The Association of KRAS Mutation With Primary Tumor Location and Survival in Patients Undergoing Resection of Colorectal Cancers and Synchronous Liver Metastases

Niccolo Allievi; Paolo Goffredo; Alan F. Utria; Michele Pisano; Elia Poiasina; Alessandro Lucianetti; Paige Zhou; Imran Hassan

Disclosures

Chin Clin Oncol. 2019;8(5) 

In This Article

Abstract and Introduction

Abstract

Background: Recent evidence suggests that a mutation in the KRAS gene has a significant impact on the clinical behavior and prognosis of patients with metastatic colorectal cancer. The KRAS mutation (m-KRAS) has been associated with decreased survival among patient undergoing treatment with a curative and palliative intent. This is believed to be secondary to a reduced response to anti-EGFR chemotherapy agents and a more intrinsically aggressive biology. The aims of this study were to identify risk factors for m-KRAS in patients with curatively resected colorectal cancer and synchronous liver metastases and to assess its association with disease-specific survival (DSS).

Methods: The Surveillance, Epidemiology and End Results (SEER) Database was surveyed for patients undergoing resection of colorectal cancer and synchronous liver metastases from 2010 to 2015.

Results: A total of 806 patients were included, of which 40% had m-KRAS. Right-sided primary lesions (OR 2.56, 95% CI: 1.90–3.44, P<0.001) and African-American ethnicity (OR 1.58, 95% CI: 1.05–2.40, P=0.03) were independently associated with m-KRAS on multivariable analysis. Compared to wild-type KRAS (wt-KRAS), m-KRAS was associated with decreased 3- and 5-year DSS (59% vs. 50% and 29% vs. 21%, respectively, P=0.024). After adjusting for confounders, a decreased DSS was observed in patients with right-sided lesions (HR 1.68, 95% CI: 1.32–2.12, P<0.001), while m-KRAS was associated with a trend toward decreased DSS (HR 1.15, 95% CI: 0.91–1.46, P=0.24).

Conclusions: In patients undergoing surgical resection of colorectal cancer and synchronous liver metastases, m-KRAS was associated with right-sided lesions and African-American ethnicity. Compared to wt-KRAS, m-KRAS was associated with a reduced DSS. Additionally, right-sided lesions were an independent negative prognostic factor for DSS.

Introduction

Colorectal cancer has an annual global incidence of 1.65 million cases.[1] At the time of diagnosis, up to 25% of patients already have liver metastases and an additional 25% will develop hepatic metastases during the course of their disease.[2] The median overall survival (OS) for patients with metastatic colorectal cancer that is treated with a palliative intent with multi-agent chemotherapy is approximately 30 months.[3] Although surgical indications and timing of resections in colorectal cancer and liver metastases are still a matter of debate, hepatic metastasectomy with resection of the primary tumor remains the only potentially curative treatment.[3–5] Mutations of the Kirsten Rat Sarcoma viral antigen homolog (KRAS) gene are found in about 40% of patients[6] with metastatic colorectal cancer. The determination of KRAS status is a relevant prognostic characteristic in these patients, as mutated KRAS (m-KRAS) reflects a poor response to anti-EGFR immunotherapy[3] and is associated with an increased cumulative incidence of metastatic disease as well as an adverse prognosis.[6–8]

In recent years, the molecular pathways of oncogenesis in colorectal cancer and the intrinsic differences between right-sided and left-sided lesions have been investigated. Two meta-analyses[6,9] of institutional studies evaluating the prognostic significance of m-KRAS in patients treated with surgical resection of primary colorectal cancer and synchronous hepatic metastases, observed that m-KRAS was associated with decreased OS and disease-free survival (DFS). More recently, a study[10] using the National Cancer Database (NCDB) confirmed the negative prognostic impact of m-KRAS in colorectal cancer with synchronous liver metastases and demonstrated that m-KRAS was associated with right-sided lesions and African-American ethnicity. Two main limitations of the NCDB are the lack of data on disease-specific survival (DSS) and the limited generalizability to the United States (U.S.) population as this database only collects data from the Commission on Cancer (CoC) affiliated Hospitals.

Therefore, aim of this study was to analyze the impact of m-KRAS on DSS as well as its associated risk factors in patients undergoing resection of colorectal cancer and synchronous liver metastases in a U.S. population-based cohort utilizing the Surveillance, Epidemiology and End Results (SEER) database.

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