Original studyPrognostic Value of the Combination of Circulating Tumor Cells Plus KRAS in Patients With Metastatic Colorectal Cancer Treated With Chemotherapy Plus Bevacizumab
Introduction
The CellSearch System (Veridex LLC, Raritan, NJ) has been approved by the US Food and Drug Administration for the detection and enumeration of circulating tumor cells (CTCs) in the peripheral blood of patients with breast, prostate, and colorectal cancer. This semiautomated immunomagnetic method for quantification of CTCs has been validated by 3 centers in the United States and Europe.1 A threshold of at least 3 CTCs per 7.5 mL blood was chosen and validated to stratify patients into favorable and unfavorable prognostic groups in a prospective multicenter study conducted in 430 patients with metastatic colorectal cancer.2 In a prospective trial in patients treated with first-line chemotherapy plus bevacizumab, CTC count at baseline appeared to be the strongest predictor of progression-free survival (PFS) and overall survival (OS).3 Similar results were obtained by our group in a recent phase III trial in which patients with metastatic colorectal cancer were treated with first-line oxaliplatin, capecitabine, and bevacizumab.4
The prognostic role of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) status in patients with metastatic colorectal cancer receiving bevacizumab-based treatment is controversial. A subgroup analysis according to KRAS status of a phase III trial of bevacizumab plus chemotherapy in patients with metastatic colorectal cancer was suggestive that final outcomes were worse in patients with KRAS mutations than in patients with wild-type tumors.5 Recent results observed by our group in a subgroup analysis of the MACRO (Maintenance Treatment in Advanced Colorectal Cancer) trial are in line with this finding.6 In contrast, in several other studies,7, 8, 9 KRAS status did not influence PFS or OS in patients receiving bevacizumab.
The aim of this retrospective analysis of the MACRO trial is to evaluate the prognostic role of the combination of baseline CTC count and KRAS status in patients receiving oxaliplatin, capecitabine, and bevacizumab as first-line therapy for metastatic colorectal cancer.
Section snippets
Materials and Methods
Full methodological details of the MACRO trial have been published.10
KRAS Mutation Analysis
Evaluation of KRAS status in tumor samples was performed retrospectively. Because KRAS analysis is standard practice in Spain, sample analysis was performed at the treating center or centrally using the TheraScreen DxS KRAS Mutation Kits, (Manchester, UK). Participating centers sent KRAS status findings to the data-collection center. Data were obtained on KRAS status (ie, wild-type or mutation), the type of mutation found (ie, 12 Ala, 12 Arg, 12 Asp, 12 Cys, 12 Ser, 12 Val, or 13 Asp), and the
Results
The characteristics of patients included in this subanalysis are shown in Table 1. Patients in the biological marker substudy received XELOX plus bevacizumab (n = 79) or XELOX plus bevacizumab followed by single-agent bevacizumab (n = 79). Some imbalances in potential clinical prognostic factors were found. Prior exposure to adjuvant chemotherapy was more common in group 1 (< 3 CTCs and KRAS wild-type) and group 2 (< 3 CTCs and KRAS mutated), and prior adjuvant radiotherapy was more common in
Discussion
Both baseline CTC count and KRAS mutation status have been shown to be prognostic factors for PFS and OS in patients with metastatic colorectal cancer receiving first-line chemotherapy plus bevacizumab.4, 6 In this post hoc analysis, we found that both factors are independent prognostic factors for patient outcomes and may have an additive prognostic role to select a subgroup of patients with poor outcomes when treated with first-line chemotherapy plus bevacizumab. Median PFS and OS times for
Conclusions
This post hoc analysis of the MACRO trial showed that baseline CTC count and KRAS status are independent prognostic factors that can be used in combination to select different subgroups of patients (ie, low, intermediate, and high risk). These factors should be taken into account in the design of future phase III trials of bevacizumab-containing therapy in patients with metastatic colon cancer. Furthermore, new therapeutic approaches may be carried out in patient populations selected using
Acknowledgments
The authors thank the following physicians for their cooperation and support, and for caring for the patients in this study: E. Aranda, A. Gómez (H. Reina Sofía); E. Díaz Rubio, J. Sastre (H. Universitario Clínico San Carlos); F. Rivera (H. Marqués de Valdecilla); B. Massutí, A. Yuste (H. General Universitario de Alicante); M. Valladares (C. H. Universitario La Coruña); A. Abad (ICO. H. Germans Trias i Pujol ); M. Gallén (H. del Mar); M. Benavides (H. Universitario Carlos Haya); E. Marcuello,
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