Background
Colorectal cancer (CRC) represents 10% of cancer incidence globally, and it is the fourth leading cause of cancer-related deaths worldwide. South Korea has one of the highest incidences of CRC in the world [
1]. The survival of metastatic CRC has gradually been improved with advancements in medical therapy, which include not only the development of new drugs but also the discovery of predictive biomarkers.
Previous studies have suggested that primary tumor location (PTL) may be a surrogate for tumor biology that may affect treatment outcomes [
2,
3]. In terms of embryology and molecular carcinogenesis, CRC can be divided into distinct disease entities according to the PTL; the right side of the colon, including the cecum, the ascending colon, and the transverse colon is derived from the midgut, while the remaining parts of the colon and rectum come from the hindgut [
2]. Tumors of the right colon (RC) tend to more frequently exhibit a poorly differentiated histology,
BRAF mutation, a hypermethylated phenotype, and microsatellite instability (MSI), while
c-MYC expression occurs more commonly in tumors of left colon and rectum(LC) than in those in the RC [
2,
4,
5].
The prognostic and predictive implications of PTL have been addressed in numerous studies, but there is no clear consensus on the role of PTL in treatment decisions. Generally, RC cancer is associated with poorer survival compared to LC cancer [
6,
7], and recent evidences have shown that patients with RC cancer may respond poorly to anti-epidermal growth factor receptor (EGFR) antibodies, such as cetuximab or panitumumab, which are the backbone of treatment for metastatic CRC [
8,
9]. However, the predictive value of PTL should be analyzed in consideration of
RAS mutation,the most powerful predictor of response of anti-EGFR antibodies [
10,
11].
In our current study, we investigated the association between PTL and clinical outcomes in RAS wild-type metastatic CRC patients who received cetuximab as a salvage treatment.
Discussion
We observed in our current analysis that RC was associated with poor OS and PFS outcomes in RAS wild-type metastatic CRC patients treated with cetuximab as salvage therapy. OS was still poorer in the RC group when BRAF mutants were excluded. These findings suggest that PTL may be a factor in deciding on salvage chemotherapy with cetuximab in RAS wild-type patients.
Several studies have suggested that clinical benefits from anti-EGFR treatment may differ according to PTL. In data from a phase II trial of cetuximab-based chemotherapy, LC cancer was found to be associated with significantly longer PFS and OS than RC cancer in
KRAS exon 2 wild-type patients [
9]. Similarly, the NCIC CO.17 trial, a phase III study that compared cetuximab with the best supportive care in refractory metastatic CRC, showed that patients with LC cancer had benefit from cetuximab in terms of PFS, but those with RC cancer did not in
KRAS exon 2 wild-type population [
8]. Post-hoc analysis of the CALGB 80405 trial, a phase III trial that compared cetuximab and bevacizumab in front-line settings, also showed that cetuximab-treated
KRAS exon 2 wild-type patients with RC cancer had markedly poorer survival than those with LC cancer (16.7 months in RC and 36.0 in LC,
p < 0.0001) [
15]. All of these analyses were performed in
KRAS exon 2 wild-type patients, so the possibility that
RAS mutations other than
KRAS exon 2 may have contributed to the relatively poorer outcome in RC cancer in these studies could not be excluded. Recent studies for
RAS wild-type subgroup of randomized trials which compared anti-EGFR treatment with chemotherapy +/− bevacizumab addressed this issue, by showing OS, PFS and objective response rate with anti-EGFR treatment was poorer in RC cancer than in LC cancer [
16,
17].
A strength of our present study is that we excluded all
RAS mutants from our analysis using a highly sensitive high-throughput method, the SequenomMassARRAY system. Our previous study showed that this method was more helpful for selecting candidates for cetuximab treatment than less-sensitive Sanger sequencing [
14]. This means that the poorer outcomes with anti-EGFR treatment in RC cancer than in LC cancer were maintained even after all
RAS mutants with low-allele frequency were excluded.
We further found in our analysis that
BRAF and
PIK3CA mutants were enriched in RC cancer, as shown in previous studies [
5], which may partly explain the different therapeutic effects of anti-EGFR according to the PTL. However, the difference in OS was still retained, even after excluding
BRAF mutants. Although we should be careful interpreting this subset analysis due to small sample size and relatively low proportion of RC (in
RAS and
BRAF wild-type subgroup,
n = 14 for RC compared to
n = 139 in LC), PTL may be associated with poor prognostic biological features other than
RAS or
BRAF mutation. The prognostic impact of PTL irrespective of
RAS and
BRAF mutation was also suggested by subgroup analyses of 3 randomized trials on anti-EGFR vs. chemotherapy +/− bevacizumab (FIRE3, PRIME, and PEAK), which showed poor prognosis of RC in patients with
RAS/BRAF wild-type metastatic CRC [
18,
19].
Recent studies have suggested that biologic features of RC cancer that may explain the poor prognosis or resistance to anti-EGFR treatment. A translational study in PETACC-3 trial reported that
BRAF-mutant-like tumors, which were
BRAF wild-type but shared similar gene expression profile with
BRAF mutant tumors, were enriched in RC and had poor prognosis [
20]. The abundant expression of epiregulin and amphiregulin, which are known to be predictors of good response to anti-EGFR treatment, was shown to be more prevalent in LC cancer than in RC cancer [
21]. On the other hand, MiR-31-3p, a poor predictor for anti-EGFR response, was shown to be overexpressed more frequently in RC cancer than in LC cancer [
22]. In addition, Consensus Molecular Subtype (CMS)1, which is associated with a poorer survival rate after relapse, is more common in RC [
23]. However, there might be more unknown features of biologic relevance of PTL, since recent translational study from CALGB 80405 showed PTL was independent prognostic factor when adjusted to
BRAF mutation, MSI and CMS [
24].
It is uncertain whether PTL is just a negative prognostic indicator reflecting tumor biology irrespective of treatment or is a genuine predictive marker of the response to anti-EGFR treatment. In CALGB 80405 trial, the OS was better in LC than in RC cancer in bevacizumab-treated patients, although the interaction between the PTL and the treatment (cetuximab versus bevacizumab) was significant (
p = 0.005) [
15]. This prognostic as well as predictive impact of PTL was consistently shown by the pooled analysis of 6 randomized trials (5 in first-line and 1 in second-line setting) on anti-EGFR in terms of OS and PFS although the interaction between sidedness and treatment effect was not always significant in all of the trials [
16]. However, in NCIC CO.17 study, a randomized study in chemo-refractory setting, PFS and OS in the best supportive care arm was not affected by PTL, implying that it was not prognostic, but only predictive of PFS benefit from cetuximab (interaction
p = 0.002) [
8]. To date, collective evidences are suggesting high likelihood of no clinical benefit from anti-EGFR in RC cancer, at least in first-line setting, and possibly in later-line treatment. PTL seems to be also prognostic for metastatic CRC in first-line setting, but unclear in chemo-refractory patients.
In our current study, PTL showed a significant relationship with OS in multivariable analysis, but not in PFS; the prognostic impact of PTL seems to be more prominent than the predictive role in these results. However, the limitations of our present analysis hamper such an interpretation; the sample size of our patients with RC cancer was too small and we did not include a control group without cetuximab. Thus, it was difficult to conclude whether PTL is purely prognostic or predictive from our present study.
The characteristics of our study patients were comparable to those of previous reports, namely frequent poorly differentiated histology and peritoneal seeding, as well as the mutation profile previously mentioned [
2,
6,
25]. However, the proportion of RC patients in our study population was relatively too small (13.5%, 23/170) to have adequate power of comparison according to PTL. This probably resides in the low proportion of proximal colon cancer in Korean populations: 18.6% in male and 24.2% in female according to 2009 statistics from national registry [
26]. This is consistent with the racial difference in subsite-specific CRC incidence in United States; Asia-Pacific islanders had lowest proportion of proximal colon cancer (28% in male, 34% in female) compared to other racial groups (usually ≥40%) [
27]. The association of racial difference in subsite distribution and prognosis according to treatment warrants further investigation.
Our current study had other limitations, including its retrospective nature, the heterogeneous regimen of cetuximab, insufficient information on MSI, and the lack of biological information other than hotspot mutation profiles, such as gene expression or the CpG island methylation profile.