab with FOLFIRI compared with FOLFIRI alone as second-line treatment for metastatic colorectal cancer, Clin Cancer Res, 2015;21:5469–79.
6. Gong J, Cho M, Fakih M, RAS and BRAF in metastatic colorectal cancer management, J Gastrointest Oncol, 2016;7:687–704.
7. Distler P, Holt PR, Are right- and left-sided colon neoplasms distinct tumors?, Dig Dis, 1997;15:302–11.
8. Glebov OK, Rodriguez LM, Nakahara K, et al., Distinguishing right from left colon by the pattern of gene expression, Cancer Epidemiol Biomarkers Prev, 2003;12:755–62.
9. Missiaglia E, Jacobs B, D’Ario G, et al., Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features, Ann Oncol, 2014;25:1995–2001.
10. Meguid RA, Slidell MB, Wolfgang CL, et al., Is there a difference in survival between right- versus left-sided colon cancers?, Ann Surg Oncol, 2008;15:2388–94.
11. Weiss JM, Pfau PR, O’Connor ES, et al., Mortality by stage for right- versus left-sided colon cancer: analysis of surveillance, epidemiology, and end results–Medicare data,J Clin Oncol, 2011;29:4401–9.
12. Benedix F, Kube R, Meyer F, et al., Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival,Dis Colon Rectum, 2010;53:57–64.
13. Warschkow R, Sulz MC, Marti L, et al., Better survival in right-sided versus left-sided stage I–III colon cancer patients, BMC Cancer, 2016;16:554.
14. Zhang Y, Ma J, Zhang S, et al., A prognostic analysis of 895 cases of stage III colon cancer in different colon subsites, Int J Colorectal Dis, 2015;30:1173–83.
15. Kerr DJ, Domingo E, Kerr R, Is sidedness prognostically important across all stages of colorectal cancer?, Lancet Oncol, 2016;17:1480–2.
16. Holch JW, Ricard I, Stintzing S, et al., The relevance of primary tumour location in patients with metastatic colorectal cancer: a meta-analysis of first-line clinical trials, Eur J Cancer, 2017;70:87–98.
17. Moretto R, Cremolini C, Rossini D, et al., Location of primary tumor and benefit from anti-epidermal growth factor receptor monoclonal antibodies in patients with RAS and BRAF wild-type metastatic colorectal cancer, Oncologist, 2016;21:988–94.
18. De Roock W, Claes B, Bernasconi D, et al., Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis, Lancet Oncol, 2010;11:753–62.
19. Brule SY, Jonker DJ, Karapetis CS, et al., Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17, Eur J Cancer, 2015;51:1405–14.
20. Wang F, Bai L, Liu TS, et al., Right-sided colon cancer and left-sided colorectal cancers respond differently to cetuximab, Chin J Cancer, 2015;34:384–93.
21. Tejpar S, Stintzing S, Ciardiello F, et al., Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials, JAMA Oncol, 2017;3:194–201.
22. Boeckx N, Toler A, Op de Beeck K, et al., Primary tumor sidedness impacts on prognosis and treatment outcome: results from three randomized studies of panitumumab plus chemotherapy versus chemotherapy plus panitumumab, Ann Oncol, 2016;27:15–42.
23. Heinemann V, von Weikersthal LF, Decker T, et al., FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial, Lancet Oncol, 2014;15:1065–75.
24. Venook A, Niedzwiecki D, Lenz H, et al., CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC), J Clin Oncol, 2014;32(Suppl):abst LBA4.
25. Venook A, Niedzwiecki D, Innocenti F, et al., Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance), J Clin Oncol, 2016;34(Suppl):abstr 3504.
26. Cremolini C, Loupakis F, Antoniotti C, et al., FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study, Lancet Oncol, 2015;16:1306–15.
Keywords: Sidedness, colorectal cancer, epidermal growth factor, metastatic disease, cetuximab, panitumumab, bevacizumab, chemotherapy