Transverse colon cancer: a call for focused research in an understudied heterogenous disease

Colorectal cancer is a heterogenous disease, with significant differences in embryologic origins, mutational profiles, histology, response to systemic therapy and prognosis based on primary tumor location within the colon (1). The distinction of right and left sided colorectal cancer has been created to reflect these differences, with right sided including the cecum, ascending colon and transverse colon, and left sided including the splenic flexure, descending colon, sigmoid colon and rectum. However, the precise categorization of the transverse colon remains controversial due to its derivation from both the midgut and hindgut, and demonstration of characteristics of both right and left sided cancers (2). This continuum of disease and the relative rarity of transverse colon cancer has historically lent investigators to include transverse colon cancer within right sided disease or exclude transverse colon cancer from trials. This has potentially limited our thorough understanding of transverse colon cancer and impedes treatment optimization for this patient population (3).

Transverse colon cancer represents an estimated 10% of all colon cancers, with estimates of right sided colorectal cancer ranging between 54% to 67% (4,5). However, those diagnosed under the age of 50 years, largely present with left sided disease, at an estimated 65% of total cases (6). Embryologically, the proximal 2/3 of the transverse colon originates from the midgut, while the distal 1/3 derives from the hindgut (4). This variation in origin results in differences in disease presentation, histology and mutational profile within the transverse colon itself. Right sided colorectal cancer, deriving from the midgut, often presents as mucinous adenocarcinomas or sessile serrated adenomas with flat morphology. In contrast, left sided colorectal cancer derives from the hindgut, exhibits typical adenocarcinomas, with polypoid morphology (7,8). Studies indicate that right sided colorectal cancer more often affects female patients and patients of older age, with left sided colorectal cancer having a male predominance and more frequently affects younger patients (8). Severity of disease at presentation and sites of metastasis also vary, with right sided colorectal cancer more often exhibiting higher T stage, poor differentiation, and peritoneal metastasis, whereas left sided colorectal cancer is more frequently found to have lower T stage, more differentiated tumors and more likely to develop pulmonary and hepatic metastasis (8-10). Due to the combined origins of transverse colon cancer, clear clinical and pathological features of these tumors have been difficult to define.

The multifarious presentation of colon cancer is preceded by its underlying mutational profiles. Right sided colorectal cancers exhibit higher rates of BRAF, KRAS, PIK3CA, CTNNB1, SMAD4 mutations and microsatellite instability (MSI-H). Left sided colorectal cancers more often follow the chromosomal instability (CIN) pathway, observing mutations in TP53, APC, KRAS, PIK3CA, SMAD4, NRAS, FBXw7, TCF7L2 along with APC deletions, Wnt and RAS pathway activation (1,2). Although commonly considered a right sided disease, transverse colon cancer has been found to have mutational clusters that vary relative to other right sided locations. In fact, when directly comparing mutational clusters of transverse colon cancer to right and left sided colorectal cancers, the transverse colon had statistically significant differences to right sided mutational clusters, but no statistically significant difference to left sided disease (2). In another analysis of a cohort of transverse colon cancer patients, transverse colon cancer had higher rates of BRAF mutations and MSI-H phenotype in line with right sided colorectal cancer, yet the majority of patients harbored KRAS wild type tumors, aligning with the left sided colorectal cancer mutational profile. When delineating these patients by the original tumor location within the transverse colon, the majority of the MSI-H phenotype were found originating in the proximal 2/3 of the transverse colon, and KRAS wild type tumors were found mostly in tumors originating from the distal 1/3 of the transverse colon. These findings were ultimately consistent with characteristics of the tumor’s embryologic origin (4). Prognostically, right sided colorectal cancer has an inferior prognosis relative to left sided disease across age, gender, ethnicity and year of diagnosis (11). Transverse colon cancer appears to align with right sided colorectal cancer, demonstrating higher stages at presentation, less tumor differentiation, and poor prognosis, with later line treatment options agnostic to original primary tumor location (4,12).

Currently, treatment of resectable transverse colon cancer does not vary from standard fluoropyrimidine based adjuvant therapy, however, stage IV disease follows the treatment paradigm of right sided colon cancers (13). Cytotoxic chemotherapy with the addition of vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab has shown to improve overall survival (OS) and remains the standard targeted agent in this setting (14,15). Targeting epidermal growth factor receptor (EGFR) signaling was examined by pivotal first line therapy trials such as CRYSTAL, which confirmed the utility of the addition of EGFR inhibitors-based therapy in RAS wild type tumors to cytotoxic chemotherapy, in addition to FIRE-3 which suggested OS benefit of the EGFR in combination with FOLFIRI in RAS wild type patients over the use of bevacizumab. However, neither trial stratified based on sidedness of the primary tumor, until retrospective analysis of both trials indicated superior objective response rate, progression-free survival (PFS) and OS with the addition of cetuximab to chemotherapy for left sided colorectal cancer, compared to minimal efficacy seen in right sided wild type tumors (16-18). CALG/SWOG 80405 was one of the first trials to suggest significantly worse survival for KRAS wild type right sided colorectal cancer treated with cetuximab plus chemotherapy relative to left sided disease (19). Most recently, the PARADIGM trial prospectively found that the efficacy of anti-EGFR therapy derives from RAS wild type left sided colorectal cancer, with right sided disease showing no significant difference in OS between anti-EGFR therapy or bevacizumab in addition to chemotherapy (20).

Given the lack of stratification for transverse colon cancer in the above landmark trials, and the paucity of specific transverse colon cancer outcomes or dedicated transverse colon cancer therapy investigations, Solar Vasconcelos et al. sought to examine the efficacity of anti-EGFR therapeutic agents in the treatment of transverse colon adenocarcinoma via a retrospective pooled population analysis of two prospective randomized Canadian Cancer Trials Group/Australian Gastro-Intestinal Trials Group (CTG/AGITG) trials. CCTG/AGITG CO.17 and CO.20 both enrolled patients with heavily pre-treated metastatic colorectal cancer, that had adequate performance status and had no previous exposure to anti-EGFR therapy (21). CO.17 randomized EGFR positive patients to cetuximab plus supportive care (SC) or SC alone. Notably, the trial did not require prospective RAS/BRAF testing, however, KRAS/NRAS exons 2-4 and BRAF V600E genotyping was performed in later correlative analyses and was utilized by Solar Vasconcelos et al. in their patient selection. CCTG/AGITG CO.20 randomized the same patient population to receive cetuximab plus brivanib alaninate (a multi-targeted tyrosine kinase inhibitor) versus cetuximab plus placebo, with KRAS wild type testing performed after trial initiation, resulting in exclusion of KRAS exon 2 mutated patients (22-25).

Authors of this analysis pooled data from patients with confirmed KRAS/NRAS/BRAF wild type tumors from both arms of CO.17 and KRAS from the single agent cetuximab arm in CO.20. Analyses were then performed based on the location of the primary tumor. Right sided tumors were defined as originating from the cecum distally to the hepatic flexure and left sided tumors originating at the splenic flexure distally to the rectum. The remaining tumors were considered in the transverse colon. A total of 553 patients were included, with most patients diagnosed with left sided primary tumors (75.9%). Transverse colon primary tumors were only found in 32 patients (5.8%), with the remaining considered right sided primary tumors (18.35%). The overwhelming majority (82.6%) received cetuximab, while 17.4% received SC alone. Outcomes including PFS and OS were examined for each primary tumor location comparing patients treated with cetuximab vs. SC alone. Survival outcomes were also analyzed for all patients treated with cetuximab based on primary tumor location, using patients with a transverse colon primary tumor as a reference. Additionally, using primary tumor location of the rectum as a reference, authors analyzed the outcomes of nine distinct areas of the colon (cecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, sigmoid, rectosigmoid junction, rectum). Multivariate analysis controlled for primary tumor location, treatment, and multiple baseline characteristics including stage at presentation, histologic tumor grade, lymph node involvement, tumor T-stage, metastatic or recurrent disease at presentation, time from initial diagnosis to randomization, number of previous systemic chemotherapies, number of organs with metastatic disease, presence of lung or liver metastases, basic demographic information (age, sex, performance status) and laboratory values.

Baseline characteristic analysis revealed that relative to patients with right or left side primary tumors, patients with transverse colon primary tumors had more poorly differentiated histologic grade (43.3%), more metachronous disease and peritoneal/retroperitoneal disease at presentation (50% and 21.9% respectively), had less liver or lung metastasis at presentation (21.9%), and were more often allocated to SC as primary treatment (31.2%).

When evaluating the efficacy of cetuximab within each primary tumor location, patients with transverse and right sided colon cancer did not see a statistically significant benefit in PFS or OS relative to SC alone, whereas left sided tumors saw improvement in both PFS and OS [hazard ratio (HR) 0.37, 0.51 respectively]. The use of cetuximab yielded similar minimal response rates in right sided and transverse tumors, no statistically significant difference in disease control rates (DCR) in right sided or transverse colon tumors relative to SC, and a lack of objective responses in transverse tumors. This was unlike left sided tumors, which exhibited a 10.4% objective response rate and significant improvement in DCR to 60.7% vs. 13.5% with SC alone. Outcomes were similar when examining only patients randomized to cetuximab, indicating no statistically significant difference in DCR, PFS or OS between right sided tumors and transverse tumors, but significantly inferior outcomes of patients with transverse colon tumors relative to left sided tumors.

As mentioned above, the authors analyzed the efficacy of cetuximab based on nine subsites within the colon, including: cecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, sigmoid colon, rectosigmoid junction, and rectum. Using the rectum as the reference group, multivariate analysis indicated patients with primary transverse colon malignancy had a significantly worse PFS and OS when treated with cetuximab relative to the rectum. Finally, the authors evaluated the prognostic impact of the tumor origination in the transverse colon, assessed by evaluating the PFS and OS of patients receiving SC alone, with the transverse colon as the reference. No statistically significant differences in PFS and OS were observed between the transverse colon and right and left sided primary tumors, however, numerically, left sided cancers had improved PFS and OS (HR 0.75 and 0.54 respectively) (Table 1) (21).

Overall, the authors’ results reinforce the general perception that the transverse colon exhibits treatment responses similar to that of right sided colon cancers, with poor response to EGFR inhibitors, and similar prognostic features. This analysis is an important contribution to the paucity of literature addressing the treatment of transverse colon cancer, especially in the treatment refractory setting, and further clarifies the biological behavior of the disease. However, the authors recognize the limitations of their analysis. The study was a retrospective pooled analysis, with a very small patient population of transverse colon cancer, limiting the statistical power and causal relationships that can be determined. Additionally, CCTG/AGITG CO.20 likely included RAS and BRAF mutant colon cancers as patients were only screened for KRAS exon 2. Though the authors do note that if there were a high percentage of these cases included, there would have been a decreased ability to find statistical significance between the included cohorts. Further, although these results align with first line treatment studies of anti-EGFR therapy in combination with cytotoxic chemotherapy, indicating benefit only in left sided colorectal cancer, this pooled analysis was limited to treatment in the refractory setting. Therefore, it is difficult to draw clear conclusions of the efficacy of these interventions for transverse colon cancer in the front-line setting. This highlights the lack of data for the optimal treatment of transverse colon cancer in the first line setting and necessitates the evaluation of therapeutic agents for this subset of colon cancer.

We greatly appreciate the authors’ efforts to advance the care of this understudied patient population. Yet, we believe there is still significant work that needs to be done to optimize the care for patients with transverse colon cancer. Tumor characteristics and treatment response based on the right and left colon cancer models does not remain consistent amongst studies. For example, one very large observational study did observe that age, tumor grade and histological subtype had a linear correlation with distance from the ileocecal valve, consistent with the right and left colon cancer model, however, more aggressive phenotypes were observed in cecal and splenic flexure tumors, with less aggressive characteristics seen with ascending and descending colon (10). This underscores that this predetermined cut off right and left sided colorectal cancer does not fully encompass the fundamental complexity of colon cancer development.

Moreover, biologic behavior and efficacy of treatment may likely vary between locations in the transverse colon alone due to the differences in embryologic origin and associated mutational features. There is a significant need for clinical trials to include stratification based on tumor location within the colon, including the specific location of tumors within the transverse colon, so that differences in therapeutic responses can be ascertained between primary tumor origins. Due to the relative rarity of transverse colon cancer, the analysis of real-world data could prove crucial to our understanding of this disease. Ultimately, to properly inform our patients of their optimal treatment options and prognosis, it is imperative for future clinical trials to not only include patients with transverse colon cancer, but also have dedicated therapeutic trials for transverse colon cancer We believe that grouping transverse colon cancer solely within right sided disease may prove to be suboptimal, and that judicious categorization based on embryologic origin, mutational profile and tumor characteristics is imperative to attain ideal outcomes.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-312/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-312/coif). C.C. reports payment for consulting and advisory board participation with Taiho Pharmaceutical, and consulting payments from Targeted Oncology, Curio Science. He also reports travel expenses paid by PRECISCA to their annual conference. E.D. reports grant support and support for clinical trial conduct paid to her institution from: Ely Lilly, Pfizer, Astrazeneca, Zymeworks, Lutris, Leap Therapeutics, Relay, Dragonfly, NGM therapeutics, Incyte, Kinate, Gilead and Ipsen. She received honoraria for lecture from Pfizer. She received payment for advisory board participation from: Agenus, Amgen, Olympus, Incyte, Taiho, Helsinn, G1 therapeutics. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Baran B, Mert Ozupek N, Yerli Tetik N, et al. Difference Between Left-Sided and Right-Sided Colorectal Cancer: A Focused Review of Literature. Gastroenterology Res 2018;11:264-73. [Crossref] [PubMed]
2. Loree JM, Pereira AAL, Lam M, et al. Classifying Colorectal Cancer by Tumor Location Rather than Sidedness Highlights a Continuum in Mutation Profiles and Consensus Molecular Subtypes. Clin Cancer Res 2018;24:1062-72. [Crossref] [PubMed]
3. 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. [Crossref] [PubMed]
4. Roberto M, Arrivi G, Lo Bianco F, et al. Evaluation of Prognostic Factors for Survival in Transverse Colon Cancer. Cancers (Basel) 2020;12:2457. [Crossref] [PubMed]
5. 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. [Crossref] [PubMed]
6. Kearney DE, Cauley CE, Aiello A, et al. Increasing Incidence of Left-Sided Colorectal Cancer in the Young: Age Is Not the Only Factor. J Gastrointest Surg 2020;24:2416-22. [Crossref] [PubMed]
7. Marzouk O, Schofield J. Review of histopathological and molecular prognostic features in colorectal cancer. Cancers (Basel) 2011;3:2767-810. [Crossref] [PubMed]
8. Nawa T, Kato J, Kawamoto H, et al. Differences between right- and left-sided colon cancer in patient characteristics, cancer morphology and histology. J Gastroenterol Hepatol 2008;23:418-23. [Crossref] [PubMed]
9. 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. [Crossref] [PubMed]
10. Benedix F, Schmidt U, Mroczkowski P, et al. Colon carcinoma--classification into right and left sided cancer or according to colonic subsite?--Analysis of 29,568 patients. Eur J Surg Oncol 2011;37:134-9. [Crossref] [PubMed]
11. Schrag D, Weng S, Brooks G, et al. The relationship between primary tumor sidedness and prognosis in colorectal cancer. J Clin Oncol 2016;34:3035. [Crossref]
12. Kim K, Kim YW, Shim H, et al. Differences in clinical features and oncologic outcomes between metastatic right and left colon cancer. J BUON 2018;23:11-8. [PubMed]
13. Gill S, Loprinzi CL, Sargent DJ, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol 2004;22:1797-806. [Crossref] [PubMed]
14. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42. [Crossref] [PubMed]
15. Kabbinavar FF, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005;23:3697-705. [Crossref] [PubMed]
16. Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:1408-17. [Crossref] [PubMed]
17. 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. [Crossref] [PubMed]
18. 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. [Crossref] [PubMed]
19. Venook AP, Niedzwiecki D, Lenz HJ, et al. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA 2017;317:2392-401. [Crossref] [PubMed]
20. Watanabe J, Muro K, Shitara K, et al. Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA 2023;329:1271-82. [Crossref] [PubMed]
21. Solar Vasconcelos JP, Chen N, Titmuss E, et al. Transverse Colon Primary Tumor Location as a Biomarker in Metastatic Colorectal Cancer: A Pooled Analysis of CCTG/AGITG CO.17 and CO.20 Randomized Clinical Trials. Clin Cancer Res 2024;30:1121-30. [Crossref] [PubMed]
22. Jonker DJ, O'Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007;357:2040-8. [Crossref] [PubMed]
23. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757-65. [Crossref] [PubMed]
24. Siu LL, Shapiro JD, Jonker DJ, et al. Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal carcinoma: the NCIC Clinical Trials Group and AGITG CO.20 Trial. J Clin Oncol 2013;31:2477-84. [Crossref] [PubMed]
25. Loree JM, Dowers A, Tu D, et al. Expanded Low Allele Frequency RAS and BRAF V600E Testing in Metastatic Colorectal Cancer as Predictive Biomarkers for Cetuximab in the Randomized CO.17 Trial. Clin Cancer Res 2021;27:52-9. [Crossref] [PubMed]