Introduction
The idea of personalized medicine was introduced to the treatment of metastatic colorectal cancer (mCRC) when
KRAS codon 12/13 mutations were identified as negative predictors of anti-EGFR-antibody (EGFR-mAB) treatment. Consequently, only patients with
KRAS codon 12/13 wild-type tumors were subjected to cetuximab or panitumumab treatment (Douillard et al.
2013; Huang et al.
2012; Modest et al.
2012; Douillard et al.
2010; Bokemeyer et al.
2011; Amado et al.
2008). This
KRAS codon 12/13 wild-type population already excluded about 40 % of all patients and was associated with improved response rates (objective response rates, ORRs), progression-free survival (PFS) and overall survival (OS) in patients receiving EGFR-mABs. However, ORR in clinical trials investigating EGFR-based first-line regimens was usually <60 %, indicating that
KRAS codon 12/13 wild-type alone was not a sufficient condition to predict response (Douillard et al.
2013; Modest et al.
2012; Van Cutsem et al.
2011; De Roock et al.
2010; Stintzing et al.
2009). The identification of additional negative predictors such as
KRAS exon 3/4 and
NRAS exon 2–4 mutations created a new target population for EGFR-mABs: patients with RAS wild-type tumors. This population comprises about 50 % of all patients with mCRC with a benefit in median OS following EGFR-targeted first-line therapy of 5–7 months (Douillard et al.
2013; Stintzing et al.
2009).
Taking into account that even RAS wild-type tumors potentially do not define the perfect marker for response to EGFR-mABs, additional biomarkers are needed. This question was recently addressed by retrospective evaluations of patients receiving cetuximab treatment in further treatment lines. The efficacy of cetuximab was determined to be modulated by the location of the primary tumor (Missiaglia et al.
2013; Brule et al.
2013). Due to this initial evidence, the question was raised whether the location of the primary tumor in colorectal cancer can serve as a prognostic marker and potentially as a predictive marker for treatment with EGFR-mABs. To our knowledge, the effect of primary tumor location on outcome has not been shown in a mCRC study population receiving first-line treatment with cetuximab.
The AIO KRK-0104 trial randomized patients to CAPIRI plus cetuximab or CAPOX plus cetuximab. With reference to this design, we hypothesized that primary tumor location of the left colon might have a favorable prognostic effect in patients with KRAS wild-type tumors, but not in patients with KRAS mutant tumors.
Discussion
Personalized treatment of mCRC patients is entering daily routine in clinical practice. The more tumor sub-classifications based on molecular markers are defined, the higher the chance is to identify positive and negative predictors and consequently to specify different strategies of therapy. Clinical data have proven that mutant RAS genes are negative predictive biomarkers and that patients with a
KRAS/NRAS mutation do not benefit from an EGFR-mAB-based therapy (De Roock et al.
2010; Peeters et al.
2013a,
b; Andre et al.
2013). Therefore, mutations of
KRAS and
NRAS represent an established negative predictor of EGFR-mAB efficacy. The role of
BRAF in first-line treatment of mCRC is described as a negative prognostic marker, but not as a predictive marker in terms of EGFR-mAB therapy (Douillard et al.
2013). Recently, it has been suggested that, in addition to RAS mutations, the primary tumor location might play a crucial role for efficacy of EGFR-mABs (Douillard et al.
2013; Missiaglia et al.
2013).
For this reason, we hypothesized that in the AIO KRK-0104 trial primary tumor location in the left colon might have a favorable prognostic effect in patients with KRAS wild-type tumors, but not in patients with KRAS mutant tumors when receiving cetuximab-based first-line therapy. In fact, OS and PFS differed significantly when comparing left- to right-sided tumors. This effect was driven by patients with KRAS codon 12/13 wild-type tumors and seemed also present in those patients that presented with KRAS codon 12/13 wild-type but BRAF V600E mutant tumors. By contrast, in patients with KRAS codon 12/13 mutant tumors, the primary tumor location was not associated with significant differences in terms of OS or PFS. This interaction of KRAS mutation and primary tumor location was found to be significant for both OS and PFS. No significant impact of primary tumor location on response rates was observed in this study. Taking the difference in patients with KRAS wild-type tumors into account (64 % vs. 43 % in patients with left-sided vs right-sided primary tumor), this could be interpreted as a consequence of missing sample size for this endpoint.
Our results are supported by a recent analysis of the NCIC CTG CO.17 trial (that investigated cetuximab plus best supportive care (BSC) versus BSC alone), which reported less striking cetuximab-induced effects in patients with
KRAS codon 12/13 wild-type, right-sided tumors as compared with patients bearing a left-sided tumor (Brule et al.
2013). A similar observation was reported by Missiaglia and colleagues who observed a longer PFS in refractory patients that received cetuximab treatment if the primary tumor was left-sided as compared to right-sided tumors (Missiaglia et al.
2013).
As described above, we grouped patients in left-sided versus right-sided tumors, which included tumors from cecum to the distal part of the transverse colon. This distinction corresponds to the midgut versus hindgut definition and is modified counting the total colon transversum as right-sided colon. Nevertheless, the strict separation of different tumor locations is questioned by the “continuum hypothesis,” which postulates that molecular features of the tumor gradually change along bowel subsides, rather than change abruptly at splenic flexure (Yamauchi et al.
2012a,
b). As shown in Figs.
1a and
2a, a trend toward specific OS and PFS could possibly be derived from the exact primary tumor location of the colon, but possibly not according to the physiological course of the colon. Clearly, our data concerning this issue are limited by sample size.
As samples from the AIO KRK-0104 trial were only tested for
KRAS exon 2 codon 12/13 mutations, but not for
KRAS exon 3, 4 or
NRAS mutations, our data might contain a bias of approximately 10 % hidden mutations that we cannot identify due to lacking tumor material. In our cohort, the impact of left- versus right-sided tumors was specifically strong in
BRAF mutant tumors. This finding might be explainable by sample size and MSI/MSS status that is unknown for the tumors of AIO KRK-0104 trial cohort. It might have been suspected that the whole side effect might be influenced by
BRAF/MSI/MSS status, since
BRAF mutations are known to be more frequent in right-sided colorectal cancer (Pai et al.
2012; Popovici et al.
2013). However, even after excluding
BRAF mutant tumors from the
KRAS codon 12/13 wild-type cohort, the strong prognostic effect of left-sided primary tumors seemed still present (hazard ratio for OS: 0.60). It might be concluded that in mCRC
BRAF mutation interacts in the left- versus right-sided tumor story, but is not the only reason for the observed differences.
Our data are limited by several aspects. As discussed above, we distinguished between KRAS mutant and non-mutant only and did not take other RAS mutations into account. Furthermore, this study only consists of a rather small population that might lead to biases, especially in the KRAS mutant cohort. Furthermore, treatment differences between oxaliplatin- and irinotecan-treated patients could not be excluded.
In conclusion, our data correspond favorably with other publications investigating EGFR-mAB use and primary tumor location in mCRC. The interaction of primary tumor location and
KRAS mutations suggests that primary tumor location might be an additional biomarker for EGFR-mABs. Corresponding pathological findings to explain this phenomenon are still lacking and could be more complex than RAS mutations (Missiaglia et al.
2013; Maus et al.
2013). Data from randomized phase III trials such as CRYSTAL, PRIME and FIRE 3 are necessary to draw definite conclusions concerning the restriction of EGFR-mAbs to patients with RAS wild-type left-sided mCRC.
Acknowledgments
We thank all of the patients and their families, the participating centers of this trial and the entire medical staff who contributed to patient care and data collection. We also thank Matthias Wolff for expert secretarial help and organization. S. Stintzing is currently granted a postdoctoral fellowship by the German Cancer Aid (Mildred Scheel Foundation). The AIO KRK-0104 trial was supported by Merck Serono, Roche and Pfizer.