KRAS mutation in patients undergoing hepatic resection for colorectal liver metastasis: A biomarker of cancer biology or a byproduct of patient selection?

Patients with colorectal cancer (CRC) have experienced remarkable progress in a range of surgical and oncologic management strategies over the past decades, with a corresponding improvement in survival. 1 As a consequence, the course of disease has changed both in terms of recurrence patterns and long-term outcomes, as evidenced from national cohort studies. 2,3 The majority of patients with CRC will develop disease recurrence within the first 2 years, and >50% of these individuals will develop a single-organ recurrence, of whom less than one-third will be offered metastatic surgery. The liver is the most frequent site of disease recurrence. As resectability criteria have changed over the past 20 years, with changes in preoperative techniques (eg, the use of forced liver hypertrophy and staged resection procedures) noted among others, 4 it has both increased the number of surgical resections and also improved outcomes. Indeed, improvements in patient selection and surgical techniques have resulted in improved outcomes after hepatic resection for patients with a colorectal liver metastasis (CRLM), with 5-year and 10-year overall survival rates reported to be as high as 40% and 20%, respectivley. 5 However, the selection of operability and resectability remains a controversial topic and continues to be based largely on subjective judgment with considerable variation noted among clinicians, even those deemed to be leading experts in the field. 6 Furthermore, metastasis detection and patient selection have improved with better imaging modalities, including contrast-enhanced ultrasonography, computed tomography, and positron emission tomography scanning. However, even imaging has its limitations, including the problem of “disappearing liver metastasis,” which are increasingly noted after neoadjuvant chemotherapy. 7 Furthermore, the practice of routine perioperative chemotherapy differs between continents and remains an area of debate, with results from preoperative chemotherapy trials demonstrating only a modest increase in survival at the subsequent cost of increased surgical morbidity. Even among patients with a complete pathological response, long-term remission occurs in only 20% to 50% of patients treated with systemic therapy. Consequently, and despite the many advances, the majority of patients who undergo hepatic resection for CRLMs experience disease recurrence and die of the disease. Thus, understanding the underlying biology, both for improved prediction and for defining new therapeutic targets, becomes important. CRC progression follows distinct pathways of genetic instability with defined clinical outcomes and associated molecular features. Proposed clinical-morphological-genetic classifications for classifying patients into distinct prognostic groups have not replaced TNM staging for prognosis; in patients with primary resectable disease, lymph node status remains the most prognostic feature, despite its controversial standing. However, some genetic features have appeared as potential predictive and prognostic factors, including KRAS mutation status. KRAS is an oncogene located downstream of the epidermal growth factor receptor (EGFR), which is the target for anti-EGFR treatment, such as cetuximab. It is interesting to note that patients with KRAS wild-type status respond best to anti-EGFR treatment. KRAS is known as an early mutated event in CRC and is found in approximately 15% of patients with advanced adenomas and in 35% to 45% of patients with primary CRC (TNM stages I-III). 8,9 The frequency of KRAS mutations in patients with a CRLM