Elsevier

Clinical Colorectal Cancer

Volume 12, Issue 4, December 2013, Pages 280-286
Clinical Colorectal Cancer

Original study
Prognostic Value of the Combination of Circulating Tumor Cells Plus KRAS in Patients With Metastatic Colorectal Cancer Treated With Chemotherapy Plus Bevacizumab

https://doi.org/10.1016/j.clcc.2013.06.001Get rights and content

Abstract

Objective

Circulating tumor cells (CTCs) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) status were identified as prognostic factors for progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer treated with chemotherapy and bevacizumab in analyses of the MACRO (Maintenance Treatment in Advanced Colorectal Cancer) trial. In this post hoc analysis of the MACRO trial, the potential additive effect of these 2 factors on patient outcomes was explored.

Methods

A total of 158 of the 480 patients involved in the MACRO trial were included in the biological marker substudy. CTC isolation and enumeration were centralized and performed using the CellSearch System (Veridex LLC, Raritan, NJ) in 7.5 mL of whole blood. Evaluation of KRAS status was performed retrospectively by the standard method used at each center. PFS and OS were analyzed by the Kaplan–Meier method according to CTC count and KRAS status.

Results

Patients with < 3 CTC per 7.5 mL blood at baseline and KRAS wild-type tumors had a median PFS of 14.2 months compared with 6.2 months in patients with ≥ 3 CTCs and KRAS mutated tumors (P < .0001; hazard ratio, 3.0; 95% confidence interval, 1.8-5.2). Similar findings were observed for OS (28.9 and 13.7 months, respectively, P = .0004; hazard ratio 2.8; 95% confidence interval, 1.6-4.9). Multivariate analyses showed that CTC count ≥ 3 and KRAS status were the only independent prognostic factors for both PFS and OS.

Conclusions

This post hoc analysis showed that CTC count and KRAS status were independent prognostic factors for outcomes in patients with metastatic colorectal cancer treated with bevacizumab ± chemotherapy. These factors should be taken into account in the design of future phase III trials.

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,

References (12)

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