Abstract
Purpose:
Sidedness is prognostic and predictive of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). Transverse colon has been historically excluded from several analyses of sidedness and the optimal division between left- and right-sided colorectal cancer is unclear. We investigated transverse colon primary tumor location as a biomarker in mCRC.
Experimental Design:
Pooled analysis of CCTG/AGITG CO.17 and CO.20 trials of cetuximab in chemotherapy-refractory mCRC. Outcomes of patients with RAS/BRAF wild-type (WT) mCRC from CO.17 and KRAS WT mCRC from CO.20 were analyzed according to location.
Results:
A total of 553 patients were analyzed, 32 (5.8%) with cancers from the transverse, 101 (18.3%) from right, and 420 from (75.9%) left colon. Transverse mCRC failed to reach significant benefit from cetuximab versus best supportive care (BSC) for overall survival [OS; median, 5.9 vs. 2.1 months; HR, 0.63; 95% confidence interval (CI), 0.28–1.42; P=0.26] and progression-free survival (PFS; median, 1.8 vs. 1.3 months; HR, 0.57; 95% CI, 0.26–1.28; P=0.16). Analyzing exclusively patients randomized to cetuximab, right-sided and transverse had comparable outcomes for OS (median, 5.6 vs. 5.9 months; HR, 0.82; 95% CI, 0.50–1.34; P=0.43) and PFS (median, 1.9 vs. 1.8 months; HR, 0.78; 95% CI, 0.49–1.26; P=0.31). Patients with left-sided mCRC had superior outcomes with cetuximab compared with transverse for OS (median, 9.7 vs. 5.9 months; HR, 0.42; 95% CI, 0.27–0.67; P=0.0002) and PFS (median, 3.8 vs. 1.8 months; HR, 0,49; 95% CI, 0.31–0.76; P=0.001). Location was not prognostic in patients treated with BSC alone.
Conclusions:
Transverse mCRC has comparable prognostic and predictive features with right-sided mCRC.
Translational Relevance.
Primary tumor location is prognostic in metastatic colorectal cancer (mCRC) and predictive for anti-EGFR benefit. Pivotal studies of sidedness have excluded the transverse colon or analyzed it with right-sided cancers. We sought to investigate the prognostic and predictive features of the transverse colon as a unique entity in a pooled analysis of biomarker-selected patients from two randomized trials of cetuximab in the chemotherapy-refractory setting. In our analysis, patients with mCRC from the transverse colon showed comparable outcomes with cetuximab with right-sided and worse outcomes than left-sided tumors. Transverse colon cancers did not have a significantly different prognosis compared with left- or right-sided in patients receiving BSC alone.
Introduction
Primary tumor location, also commonly referred to as sidedness, is prognostic in all stages of colorectal cancer, with better outcomes for patients whose cancer arises from the left side (1). Sidedness is also predictive of anti-EGFR therapy benefit in the first-line treatment for patients with RAS/BRAF wild-type (WT) left-sided metastatic colorectal cancer (mCRC) whereas patients with right-sided RAS/BRAF WT mCRC should preferentially receive chemotherapy plus bevacizumab (2–6). These findings have been incorporated into treatment guidelines for patients with advanced colorectal cancer and are now the standard of care (4–6).
The transverse colon represents the embryological transition between the midgut and hindgut, with its proximal two thirds arising from the former and the distal third from the latter. Most studies analyzing sidedness have excluded the transverse colon, due to its less common prevalence and lack of clarity around the optimal cutoff point, or classified it as right-sided (2, 3, 7). There is little available evidence assessing the optimal cutoff point between left- and right-sided cancers and identifying whether transverse colon cancers are more left- or right-sided may impact treatment selection.
Previous work has demonstrated that colorectal cancer arising from the transverse colon has distinct mutational profile and consensus molecular subtype (CMS) frequencies when compared with left- and right-sided colorectal cancer (8). In addition, mutational profiles from transverse colorectal cancer differed from right-sided colorectal cancer and a division before the transverse colon optimized the prognostic differences between left- and right-sided cancers in this retrospective study (8). Given the scarcity of specific information about treatment outcomes for mCRC arising from the transverse colon, we aimed to investigate anti-EGFR efficacy in the transverse colon. To address this gap in the literature, we conducted a retrospective analysis of a pooled population from two prospective randomized trials: Canadian Cancer Trials Group (CCTG)/Australasian Gastro-Intestinal Trials Group (AGITG) CO.17 and CO.20 (9–11).
Materials and Methods
Included studies
The CCTG/AGITG CO.17 and CO.20 designs, interventions, enrollment eligibility, and results have been reported previously (9–11). Figure 1 shows the two trials and this pooled analysis schema. In summary, CO.17 was a prospective randomized phase III trial of cetuximab versus best supportive care (BSC) in 572 patients with pretreated metastatic EGFR-positive colorectal cancer (9, 10). The trial did not require prospective biomarker testing for mutations in RAS/BRAF as an inclusion criteria but subsequent genotyping of KRAS exons 2,3,4; NRAS exons 2,3,4; and BRAF (V600E) was conducted in other correlative studies and available results were used for this analysis (10, 12). CO.20 was a prospective randomized phase III trial of cetuximab plus brivanib alaninate versus cetuximab plus placebo in 750 patients with metastatic, chemotherapy-refractory colorectal cancer that underwent a protocol amendment to exclude KRAS exon 2–mutated patients with mCRC after KRAS had been identified as a biomarker (11). CO.20 has not undergone further KRAS, NRAS, and BRAF testing. Both studies were approved by the appropriate institutional review boards and conducted in accordance with the Declaration of Helsinki and International Ethical Guidelines for Biomedical Research Involving Human Subjects. All patients provided informed written consent before enrollment.
Figure 1.
CO.17 and CO.20 trials schema and patient selection for pooled analysis.
Patient selection
Data from patients with KRAS/NRAS exons 2,3,4 (RAS) and BRAF V600 E (BRAF) WT mCRC from both arms of CO.17 and patients with KRAS exon 2 (KRAS) WT mCRC randomized to single-agent cetuximab in CO.20 were pooled. Patients from CO.17 with a known RAS/BRAF mutation or unknown RAS/BRAF status as well as patients from CO.20 with a known KRAS mutation or unknown KRAS exon 2 status were excluded from this analysis (Fig. 1). Patient characteristics and outcomes were analyzed according to primary tumor location defined as right (from cecum to hepatic flexure), left (from splenic flexure to rectum), and transverse. As these trials were potentially registrational, source documents were available for pathology, surgical, and endoscopic interventions. These were submitted to CCTG and were reviewed previously. Sidedness annotation was extracted from these relevant source documents for each patient by one of the authors for one of the original studies looking at right versus left sidedness (13).
Statistical analysis
Baseline demographic characteristics and known prognostic features were compared by location (right, left, and transverse) using standard descriptive statistics. Time-to-event outcomes such as overall survival (OS) and progression-free survival (PFS) were analyzed for each location in all patients comparing cetuximab with BSC and exclusively in patients treated with cetuximab with the transverse colon as a reference, using Cox regression and estimated with the Kaplan–Meier method. We also analyzed clinical outcomes of nine distinct subsites within the three colonic segments using the rectum as a reference. Univariate analyses were performed using the log-rank test. The Cox proportional hazards model was used for multivariate analysis controlling for primary tumor location, treatment, and the following baseline characteristics with P ≤ 0.1 after the univariate analysis: age (<65 vs. ≥65 years), gender (male vs. female), ECOG performance status (0 or 1 vs. 2), BMI (<20 vs. 20–25 vs. >25 kg/m2), disease at presentation (metastatic vs. recurrent), stage at presentation (I or II or III vs. IV), tumor t-stage (T1 or T2 or T3 vs. T4), lymph node status (negative vs. positive), histologic grade of primary tumor (well or moderate vs. poorly differentiated), time from initial diagnosis to randomization (<2 vs. ≥2 years), lactate dehydrogenase (LDH; higher than the upper limit of normal vs. lower), alkaline phosphatase higher than the upper limit of normal vs. lower), hemoglobin (CTCAE grade≥1 vs. grade 0), number of previous chemotherapy drug classes (>2 vs. ≤2), number of organ sites with metastatic disease (>2 vs. ≤2), and presence of liver or lung metastases (yes vs. no). PFS was defined as the time from randomization until progression or death from any cause. OS was defined as the time from randomization until death from any cause. Objective response rate (ORR) and disease control rate (DCR) were defined per modified RECIST 1.0 criteria (14).
Data availability
Data used for this analysis were part of a clinical trial and are housed at the CCTG. An investigator who wishes to analyze data from this work must make a formal request to the CCTG using the specific form available at https://www.ctg.queensu.ca/docs/public/policies/TMG-FRM-0199-Application-for-Data-Sharing-V2-2017Feb23.docx. The application must be submitted to datasharing@ctg.queensu.ca. CCTG will review requests according to the institution's Data Sharing and Access Policy available at https://www.ctg.queensu.ca/docs/public/policies/DataSharingandAccessPolicy.pdf.
Results
Pooled analysis population and baseline characteristics
A total of 553 patients were included in this pooled analysis, 201 (36.3%) from CO. 17 and 352 (63.7%) from the CO.20 trial. The majority, 457 (82.6%), received cetuximab and 96 patients (17.4%) were treated with BSC alone. All patients were KRAS WT. The 201 (36.3%) patients enrolled in the CO.17 trial had expanded RAS/BRAF genotyping and were identified as all-RAS/BRAF WT. The transverse colon was the primary tumor location for 32 (5.8%) patients, whereas the right and left colon were defined as the primary location for 101 (18.3%) and 420 (75.9%) patients, respectively (Fig. 1).
Baseline patient, disease, and treatment characteristics by site of primary tumor are shown in Table 1. The age, sex, ECOG, stage at presentation, number of previous chemotherapy regimens, and the trial of enrollment were not significantly different between groups. Conversely, the disease presentation, histologic grade of the primary tumor, time from initial diagnosis to randomization, presence of liver and lung metastasis, presence of peritoneal and retroperitoneal metastasis, and treatment varied significantly according to primary tumor location.
Table 1.
Baseline patient, disease, and treatment characteristics by primary tumor location.
| Characteristic | Transverse colon (n = 32) | Right-sided (n = 101) | Left-sided (n = 420) | P value |
|---|---|---|---|---|
| Median age in years (range) | 61.3 (35.1–85.2) | 65.2 (27–87.7) | 63.1 (28.1–88.1) | 0.31 |
| Sex | 0.08 | |||
| Female | 15 (46.9) | 43 (42.6) | 139 (33.1) | |
| Male | 17 (53.1) | 58 (57.4) | 281 (66.9) | |
| ECOG performance status | 0.54 | |||
| 0 | 8 (25) | 31 (30.7) | 132 (31.4) | |
| 1 or 2 | 24 (75) | 70 (69.3) | 288 (68.6) | |
| Disease at presentation | 0.03 | |||
| Synchronous metastases | 16 (50) | 68 (67.3) | 223 (53.1) | |
| Metachronous metastases | 16 (50) | 33 (32.7) | 197 (46.9) | |
| Histologic grade of primary tumor | <.0001 | |||
| Well differentiated | 3 (10) | 5 (5.5) | 35 (8.9) | |
| Moderately differentiated | 14 (46.7) | 60 (65.9) | 307 (78.1) | |
| Poorly differentiated | 13 (43.3) | 26 (28.6) | 51 (13) | |
| Time from initial diagnosis to randomization (years) | <.0001 | |||
| Median (range) | 1.8 (0.5–8.3) | 1.8 (0.2–13.2) | 2.7 (0.1–15.7) | |
| Number of previous chemotherapy regimens | 0.13 | |||
| ≤2 | 4 (12.5) | 4 (4) | 20 (4.8) | |
| >2 | 28 (87.5) | 97 (96) | 400 (95.2) | |
| Presence of liver and lung metastases | 0.0009 | |||
| Yes | 25 (78.1) | 81 (81.8) | 383 (92.3) | |
| No | 7 (21.9) | 18 (18.2) | 32 (7.7) | |
| Peritoneal or retroperitoneal metastases | 0.02 | |||
| Yes | 4 (12.5) | 11 (11.1) | 19 (4.6) | |
| No | 28 (87.5) | 88 (88.9) | 396 (95.4) |
Overall, patients with mCRC arising from the transverse colon had a higher proportion of metachronous presentation (50%; P = 0.03), poorly differentiated histological grade (43.3%; P<0.0001), and BSC as treatment allocation (31.2%; P=0.04) when compared with patients with cancer arising from the right and left colon. They also presented more commonly with no liver and lung metastases (21.9%; P=0.0009) but more frequently with peritoneal and retroperitoneal metastases (12.5%; P=0.02) with these differences being more pronounced in comparison with patients with primary colorectal cancer from the left colon.
Clinical outcomes of transverse colon as primary tumor location according to treatment
OS and PFS by primary tumor location and treatment are shown in Fig. 2 and in Supplementary Table S1. A statistically significant benefit from cetuximab versus BSC was not observed in patients with primary tumors originating in the transverse colon for OS (median, 5.9 vs. 2.1 months; HR, 0.63; 95% CI, 0.28–1.42; P = 0.26) or for PFS (median, 1.8 vs. 1.3 months; HR, 0.57; 95% CI, 0.26–1.28; P = 0.16). A similar finding was observed for patients with primary tumors from the right colon for OS (median, 5.6 vs. 4.7 months; HR, 0.68; 95% CI, 0.35–1.32; P = 0.25) and PFS (median, 1.9 vs. 1.9 months; HR, 0.70; 95% CI, 0.38–1.30; P = 0.25). Conversely, there was a significant improvement in OS (median, 9.7 vs. 4.9 months; HR, 0.51; 95% CI, 0.39–0.68; P < 0.0001) and PFS (median, 3.8 vs. 1.8 months; HR, 0.37; 95% CI, 0.28–0.48; P < 0.0001) associated with the use of cetuximab in comparison with BSC for patients with primary tumor location in the left colon. There was no significant interaction between sidedness, treatment, and outcomes on multivariate analysis using the transverse colon as a reference group for OS (right-sided vs. transverse P = 0.27; left-sided vs. transverse P = 0.71) or PFS (right-sided vs. transverse P = 0.82; left-sided vs. transverse P = 0.63).
Figure 2.
Overall survival (A) and progression-free survival (B) by primary site and treatment.
No objective response was observed in patients treated with cetuximab whose primary tumor location was in the transverse colon (ORR, 0%; 95% CI, 0–15.4). The response rate in patients with right-sided colorectal cancer was comparable with those with transverse (ORR, 3.4%; 95% CI, 0.7–9.5), whereas patients with left-sided colorectal cancer had a higher response rate (ORR, 10.4%; 95% CI, 7.4–14.1). As expected, no treatment response was observed in the patients treated with BSC alone regardless of primary tumor location, precluding formal statistical comparison with cetuximab-treated patients.
Finally, there was no statistically significant difference in the DCR for patients with metastatic transverse colon cancer treated with cetuximab versus BSC (DCR, 27.3% vs. 20.0%; OR, 1.50; 95% CI, 0.25–9.18; P = 0.66). Analogous findings were observed for patients with right-sided mCRC (DCR, 33.7% vs. 16.7%; OR, 2.54; 95% CI, 0.52–12.3; P = 0.25). Meanwhile, patients with left-sided mCRC presented a statically superior rate of disease control when treated with cetuximab in comparison with BSC (DCR, 60.7% vs. 13.5%; OR, 9.88; 95% CI, 4.91–19.90; P < 0.0001). No significant interaction between sidedness, treatment, and DCR was observed on multivariate analysis using the transverse colon as a reference group (right-sided vs. transverse, P = 0.39; left-sided vs. transverse, P = 0.05). Supplementary Table S2 summarizes the results for ORR and DCR by primary tumor location and treatment.
Clinical outcomes for patients with metastatic transverse colon cancer treated with cetuximab
OS and PFS were also analyzed exclusively in patients randomized to cetuximab according to the location of the primary tumor using the transverse group as a reference for comparisons (Fig. 3). Patients treated with cetuximab whose primary tumor was in the transverse colon had comparable outcomes with those whose primary tumors were right-sided and inferior outcomes to those with left-sided primary colorectal cancer. The OS (median, 9.7 vs. 5.9 months; HR, 0.42; 95% CI, 0.27–0.67; P = 0.0002) and PFS (median, 3.8 vs. 1.8 months; HR, 0.49; 95% CI, 0.31–0.76; P = 0.001) differences were statistically significant for the comparison of left with transverse groups. Meanwhile, no significant differences for OS (median, 5.6 vs. 5.9 months; HR, 0.82; 95% CI, 0.50–1.34; P = 0.43) and PFS (median, 1.9 vs. 1.8 months; HR, 0.78; 95% CI, 0.49–1.26; P = 0.31) were observed between right and transverse groups.
Figure 3.
Overall survival (A) and progression-free survival (B) by primary tumor location in patients receiving cetuximab.
Multivariate analysis for OS and PFS are shown in the Supplementary Tables S3 and S4. The results confirmed no significant difference between right-sided and transverse mCRC in OS (HR, 0.74; 95% CI, 0.41–1.31; P = 0.30) and PFS (HR, 0.79; 95% CI, 0.46–1.36; P = 0.40). However, outcomes for patients with left-sided cancer remained superior when compared with transverse for OS (HR, 0.40; 95% CI, 0.24–0.68; P=0.0006) and PFS (HR, 0.48; 95% CI, 0.29–0.79; P = 0.004).
Given that no response was observed in patients from the transverse group treated with cetuximab (ORR, 0%; 95% CI, 0%–15.4%), a formal statistical comparison with the right-sided (ORR, 3.4%; 95% CI, 0.7–9.5) and left-sided groups was not performed (ORR, 10.4%; 95% CI, 7.4–14.1). DCR was not statistically different between right-sided and transverse mCRC (DCR, 33.7% vs. 27.3%; OR, 1.36, 95% CI, 0.48–3.82; P = 0.58); however, DCR was superior for the left-sided group in comparison with the transverse group (DCR, 60.7% vs. 27.3%; OR, 4.12, 95% CI, 1.57–10.78; P = 0.004). Supplementary Fig. S1 summarizes the cetuximab RR and DCR by primary tumor location.
Clinical outcomes for patients with mCRC treated with cetuximab according to subsites of primary tumor location
We investigated the clinical outcomes of patients treated with cetuximab, taking into consideration primary tumor location as 9 distinct subsites. A total of 414 patients (74.9%) had information available for this analysis and were distributed as follows: 37 cecum (8.9%), 22 ascending colon (5.3%), 6 hepatic flexure (1.4%), 22 transverse colon (5.3%), 8 splenic flexure (1.9%), 15 descending colon (3.6%), 111 sigmoid colon (26.8%), 63 rectosigmoid junction (15.2%), and 130 rectum (31.4%). Hazard ratios for PFS and OS from univariate and multivariate analysis for of each subsite were compared using the rectum group as a reference. Models are available on Supplementary Tables S5 and S6.
After multivariate analysis, patients with primary tumor location on the transverse colon presented significantly worse OS (HR, 1.97; 95% CI, 1.06–3.65; P = 0.03) and PFS (HR, 2.0; 95% CI, 1.13–3.54; P = 0.02) in comparison with patients with primary tumor location on the rectum when treated with cetuximab. A similar finding was observed for patients whose primary tumor location was in the cecum albeit for PFS only (HR, 2.06; 95% CI, 1.22–3.50; P = 0.007). No other subsite group presented a statistically significant difference in outcomes when compared with the rectum. Figure 4 illustrates the multivariate analysis of outcomes for patients treated with cetuximab according to subsites of primary tumor location.
Figure 4.
Outcomes of patients treated with cetuximab according to subsites of primary tumor location.
Prognostic features of the transverse colon as primary tumor location
To assess the prognostic impact of transverse colon as primary tumor location, we analyzed OS and PFS from patients treated with BSC alone using the transverse group as a reference. The results are shown in Fig. 5. No statistically significant differences were observed between right-sided and transverse for OS (median, 4.7 vs. 2.1 months; HR, 0.70; 95% CI, 0.28–1.74; P = 0.45) or PFS (median, 1.9 vs. 1.3 months; HR, 0.80; 95% CI, 0.33–1.93; P = 0.62). Similar findings were observed when comparing left-sided and transverse for OS (median, 4.9 vs. 2.1 months; HR, 0.56; 95% CI, 0.28–1.14; P = 0.11) and PFS (median, 1.8 vs. 1.3 months; HR, 0.80; 95% CI, 0.40–1.60; P = 0.52).
Figure 5.
Overall survival (A) and progression-free survival (B) by primary tumor location in patients receiving supportive care.
These results were corroborated with multivariate analysis that demonstrated no significant difference observed between right-sided and transverse mCRC for OS (HR, 0.89; 95% CI, 0.31–2.57; P = 0.83) and PFS (HR, 0.83; 95% CI, 0.34–2.00; P = 0.67), as well as between left-sided and transverse for OS (HR, 0.54; 95% CI, 0.21–1.37; P = 0.20) and PFS (HR, 0.75; 95% CI, 0.37–1.52; P = 0.42). The model is available in the Supplementary Tables S7 and S8.
Discussion
This pooled analysis of individual patient data from two randomized trials investigating cetuximab use in the chemotherapy-refractory setting provides relevant information regarding the predictive and prognostic features of transverse colon as a primary tumor location in mCRC. The results indicate that, when treated with single-agent cetuximab, transverse mCRC has comparable clinical outcomes with right-sided mCRC and inferior outcomes when compared with primary tumor location on the left side. This enforces the optimal division for left- versus right-sided colorectal cancer at the splenic flexure.
mCRCs arising from different segments within the colon have distinct mutational profiles and possibly different responses to anti-EGFR treatment (8). In previous work, our group retrospectively analyzed 17 patients with tumors arising from the transverse colon and identified a signal of clinical benefit of anti-EGFR, with the caveat that all received anti-EGFR treatment in combination with a cytotoxic and in different lines of treatment (8). Similarly, another small retrospective study showed promising activity of anti-EGFR when used after the first-line setting in patients with microsatellite stable RAS/BRAF WT transverse colorectal cancer (15). On the other hand, Alig and colleagues (16) conducted a pooled analysis of individual patients known to have RAS/BRAF WT mCRC from five randomized trials dividing the colon into six subsites. Like the findings of this study, they showed no benefit of anti-EGFR in the transverse colon, with the caveat that due to the low number of patients, right flexure and true transverse colon were analyzed as a single group. Interestingly, the only observed benefit of anti-EGFR therapy was for patients with primary tumor location in the sigmoid colon and rectum.
One of the important characteristics of our pooled analysis is the presence of patients managed with BSC alone. This allowed us to investigate the prognostic feature of untreated chemotherapy-refractory transverse mCRC. As expected in this clinical scenario, OS and PFS were poor. Patients with primary tumor location in the transverse colon treated with BSC showed numerically but not statistically inferior OS and PFS when compared with the other primary tumor locations. Data from a previously published population-based study and meta-analysis showed that the prognostic utility of sidedness declines over treatment lines and that sidedness may not be informative in later-line studies (17). The reason for that is not well defined but one possible explanation is the death of patients with unfavorable characteristics early on during the disease course, resulting in a selection of individuals with better prognosis for subsequent lines of treatment (17). In this case, a significant reduction in the proportion of patients with right-sided mCRC in latter-line trials would be expected as they are known to have a worse outcome at baseline. In our pooled analysis, the distribution of the primary tumor location does not seem to be notably different from that of other studies in first or later lines (2, 18–20). Future populational analysis looking at treatment attrition rate in mCRC by sidedness could further clarify this issue.
Our work also showed that patients with left-sided mCRC achieved statistically significant and clinically meaningful benefits from the use of cetuximab as a single agent when compared with BSC in OS and PFS. These findings are concordant with the results of previous efforts such as the landmark analysis of the CALGB/SWOG 80405, CRYSTAL, and FIRE-3 trials, as well as the recent confirmatory randomized phase III clinical trial PARADIGM, further validating left-sidedness as predictive of anti-EGFR therapy benefit in a distinct population of chemotherapy-refractory patients (21–23). Most current guidelines restrict the predictive utility of sidedness to the first-line setting (4, 5). Although the data for the second and later lines are less robust and more controversial, some previous studies in this setting have shown superior outcomes for anti-EGFR treatment in left-sided mCRC as well as limited activity in right-sided mCRC (13, 24, 25) in keeping with the findings of our work. As such, we believe that clinicians have to be aware of these results when sequencing treatment with anti-EGFR antibodies in subsequent lines of treatment of mCRC, and guidelines should acknowledge the uncertainties and potential reduced efficacy for patients with right-sided disease.
Given the similar outcomes of patients with primary tumor location on the right and transverse colon, our findings resonate with previous studies that dichotomized the primary tumor location analysis of mCRC in the left and right accordingly to the approximate embryological transition point in the transverse colon (2, 3, 13, 22, 26). This moves the field forward by helping to confirm the currently identified transition point of the splenic flexure—given that many of the prior studies excluded transverse colon cancers or did not ask the question of what is the ideal transition point (2, 3, 21, 22, 26).
Our study has limitations that need to be taken under consideration when interpreting its results. First, the design consists of an exploratory retrospective pooled analysis from two randomized trials and the data are based partially on non-randomized comparisons given the inclusion of the control arm of the CCTG/AGITG CO.20 trial. As such, the results are hypothesis-generating and should not be used to establish a definitive causal inference. Second, the number of patients with primary tumors from the transverse colon is small in keeping with its relative rarity (7). This results in a potential loss of power and therefore reduced precision of the estimations and increased uncertainty of some of the findings. For instance, a non-statistically significant but potentially clinically meaningful difference of 3.8 months in OS favoring cetuximab over BSC in the transverse colon group was observed. It is not possible to establish whether this is a random finding or a signal of a gradient of anti-EGFR efficacy when moving from the right colon to the left. A similar caveat can be observed in the prognosis analysis from patients treated with BSC, where the reduced number of patients with transverse mCRC may have precluded the finding of a significantly worse outcome in this group. Future efforts could clarify this by pooling our results with other studies to increase statistical power. Finally, given that only KRAS exon 2 genotyping data were available for patients from the CCTG/AGITG CO.20 trial there will be some NRAS and BRAF mutant colon cancers included in the CO.20 data. However, we expect that this would have biased our results in the opposite direction, making it less likely for us to show statistically significant differences between groups. In addition, given the less common nature of these alterations as shown on a recent metanalysis of 275 studies from 77,104 patients with mCRC where the prevalence of BRAF and NRAS mutations were, respectively, 7.1% and 4.1%, the expected frequency in our cohort would not significantly impact our results (27). Despite these limitations, the assessment of single-agent anti-EGFR therapy in comparison with a non-interventional control arm provides a unique ability to assess primary tumor location as a biomarker without confounding from concurrent therapies and is an important contribution to the field.
Conclusion
In this pooled analysis, transverse mCRC presented comparable prognostic and predictive features with right-sided mCRC. As such, the optimal division for right versus left sidedness analysis should be after the transverse colon, confirming the accepted transition point of the splenic flexure. In keeping with previous studies of earlier lines of treatment, left-sided primary tumor location was predictive of greater cetuximab benefit and a better overall prognosis when single-agent cetuximab was used in the chemotherapy-refractory setting.
Supplementary Material
Supplementary data
This article is featured in Highlights of This Issue, p. 1071
Footnotes
Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
Authors' Disclosures
R. Goodwin reports grants from Pfizer; other support from Pfizer, Merck, Taiho, and Amgen; and grants from Ipsen outside the submitted work; R. Goodwin also reports on Ad Board for following BMS, Astra Zeneca, Ipsen, and Eisai as well as reports enrolling many patients on clinical trials. D.J. Jonker reports other support from Canadian Cancer Trials Group during the conduct of the study. T. Price reports personal fees from Servier, Amgen, and MSD outside the submitted work. J.R. Zalcberg reports leadership in ICON Group and Lipotek; stock and other ownership interests in Amarin Corporation, Biomarin, Concert Pharmaceuticals, Frequency Therapeutics, Gilead Sciences, Madrigal Pharmaceuticals, Moderna Therapeutics, Novavax, Opthea, Orphazyme, Twist Bioscience, UniQure, and Zogenix; honoraria from Deciphera, Gilead Sciences, Halozyme, Merck Serono, MSD Oncology, Specialised Therapeutics, Targovax, and Viatris; a consulting or advisory role in 1Globe Health Institute, Alloplex Biotherapeutics Inc, Center for Emerging & Neglected Diseases (CEND), Deciphera, FivepHusion, Genor BioPharma, Lisata, Merck Sharp & Dohme, NOUS Group, Novotech, Revolution Medicines, and Specialised Therapeutics; and research funding from AstraZeneca (Inst), Bristol Myers Squibb (Inst), Eisai (Inst), Ipsen (Inst), IQvia (Inst), Medtronic (Inst), MSD Oncology (Inst), Mylan (Inst), and Pfizer (Inst). C.S. Karapetis reports personal fees from Amgen, Merck, Roche, Servier, AstraZeneca, MSD, Gilead, and BeiGene outside the submitted work. L. Siu reports grants from Bristol Myers Squibb during the conduct of the study; grants from Merck, Pfizer, AstraZeneca, Roche, GlaxoSmithKline, Voronoi, Arvinas, Navire, Relay, Daiichi Sankyo, Amgen, Marengo, Medicenna, Tubulis, LTZ Therapeutics, and Pangea; and personal fees from Novartis, Pfizer, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, AstraZeneca, Merck, Bayer, AbbVie, Amgen, Symphogen, Mirati, BioNTech, 23andMe, EMD Serono, Agios, and Treadwell Therapeutics outside the submitted work. J. Simes reports grants from Merck during the conduct of the study as well as grants from BMS, Bayer, Roche, Pfizer, and Amgen outside the submitted work. J.M. Loree reports grants from Bristol Myers Squibb during the conduct of the study; grants and personal fees from Amgen and Bayer; personal fees from Eisai, Novartis, Taiho, and AstraZeneca; and grants from SAGA Diagnostics and Personalis outside the submitted work. No disclosures were reported by the other authors.
Authors' Contributions
J.P. Solar Vasconcelos: Conceptualization, data curation, formal analysis, visualization, methodology, writing–original draft, project administration, writing–review and editing. N. Chen: Resources, data curation, software, formal analysis, validation, methodology, writing–review and editing. E. Titmuss: Resources, data curation, validation, visualization, writing–review and editing. D. Tu: Resources, data curation, formal analysis, supervision, validation, investigation, methodology, writing–review and editing. S.Y. Brule: Resources, investigation, methodology, writing–review and editing. R. Goodwin: Resources, investigation, methodology, writing–review and editing. D.J. Jonker: Resources, investigation, methodology, writing–review and editing. T. Price: Resources, investigation, methodology, writing–review and editing. J.R. Zalcberg: Resources, investigation, methodology, writing–review and editing. M.J. Moore: Resources, investigation, methodology, writing–review and editing. C.S. Karapetis: Resources, investigation, methodology, writing–review and editing. L. Siu: Resources, investigation, methodology, writing–review and editing. J. Shapiro: Resources, investigation, methodology, writing–review and editing. J. Simes: Resources, investigation, methodology, writing–review and editing. S. Gill: Resources, investigation, methodology, writing–review and editing. C.J. O'Callaghan: Resources, data curation, investigation, methodology, writing–review and editing. J.M. Loree: Conceptualization, resources, formal analysis, supervision, funding acquisition, visualization, methodology, writing–original draft, project administration, writing–review and editing.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary data
Data Availability Statement
Data used for this analysis were part of a clinical trial and are housed at the CCTG. An investigator who wishes to analyze data from this work must make a formal request to the CCTG using the specific form available at https://www.ctg.queensu.ca/docs/public/policies/TMG-FRM-0199-Application-for-Data-Sharing-V2-2017Feb23.docx. The application must be submitted to datasharing@ctg.queensu.ca. CCTG will review requests according to the institution's Data Sharing and Access Policy available at https://www.ctg.queensu.ca/docs/public/policies/DataSharingandAccessPolicy.pdf.