Sidedness matters: Colon cancer outcomes in low-resource settings

Abstract

Colon cancer (CC) laterality (right vs left) is recognized as a key determinant of clinical outcomes and treatment decisions in metastatic CC. Right-sided CC (RCC) often presents in older individuals and is associated with higher rates of Kirsten rat sarcoma viral oncogene homolog and v-raf murine sarcoma viral oncogene homolog B1 mutations and deficient mismatch repair, leading to microsatellite instability-high status. Left-sided CC typically presents in younger individuals, demonstrates a more favorable prognosis, and is often Kirsten rat sarcoma viral oncogene homolog/neuroblastoma RAS viral oncogene homolog/v-raf murine sarcoma viral oncogene homolog B1 wild-type, making it more responsive to anti-epidermal growth factor receptor therapy. RCC typically responds poorly to anti-epidermal growth factor receptor agents; however, it may benefit from triplet chemotherapy (5-fluorouracil + leucovorin + oxaliplatin + irinotecan) with or without anti-angiogenic agents. Comprehensive molecular profiling remains challenging in low-resource settings due to limited access to advanced diagnostic tools. This review explores key epidemiological and molecular differences between RCC and left-sided CC. In the absence of complete genomic data, tumor sidedness can be a helpful guide for making treatment decisions. Here, we propose a practical algorithm that integrates basic immunohistochemistry to assess a tumor’s mismatch repair status and laterality, potentially facilitating therapy selection in resource-constrained environments. Recognizing laterality-specific trends in prognosis and treatment response can improve personalized care and outcomes for patients with CC in these environments, highlighting the essential role of cost-effective biomarker strategies.

Key Words: Colon cancer; Sidedness; Tailored therapy; Mismatch repair; Consensus molecular subtypes

Core Tip: Colon tumor sidedness is a practical compass for determining treatment. This review synthesizes epidemiologic, molecular, and clinical differences between right-sided colon cancer (RCC) and left-sided colon cancer (LCC). Older patients with RCC more frequently exhibit microsatellite instability-high status/deficient mismatch repair (MMR), Kirsten rat sarcoma viral oncogene homolog/v-raf murine sarcoma viral oncogene homolog B1 mutations, poorer prognosis in metastatic disease, and limited benefit from anti-epidermal growth factor receptor (EGFR). LCC is more often RAS/v-raf murine sarcoma viral oncogene homolog B1 wild-type and EGFR-responsive. We propose a low-resource plan: Prioritize MMR immunohistochemistry; consider immunotherapy for deficient MMR/microsatellite instability-high; use 5-fluorouracil + leucovorin + oxaliplatin + irinotecan ± anti-angiogenic agents for RCC and doublet ± anti-angiogenic therapy for LCC; restrict anti-EGFR to confirmed wild-type disease.

INTRODUCTION

The management of metastatic colon cancer (CC) has significantly advanced in recent years. Historically, treatment decisions were primarily guided by anatomical and histopathological factors, such as tumor grade and stage; however, advances in molecular oncology have currently enabled the identification of specific biomarkers that predict prognosis and therapeutic responsiveness. Specifically, mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and v-raf murine sarcoma viral oncogene homolog B1 (BRAF); mismatch repair (MMR) status; and microsatellite instability (MSI) have become crucial for determining systemic therapy suitability[1]. Patients with wild-type KRAS, NRAS, or BRAF may respond favorably to anti-epidermal growth factor receptor (EGFR) therapies such as cetuximab or panitumumab. Conversely, patients with KRAS, NRAS, or BRAF mutations are more likely to respond well to anti-angiogenic drugs such as bevacizumab and aflibercept[2]. BRAF-mutant CC is associated with a poor prognosis, often requiring intensive treatment strategies such as triplet chemotherapy regimens [e.g., 5-fluorouracil + leucovorin + oxaliplatin + irinotecan (FOLFOXIRI)] and targeted inhibitors of both BRAF and MEK[3]. In the KEYNOTE-177 trial, pembrolizumab and nivolumab, both immune checkpoint inhibitors, demonstrated significant efficacy in treating patients with deficient MMR (dMMR) or MSI-high (MSI-H) metastatic CC[4].

Despite these significant advances, implementing routine molecular profiling remains challenging in low-resource settings due to high costs and limited infrastructure, which restrict access to techniques such as reverse transcription polymerase chain reaction, immunohistochemistry (IHC), and next-generation sequencing. In such settings, tumor laterality, specifically the distinction between right-sided CC (RCC) and left-sided CC (LCC), may serve as a surrogate marker to inform therapeutic decisions. Multiple studies have indicated that RCC and LCC differ in their epidemiology, clinical outcomes, and molecular features[5]. Recognizing and leveraging these distinctions may provide a practical framework for initial treatment selection in environments where comprehensive molecular testing is not readily available.

This article summarizes the key differences between RCC and LCC regarding their epidemiology, molecular profiles, prognoses, and therapeutic implications. Additionally, it proposes a stepwise management framework for resource-limited settings, highlighting how tumor sidedness can guide decisions regarding chemotherapy, biological therapies, and immunotherapy.

RCC

RCC, defined as tumors arising from the cecum to the proximal transverse colon, exhibits distinct epidemiological patterns. Data suggest that RCC is more common in individuals over 65 years of age, women, and African Americans. The average age at diagnosis for RCC is 70 years, which is higher than the median age for LCC[6]. While the overall incidence of CC has been declining in certain regions due to screening programs, recent trends highlight an increase in earlier-onset RCC among African American patients[7]. This indicates that an interplay of genetic, environmental, and socioeconomic factors may influence RCC pathogenesis differently than for LCC[8].

Numerous studies have shown that patients with metastatic RCC have poorer survival outcomes than those with LCC. One retrospective analysis reported a median overall survival (OS) of 16.4 months for patients with RCC vs 23.4 months for those with LCC[6]. Similarly, another study reported 3-year survival rates of 17.7% for patients with stage IV RCC and 28.6% for those with stage IV LCC; however, this difference was only statistically significant under univariate analysis[9]. By contrast, earlier-stage RCC (e.g., stage II) demonstrates relatively favorable outcomes, particularly following successful surgical resection. Certain stage II subgroups (e.g., MSI-H) have better prognoses than their LCC counterparts; however, metastatic RCC is always associated with a worse prognosis[10].

MMR proteins, namely MutL homolog (MLH) 1, MutS homolog (MSH) 2, MSH6, and PMS2, are critical for genomic stability. Deficiency in these proteins leads to the MSI-H phenotype, often associated with hypermethylation of the MLH1 promoter in sporadic tumors. MSI-H is more common in RCC, with prevalence reaching up to 25.5% in ascending colon tumors[11]. Patients with MSI-H tumors typically present with specific clinicopathological features, including larger primary tumor size, mucinous histology, and fewer lymph node metastases. In patients with localized disease, MSI-H status is associated with a more robust anti-tumor immune response, resulting in improved outcomes such as disease-free survival and OS[12]. The necessity of adjuvant chemotherapy in stage II MSI-H/dMMR tumors is controversial, because these patients often have favorable prognoses and may not benefit from the treatment[13].

RCC is distinguished by its molecular profile, which frequently includes mutations in the KRAS, NRAS, and BRAF genes. Studies have reported higher rates of KRAS mutations in RCC, occurring in up to 46.3% of cases[14]. Additionally, BRAF mutations, which are strongly associated with poor prognoses, occur in up to 16.3% of RCC cases, a notably higher rate than in LCC cases[14]. BRAF mutations and MSI-H frequently occur together in RCC, contributing to the aggressive nature of these tumors. NRAS mutations are less common, typically occurring in about 1.6%-4.1% of metastatic cases[15].

Colorectal tumors can be classified into four consensus molecular subtypes (CMS) with distinct molecular and clinical attributes: CMS1 (MSI-immune), CMS2 (canonical), CMS3 (metabolic), and CMS4 (mesenchymal)[16]. RCC tumors are more commonly classified as CMS1 and CMS3. CMS1 is characterized by high immune infiltration, MSI, and hypermutation, which partially explains the favorable immunotherapy responses observed in certain RCC subsets treated with immunotherapy. CMS3 tumors, which are more common in the proximal colon, exhibit distinctive metabolic reprogramming that underscores the fundamental molecular difference between RCC and LCC. They display a “metabolic switch” characterized by pronounced aerobic glycolysis (Warburg phenotype), increased reliance on exogenous glutamine for anaplerosis, and activation of nutrient-sensing phosphoinositide 3-kinase-protein kinase B signaling, promoting rapid biomass synthesis and relative resistance to standard cytotoxic agents. These metabolic features of CMS3 distinguish it from the immune-driven CMS1 and stromal-rich CMS4 subtypes, and help explain the variation in pathogenesis, treatment sensitivities, and clinical outcomes observed between RCC and LCC. Emerging preclinical data further suggest that targeted inhibition of phosphoinositide 3-kinase or glutaminase may selectively impair CMS3 tumors. These findings suggest the potential for developing novel treatment strategies targeting metabolism, potentially combining therapies and better tailoring treatments to patients based on specific tumor characteristics[17].

LCC

LCC includes tumors originating from the distal transverse colon to the rectum (i.e. descending colon, sigmoid colon, and rectum). LCC tends to occur in younger individuals, with a higher incidence observed in males and White populations. Globally, LCC incidence varies, likely influenced by evolving dietary and lifestyle factors, screening initiatives, and genetic predispositions[7].

Patients with stage I, III, and IV LCC tend to have improved OS compared to those with RCC. This difference has become more pronounced with the emergence of modern chemotherapy combinations, such as fluorouracil, leucovorin, oxaliplatin (FOLFOX) and fluorouracil, leucovorin, irinotecan[18]. However, certain subsets of stage II RCC, particularly those with mucinous or signet ring cell histology, exhibit comparable or better prognostic outcomes than LCC. Therefore, the significance of tumor sidedness in determining prognosis may vary based on disease stage, histological subtype, and other patient-specific factors[19].

Compared to RCC, MSI-H/dMMR status is significantly less common in LCC. Gutierrez et al[11] reported that only 7.6% of sigmoid colon tumors and 5.4% of rectosigmoid tumors displayed MSI-H/dMMR, a marked contrast to the prevalence observed in ascending colon tumors. This difference could be partly attributed to lower MLH1 promoter hypermethylation rates in LCC, combined with distinct genetic and epigenetic trajectories that underpin LCC carcinogenesis.

KRAS mutations in LCC occur in about 35.8% of metastatic cases, although reported frequencies range from 36.7% to 46.6% depending on the population studied and molecular detection methods used[14]. BRAF mutations are less prevalent in LCC, occurring in approximately 4.3% of cases, whereas NRAS mutations occur in 6%[15]. The lower prevalence of BRAF mutations partially accounts for the comparatively favorable prognosis of LCC in metastatic disease.

LCC is more frequently associated with CMS2 and CMS4 classifications. CMS2 tumors are driven by Wnt and v-myc avian myelocytomatosis viral oncogene homolog signaling pathways and exhibits traits typical of epithelial cells. CMS4 tumors are characterized by pronounced stromal components, angiogenesis, and transforming growth factor beta signaling. These molecular features partially explain the clinicopathological and therapeutic differences between LCC and RCC[17]. Large-scale genomic analyses have identified KRAS G12D/G13D, NRAS Q61K, and BRAF V600E as the dominant driver variants in metastatic CC. In pooled cohorts, KRAS G12D/G13D is detected in about 46% of RCC vs about 36% of LCC, whereas BRAF V600E shows a marked enrichment in RCC (about 16%) compared with LCC (about 4%). NRAS Q61K displays the reverse pattern, being slightly more common in LCC (about 6%) than RCC (about 2%)[17].

RCC VS LCC

In low-resource settings, the absence of comprehensive molecular assays (e.g., next generation sequencing or PCR-based assays) to determine KRAS, NRAS, BRAF, or MSI status significantly hinders patient access to personalized treatment. While national and international guidelines recommend basing first-line treatment decisions on molecular profiles, tumor laterality can serve as a pragmatic and cost-effective surrogate to guide these decisions when molecular profiling is unavailable[20]. To address this gap, we propose a simplified algorithm for managing adjuvant and palliative therapy based on tumor sidedness, designed for situations where molecular test results are incomplete or unobtainable.

Adjuvant chemotherapy is typically recommended for patients with stage III colorectal cancer and certain patients with high-risk stage II disease. A study by Cavadas et al[21] found no significant differences in survival or recurrence rates among tumors in specific anatomical regions within the right colon, whereas another study reported a 5% higher risk of mortality compared to LCC[22]. In the absence of molecular tests, the decision to administer adjuvant chemotherapy to patients with stage II disease may be based on clinical risk factors. In stage II RCC, the potential for undetected MSI-H/dMMR status must also be considered, which is associated with more favorable prognoses and potentially reduced from adjuvant chemotherapy. Conversely, treatment decisions for stage II LCC rely on standard risk factors such as T4 Lesions, inadequate lymph node sampling, or obstructions/perforations. In all cases, MMR status should be assessed using IHC, which is a simpler, more cost-effective test compared to a full MSI analysis, and can be used to guide treatment decisions based on dMMR status[23]. This initial step is particularly important for metastatic RCC cases, even in low-resource settings. Patients whose tumors show dMMR in genes like MLH1, MSH2, MSH6, or PMS2 may be candidates for immunotherapy such pembrolizumab. Immunotherapy is generally not recommended without confirming dMMR/MSI-H status, as the benefits are greatest in these specific tumors[24].

For relatively fit patients with a high RCC tumor burden, triplet chemotherapy regimens (e.g., FOLFOXIRI) may be a preferred treatment option. The TRIBE2 study and others showed that FOLFOXIRI ± bevacizumab is effective for treating BRAF mutations, which occur frequently in RCC[25]. RCC generally responds less favorably to anti-EGFR agents (e.g., cetuximab and panitumumab), even in cases where KRAS, NRAS, and BRAF are found to be wild-type. Post-hoc analyses of trials like FIRE-3 and CALGB/SWOG 80405 have suggested that anti-EGFR therapy primarily benefits patients with LCC[26]. Consequently, in metastatic RCC cases, if molecular testing is not available and the tumor is presumed or known to be KRAS/NRAS/BRAF wild-type, anti-EGFR therapy is unlikely to be beneficial. In such cases, anti-angiogenic strategies using bevacizumab or aflibercept should be considered in combination with chemotherapy[27]. For physically fit patients with RCC where KRAS, NRAS, and BRAF status is unknown, triplet chemotherapy, with or without an anti-angiogenic agent, is a reasonable approach due to the higher likelihood of BRAF or KRAS mutations, which are associated with poor outcomes from anti-EGFR therapy[28].

LCC exhibits a heterogeneous distribution of mutations and CMS subtypes (i.e. CMS2 and CMS4). Because LCC exhibits KRAS/NRAS/BRAF mutations less frequently than RCC, anti-EGFR therapy may offer greater benefits in patients with LCC[29]. While determining KRAS, NRAS, and BRAF mutation statuses can be challenging in resource-limited settings, the predictive value of these markers for anti-EGFR therapy makes them particularly critical for making informed decisions about LCC treatment[30]. Therefore, if targeted testing is possible, these markers should be prioritized. In the absence of molecular data, empiric use of anti-EGFR agents is not typically recommended, as patients with undetected mutations could be exposed to a therapy that confers no benefits and potential toxicity. In low-resource environments, or when molecular profiling is unavailable, a doublet chemotherapy regimen (e.g., FOLFOX or capecitabine plus oxaliplatin) is often employed. LCC tends to have a relatively better prognosis than RCC, meaning clinicians can implement less intensive regimens if there are any concerns about toxicity or comorbidities[31]. Similar to RCC, anti-angiogenic therapy (e.g., bevacizumab) may be used in combination with chemotherapy to enhance progression-free survival.

CONCLUSION

RCC and LCC exhibit notable differences in their epidemiology, molecular characteristics, and clinical outcomes. RCC is more common in older individuals and is associated with MSI-H/dMMR, BRAF, or KRAS mutations, and poorer prognoses in metastatic cases. LCC, which is more common in younger individuals, demonstrates lower rates of MSI-H and BRAF mutations and is typically KRAS/NRAS/BRAF wild-type, making it a better candidate for anti-EGFR therapy. These distinctions underscore the importance of tumor laterality as an interim guide for therapy selection when complete molecular profiling is unavailable (Table 1).

Table 1 Clinicopathological and molecular differences between right- and left-sided colorectal cancer.

Clinical characteristic	Right	Left
Clinical presentation	More common in older patients, women, and individuals of African descent	More common in younger patients, men, and White populations
MMR or MSI	dMMR more frequent (25.5% in ascending colon)	pMMR more frequent (7.6% in sigmoid colon)
	Higher MLH1 promoter hypermethylation[11]	Lower MLH1 promoter hypermethylation[11]
KRAS and NRAS	Similar frequencies (46.3%)	Similar frequencies (35.8%)
BRAF	More frequent (16.3%)	Less frequent (4.3%)
CMSs	CMS1 and CMS3	CMS2 and CMS4
Response to anti-EGFR therapy	Low response	Favorable response
Prognosis[32]	Stage III 5-year OS: 66.9%	Stage III 5-year OS: 81.8%
	Stage IV 5-year OS: 40.4%	Stage IV 5-year OS: 54.9%

MMR: Mismatch repair; MSI: Microsatellite instability; KRAS: Kirsten rat sarcoma viral oncogene homolog; NRAS: Neuroblastoma RAS viral oncogene homolog; BRAF: V-raf murine sarcoma viral oncogene homolog B1; CMS: Consensus molecular subtype; dMMR: Deficient mismatch repair; MLH1: MutL homolog 1; EGFR: Epidermal growth factor receptor; OS: Overall survival; pMMR: Proficient mismatch repair.

In low-resource settings, combining basic molecular testing (i.e. MMR IHC) with information about tumor laterality can help guide cancer treatment decisions. For RCC cases, triplet chemotherapy (FOLFOXIRI) ± an anti-angiogenic agent is often favored, whereas immunotherapy is reserved for tumors with confirmed dMMR status. In LCC cases, doublet chemotherapy (FOLFOX or capecitabine plus oxaliplatin) ± an anti-angiogenic agent is suitable. Testing for KRAS, NRAS, and BRAF mutations is needed in deciding if anti-EGFR therapy is appropriate for patients with LCC.

These recommendations highlight the need to prioritize essential biomarker tests (e.g., MMR IHC) in resource-limited settings, given their significant impact on predicting disease course and guiding treatment decisions. While tumor laterality provides a valuable and cost-effective surrogate marker for selecting initial treatment, it is not a substitute for comprehensive molecular profiling (Figure 1). Efforts to improve access to molecular testing will be critical for providing effective, personalized treatment to patients with metastatic CC.

Figure 1 Proposed treatment algorithm stratified by tumor sidedness for unresectable stage IV colorectal cancer in low-resource settings. CRC: Colorectal cancer; KRAS: Kirsten rat sarcoma viral oncogene homolog; NRAS: Neuroblastoma RAS viral oncogene homolog; BRAF: V-raf murine sarcoma viral oncogene homolog B1; MMR: Mismatch repair; IHC: Immunohistochemistry; wt: Wild-type; MSI-H: Microsatellite instability-high; dMMR: Deficient mismatch repair; pMMR: Proficient mismatch repair; EGFR: Epidermal growth factor receptor.