Next Article in Journal
Influence of Intraoperative Blood Loss on Tumor Recurrence after Surgical Resection in Hepatocellular Carcinoma
Next Article in Special Issue
Pancreatic Adenocarcinoma: Real World Evidence of Care Delivery in AccessHope Data
Previous Article in Journal
Haemoadsorption Combined with Continuous Renal Replacement Therapy in Abdominal Sepsis: Case Report Series
Previous Article in Special Issue
Combining Preoperative Clinical and Imaging Characteristics to Predict MVI in Hepatitis B Virus-Related Combined Hepatocellular Carcinoma and Cholangiocarcinoma
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JPM
Volume 13
Issue 7
10.3390/jpm13071114
jpm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Impact of Colorectal Cancer Sidedness and Location on Therapy and Clinical Outcomes: Role of Blood-Based Biopsy for Personalized Treatment

by
Sasha Waldstein
1,2,
Marianne Spengler
1,3,
Iryna V. Pinchuk
4 and
Nelson S. Yee
5,*
1
Division of Hematology-Oncology, Department of Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA 17033, USA
2
Vancouver Clinic, Vancouver, WA 98664, USA
3
Wellspan Medical Oncology & Hematology, Lebanon, PA 17042, USA
4
Division of Gastroenterology and Hepatology, Department of Medicine, Penn State College of Medicine, Cancer Control Program, Penn State Cancer Institute, Hershey, PA 17033, USA
5
Division of Hematology-Oncology, Department of Medicine, Penn State Health Milton S. Hershey Medical Center, Next-Generation Therapies Program, Penn State Cancer Institute, Hershey, PA 17033, USA
*
Author to whom correspondence should be addressed.
J. Pers. Med. 2023, 13(7), 1114; https://doi.org/10.3390/jpm13071114
Submission received: 30 May 2023 / Revised: 5 July 2023 / Accepted: 6 July 2023 / Published: 10 July 2023
(This article belongs to the Special Issue Personalized Diagnosis, Treatment, and Prognosis of Gastrointestinal Oncology)
Browse Figures
Review Reports Versions Notes

Abstract

:
Colorectal cancer is one of the most common malignant diseases in the United States and worldwide, and it remains among the top three causes of cancer-related death. A new understanding of molecular characteristics has changed the profile of colorectal cancer and its treatment. Even controlling for known mutational differences, tumor side of origin has emerged as an independent prognostic factor, and one that impacts response to therapy. Left- and right-sided colon cancers differ in a number of key ways, including histology, mutational profile, carcinogenesis pathways, and microbiomes. Moreover, the frequency of certain molecular features gradually changes from the ascending colon to rectum. These, as well as features yet to be identified, are likely responsible for the ongoing role of tumor sidedness and colorectal subsites in treatment response and prognosis. Along with tumor molecular profiling, blood-based biopsy enables the identification of targetable mutations and predictive biomarkers of treatment response. With the application of known tumor characteristics including sidedness and subsites as well as the utilization of blood-based biopsy, along with the development of biomarkers and targeted therapies, the field of colorectal cancer continues to evolve towards the personalized management of a heterogeneous cancer.

1. Introduction

In recent years, the differences between tumors originating from the right versus left side of the colon have been a focus of clinical investigation and biomedical research. Patients with right-sided colon cancer typically present with gastrointestinal bleeding and iron-deficiency anemia, whereas left-sided colon cancer usually manifests as colicky abdominal pain with changes in bowel habits and intestinal obstruction. It has become apparent that prognosis differs depending on tumor sidedness, and that response to therapy is impacted by tumor site of origin. An improved understanding of these unique differences has created new strategies for targeted therapy. The right, or proximal, colon is most often defined as the cecum, ascending colon, and the proximal two-thirds of the transverse colon. The left, or distal, colon includes the last one-third of the transverse colon, the descending colon, the sigmoid colon, and the rectum. The right colon originates from the midgut and is supplied by the superior mesenteric artery, whereas the left colon originates from the hindgut and is supplied by the inferior mesenteric artery [1,2]. In addition to basic anatomy and embryology, the differences span a wide range of characteristics, including epidemiologic features and morphology, as well as carcinogenic pathways, molecular mutations, the microbiome, and predisposition by antibiotics.
Colorectal cancer (CRC) is the third most common cancer worldwide and the fourth in the United States [3,4]. Based on the Surveillance, Epidemiology, and End Results (SEER) Program, there has been an overall downward trend in new CRC cases, with an annual decreased incidence of 2.3% on average. This downward trend is evident for patients older than the age of 55. However, there has been a clear increase in incidence in younger populations, starting from the age of 20 [5]. This early-onset CRC predominately originates from the left side of the colon [6]. Regardless of family history, and after excluding inherited syndromes and inflammatory bowel disease, the Cleveland Clinic identified that 83% of early-onset CRC in the study population originated from the left colon. This was similarly shown in a Mayo Clinic cohort [7]. Right-sided tumors are more common in older patients, and generally have a slight female predominance. The underlying causes for these epidemiologic trends remain largely unknown, but it is apparent that the differences in CRC, in terms of sidedness, are present even at this population level. With a growing understanding of the unique molecular and predisposing properties of right- versus left-sided CRC, these population trends may begin to be explained. The clinical features of right- vs. left-sided CRC are summarized in Figure 1.
In this article, we review the clinically important aspects of CRC relating to tumor sidedness, with updated data from the published literature. First, we provide an overview of the differences in genetic mutations and microbiota between right- and left-sided CRC. Special emphasis is placed on the difference in molecular profiles and microbiota that are relevant to targeted therapeutics and clinical outcomes. The prognosis of CRC at different stages, with relevance to tumor sidedness, is presented, as well as current treatment and investigational approaches. The emerging application of blood-based biopsy for precision treatment of right- versus left-sided CRC is highlighted.

2. Differences in Morphology and Genetic Mutations

There are striking differences in morphology and mutational status with regard to the sidedness of CRC. Right-sided CRCs are more commonly mucinous adenocarcinomas following a sessile serrated pathway, with a flat morphology and highly immunogenic component with increased T cell infiltration. In contrast, the left-sided CRC is often tubular villous, polypoid, and with a low immunogenic component [8]. In addition to these morphological characteristics, there is heterogeneity in mutational burden.
Studies have demonstrated that left-sided tumors are more likely to have mutations affecting APC and TP53 through chromosomal instability, the most common pathway for sporadic CRC [9,10,11]. Left-sided tumors also have higher rates of EGFR mutation and HER2 amplification [9]. On the other hand, a high degree of microsatellite instability (MSI-high), responsible for 10–15% of sporadic CRC, is present in about 22% of right-sided tumors as compared to 5% on the left. The CpG island methylator phenotype (CIMP-high) is also more common on the right, as are mutations of PIK3CA and PTEN [10]. Finally, BRAF mutations are present in 25% of right-sided CRC, as compared to 10% of left-sided cancers [10]. These tumor molecular profiles were also consistent in adolescent and young adult CRC, with higher mutation rates of BRAF, KRAS, and PIK3CA in right-sided tumors, as well as DNA mismatch repair gene mutations [12]. The morphological and genetic mutational features of right- and left-sided CRC are summarized in Figure 2.
However, these molecular features do not abruptly change at splenic flexure as demonstrated in a study involving 1443 CRC cases in 2 prospective cohorts [13]. The findings of this study indicate that the frequency of CIMP-high, MSI-high, and BRAF mutation gradually increases from the rectum to ascending colon. Interestingly, this trend in the changing frequencies of CIMP-high, MSI-high, and BRAF mutations as observed along the rectum to ascending colon is not displayed in cecal carcinomas, which exhibit a high frequency of KRAS mutations [13]. These findings are extended in a study of CRC from 1876 patients demonstrating that the prevalence of mutations differs among tumors located on the same side of the colon [14]. Specifically, the frequency of BRAFV600 mutations increases from the cecum to the hepatic flexure. From the right colon to left colon, the rates of TP53 and APC mutations decrease. There are variations in the MAP kinase and PIK3CA-mTOR-AKT pathways among tumors located within the same side of the colon. The mutational profiles of tumors in the transverse colon are significantly different from those in the right colon, but not tumors in the left colon [14]. Variations of tumor genetic alterations in different locations along the colorectum are clearly important in disease biology, and they also have important implications in patient prognosis and treatment responses.

3. Differences in the Gut Microbiome

The complex role of the microbiome in the pathogenesis of CRC, including the relation to tumor sidedness, has been extensively studied and reviewed [15,16]. Dysbiosis of the gut microbiome can contribute to the initiation and progression of malignant neoplasms, particularly CRC. The microbiota may potentiate malignant transformation through several mechanisms. These include the production of carcinogenic toxins, modulation of inflammatory pathways, dysregulation of epithelial signaling pathways, and DNA damage-driven genomic instability [16].
The composition of the microbiota has been found to have a modest gradient and variability across the colon, such as the relative abundance of Fusobacterium found in left-sided tumors [17]. Bacterial biofilms have been found to be present in 89% of right-sided CRC as compared to 12% of those on the left. Those patients with biofilms identified in their tumors also had biofilms present in their normal colonic mucosa [18]. It has been hypothesized that the increased propensity for cancer development in the setting of biofilms is associated with high immunogenicity, and there are complex interactions among the microorganisms and carcinogenic pathways [19].
Relating to the microbiome, the use of antibiotics for treating infection has been linked to varied effects on the risk of CRC [16,20,21]. The associations between antibiotic use and risk of CRC by tumor site have been examined [20,22]. Quinolones and sulfonamides and/or trimethoprims were significantly associated with an increased risk of cancer in the proximal colon but not the distal colon. On the other hand, nitrofurantoins, macrolides and/or lincosamides, and metronidazoles and/or tinidazoles were significantly associated with decreased risk of rectal cancer [22].
These lines of evidence indicate distinct microbiota in right- and left-sided CRC, suggesting a tumor site-specific effect of the gut microbiome in colorectal carcinogenesis. The understanding of the role of the microbiome in CRC will continue to expand, and these data highlight the need to continue to study CRC as a diverse entity that changes in nature along the course of the colorectum.

4. Prognosis and Tumor Recurrence

Though there is heterogeneity within and between the right- and left-sided CRC, there is substantial evidence that tumor sidedness represents a surrogate for known mutations, and those yet to be identified, that relate to prognosis. Right-sided CRC has many adverse features, such as higher rates of BRAF mutations, sessile serrated pathways of carcinogenesis, and MSI-high (MSI-H) disease. A meta-analysis demonstrated an absolute 19% reduced risk of death in left- as compared to right-sided colon cancer [23]. Importantly, this difference in mortality was not explained by race, cancer stage, chemotherapy, or year of study. Other studies have also shown that the relatively poor prognosis of right-sided metastatic CRC (mCRC) is independent of disease burden and known mutational status [24]. This reinforces that tumor sidedness serves as a proxy for additional prognostic factors that have yet to be identified. Considering the distinct profiles of right- versus left-sided mCRC, studies that stratify treatment by tumor site of origin have been essential to determining appropriate treatment.
The impact of tumor sidedness on clinical outcomes has also been investigated in localized colon cancer. In a retrospective study of 1632 patients in Korea, of which 15.8% had stage I, 36.3% stage II, and 47.9% stage III disease, those with right-sided colon cancer were found to have significantly increased risk of locoregional tumor recurrence [25]. The time to locoregional recurrence was significantly decreased in patients with right-sided colon cancer as compared to those with left-sided tumor, with a hazard ratio (HR) of 2.35 and p value < 0.001. The rate of 5-year locoregional recurrence was higher in patients with right-sided colon cancer (8.5%) than those with left-sided tumors. Other analyses of only stage I and stage II disease have found improved survival in those patients with right-sided tumors, potentially at least somewhat related to proportionally increased rates of MSI-H disease in that cohort which has been associated with a better prognosis in this early-stage disease [26,27].
In a retrospective study using the National Cancer Database, the benefit of adjuvant chemotherapy in patients with surgically resected stage II colon cancer, including the impact of tumor sidedness, was investigated [27]. Regardless of high-risk features, such as pathological tumor (T) stage 4 status and fewer than 12 lymph nodes examined, adjuvant chemotherapy was associated with improved overall survival (OS). In the sub-group analysis, patients with left-sided colon cancer received adjuvant chemotherapy more often (25.6%) than patients with right-sided tumors (17.9%) or transverse colon cancer (20.4%). In those that did not receive adjuvant chemotherapy, right-sided tumors had better OS outcomes as compared to those on the left, with an adjusted HR of 0.92. With the use of adjuvant chemotherapy, the 5-year survival rates were the same, and the difference was negated. This further helps delineate within this population those that would most benefit from adjuvant therapy. However, the impact of tumor sidedness on survival in patients with stage II colon cancer receiving adjuvant chemotherapy will need to be confirmed in prospective clinical studies.
The impact of tumor sidedness on survival in patients with stage III CRC seems to follow similar trends to that for mCRC. A study based on SEER data found that, although stage I–II right-sided disease had a lower risk of mortality than the left (left colon HR 1.09, rectum HR 1.36), there was a higher risk of mortality in right-sided stage III as well as stage IV disease, with a p value < 0.001 for each. In studies of patients with stage III disease, despite similar use of adjuvant chemotherapy, those with right-sided CRC had higher recurrence rates and decreased OS [28,29]. In one analysis, HR for right-sided CRC was 1.78 for recurrence, and right sidedness was an independent predictor of peritoneal recurrence specifically [28]. Therefore, although left- and right-sided CRC seem to have similar survival outcomes with adjuvant therapy in stage II disease, those patients with stage III disease and right-sided CRCs still have worse clinical outcomes than their left-sided counterparts.
The prognostic impact of the primary tumor sidedness in mCRC has also been investigated. In this study, the association between primary tumor sidedness and overall survival in patients with mCRC receiving first-line chemotherapy with or without bevacizumab in three independent cohorts was evaluated [30]. The results of this study indicate that patients with left-sided colon tumor had superior OS as compared with those with right-sided tumor, and there is no dependent relationship with the efficacy of bevacizumab. In agreement with this finding, another study demonstrated that the five-year OS rate of patients with left-sided colon cancer is superior to those with right-sided tumor [31]. Moreover, this difference in survival rate is independent of the KRAS mutational status and treatment with a biological agent (epidermal growth factor receptor inhibitor or bevacizumab). These data support the primary tumor sidedness as an important prognostic factor in patients with mCRC.
Moreover, the tumor location subsites of CRC have prognostic significance. In a study of 1876 patients with CRC with a median follow-up of 46.5 months, as compared to rectal tumors, the hazard ratios for OS in tumors located in the cecum, ascending colon, hepatic flexure, and transverse colon are 1.69, 1.72, 1.98, and 1.38, respectively [14]. In a recent study utilizing a consortium dataset of 13,101 patients with CRC, colon-cancer-specific survival was analyzed in relation to tumor location and molecular features [32]. A significant trend was demonstrated for improved survival in patients with cancer located in the cecum towards the sigmoid colon. For tumors with non-MSI-high, a significant trend for improved survival was shown in sigmoid colon with a hazard ratio of 0.80 relative to the cecum. An inverse trend was exhibited for tumors with MSI-high, and the lowest survival for tumors located in the sigmoid colon with a hazard ratio of 2.13 [32].

5. Impact of Tumor Sidedness on Treatment and Clinical Outcomes in Metastatic CRC

As knowledge of the distinguishing characteristics of left- and right-sided mCRC emerged, core studies of the treatment for mCRC were retrospectively analyzed by tumor side of origin. Chemotherapy with FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin, irinotecan) has been the mainstay of treatment for mCRC. The addition of bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, or anti-epidermal growth factor receptor (EGFR) therapy, with either cetuximab or panitumumab, have been studied and have shown benefit. Bevacizumab was originally shown to have an OS benefit when added to chemotherapy for mCRC, with a median OS of 20.3 months as compared to 15.6 months with chemotherapy alone, with p < 0.001 [33]. A retrospective analysis of that population and others treated with this therapy showed that the benefit of bevacizumab with chemotherapy was independent of primary tumor sidedness [34].
Anti-EGFR therapy has a more disparate effect. The CRYSTAL study showed improved progression-free survival (PFS) of cetuximab in addition to FOLFIRI as compared to chemotherapy alone on initial analysis. Subsequent analysis of those patients with KRAS wild-type tumors showed a similar result, with a median OS of 23.5 months as compared to 20 months with chemotherapy alone (p = 0.0093) [35]. The PRIME study similarly showed the benefit of panitumumab in addition to chemotherapy in this population [36]. However, on retrospective stratified analysis of these studies, a more varied response was observed. For tumors with a left-sided origin, the benefit of cetuximab and panitumumab was similar to results reported in the original studies. However, when the right-sided tumor population was analyzed, there was no difference in survival between chemotherapy alone and the addition of cetuximab. After stratification by sidedness, both in the CRYSTAL and PRIME studies, there was found to be no OS benefit from the addition of an EGFR inhibitor to chemotherapy for mCRC of right-sided origin. [37,38]. Based on these data, anti-EGFR therapy was determined not to be beneficial in right-sided mCRC, but it remains an option for those with left-sided cancers.
Subsequent studies directly compared bevacizumab to anti-EGFR therapy, and similarly showed critical differences in treatment effect once the studied population was stratified by tumor sidedness. The FIRE-3, PEAK, and CALGB/SWOG 80,405 studies each evaluated chemotherapy plus bevacizumab or anti-EGFR therapy for KRAS wild-type mCRC. In FIRE-3 as well as PEAK, an OS benefit of anti-EGFR therapy, with cetuximab or panitumumab, respectively, over bevacizumab was demonstrated. This was not confirmed in the larger CALGB 80,405 study, which showed a median OS of about 30 months with both treatment regimens [39,40,41]. Each of these studies was later retrospectively stratified by tumor sidedness. The population of patients in the FIRE-3 trial with tumors originating from the left side of the colon had similar results as before stratification, with a median OS of 38.3 months with the addition of cetuximab, as compared to 28 months with bevacizumab, to FOLFIRI (p = 0.002) [37]. On analysis of right-sided tumors, there was no statistically significant difference in median OS between bevacizumab and cetuximab. Stratification of the PEAK trial by tumor sidedness demonstrated similar results [38]. When the same analysis was performed on the CALGB/SWOG 80,405 population, there was again an OS benefit with either bevacizumab or cetuximab for patients with left-sided tumors. However, right-sided tumors of origin appeared to do worse with the addition of cetuximab to chemotherapy as compared to bevacizumab, with a striking difference in median OS of 18.4 months as compared to 34.4 months, respectively [42]. An additional study of the California Cancer Registry supported this finding, with right-sided mCRC having an OS HR of 1.31 for cetuximab and chemotherapy as compared to HR of 0.93 for bevacizumab plus chemotherapy [43]. These subgroup analyses further support the need to address sidedness within trials of CRC, as this has changed the landscape for appropriate treatment recommendations.
Though the retrospective nature of these evaluations limits study design and conclusions, a convincing pattern, repeated in multiple studies, has emerged in patients treated with anti-EGFR antibodies beyond first-line treatment. In chemotherapy-refractory mCRC with primary left-sided tumor harboring wild-type KRAS, cetuximab significantly improved PFS as compared to best supportive care (5.4 months vs. 1.8 months, respectively, p < 0.001), but not in those with primary right-sided tumor (1.9 months vs. 1.9 months, respectively, p = 0.26) [44]. In agreement with this finding, for patients with either untreated and previously treated mCRC harboring wild-type RAS and BRAF, cetuximab either alone or in combination with irinotecan (if refractory to previous irinotecan) produced a disease control rate of 80% (partial response 40.7%, stable disease 39%) in patients with left-sided tumors of origin as compared to right-sided tumor (partial response 0%, stable disease 15.4%) [45]. This exemplifies the way in which primary tumor sidedness greatly affects response to treatment, even when known mutational abnormalities are controlled for. As a result of these studies, the current guidelines recommend EGFR inhibition only for left-sided tumors of origin with wild-type RAS and BRAF, whereas bevacizumab is indicated regardless of primary tumor sidedness.
The intensity of chemotherapy has also been studied in mCRC, and differences in treatment effect have again been shown with regard to the tumor site of origin. The TRIBE study evaluated the effect of FOLFOXIRI plus bevacizumab as compared to FOLFIRI plus bevacizumab [46]. PFS was found to be improved in the FOLFOXIRI group, and an updated OS analysis of the intention-to-treat population showed a median of 29.8 months with FOLFOXIRI as compared to 25.8 months with FOLFIRI, and the difference reached statistical significance [47]. This study population was subsequently stratified by the side of tumor origin. There was no difference in OS for left-sided tumors that received FOLFIRI vs. FOLFOXIRI plus bevacizumab, but there was an OS HR of 0.56 for right-sided tumors with the more intensive chemotherapy [48]. When RAS and BRAF WT-only tumors were evaluated, the HR was 0.5 for right-sided tumors as compared to HR of 0.88 for left-sided tumors, which was not statistically significant. The number of patients in this analysis was small, and there were increased toxicities with the intensive therapy. Though the retrospective nature of this study limits its conclusions, especially given that right-sided tumors are less common and therefore relatively less represented, it provides further evidence for the consideration of sidedness in guiding the initial intensity of therapy and the need to address sidedness in CRC treatment approaches and research. The clinical outcomes of these mCRC treatments, with regard to tumor sidedness, are summarized in Table 1.

6. Molecular Target-Based Treatment

Stratifying treatment of mCRC by tumor sidedness demonstrated how the primary site of tumor origin, a proxy for differences in tumor characteristics that are either known or yet to be identified, can make a significant impact on clinical outcomes. Through improved understanding of these differences and the pursuit of targeted approaches, new therapeutic advances have been made in the field of mCRC. Right-sided tumors, as discussed previously, have poor prognosis which, at least in part, is due to key differences in mutational status, apparent resistance to anti-EGFR therapy, and increased rates of MSI. There is therefore an opportunity to individual treatment by targeting these features to improve outcomes, with initial trials summarized in Table 2.
Through molecular testing and application of targeted therapy, new treatment options have been made available to patients with mCRC. The BEACON trial investigated targeted therapy of BRAF V600E mutated mCRC, more common in right-sided CRC, with either triplet therapy (encorafenib, binimetinib, and cetuximab), doublet therapy (encorafenib and cetuximab), or the investigator’s choice of either cetuximab plus irinotecan or FOLFIRI. Inhibition of BRAF with encorafenib and EGFR with cetuximab, with or without additional MEK inhibition by binimetinib, addresses the way in which single agent EGFR or BRAF inhibition are bypassed by the tumors for sustained cell growth and proliferation. Initial reports showed increased OS with both triplet and doublet regimens as compared to the control [49]. Almost two thirds of patients had right-sided tumors in origin, consistent with known patterns of BRAF mutational prevalence along the colon. An updated analysis of these data showed no difference between the doublet versus triplet regimen in terms of OS, with median of 9.3 months, but with increased side effect profile of additional MEK inhibition by binimetinib. Therefore, the doublet therapy has been FDA approved in this BRAF V600E mutated population [50].
Additional studies of mutational targeting have addressed HER2 amplified tumors, which account for approximately 2–4% of all, predominately left-sided, mCRC. In both MyPathWay and HERACLES, treatment was aimed against HER2. In MyPathWay, a phase 2 trial, patients with treatment-refractory mCRC, with confirmed HER2 amplification, were administered pertuzumab and trastuzumab. An objective response was seen in 32% of patients, of which 57 were enrolled at the time of initial publication [51]. HERACLES also is a phase 2 trial for patients with HER2 amplified mCRC refractory to standard frontline treatments. These patients were administered trastuzumab and lapatinib. Fairly similar to the outcomes from MyPathWay, 30% of patients had an objective response, of the 27 patients initially enrolled [52]. This provides an additional treatment option for patients with HER2 amplification and highlights the need for the identification of such patients to offer this subsequent treatment.
Immunotherapy has also gained an increasing role in mCRC, as there has been heightened recognition of the prevalence of MSI-H disease, especially among the challenging right-sided mCRC population. Checkmate–142 was a phase II trial of low dose ipilimumab and nivolumab for patients with MSI-H disease. As first-line therapy, updated analysis showed an overall response rate of 60%, with median duration of response, PFS, and OS not yet reached after 19.9 months of median follow-up [53,54]. In this study, 55% of patients had right-sided colon cancer, with an additional 13% originating from the transverse colon, consistent with known differences in carcinogenesis pathways along the colon. Pembrolizumab has also been studied for first-line treatment of mismatch repair deficient tumors. The phase III Keynote-177 study showed a 48% PFS with pembrolizumab at 24 months as compared to 19% with chemotherapy. Median duration of response was not yet reached [55]. As a result of this study, pembrolizumab has been approved for first line treatment of MSI-H mCRC. The results for clinical trials using these targeted approaches, based on mutational status, for the treatment of mCRC are summarized in Table 2.
These molecularly targeted approaches have advanced the field of mCRC by individualizing therapy rather than treating all mCRC cases as a homogenous entity. Given the effectiveness of this targeted approach, methods to further characterize cancers, as well as monitor response and resistance patterns during treatment, are essential. Liquid biopsy holds great promise in filling this role and allowing for patient-tailored treatment.

7. Blood-Based Biopsy for Personalized Treatment

While tissue biopsy is the standard of care for diagnosing and molecularly profiling cancer, liquid (primarily blood-based) biopsy has emerged as a valuable tool in precision oncology for many cancer types, including CRC [56,57]. It is a relatively non-invasive and time- and cost-efficient technology for molecular profiling at the time of diagnosis or recurrence of disease, monitoring of tumor response to treatment, identification of resistance mechanisms, and revealing tumor heterogeneity. Current guidelines for mCRC require molecular profiling for RAS, BRAF, HER2, and MSI/MMR (microsatellite instability/mismatch repair) for optimal therapy selection [58], regardless of whether the primary tumor is left- or right-sided, or even in which colorectal subsite the tumor is located. Tissue-based analysis of RAS and BRAF mutations prior to initiation of treatment is necessary because patients with RAS and/or BRAF mutated tumors do not respond to anti-EGFR therapy. Blood-based biopsy has emerged as a useful tool for determining circulating tumor cells and circulating tumor DNA (ctDNA), and it potentially plays a role in personalized treatment of CRC. In a recent study, ctDNA can help guide the use of adjuvant chemotherapy in patients with stage II colon cancer [59]. Whether a ctDNA-based approach can guide the personalized treatment of right- vs. left-sided localized CRC or mCRC remains to be investigated.
Characterization of circulating tumor cells (CTC) in plasma has enabled the identification of differences in cancer biology and metastatic potential between left- and right-sided colon cancers, both quantitatively and qualitatively. In a retrospective analysis, 84 patients with metastatic CRC were subdivided according to tumor sidedness [60]. Despite containing the lowest median number of cells, CTC in left-sided CRC patients had the highest prognostic impact in terms of time to progression, at 11.1 months in patients with positive CTC as compared to 25.6 months in those with negative CTC. This inferior outcome was explained by the phenotypic heterogeneity exhibited by CTC from distal tumors, mainly the mesenchymal phenotype which allows epithelial cancer cells to acquire properties that facilitate their dissemination from the primary tumor site. This is in contrast to CTC from right-sided colon cancer, which despite being found in higher numbers, had little prognostic impact owing to the discovery that 80% of these cells exhibited an apoptotic pattern in comparison to only 10% from left-sided colon and rectal cancer.
Right- and left-sided CRC have divergent gene expression and mutation profiles, and, in addition to the expanding role it already plays, liquid biopsy has the potential to identify new molecular drivers of disease and resistance for which targeted therapies can be developed, thereby improving the outcomes of this patient population. Using whole-exome sequencing of plasma cell-free DNA from patients with gastrointestinal cancer including CRC, potential advantages of cfDNA over tissue biopsy for identification of acquired resistance alterations with therapeutic implications were suggested [61]. Future investigation of liquid biopsy in right- vs. left-sided CRC in localized stages to guide adjuvant therapy as well as the metastatic setting for selection of treatment will be indicated.

8. Conclusions and Future Perspectives

Right- and left-sided CRC have known differences in morphology, molecular mutations, and microbiomes. These differences, and those yet to be identified, lead to a worse prognosis in advanced tumors originating from the right side as well as varied responses to treatment. This is exemplified by the retrospective analyses of key studies regarding the treatment of mCRC based on sidedness, which have highlighted this disparate response. While bevacizumab, in addition to chemotherapy, benefits mCRC outcomes regardless of primary tumor sidedness, anti-EGFR therapy leads to longer OS in left-sided tumors of origin but not right-sided cancers. Apparently, CRC is not a single uniform entity, but rather a diverse tumor population that needs to be treated with a targeted approach. Though some of these factors seem to be reflected by tumor sidedness and location, the differences seen in prognosis and treatment are likely a result of a more complex set of specific unique features yet to be identified. In particular, the impact of tumor location in colorectal subsites on treatment response in relation to tumor sidedness remains largely unexplored.
Liquid (blood-based biopsy) with analysis of ctDNA has been utilized in patients with various malignant diseases including CRC to identify genetic alterations and guide selection of therapy. In addition, determination of ctDNA has been used to monitor tumor response to treatment, detect minimal residual disease and tumor recurrence, and help elucidate resistance mechanism. However, the role of liquid biopsy for identifying therapeutic targets and predictive biomarkers for treatment with regard to right- vs. left-sided CRC as well as the tumor location in colorectal subsites remains to be determined.
The importance of stratifying clinical and translational studies based on tumor sidedness and location has become clear, as has the need for continued study of the features that distinguish right- versus left-sided mCRC as well as their location subsites and the way to detect those characteristics. With the identification of specific mutations, gene amplifications, and MSI-H status, the landscape of treatment for mCRC has expanded and become more targeted with new options available for the disease subtypes. With a greater understanding of these diverse tumor characteristics, and the ability to more readily identify those features by tumor molecular profiling and liquid biopsy, personalized treatment can be pursued to improve the clinical outcomes of patients with CRC.

Author Contributions

Conceptualization, S.W., M.S. and N.S.Y.; methodology, S.W., M.S. and N.S.Y.; formal analysis, S.W., M.S. and N.S.Y.; writing—original draft preparation, S.W., M.S., I.V.P. and N.S.Y.; writing—review and editing, S.W., M.S., I.V.P. and N.S.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This project is funded, in part, under a grant 141597-216 with the Pennsylvania Department of Health using Tobacco CURE Funds. The Department specifically disclaims responsibility for any analyses, interpretations, or conclusions.

Data Availability Statement

Publicly available datasets were analyzed in this study.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Iacopetta, B. Are there two sides to colorectal cancer? Int. J. Cancer 2002, 101, 403–408. [Google Scholar] [CrossRef] [PubMed]
  2. Mik, M.; Berut, M.; Dziki, L.; Trzcinski, R.; Dziki, A. Right- and left-sided colon cancer—Clinical and pathological differences of the disease entity in one organ. Arch. Med. Sci. 2017, 13, 157–162. [Google Scholar] [CrossRef]
  3. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [Green Version]
  4. Siegel, R.L.; Miller, K.D.; Wagle, N.S.; Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin. 2023, 73, 17–48. [Google Scholar] [CrossRef]
  5. Siegel, R.L.; Fedewa, S.A.; Anderson, W.F.; Miller, K.D.; Ma, J.; Rosenberg, P.S.; Jemal, A. Colorectal Cancer Incidence Patterns in the United States, 1974-2013. J. Natl Cancer Inst. 2017, 109, djw322. [Google Scholar] [CrossRef] [Green Version]
  6. Lior, S.; Kalady, M.F.; Church, J.M. Left-Sided Dominance of Early-Onset Colorectal Cancers: A rationale for screening flexible sigmoidoscopy in the young. Dis. Colon Rectum 2018, 61, 897–902. [Google Scholar] [CrossRef]
  7. Kasi, P.M.; Shahjehan, F.; Cochuyt, J.J.; Li, Z.; Colibaseanu, D.T.; Merchea, A. Rising Proportion of Young Individuals with Rectal and Colon Cancer. Clin. Color. Cancer 2019, 18, e87–e95. [Google Scholar] [CrossRef] [Green Version]
  8. Baran, B.; Mert Ozupek, N.; Yerli Tetik, N.; Acar, E.; Bekcioglu, O.; Baskin, Y. Difference Between Left-Sided and Right-Sided Colorectal Cancer: A Focused Review of Literature. Gastroenterol. Res. 2018, 11, 264–273. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Missiaglia, E.; Jacobs, B.; D’Ario, G.; Di Narzo, A.; Soneson, C.; Budinska, E.; Popovici, V.; Vecchione, L.; Gerster, S.; Yan, P.; et al. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann. Oncol. 2014, 25, 1995–2001. [Google Scholar] [CrossRef] [PubMed]
  10. Salem, M.E.; Weinberg, B.A.; Xiu, J.; El-Deiry, W.S.; Hwang, J.J.; Gatalica, Z.; Philip, P.A.; Shields, A.F.; Lenz, H.-J.; Marshall, J.L. Comparative molecular analyses of left-sided colon, right-sided colon, and rectal cancers. Oncotarget 2017, 8, 86356–86368. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  11. Kim, K.; Castro, E.J.T.; Shim, H.; Advincula, J.V.G.; Kim, Y.W. Differences Regarding the Molecular Features and Gut Microbiota Between Right and Left Colon Cancer. Ann. Coloproctol. 2018, 34, 280–285. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Salem, M.E.; Battaglin, F.; Goldberg, R.M.; Puccini, A.; Shields, A.F.; Arguello, D.; Korn, W.M.; Marshall, J.L.; Grothey, A.; Lenz, H.-J. Molecular analyses of left- and right-sided tumors in adolescents and young adults with colorectal cancer. Oncologist 2020, 25, 404–413. [Google Scholar] [CrossRef] [Green Version]
  13. Yamaguchi, M.; Morikawa, T.; Kuchiba, A.; Imamura, Y.; Qian, Z.R.; Nishihara, R.; Liao, X.; Waldron, L.; Hoshida, Y.; Huttenhower, C.; et al. Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut 2012, 61, 847–854. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Loree, J.M.; Pereira, A.A.L.; Lam, M.; Willauer, A.N.; Raghav, K.; Dasari, A.; Morris, V.K.; Advani, S.; Menter, D.G.; Eng, C.; 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, 1062–1072. [Google Scholar] [CrossRef] [Green Version]
  15. Tarashi, S.; Siadat, S.D.; Badi, S.A.; Zali, M.; Biassoni, R.; Ponzoni, M.; Moshiri, A. Gut Bacteria and their Metabolites: Which one is the Defendant for Colorectal Cancer? Microorganisms 2019, 7, 561. [Google Scholar] [CrossRef] [Green Version]
  16. Mohamed, A.; Menon, H.; Chulkina, M.; Yee, N.S.; Pinchuk, I.V. Drug-Microbiota Interaction in Colon Cancer Therapy: Impact of Antibiotics. Biomedicines 2021, 9, 259. [Google Scholar] [CrossRef] [PubMed]
  17. Gao, R.; Kong, C.; Huang, L.; Li, H.; Qu, X.; Liu, Z.; Lan, P.; Wang, J.; Qin, H. Mucosa-associated microbiota signature in colorectal cancer. Eur. J. Clin. Microbiol. Infect. Dis. 2017, 36, 2073–2083. [Google Scholar] [CrossRef]
  18. Dejea, C.M.; Wick, E.C.; Hechenbleikner, E.M.; White, J.R.; Welch, J.L.M.; Rossetti, B.J.; Peterson, S.N.; Snesrud, E.C.; Borisy, G.G.; Lazarev, M.; et al. Microbiota organization is a distinct feature of proximal colorectal cancers. Proc. Natl. Acad. Sci. USA 2014, 111, 18321–18326. [Google Scholar] [CrossRef] [PubMed]
  19. Tomkovich, S.; Dejea, C.M.; Winglee, K.; Drewes, J.L.; Chung, L.; Housseau, F.; Pope, J.L.; Gauthier, J.; Sun, X.; Mühlbauer, M.; et al. Human colon mucosal biofilms from healthy or colon cancer hosts are carcinogenic. J. Clin. Investig. 2019, 129, 1699–1712. [Google Scholar] [CrossRef]
  20. Zhang, J.; Haines, C.; Watson, A.J.M.; Hart, A.R.; Platt, M.J.; Pardoll, D.M.; Cosgrove, S.E.; Gebo, K.A.; Sears, C.L. Oral antibiotic use and risk of colorectal cancer in the United Kingdom, 1989–2012: A matched case-control study. Gut 2019, 68, 1971–1978. [Google Scholar] [CrossRef] [PubMed]
  21. Armstrong, D.; Dregan, A.; Ashworth, M.; White, P.; McGee, C.; de Lusignan, S. The association between colorectal cancer and prior antibiotic prescriptions: Case control study. Br. J. Cancer 2020, 122, 912–917. [Google Scholar] [CrossRef] [PubMed]
  22. Lu, S.S.M.; Mohammed, Z.; Häggström, C.; Myte, R.; Lindquist, E.; Gylfe, A.; Van Guelpen, B.; Harlid, S. Antibiotics Use and Subsequent Risk of Colorectal Cancer: A Swedish Nationwide Population-Based. J. Natl. Cancer Inst. 2021, 114, djab125. [Google Scholar] [CrossRef]
  23. Petrelli, F.; Tomasello, G.; Borgonovo, K.; Ghidini, M.; Turati, L.; Dallera, P.; Passalacqua, R.; Sgroi, G.; Barni, S. Prognostic Survival Associated with Left-Sided vs Right-Sided Colon Cancer: A Systematic Review and Meta-Analysis. JAMA Oncol. 2017, 3, 211–219. [Google Scholar] [CrossRef]
  24. Matos, I.; Ortiz, C.; Elez, E.; Argiles, G.; Grasselli, J.; Macarulla, T.; Capdevila, J.; Alsina, M.; Sauri, T.; Hierro, C.; et al. Prognostic impact of primary tumor site location in metastatic colorectal cancer (mCRC). J. Clin. Oncol. 2016, 34, 578. [Google Scholar] [CrossRef]
  25. Park, J.H.; Kim, M.J.; Park, S.C.; Hong, C.W.; Sohn, D.K.; Han, K.S.; Oh, J.H. Difference in time to locoregional recurrence between patients with right-sided and left-sided colon cancers. Dis. Colon Rectum. 2015, 58, 831–837. [Google Scholar] [CrossRef] [PubMed]
  26. Li, Y.; Feng, Y.; Dai, W.; Li, Q.; Cai, S.; Peng, J. Prognostic Effect of Tumor Sidedness in Colorectal Cancer: A SEER-Based Analysis. Clin. Color. Cancer 2019, 18, e104–e116. [Google Scholar] [CrossRef]
  27. Mukkamalla, S.K.R.; Huynh, D.V.; Somasundar, P.S.; Rathore, R. Adjuvant chemotherapy and tumor sidedness in stage II colon cancer: Analysis of the National Cancer data base. Front. Oncol. 2020, 10, 568417. [Google Scholar] [CrossRef]
  28. Lee, J.M.; Han, Y.D.; Cho, M.S.; Hur, H.; Min, B.S.; Lee, K.Y.; Kim, N.K. Impact of tumor sidedness on survival and recurrence patterns in colon cancer patients. Ann. Surg. Treat. Res. 2019, 96, 296–304. [Google Scholar] [CrossRef] [Green Version]
  29. Nakamura, Y.; Hokuto, D.; Koyama, F.; Matsuo, Y.; Nomi, T.; Yoshikawa, T.; Kamitani, N.; Sadamitsu, T.; Takei, T.; Matsumoto, Y.; et al. The prognosis and recurrence pattern of right- and left- sided colon cancer in Stage II, Stage III, and liver metastasis after curative resection. Ann. Coloproctol. 2020, 10, 3393. [Google Scholar] [CrossRef]
  30. Loupakis, F.; Yang, D.; Yau, L.; Feng, S.; Cremolini, C.; Zhang, W.; Maus, M.K.H.; Antoniotti, C.; Langer, C.; Scherer, S.J.; et al. Primary tumor location as a prognostic factor in metastatic colorectal cancer. J. Natl. Cancer Inst. 2015, 107, dju427. [Google Scholar] [CrossRef] [Green Version]
  31. Kamran, S.C.; Clark, J.W.; Zheng, H.; Borger, D.R.; Blaszkowsky, L.S.; Allen, J.N.; Kwak, E.L.; Wo, J.Y.; Parikh, A.R.; Nipp, R.D.; et al. Primary tumor sidedness is an independent prognostic marker for survival in metastatic colorectal cancer: Results from a large retrospective cohort with mutational analysis. Cancer Med. 2018, 7, 2934–2942. [Google Scholar] [CrossRef]
  32. Ugai, T.; Akimoto, N.; Haruki, K.; Harrison, T.A.; Cao, Y.; Qu, C.; Chan, A.T.; Campbell, P.T.; Berndt, S.I.; Buchanan, D.D.; et al. Prognostic role of detailed colorectal location and tumor molecular features: Analyses of 13,101 colorectal cancer patients including 2994 early-onset cases. J. Gastroenterol. 2023, 58, 229–245. [Google Scholar] [CrossRef]
  33. Hurwitz, H.; Fehrenbacher, L.; Novotny, W.; Cartwright, T.; Hainsworth, J.; Heim, W.; Berlin, J.; Baron, A.; Griffing, S.; Holmgren, E.; et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 2004, 350, 2335–2342. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Loupakis, F.; Hurwitz, H.I.; Saltz, L.; Arnold, D.; Grothey, A.; Nguyen, Q.L.; Osborne, S.; Talbot, J.; Srock, S.; Lenz, H.-J. Impact of primary tumour location on efficacy of bevacizumab plus chemotherapy in metastatic colorectal cancer. Br. J. Cancer 2018, 119, 1451–1455. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Van Cutsem, E.; Köhne, C.-H.; Láng, I.; Folprecht, G.; Nowacki, M.P.; Cascinu, S.; Shchepotin, I.; Maurel, J.; Cunningham, D.; Tejpar, S.; 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, 2011–2019. [Google Scholar] [CrossRef] [Green Version]
  36. Douillard, J.-Y.; Oliner, K.S.; Siena, S.; Tabernero, J.; Burkes, R.; Barugel, M.; Humblet, Y.; Bodoky, G.; Cunningham, D.; Jassem, J.; et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N. Engl. J. Med. 2013, 369, 1023–1034. [Google Scholar] [CrossRef] [Green Version]
  37. Tejpar, S.; Stintzing, S.; Ciardiello, F.; Tabernero, J.; Van Cutsem, E.; Beier, F.; Esser, R.; Lenz, H.-J.; Heinemann, V. 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. [Google Scholar] [CrossRef]
  38. Boeckx, N.; Koukakis, R.; de Beeck, K.O.; Rolfo, C.; Van Camp, G.; Siena, S.; Tabernero, J.; Douillard, J.-Y.; André, T.; Peeters, M. Primary tumor sidedness has an impact on prognosis and treatment outcome in metastatic colorectal cancer: Results from two randomized first line panitumumab studies. Ann. Oncol. 2017, 28, 1862–1868. [Google Scholar] [CrossRef] [PubMed]
  39. Rivera, F.; Karthaus, M.; Hecht, J.R.; Sevilla, I.; Forget, F.; Fasola, G.; Canon, J.-L.; Guan, X.; Demonty, G.; Schwartzberg, L.S. Final analysis of the randomized PEAK trial: Overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma. Int. J. Color. Dis. 2017, 32, 1179–1190. [Google Scholar] [CrossRef] [Green Version]
  40. Heinemann, V.; von Weikersthal, L.F.; Decker, T.; Kiani, A.; Vehling-Kaiser, U.; Al-Batran, S.-E.; Heintges, T.; Lerchenmüller, C.; Kahl, C.; Seipelt, G.; 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, 1065–1075. [Google Scholar] [CrossRef]
  41. Venook, A.P.; Niedzwiecki, D.; Lenz, H.-J.; Innocenti, F.; Fruth, B.; Meyerhardt, J.A.; Schrag, D.; Greene, C.; O’Neil, B.H.; Atkins, J.N.; 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, 2392–2401. [Google Scholar] [CrossRef] [Green Version]
  42. Venook, A.P.; Ou, F.-S.; Lenz, H.-J.; Kabbarah, O.; Qu, X.; Niedzwiecki, D.; Zemla, T.; Goldberg, R.M.; Hochster, H.S.; O’Neil, B.H.; et al. Primary (1°) tumor location as an independent prognostic marker from molecular features for overall survival (OS) in patients (pts) with metastatic colorectal cancer (CRC): Analysis of CALGB/SWOG 80405 (Alliance). J. Clin. Oncol. 2017, 35, 3503. [Google Scholar] [CrossRef]
  43. Aljehani, M.A.; Morgan, J.W.; Guthrie, L.A.; Jabo, B.; Ramadan, M.; Bahjri, K.; Lum, S.S.; Selleck, M.; Reeves, M.E.; Garberoglio, C.; et al. Association of primary tumor site with mortality in patients receiving bevacizumab and cetuximab for metastatic colorectal cancer. JAMA Surg. 2018, 153, 60–67. [Google Scholar] [CrossRef]
  44. Brulé, S.Y.; Jonker, D.J.; Karapetis, C.S.; O’Callaghan, C.J.; Moore, M.J.; Wong, R.; Tebbutt, N.C.; Underhill, C.; Yip, D.; Zalcberg, J.R.; et al. Location of colon cancer (right-sided versus left-sided) as aprognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur. J. Cancer 2015, 51, 1405–1414. [Google Scholar] [CrossRef]
  45. Moretto, R.; Cremolini, C.; Rossini, D.; Pietrantonio, F.; Battaglin, F.; Mennitto, A.; Bergamo, F.; Loupakis, F.; Marmorino, F.; Berenato, R.; 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, 988–994. [Google Scholar] [CrossRef] [Green Version]
  46. Loupakis, F.; Cremolini, C.; Masi, G.; Lonardi, S.; Zagonel, V.; Salvatore, L.; Cortesi, E.; Tomasello, G.; Ronzoni, M.; Spadi, R.; et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N. Eng. J. Med. 2014, 371, 1609–1618. [Google Scholar] [CrossRef] [Green Version]
  47. Cremolini, C.; Loupakis, F.; Antoniotti, C.; Lupi, C.; Sensi, E.; Lonardi, S.; Mezi, S.; Tomasello, G.; Ronzoni, M.; Zaniboni, A.; 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, 1306–1315. [Google Scholar] [CrossRef]
  48. Cremolini, C.; Antoniotti, C.; Lonardi, S.; Bergamo, F.; Cortesi, E.; Tomasello, G.; Moretto, R.; Ronzoni, M.; Racca, P.; Loupakis, F.; et al. Primary tumor sidedness and benefit from FOLFOXIRI plus bevacizumab as initial therapy for metastatic colorectal cancer. Retrospective analysis of the TRIBE trial by GONO. Ann. Oncol. 2018, 29, 1528–1534. [Google Scholar] [CrossRef]
  49. Kopetz, S.; Grothey, A.; Yaeger, R.; Van Cutsem, E.; Desai, J.; Yoshino, T.; Wasan, H.; Ciardiello, F.; Loupakis, F.; Hong, Y.S.; et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E –Mutated Colorectal Cancer. N. Engl. J. Med. 2019, 381, 1632–1643. [Google Scholar] [CrossRef] [Green Version]
  50. Kopetz, S.; Grothey, A.; Van Cutsem, E.; Yaeger, R.; Wasan, H.S.; Yoshino, T.; Desai, J.; Ciardiello, F.; Loupakis, F.; Hong, Y.S.; et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E metastatic colorectal cancer: Updated survival results from a randomized, three-arm, phase III study versus choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). J. Clin. Oncol. 2020, 38, 4001. [Google Scholar] [CrossRef]
  51. Meric-Bernstam, F.; Hurwitz, H.; Raghav, K.P.S.; McWilliams, R.R.; Fakih, M.; VanderWalde, A.; Swanton, C.; Kurzrock, R.; Burris, H.; Sweeney, C.; et al. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): An updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2019, 20, 518–530. [Google Scholar] [CrossRef] [PubMed]
  52. Sartore-Bianchi, A.; Trusolino, L.; Martino, C.; Bencardino, K.; Lonardi, S.; Bergamo, F.; Zagonel, V.; Leone, F.; Depetris, I.; Martinelli, E.; et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2 –positive metastatic colorectal cancer (HERACLES): A proof-of-concept, multicentre, open label, phase 2 trial. Lancet Oncol. 2016, 17, 738–746. [Google Scholar] [CrossRef]
  53. Lenz, H.-J.; Van Cutsem, E.; Limon, M.; Wong, K.; Hendlisz, A.; Aglietta, M.; Garcia-Alfonso, P.; Neyns, B.; Luppi, G.; Cardin, D.; et al. Durable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). Ann. Oncol. 2018, 29, viii714. [Google Scholar] [CrossRef]
  54. Lenz, H.-J.; Lonardi, S.; Zagonel, V.; Van Cutsem, E.; Limon, M.L.; Wong, K.Y.M.; Hendlisz, A.; Aglietta, M.; Garcia-Alfonso, P.; Neyns, B.; et al. Nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite instability-high/DNA mismatch repair deficient metastatic colorectal cancer: Clinical update. J. Clin. Oncol. 2020, 38, 11. [Google Scholar] [CrossRef]
  55. Andre, T.; Shiu, K.-K.; Kim, T.W.; Jensen, B.V.; Jensen, L.H.; Punt, C.J.A.; Smith, D.M.; Garcia-Carbonero, R.; Benavides, M.; Gibbs, P.; et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 study. J. Clin. Oncol. 2020, 38, LBA4. [Google Scholar] [CrossRef]
  56. Vacante, M.; Ciuni, R.; Basile, F.; Biondi, A. The liquid biopsy in the management of colorectal cancer: An overview. Biomedicines 2020, 8, 308. [Google Scholar] [CrossRef]
  57. Kolencik, D.; Shishido, S.N.; Pitule, P.; Mason, J.; Hicks, J.; Kuhn, P. Liquid biopsy in colorectal carcinoma: Clinical applications and challenges. Cancers 2020, 12, 1376. [Google Scholar] [CrossRef]
  58. Kastrisiou, M.; Zarkavelis, G.; Pentheroudakis, G.; Magklara, A. Clinical application of next-generation sequencing as a liquid biopsy technique in advanced colorectal cancer: A trick or a treat? Cancers 2019, 11, 1573. [Google Scholar] [CrossRef] [Green Version]
  59. Tie, J.; Cohen, J.D.; Lahouel, K.; Lo, S.N.; Wang, Y.; Kosmider, S.; Wong, R.; Shapiro, J.; Lee, M.; Harris, S.; et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. N. Engl. J. Med. 2022, 386, 2261–2272. [Google Scholar] [CrossRef]
  60. Nicolazzo, C.; Raimondi, C.; Gradilone, A.; Emiliani, A.; Zeuner, A.; Francescangeli, F.; Belardinilli, F.; Seminara, P.; Loreni, F.; Magri, V.; et al. Circulating Tumor Cells in Right- and Left-Sided Colorectal Cancer. Cancers 2019, 11, 1042. [Google Scholar] [CrossRef] [Green Version]
  61. Parikh, A.R.; Leshchiner, I.; Elagina, L.; Goyal, L.; Levovitz, C.; Siravegna, G.; Livitz, D.; Rhrissorrakrai, K.; Martin, E.E.; Van Seventer, E.E.; et al. Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers. Nat. Med. 2019, 25, 1415–1421. [Google Scholar] [CrossRef]
Jpm 13 01114 g001 550
Figure 1. Clinical and pathological features of right- vs. left-sided colon cancer. The features listed in one side of the colorectum are relative to the sidedness of colorectum, and they are not distinctly different with regard to tumor sidedness.
Figure 1. Clinical and pathological features of right- vs. left-sided colon cancer. The features listed in one side of the colorectum are relative to the sidedness of colorectum, and they are not distinctly different with regard to tumor sidedness.
Jpm 13 01114 g001
Jpm 13 01114 g002 550
Figure 2. Morphological and genetic mutational features of right- and left-sided colon cancer. The listed molecular features may be more common in one side of the colorectum than the other side, though the frequency of molecular features gradually changes along colorectal subsites, rather than abruptly changing at splenic flexure. CIMP-high: CpG island methylator phenotype; MSI-high: high degree of microsatellite instability.
Figure 2. Morphological and genetic mutational features of right- and left-sided colon cancer. The listed molecular features may be more common in one side of the colorectum than the other side, though the frequency of molecular features gradually changes along colorectal subsites, rather than abruptly changing at splenic flexure. CIMP-high: CpG island methylator phenotype; MSI-high: high degree of microsatellite instability.
Jpm 13 01114 g002
Table
Table 1. Median overall survival (mOS) using different treatment regimens, for mCRC in regard to tumor sidedness.
Table 1. Median overall survival (mOS) using different treatment regimens, for mCRC in regard to tumor sidedness.
StudyInterventionmOS (Months) Entire Studied PopulationmOS (Months)
Right-Sided CRC 		mOS (Months)
Left-Sided CRC
Stratified Crystal Data [34]Cetuximab + FOLFIRI vs. FOLFIRI23.5 vs. 20
(* p = 0.0093)		18.5 vs. 15
(p = 0.76)		28.7 vs. 21.7
(* p = 0.002)
Stratified FIRE-3 Data [34]Cetuximab + FOLFIRI vs. Bevacizumab + FOLFIRI33.1 vs. 25.6 months
(* p = 0.011)		18.3 vs. 23
(p = 0.28)		38.3 vs. 28
(* p = 0.002)
CALGB/SWOG 80405Cetuximab + chemotherapy vs. Bevacizumab + chemotherapy30 vs. 29 months
(p = 0.08)		18.4 vs. 34.4
(* p = 0.03)		40.3 vs. 38.7
(* p = 0.04)
PRIME trial
(KRAS WT)		Panitumumab + FOLFOX4 vs. FOLFOX4 alone23.9 vs. 19.7 months
(p = 0.17)		11.1 vs. 15.4
(p = 0.5398)
30.3 vs. 23.6
(* p = 0.0112)
Bevacizumab [30,31]
(RAS mutation was not controlled for)		Bevacizumab + chemotherapy vs. chemotherapy alone31 vs. 25.8 months
(p = 0.054)		18.3 vs. 15.6
(p = 0.085)		23.5 vs. 20.8
(* p = 0.028)
TRIBE
(KRAS and BRAF WT)		FOLFOXIRI + Bevacizumab vs. FOLFIRI + Bevacizumab41.7 vs. 33.5 months
(p = 0.52)		31.5 vs. 22.340 vs. 37.7
PEAK
(KRAS WT)		Panitumumab + mFOLFOX6 vs. Bevacizumab + mFOLFOX636.9 vs. 28.9 months
(p = 0.15)		17.5 vs. 21
(p = 0.3239)		43.4 vs. 32
(p = 0.3125)
FOLFIRI: 5-fluorouracil, leucovorin, irinotecan; FOLFOX: 5-fluorouracil, leucovorin, oxaliplatin. * p indicates statistical significance; WT: wild-type.
Table
Table 2. Efficacy of targeted therapies in mCRC based on molecular mutation status.
Table 2. Efficacy of targeted therapies in mCRC based on molecular mutation status.
Targeted MutationTrialInterventionPrimary Endpoints
BRAF V600EBEACON:
treatment refractory mCRC		Encorafenib 300 mg PO daily and Cetuximab 400 mg/m2 IV initial dose, then 250 mg/m2 IV weekly vs. control (Cetuximab/Irinotecan or FOLFIRI)OS 9.3 vs. 5.9 months
HR 0.61 (0.48 vs. 0.77)
HER2 amplificationMyPathway: treatment refractory mCRCTrastuzumab 8 mg/kg IV loading dose, followed by 6 mg/kg IV every 3 weeks plus Pertuzumab 840 mg IV loading dose followed by 420 mg IV every 3 weeksORR 32%
HER2 amplificationHERACLES: treatment refractory mCRCTrastuzumab 4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly + Lapatinib 1000 mg PO dailyORR 30%
MSI-HCheckmate-142: treatment naïve mCRCIpilimumab 1 mg/kg IV every 6 weeks and Nivolumab 3 mg/kg IV very 2 weeksORR 60%
12-month PFS 77%
12-month OS 83%
MSI-HKeynote-177: treatment naïve mCRCPembrolizumab 200 mg IV every 3 weeks
vs. chemotherapy		48% PFS at 24 months as compared to 19% with chemotherapy
(* p = 0.0002)
HR: hazard ratio; mCRC: metastatic colorectal cancer; MSI-H: microsatellite instability-high; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; (* p indicates statistical significance).
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Waldstein, S.; Spengler, M.; Pinchuk, I.V.; Yee, N.S. Impact of Colorectal Cancer Sidedness and Location on Therapy and Clinical Outcomes: Role of Blood-Based Biopsy for Personalized Treatment. J. Pers. Med. 2023, 13, 1114. https://doi.org/10.3390/jpm13071114

AMA Style

Waldstein S, Spengler M, Pinchuk IV, Yee NS. Impact of Colorectal Cancer Sidedness and Location on Therapy and Clinical Outcomes: Role of Blood-Based Biopsy for Personalized Treatment. Journal of Personalized Medicine. 2023; 13(7):1114. https://doi.org/10.3390/jpm13071114

Chicago/Turabian Style

Waldstein, Sasha, Marianne Spengler, Iryna V. Pinchuk, and Nelson S. Yee. 2023. "Impact of Colorectal Cancer Sidedness and Location on Therapy and Clinical Outcomes: Role of Blood-Based Biopsy for Personalized Treatment" Journal of Personalized Medicine 13, no. 7: 1114. https://doi.org/10.3390/jpm13071114

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop