Should Patient Selection for Colorectal Cancer Metastasectomy Involve Molecular Analysis?

Cathy Eng, MD, University of Texas MD Anderson Cancer Center, and Michael Choti, MD, Banner MD Anderson Cancer Center, offered varying opinions regarding whether molecular characteristics play a role in selecting patients with colorectal cancer for metastasectomy.

Their arguments were presented at the 2018 Great Debates and Updates in Gastrointestinal Cancers meeting (March 23, 2018; New York, NY).

Dr Eng was first to argue that molecular mutations—including RAS and BRAF—should be considered in selecting patients for metastasectomy. She began her remarks by disclosing that she is a medical oncologist, not a surgeon, and continued by identifying the objectives of therapy: palliative treatment, identifying borderline resectable patients, and always recommending surgical resection for those patients that are eligible.

Dr Eng presented data from the most recent research on the role of molecular markers in metastatic resection. A University of Texas MD Anderson Cancer Center study investigated 1151 patients from 2005 through 2015, of whom 401 underwent gene panel testing in the liver (43%), primary tumor (36%), and lung (6%). Researchers found that 95.5% of patients (n = 383) presented with at least one genetic mutation in their tumors, of which TP53 (65.6%), KRAS (48.1%), and APC (47.4%) were the most common.

The 5-year overall survival (OS) was 61.6% for patients with RAS wild-type disease compared with 34.1% for those with RAS-mutated disease. However, for p53 wild-type and mutated disease, there wasn’t a statistically significant difference in median OS. When combining the data for co-mutations, patients who had p53 and RAS mutations had a median survival of 41 months vs 62 months for those with p53 and RAS wild-type. The 5-year OS was 26% vs 55.7%, respectively (P = .003).   

Dr Eng also detailed a Japanese study that reported after a median follow-up of 84.1 months, the 4-year OS rate was 65.6% for mCRC with RAS mutation compared with 81.3% for mCRC with wild-type RAS.

In her concluding remarks, Dr Eng stressed that mutation analysis appears to have an impact on outcome for liver resection patients, but limited data exist for the role of mutation analysis in other metastatic disease sites. She reiterated that all patients should be considered for resection if their disease is surgically resectable, and mutation analysis should always be factored in when considering a borderline resectable patients.

Related: Colorectal Cancer Tumor Location Correlates With Outcomes

Next to speak was Dr Choti, who argued that molecular characteristics should not play a role in selecting patients with colorectal cancer for metastasectomy. He began his argument by defining resectability as an instance when resection of all known disease can be safely achieved. However, borderline resectable disease requires that all initial disease can be removed with “some tricks” (ie, staged resections, preoperative PVE, resection plus ablation). Additionally, Dr Choti noted that borderline resectable disease can be potentially convertible with tumor size reduction.

Dr Choti listed conventional clinicopathologic prognostic factors, and then posed the question, “Can we identify molecular biomarkers which can help characterize biologic behavior and refine our prognostic assessment?”

After sharing a multitude of clinical studies that assessed the incidence and prognostic impact of mutations (ie, KRAS, BRAF) in patients undergoing livery surgery for colorectal metastases, as well as outcomes associated with surgical procedures, Dr Choti cautioned the audience to recall various moments in recent history when gene mutations were generally believed to have a major prognostic impact on patients undergoing resection for colorectal liver metastasis. He cited such studies as “SMAD4 gene mutation predicts poor prognosis in patients undergoing resection for colorectal liver metastasis” (2018), “APC and PIK3CA Mutational Cooperatively Predicts Pathologic Response and Survival in Patients Undergoing Resection for Colorectal Liver Metastasis” (2017), and “Blood neutrophil-to-lymphocyte ratio predicts survival in patients with colorectal liver metastases treated with systemic chemotherapy” (2009).

Dr Choti remarked that tumor biology, rather than surgical technique, dictates prognosis in colorectal cancer liver metastasis, but the data shows that biomarkers such as RAS are not ready to replace the existing clinical risk scores for resectable colorectal cancer liver metastasis. Though BRAF may be highly prognostic, it is uncommon with colorectal cancer liver metastasis.

“No molecular marker has been shown to be better at predicting prognosis than traditional clinicopathologic factors such as disease-free interval and node status,” he said.

Prognostic factors do not define resectability, he concluded. The observed differences in survival with RAS-mutation disease should not preclude or impact the recommendation for metastasectomy in a resectable patient, and while molecular biomarkers may play a role in the selection of chemotherapeutic regimens or sequencing of chemotherapy and liver resection, they should not play a role in selecting patients for metastasectomy, he asserted.—Zachary Bessette