Abstract
Purpose
BRAF mutations represent the main negative prognostic factor for metastatic colorectal cancer and a supposed negative predictive factor of response to standard chemotherapy. We have explored survival difference in right-sided colon cancer (RCC) patients according to BRAF mutations, with the aim to identify any predictive factors of response to targeted-based therapy.
Methods
A retrospective study of RCC patients, with BRAF known mutation status, treated with chemotherapy (CT) from October 2008 to June 2019 in 5 Italian centers, was conducted.
Results
We identified 207 advanced RCC patients: 20.3% BRAF mutant and 79.7% BRAF wild type (wt). BRAF-mutant cancers were more likely to be pT4 (50.0% v 25.7%, p = 0.016), undifferentiated (71.4% v 44.0%, p = 0.004), KRAS wt (90.5% v 38.2%, p < 0.001), and MSI-H (41.7% v 16.2%, p = 0.019) tumors, with synchronous (52.4% v 31.5%, p = 0.018) and peritoneal metastases (38.1% v 22.4%, p = 0.003). Median overall survival (OS) was 16 v 27 months in BRAF mutant and BRAF wt (P = 0.020). In first-line setting, BRAF-mutant showed a 2ys OS of 80% in clinical trials, 32% in anti-VEGF, 14% in epidermial growth factor receptor (EGFR), and 0% in chemotherapy alone regimens (P = 0.009). BRAF-mutant patients demonstrated worse survival, regardless of targeted therapy administered. However, survival difference was statistically significant in the anti-EGFR-treated subgroup (16 v 28 months, P = 0.005 in BRAF mutant v BRAF wt, respectively).
Conclusions
Our study demonstrated that BRAF status makes the difference in treatment’s outcome. Therefore, the anti-EGFR should not be excluded in all advanced RCC but considered on a case-by-case basis.
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Introduction
Colorectal cancer (CRC) is the third most common cancer worldwide [1]. In recent years, the sidedness seems to be a well-established and relevant prognostic factor due to distinct differences in epidemiology, pathogenesis, genetic and epigenetic alterations, molecular pathways, and outcome between right (RCC) and left-side colorectal cancer (LCC) [2, 3]. Moreover, RCC is prevalent among old age patients with iron deficiency anemia at diagnosis [4] and in female gender [5] and is more likely to be diploid and to be characterized by high microsatellite instability [6], CpG island methylation, and BRAF mutations [7,8,9,10].
Furthermore, different signaling pathways are involved in the development of colon cancer: in the RCC is more prevalent the serrated pathway [11, 12], in which BRAF mutations develop and CpG island hypermethylation occurs, resulting in gene transcriptional inactivation and loss of gene function by methylation of the promoter region. Otherwise, the conventional pathway with mutations in KRAS, TP53, and APC is associated with LCC.
From this literature data, it is clear how the RCC constitutes a different entity than the LCC. All these factors may contribute to the difference observed in patient prognosis and to explain the relationship between cancer location and mortality. Several population-based studies have explored the prognostic relevance of laterality in CRC, with conflicting results [13,14,15,16,17].
Meguid et al. [13] reported that right-sided cancers had a higher risk of mortality than left-sided colorectal cancers across all stages (HR, 1.04; 95% CI, 1.02 to 1.07); it was also confirmed by a more recent meta-analysis [2], in which LCC were associated with improved survival rather than RCC (HR, 0.82; 95% CI, 0.79–0.84). The association between RCC and higher mortality is strongest for patients with stage III and IV disease [16].
Moreover, the right-sidedness seems to be also a predictive factor of response to first-line treatment in mCRC patients. A retrospective analysis from CRYSTAL and FIRE-3 trials, in patients with RAS wild-type (wt) mCRC treated with chemotherapy and epidermial growth factor receptor (EGFR) targeted agent, found a better response in LCC than RCC patients [18]. Moreover, as shown by the data of CALGB/SWOG 80405 trial, among patients with KRAS wt disease, overall survival (OS) and progression free survival (PFS) were better in those with left-sided primary tumors, while both OS and PFS were better with bevacizumab than with cetuximab in patients with right-sided primary tumors [19].
In general, BRAF mutations are present in about 10% of colorectal cancer cases but over two-thirds of BRAFV600E tumors originate in the RCC v the LCC (68 v 32%) [7]. The RCC negative prognosis seems to be related with the more frequent BRAF mutations [20, 21] which represent the main negative prognostic factor for mCRC, regardless of sidedness and other molecular factors [22]. Indeed, BRAF-mutant CRC has emerged as a distinct biologic entity, refractory to standard chemotherapy regimens approved for the treatment of metastatic CRC and associated with a dismal prognosis [23,24,25]. An effective therapy has not yet been identified although some positive data have emerged regarding the use of more intensive chemotherapy backbone plus bevacizumab as initial therapy [26] and the more recent multi-targeted therapy combinations [27,28,29,30]. Up to date, it is still not clear which is the best therapeutic strategy in RCC tumors, albeit with BRAF mutation. However, clinical trials with combining MAPK pathway targeted therapies are under investigation and could be the best therapeutic strategy [23].
This is a retrospective analysis of metastatic RCC patients referred to 5 Italian centers with the aim to evaluate the outcome of RCC patients according to BRAF status and the treatment performed.
Methods
Patients
A multi-institutional retrospective analysis of clinical data from 207 patients with right mCRC treated with chemotherapy from October 2008 to June 2019 was done. All patients with BRAF known mutation status were included in this analysis. Clinicopathological factors of patients were extrapolated from their clinical data records, including their comorbidity, grouped according to Charlson comorbidity index (CCI). CCI is a well-known method of categorizing comorbidities of patients based on the International Classification of Diseases (ICD) diagnosis codes found in administrative data, such as hospital abstracts data. Each comorbidity category has an associated weight (from 1 to 6), based on the adjusted risk of mortality or resource use, and the sum of all the weights results in a single comorbidity score for a patient. A score of zero indicates that no comorbidities were found. The higher the score, the more likely the predicted outcome will result in mortality or higher resource use. Taking into account surgery procedures, as reported in clinical data records, there were 49 minor liver resections, from solitary metastasectomy to left lateral sectionectomy, combined with right hemicolectomy, without post-operative complications. In total, 162 patients underwent right hemicolectomy at diagnosis, of which 10 laparoscopically. The study was conducted in accordance with the Declaration of Helsinki and Institutional Review Board approval.
Statistical analysis
SPSS statistical software, version 24 (SPSS Inc. Chicago, IL, USA) was used. The χ2 test and t test for unpaired data were applied to compare frequencies and means, respectively. The interaction among clinicopathologic parameters was first analyzed using univariate logistic regression. Survival curves were estimated using the Kaplan-Meier method and the log-rank test was used for the difference assessment. A multivariate Cox-proportional hazard model was used to identify independent prognostic factors for survival. All reported P values are two sided, and P values less than 0.05 are considered statistically significant.
Results
Clinicopathological characteristics
This study included 207 right-sided metastatic colon cancer patients with known BRAF mutation status. All patients’ clinicopathological characteristics are summarized in Table 1. In total, 42 (20.3%) patients had BRAF-mutant tumors and 165 (79.7%) had BRAF-wt tumors. Also, KRAS/NRAS and MSI status were considered for the analysis. According to RAS-status, 40 (20%) patients had undergone a first-line chemotherapy with an anti-EGFR target agent.
Differences in clinicopathological characteristics between BRAF-mutant and BRAF-wt tumors are reported in Table 2. BRAF-mutant RCC was significantly more likely to occur in pT4 (50.0% v 25.7%, p = 0.016), undifferentiated (71.4% v 44.0%, p = 0.004), KRAS wt (90.5% v 38.2%, p < 0.001), MSI-H (41.7% v 16.2%, p = 0.019) tumors, with synchronous (52.4% v 31.5%, p = 0.018), and peritoneal metastases (38.1% v 22.4%, p = 0.003). A higher proportion of BRAF-mutant tumors were observed in female patients, although this was not statistically significant (52.4% v 47.6% in female and male group, respectively). Moreover, the tumor onset with anemia was more common in BRAF-mutant than BRAF-wt tumors (40% v 27.3%, p = 0.065). No difference between BRAF statuses was found in right colon tumor location as well as mucinous histology or lymph node involvement.
Survival analysis
In our study, BRAF-mutant RCC showed a poorer prognosis than BRAF-wt tumors with a median OS of 16.0 (range 13.72–18.27) v 27.0 (range 21.82–31.17) months, respectively (hazard ratio [HR], 1.60; 95% CI, 1.06–2.41; P = 0.020) (Fig. 1a).
Other clinicopathological factors significantly associated with poorer survival included age > 70 years (P = 0.002), pT4 (P = 0.009), pN2 (P = 0.034), G3–4 tumor grading (P = 0.009), and lympho-vascular invasion (P = 0.013) at the histological exam. Moreover, peritoneum as metastatic site (P = 0.040) and the synchronous occurrence of metastases (P = 0.045) were associated with a worse survival. On the contrary, a good ECOG PS (P = < 0.0001), primary resected tumors (P = < 0.0001), and the upfront surgery of liver metastases (P = 0.001) were associated with better outcome. At the multivariate analysis, only BRAF status, baseline ECOG PS, and the upfront surgery of metastatic disease were independent prognostic factors of survival (Table 3).
Overall, there was non-significant difference in median OS between first-line treatment with mono or doublet chemotherapy (18.0 months, range 10.5–25.4), triplet chemo regimen (25.0 months, range 18.1–31.8), chemo plus an anti-VEGF (24.0 months, range 13–24.9) or anti-EGFR (26.0 months, range 20.9–31.1) targeted agent, and clinical trials with immunotherapy (not reached) (HR = 0.90, 95% CI 0.81–1.00, P = 0.072). (Fig. 2a) However, taking into account the first-line regimen, patients enrolled in clinical trials showed a better median progression free survival (PFS1) than others (17.0 v 6.0 v.13.0 months, in clinical trials, CT plus a target agent and triplet CT group, respectively) (HR = 0.90, 95% CI 0.82–0.99, P = 0.037) (Fig. 2b). Beyond first-line treatment, clinical trials and reintroduction of triplet CT regimen performed significantly better than the other treatment strategies (median PFS2 was 16.0 v 15.0 v 7.0 v 5.0 v 4.0 v 2.0 months in clinical trials, triplet CT, CT plus anti-EGFR, CT plus anti-VEGF, CT alone, and regorafenib/lonsurf as second line therapy, respectively) (HR = 0.69, 95% CI 0.57–0.85, P = 0.001) (Fig. 2c). Although a more intensified chemotherapy regimen seems to give more survival benefit, non-significant difference was found among third-line treatments (HR for PFS3 = 1.0, 95% CI 0.94–1.07, P = 0.883) (Fig. 2d).
In a bivariate analysis where BRAF status was stratified by treatments, there was no significant survival differences between first-line CT with anti-EGFR or anti-VEGF targets in BRAF-wt tumors (Fig. 1b), while, in BRAF-mutant tumors, 2ys OS was 80% v 32% v 14% v 0% in clinical trials, anti-VEGF, anti-EGFR, and CT alone regimen, respectively (HR = 0.63, 95% CI 0.45–0.89, P = 0.009) (Fig. 1c). In the reverse analysis where anti-EGFR- and anti-VEGF-based chemotherapies were stratified by BRAF status, we demonstrated poorer survival for BRAF-mutant tumors regardless of targeted therapy administered even if there was a significantly difference only in the subgroup of patients treated with CT plus anti-EGFR target agents, where BRAF-mutant showed a significant lower OS (HR for anti-EGFR = 16 v 28 months in BRAF-mutant v BRAF-wt tumors, P = 0.005; HR for anti-VEGF = 18 v 26 months in BRAF-mutant v BRAF-wt tumors, P = 0.509) (Fig. 3a, b).
Discussion
By now we know that RCC is a completely different entity with a different embryological origin, molecular pathways (harboring BRAF, PIK3CA, and KRAS mutations, more frequently with MSI-H phenotype), and poorer outcome than LCC [2, 12]. Furthermore, different signaling pathways are involved in the development of colon cancer: in the RCC is more prevalent the serrated pathway [11, 12], in which BRAF mutations develop and CpG island hypermethylation occurs, resulting in gene transcriptional inactivation and loss of gene function by methylation of the promoter region. Otherwise, the conventional pathway with mutations in KRAS, TP53, and APC is associated with LCC.
The worse prognosis of RCC is confirmed irrespective of the therapeutic strategy [22, 31, 32], although a triplet chemotherapy backbone plus bevacizumab as initial therapy [26] and especially a multi-targeted therapy combination seems to be the best future therapeutic choice [27,28,29,30].
Moreover, the right-sidedness seems to be also a predictive factor of response to first-line treatment in mCRC patients. On the basis of retrospective analysis of CRYSTAL, FIRE-3, and CALGB/SWOG 80405 trials, among patients with KRAS wt disease [18, 19], NCCN guidelines recommend choosing anti-EGFR plus chemo as first-line chemotherapy only in left-sided mCRC [33]. However, the NRAS and/or BRAF status was not considered in these trials.
Therefore, a better understanding of RCC behavior is crucial to explain the different response to chemotherapy and the available targeted agents.
We conducted a multi-institutional retrospective analysis of advanced RCC patients with known BRAF status and available treatment data with the aim to identify predictive factors for survival and the difference between target agents compound in first-line chemotherapy choice.
The proportion of BRAF-mutant tumors (42/207 patients) was consistent across this population and more large-scale cohorts’ study (57/201 patients), including RCC [7]. According to the recently published largest series of V600E BRAF-mutated mCRC [34], our study confirmed a median overall survival in BRAF-mutant tumors of less than 20 months and significantly worse OS in patients with an ECOG PS > 1 (P = < 0.0001), G3–4 tumor grading (P = 0.009), with lympho-vascular invasion (P = 0.013), not having the primary tumor resected (P = < 0.0001).
Moreover, according to the largest stage IV colon cancer analysis for survival [14], our study showed older age (P = 0.002), pT4 (P = 0.009), pN2 (P = 0.034), peritoneum as metastatic site (0.040), and the synchronous occurrence of metastases (P = 0.045), independent of the number of metastatic site, as significantly negative prognostic factor of survival. Actually, advanced RCC is a different entity from LCC, with a significant correlation with known negative prognostic factors such as advanced pT and pN stage, dedifferentiated tumor grading, metachronous, and peritoneal metastases. All these clinicopathological factors may contribute to the difference observed in patient’s prognosis with increasing pooled data demonstrating a shorter survival for patients with RCC than LCC [35]. On the contrary, the upfront surgery of liver metastases (P = 0.001) was associated with better outcome. Literature data showed that surgery plays an important role in the treatment of patients with limited metastatic disease of colorectal cancer [36]. Indeed, long-term survival and cure is reported in 20–50% of highly selected patients with oligometastatic disease who underwent surgery. The goal of surgery should be to resect all metastases with negative histological margins while preserving sufficient functional hepatic parenchyma. The treatment plan requires multidisciplinary evaluation and actually, as confirmed by our analysis, the surgery of primary tumor (univariate analysis) and even more the upfront surgery of liver disease (multivariate analysis) in metastatic CRC have to be always discussed with surgeons because they offer a great chance for prolonged survival in patients affected with metastatic RCC.
As previously described [34], BRAF-mutant RCC tumors was significantly reported in pT4 (P = 0.016), G3–4 tumor grading (P = 0.004) KRAS-wt (P < 0.0001), MSI-H (P = 0.019), metachronous (P = 0.018), and especially peritoneal metastases (P = 0.003).
Several trials on metastatic setting have found worsen outcomes in RCC patients rather than LCC and a different therapeutic response to the anti-EGFR targeted agents [37]. Effectively, a chemotherapy doublet or triplet plus bevacizumab was indirectly approved by retrospective, post-hoc analysis mainly focused on describing differences between RCC and LCC [38,39,40,41], as the new standard first-line chemotherapy for metastatic RCC, regardless of RAS status.
Non-significant difference was found between treatment arms, irrespective of anti-VEGF or anti-EGFR target agent first-line therapy used, although patients enrolled in clinical trials showed a better median PFS1 than CT plus target agent as well as triplet CT group (17.0 v 6.0 v.13.0 months, respectively).
In account of other molecular aspects, RCC patients are characterized by a MSI-high cancer more frequently than LCC [6] and by a higher total number of harvested lymph nodes [42] but with lower rates of node positivity [43]. The reasons for these node status differences were both anatomic and molecular: it has been shown that the right-sided colon mesentery contains a more complex lymphatic system, leading to an enhanced immune response and an increased number of lymph nodes examined after surgery [44, 45]. In our retrospective analysis, a small number of patients with MSI-H phenotype were enrolled in clinical trials with an anti-PD1 and actually reported a significant better outcome than patients who were not enrolled in clinical trials. (HR for PFS1 = 0.90, 95% CI 0.82–0.99, P = 0.037; HR for PFS2 = 0.69, 95% CI 0.57–0.85, P = 0.001). As we know by the available literature data, MSI-H CRCs have a better prognosis compared to MSS tumor and do not benefit from 5-fluorouracile adjuvant chemotherapy [46]: indeed, they have much more active immune microenvironment with severe infiltration of intra-tumor cell infiltrating-lymphocytes and furthermore showed upregulation of inhibitory checkpoints [47]. The majority of data about the prognostic impact of MSS/MSI status is in the setting of localized disease; only few studies have investigated the role of mismatch repair status in metastatic setting, mainly because of the prevalence of MSI is low, about 4% of mCRC. Although in some reports, this survival advantage seems to be independent of tumor stage [48, 49]; in others, it seems to be confined to stage II or stage III [50, 51], so the debate remains open whether MSI-H is a good prognostic factors in advanced disease. Popat and colleagues, in a meta-analysis evaluated 1277 MSI-H stage I–IV CRC patients from a total of 32 eligible studies, found that effect of MSI on prognosis was maintained in both the early and advanced settings, with a 35% reduction in the risk of death (HR 0.65, 95% CI 0.59–0.71) [52]. Our data support this hypothesis that MSI-high phenotype in the metastatic setting could have a positive prognostic role as well as it may be a positive predictive factor of response to immunotherapy.
With regard to the second-line CT, we did not find any differences between anti-VEGF or anti-EGFR target agents, with the exception of significant better survival in clinical trials and in which cases of patients resulted to be fit for reintroduction of triplet CT regimen (median PFS2 was 16.0 v 15.0 v 7.0 v 5.0 v 4.0 v 2.0 months in clinical trials, triplet CT, CT plus anti-EGFR, CT plus anti-VEGF, CT alone and regorafenib/lonsurf as second line therapy, respectively) (HR = 0.69, 95% CI 0.57–0.85, P = 0.001).
Actually, BRAF-mutant RCC patients in this study reported a median OS of 16 months (range 13.7–18.3) which was not so far from median OS reported in BRAF-mutant patients enrolled in the TRIBE trial [26], with a worse survival than BRAF-wt patients, both in anti-VEGF and anti-EGFR target agent treatment groups. In the bivariate analysis, where BRAF status was stratified by treatments, there was showed non-significant survival differences between first-line CT with anti-EGFR or anti-VEGF targets in both BRAF and RAS wt tumors (28.0 v 26.0 months, respectively. P = 0.427) (Fig. 1b). But if we looked at only BRAF-mutant tumors, 2ys OS was significantly higher in clinical trials group (80% v 32% v 14% v 0% in clinical trials, anti-VEGF, anti-EGFR plus CT, and CT alone or triplet backbone regimen, respectively; HR = 0.63, 95% CI 0.45–0.89, P = 0.009) (Fig. 1c). At the reverse analysis where anti-EGFR- and anti-VEGF-based chemotherapies were stratified by BRAF status, we demonstrated that BRAF-mutant tumors reported a poorer survival than BRAF-wt tumors, regardless of targeted therapy administered. However, RAS wt tumors treated with CT plus anti-EGFR showed a significant difference in survival according to BRAF mutation (HR for anti-EGFR = 16 v 28 months in BRAF-mutant v BRAF-wt tumors, P = 0.005; HR for anti-VEGF = 18 v 26 months in BRAF-mutant v BRAF-wt tumors, P = 0.509). (Fig. 3a, b). These data, taking into account the prevalence of BRAF mutation in RCC, may explain the more pronounced lower effect in RCC than LCC, reported in post-hoc analysis of clinical trials focused on anti-EGFR therapy in the first-line setting [53]. Indeed, it is clear that mutations not only in codon 12 or 13 of the KRAS [54, 55] but also in other downstream effectors of the EGFR signaling pathway, such as BRAF, NRAS, and PI3 kinase, might have a negative effect on response to anti-EGFR antibodies [54, 56, 57]. This fact accounts for the dismal advantage in survival found in RCC, BRAF-mutant patients treated with anti-EGFR targets. Although anti-EGFR seems to be overall ineffective in this population, recent studies have been demonstrated that anti-EGFR combined with BRAF and MEK inhibitors could be a great opportunity of better responses in patients with metastatic BRAFV600E-mutated CRC beyond first-line chemotherapy [30]; however, despite advances, OS remains far inferior for these patients compared to their BRAF-wt counterparts and the development of combination therapies to impede signaling through the MAPK pathway remains an area of active investigation.
Finally, RCC was associated with consensus molecular subtypes (CMS) different from LCC [58,59,60] and these molecular patterns may also explain the different response to targeted agents. Indeed, a retrospective analysis of the CALGB/SWOG 80405, which compared the efficacy of cetuximab v bevacizumab when added to standard first-line chemotherapy, found that RAS wt patients with CMS1 (mostly RCC patients) benefitted significantly more if they had been randomized to bevacizumab compared to cetuximab, whereas a trend towards better outcomes was observed for CMS2 patients if they had been randomized to cetuximab.
This article is limited by retrospective reporting bias of heterogeneous data regarding clinicopathological characteristics as well as different treatments. Nevertheless, we decide to describe also patients included in clinical trials due to the impressive outcome reported by these patients, whose sample number was small but actually BRAF-mutant metastatic RCC was a relatively rare and an orphan-in-drug disease. However, this small sample of patients included in this study does not affect the principle aim of our study to emphasize the negative prognosis of BRAF-mutant tumors regardless of anti-EGFR or anti-VEGF targets used. Moreover, we have reported survival curve of patients included in clinical trials, although they were a few also to raise awareness that metastatic RCC patients with BRAF-mutant status should be enrolled in clinical trials in respect to standard available treatment since their first-line chemotherapy.
Based on these observations and given the real-life results of our analysis, further studies are needed to determine if molecular signatures according to sidedness are crucial predictive markers of response to specific targeted agents and also to definitively answer the question about the best first-line chemotherapy in RAS-wt, BRAF-mutant, and RCC patients.
Conclusions
Although the limit of sample size, our study demonstrated that BRAF status makes the difference for treatment response. Therefore, a first-line CT plus an anti-EGFR targeted agent should not to be excluded in all RCC cases in advance but considered on a case-by-case basis. Meanwhile, RCC patient with BRAF-mutant tumors or with MSI-H phenotype should be enrolled in clinical trials. Certainly, a better knowledge of the main predictive factors and prospective clinical trials stratifying participants according to primary tumor location would be for helping physician to make the best therapeutic choice.
References
Stewart BW, Wild CP. World cancer report 2014. World Heal Organ. 2014.
Petrelli F, Tomasello G, Borgonovo K, Ghidini M, Turati L, Dallera P, Passalacqua R, Sgroi G, Barni S (2017) Prognostic survival associated with left-sided vs right-sided colon cancer a systematic review and meta-analysis. JAMA Oncol. 3:211–219. https://doi.org/10.1001/jamaoncol.2016.4227
Karim S, Brennan K, Nanji S, Berry SR, Booth CM (2017) Association between prognosis and tumor laterality in early-stage colon cancer. JAMA Oncol 3:1386–1392. https://doi.org/10.1001/jamaoncol.2017.1016
Beale AL, Penney MD, Allison MC (2005) The prevalence of iron deficiency among patients presenting with colorectal cancer. Color Dis 7:398–402. https://doi.org/10.1111/j.1463-1318.2005.00789.x
Cheng L, Eng C, Nieman LZ, Kapadia AS, Du XL (2011) Trends in colorectal cancer incidence by anatomic site and disease stage in the United States from 1976 to 2005. Am J Clin Oncol Cancer Clin Trials 34:573–580. https://doi.org/10.1097/COC.0b013e3181fe41ed
Markowitz SD, Bertagnolli MM (2009) Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med 361:2449–2460. https://doi.org/10.1056/NEJMra0804588
Tran B, Kopetz S, Tie J, Gibbs P, Jiang ZQ, Lieu CH, Agarwal A, Maru DM, Sieber O, Desai J (2011) Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 117:4623–4632. https://doi.org/10.1002/cncr.26086
Bufill JA (1990) Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med 113:779. https://doi.org/10.7326/0003-4819-113-10-779
Iacopetta B (2002) Are there two sides to colorectal cancer? Int J Cancer 101:403–408. https://doi.org/10.1002/ijc.10635
Distler P, Holt PR (1997) Are right- and left-sided colon neoplasms distinct tumors? Dig Dis 15:302–311. https://doi.org/10.1159/000171605
Nosho K, Irahara N, Shima K, Kure S, Kirkner GJ, Schernhammer ES, Hazra A, Hunter DJ, Quackenbush J, Spiegelman D, Giovannucci EL, Fuchs CS, Ogino S (2008) Comprehensive biostatistical analysis of CpG island methylator phenotype in colorectal cancer using a large population-based sample. PLoS One 3:e3698. https://doi.org/10.1371/journal.pone.0003698
Samowitz WS, Albertsen H, Herrick J et al (2005) Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology
Meguid RA, Slidell MB, Wolfgang CL, Chang DC, Ahuja N (2008) Is there a difference in survival between right- versus left-sided colon cancers? Ann Surg Oncol 15:2388–2394. https://doi.org/10.1245/s10434-008-0015-y
Weiss JM, Pfau PR, O’Connor ES et al (2011) Mortality by stage for right- versus left-sided colon cancer: analysis of surveillance, epidemiology, and end results-Medicare data. J Clin Oncol 29:4401–4409. https://doi.org/10.1200/JCO.2011.36.4414
Warschkow R, Sulz MC, Marti L, Tarantino I, Schmied BM, Cerny T, Güller U (2016) Better survival in right-sided versus left-sided stage I - III colon cancer patients. BMC Cancer 16:554. https://doi.org/10.1186/s12885-016-2412-0
Schrag D, Weng S, Brooks G, Meyerhardt JA, Venook AP (2016) The relationship between primary tumor sidedness and prognosis in colorectal cancer. J Clin Oncol 34:3505. https://doi.org/10.1200/jco.2016.34.15_suppl.3505
Kennecke HF, Speers C, Davies JM, Cheung WY, Lee-Ying RM (2016) Differences in relapse-free survival (RFS) and survival after relapse (SAR) in right (R) versus left (L) stage I-III colon cancer (CCa). J Clin Oncol 34:3578. https://doi.org/10.1200/jco.2016.34.15_suppl.3578
Tejpar S, Stintzing S, Ciardiello F et al (2017) 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. In: JAMA Oncology. https://doi.org/10.1001/jamaoncol.2016.3797
Venook AP, Niedzwiecki D, Innocenti F, Fruth B, Greene C, O'Neil BH, Shaw JE, Atkins JN, Horvath LE, Polite BN, Meyerhardt JA, O'Reilly EM, Goldberg RM, Hochster HS, Blanke CD, Schilsky RL, Mayer RJ, Bertagnolli MM, Lenz HJ (2016) Impact of primary (1o) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol 34:3504. https://doi.org/10.1200/jco.2016.34.15_suppl.3504
Lee GH, Malietzis G, Askari A, Bernardo D, Al-Hassi HO, Clark SK (2015) Is right-sided colon cancer different to left-sided colorectal cancer? - a systematic review. Eur J Surg Oncol 41:300–308. https://doi.org/10.1016/j.ejso.2014.11.001
Benedix F, Schmidt U, Mroczkowski P, Gastinger I, Lippert H, Kube R (2011) Colon carcinoma - classification into right and left sided cancer or according to colonic subsite? - analysis of 29 568 patients. Eur J Surg Oncol 37:134–139. https://doi.org/10.1016/j.ejso.2010.12.004
Loupakis F, Yang D, Yau L, Feng S, Cremolini C, Zhang W, Maus MKH, Antoniotti C, Langer C, Scherer SJ, Müller T, Hurwitz HI, Saltz L, Falcone A, Lenz HJ (2015) Primary tumor location as a prognostic factor in metastatic colorectal cancer. J Natl Cancer Inst 107. https://doi.org/10.1093/jnci/dju427
Lee HM, Morris V, Napolitano S, Kopetz S (2019) Evolving strategies for the management of BRAF-mutant metastatic colorectal cancer. Oncol (United States)
Taieb J, Lapeyre-Prost A, Laurent Puig P, Zaanan A (2019) Exploring the best treatment options for BRAF-mutant metastatic colon cancer. Br J Cancer 121:434–442. https://doi.org/10.1038/s41416-019-0526-2
Morris V, Overman MJ, Jiang ZQ, Garrett C, Agarwal S, Eng C, Kee B, Fogelman D, Dasari A, Wolff R, Maru D, Kopetz S (2014) Progression-free survival remains poor over sequential lines of systemic therapy in patients with BRAF-mutated colorectal cancer. Clin Colorectal Cancer 13:164–171. https://doi.org/10.1016/j.clcc.2014.06.001
Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, Mezi S, Tomasello G, Ronzoni M, Zaniboni A, Tonini G, Carlomagno C, Allegrini G, Chiara S, D'Amico M, Granetto C, Cazzaniga M, Boni L, Fontanini G, Falcone A (2015) 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 16:1306–1315. https://doi.org/10.1016/S1470-2045(15)00122-9
Ledys F, Derangère V, Réda M, Guion JF, Milliex R, Roux V, Limagne E, Arnould L, Bengrine L, Ghiringhelli F, Rébé C (2019) Anti-MEK and anti-EGFR mAbs in RAS-mutant metastatic colorectal cancer: case series and rationale. Adv Ther 36:1480–1484. https://doi.org/10.1007/s12325-019-00949-y
Bendell JC, Atreya CE, André T, Tabernero J, Gordon MS, Bernards R, van Cutsem E, Tejpar S, Sidhu R, Go WY, Allred A, Motwani M, Suttle BB, Wu Y, Hoos A, Orford KW, Corcoran RB, Schellens JHM (2014) Efficacy and tolerability in an open-label phase I/II study of MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in combination in patients (pts) with BRAF V600E mutated colorectal cancer (CRC). J Clin Oncol 32:3515. https://doi.org/10.1200/jco.2014.32.15_suppl.3515
Corcoran RB, Atreya CE, Falchook GS et al (2015) Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. In: Journal of Clinical Oncology. https://doi.org/10.1200/JCO.2015.63.2471
Kopetz S, Grothey A, Yaeger R, van Cutsem E, Desai J, Yoshino T, Wasan H, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Pfeiffer P, Orlov S, Lonardi S, Elez E, Kim TW, Schellens JHM, Guo C, Krishnan A, Dekervel J, Morris V, Calvo Ferrandiz A, Tarpgaard LS, Braun M, Gollerkeri A, Keir C, Maharry K, Pickard M, Christy-Bittel J, Anderson L, Sandor V, Tabernero J (2019) Encorafenib, binimetinib, and cetuximab in BRAF V600E–mutated colorectal cancer. N Engl J Med 381:1632–1643. https://doi.org/10.1056/NEJMoa1908075
Brulé SY, Jonker DJ, Karapetis CS et al (2015) Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer. https://doi.org/10.1016/j.ejca.2015.03.015
Boeckx N, Janssens K, Van Camp G et al (2018) The predictive value of primary tumor location in patients with metastatic colorectal cancer: a systematic review. Crit Rev Oncol Hematol 121:1–10. https://doi.org/10.1016/j.critrevonc.2017.11.003
Benson AB, Venook AP, Al-Hawary MM et al (2018) NCCN guidelines insights: colon cancer, version 2. J Natl Compr Cancer Netw. https://doi.org/10.6004/jnccn.2018.0021
Loupakis F, Intini R, Cremolini C, Orlandi A, Sartore-Bianchi A, Pietrantonio F, Pella N, Spallanzani A, Dell’Aquila E, Scartozzi M, de Luca E, Rimassa L, Formica V, Leone F, Calvetti L, Aprile G, Antonuzzo L, Urbano F, Prenen H, Negri F, di Donato S, Buonandi P, Tomasello G, Avallone A, Zustovich F, Moretto R, Antoniotti C, Salvatore L, Calegari MA, Siena S, Morano F, Ongaro E, Cascinu S, Santini D, Ziranu P, Schirripa M, Buggin F, Prete AA, Depetris I, Biason P, Lonardi S, Zagonel V, Fassan M, di Maio M (2019) A validated prognostic classifier for V600EBRAF-mutated metastatic colorectal cancer: the ‘BRAF BeCool’ study. Eur J Cancer 118:121–130. https://doi.org/10.1016/j.ejca.2019.06.008
Gowarty JL, Durham C, Wong L, Chen W (2019) Survival outcomes of left-sided versus right-sided colon cancer. J Clin Oncol 37:502. https://doi.org/10.1200/jco.2019.37.4_suppl.502
Akgül Ö, Çetinkaya E, Ersöz Ş, Tez M (2014) Role of surgery in colorectal cancer liver metastases. World J Gastroenterol 20:6113–6122. https://doi.org/10.3748/wjg.v20.i20.6113
Stintzing S, Miller-Phillips L, Modest DP, Fischer von Weikersthal L, Decker T, Kiani A, Vehling-Kaiser U, al-Batran SE, Heintges T, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Held S, Moehler M, Jagenburg A, Kirchner T, Jung A, Heinemann V (2017) Impact of BRAF and RAS mutations on first-line efficacy of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab: analysis of the FIRE-3 (AIO KRK-0306) study. Eur J Cancer 79:50–60. https://doi.org/10.1016/j.ejca.2017.03.023
Modest DP, Ricard I, Heinemann V, Hegewisch-Becker S, Schmiegel W, Porschen R, Stintzing S, Graeven U, Arnold D, von Weikersthal LF, Giessen-Jung C, Stahler A, Schmoll HJ, Jung A, Kirchner T, Tannapfel A, Reinacher-Schick A (2016) Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group. Ann Oncol 27:1746–1753. https://doi.org/10.1093/annonc/mdw261
Boeckx N, Koukakis R, de Beeck KO et al (2017) 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 28:1862–1868. https://doi.org/10.1093/annonc/mdx119
Boeckx N, Koukakis R, Op de Beeck K (2018) et al, Effect of primary tumor location on second- or later-line treatment outcomes in patients with RAS wild-type metastatic colorectal cancer and all treatment lines in patients with RAS mutations in four randomized panitumumab studies. Clin Colorectal Cancer. https://doi.org/10.1016/j.clcc.2018.03.005
Cremolini C, Antoniotti C, Lonardi S et al (2018) 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. https://doi.org/10.1093/annonc/mdy140
Mik M, Berut M, Dziki L, Trzcinski R, Dziki A (2017) Right-and left-sided colon cancer-clinical and pathological differences of the disease entity in one organ. Arch Med Sci 1:157–162. https://doi.org/10.5114/aoms.2016.58596
Guan X, Chen W, Liu Z et al (2016) Whether regional lymph nodes evaluation should be equally required for both right and left colon cancer. Oncotarget. https://doi.org/10.18632/oncotarget.11007
Bilimoria KY, Palis B, Stewart AK, Bentrem DJ, Freel AC, Sigurdson ER, Talamonti MS, Ko CY (2008) Impact of tumor location on nodal evaluation for colon cancer. Dis Colon Rectum 51:154–161. https://doi.org/10.1007/s10350-007-9114-2
Shen H, Yang J, Huang Q, Jiang MJ, Tan YN, Fu JF, Zhu LZ, Fang XF, Yuan Y (2015) Different treatment strategies and molecular features between right-sided and left-sided colon cancers. World J Gastroenterol 21:6470–6478. https://doi.org/10.3748/wjg.v21.i21.6470
Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, French AJ, Kabat B, Foster NR, Torri V, Ribic C, Grothey A, Moore M, Zaniboni A, Seitz JF, Sinicrope F, Gallinger S (2010) Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 28:3219–3226. https://doi.org/10.1200/JCO.2009.27.1825
Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, Blosser RL, Fan H, Wang H, Luber BS, Zhang M, Papadopoulos N, Kinzler KW, Vogelstein B, Sears CL, Anders RA, Pardoll DM, Housseau F (2015) The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 5:43–51. https://doi.org/10.1158/2159-8290.CD-14-0863
Lukish JR, Muro K, DeNobile J, Katz R, Williams J, Cruess DF, Drucker W, Kirsch I, Hamilton SR (1998) Prognostic significance of DNA replication errors in young patients with colorectal cancer. Ann Surg 227:51–56. https://doi.org/10.1097/00000658-199801000-00008
Benatti P, Gafà R, Barana D et al (2005) Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res 11:8332–8340. https://doi.org/10.1158/1078-0432.CCR-05-1030
Merok MA, Ahlquist T, Røyrvik EC, Tufteland KF, Hektoen M, Sjo OH, Mala T, Svindland A, Lothe RA, Nesbakken A (2013) Microsatellite instability has a positive prognostic impact on stage II colorectal cancer after complete resection: results from a large, consecutive Norwegian series. Ann Oncol 24:1274–1282. https://doi.org/10.1093/annonc/mds614
Samowitz WS, Coleman LW, Leppert M et al (2001) Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev
Popat S, Hubner R, Houlston RS (2005) Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23:609–618. https://doi.org/10.1200/JCO.2005.01.086
Ross PJ, Srikandarajah K, de Naurois J (2018) Right versus left-sided colon cancer: is it time to consider these as different diseases? AIMS Med Sci. https://doi.org/10.3934/medsci.2018.3.303
Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359:1757–1765. https://doi.org/10.1056/NEJMoa0804385
Allegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, McAllister PK, Morton RF, Schilsky RL (2009) American society of clinical oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 27:2091–2096. https://doi.org/10.1200/JCO.2009.21.9170
Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M et al (2009) Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS One 4:e7287. https://doi.org/10.1371/journal.pone.0007287
Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, Rougier P, Lievre A, Landi B, Boige V, Ducreux M, Ychou M, Bibeau F, Bouché O, Reid J, Stone S, Penault-Llorca F (2009) Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 27:5924–5930. https://doi.org/10.1200/JCO.2008.21.6796
Roepman P, Schlicker A, Tabernero J, Majewski I, Tian S, Moreno V, Snel MH, Chresta CM, Rosenberg R, Nitsche U, Macarulla T, Capella G, Salazar R, Orphanides G, Wessels LFA, Bernards R, Simon IM (2013) Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition. Int J Cancer 134:552–562. https://doi.org/10.1002/ijc.28387
Perez Villamil B, Romera Lopez A, Hernandez Prieto S, Lopez Campos G, Calles A, Lopez Asenjo JA, Sanz Ortega J, Fernandez Perez C, Sastre J, Alfonso R, Caldes T, Martin Sanchez F, Diaz Rubio E (2012) Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior. BMC Cancer 12. https://doi.org/10.1186/1471-2407-12-260
Sadanandam A, Lyssiotis CA, Homicsko K, Collisson EA, Gibb WJ, Wullschleger S, Ostos LCG, Lannon WA, Grotzinger C, del Rio M, Lhermitte B, Olshen AB, Wiedenmann B, Cantley LC, Gray JW, Hanahan D (2013) A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med 19:619–625. https://doi.org/10.1038/nm.3175
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Roberto, M., Marchetti, P., Arrivi, G. et al. The treatment paradigm of right-sided metastatic colon cancer: harboring BRAF mutation makes the difference. Int J Colorectal Dis 35, 1513–1527 (2020). https://doi.org/10.1007/s00384-020-03589-9
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DOI: https://doi.org/10.1007/s00384-020-03589-9