1. Fuerst, Mark L.

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NEW YORK-Molecular characteristics do not play a large role in selecting patients for metastasectomy, although they may be taken into account for borderline patients, said experts at a recent debate at the Great Debates & Updates in Gastrointestinal Malignancies, held March 23-24.


Molecular Characteristics Play a Role

Molecular characteristics, including RAS and BRAF mutation status, should determine the role of metastasectomy, said Cathy Eng, MD, Professor in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston.


MD Anderson studies show better survival for patients with wild-type RAS. She noted a recent study that assessed the impact of somatic gene mutations on survival among patients undergoing resection of colorectal liver metastases (Ann Surg 2017; doi:10.1097/SLA.0000000000002450). Next-generation sequencing of 50 cancer-related genes was performed from primary tumors and/or liver metastases in 401 patients undergoing colorectal liver metastases resection.


The most frequent somatic gene mutations were TP53 (65.6%) followed by KRAS (48.1%). Double mutation in RAS/TP53 was identified in nearly one-third (31.4%) of patients and was correlated with primary tumor location in the right colon.


A multivariable analysis found RAS/TP53 double mutation was an independent predictor of shorter overall survival. The negative prognostic effects of RAS and TP53 mutations were limited to tumors harboring mutations in both genes.


These preliminary analyses suggest surgical resection of liver metastases should be carefully considered in this subset of patients, she said. In conclusion, Eng noted: "Mutational analysis appears to have impact on outcome for liver resection patients. Do these findings hold true for other sites of disease? We have limited data. A patient should always be considered for resection if surgically resectable. Mutational analysis should be weighed in when considering a borderline resectable patient at all times." The bottom line is "we need to take mutational factors into account."


Molecular Characteristics Don't Play a Role

Molecular characteristics should not play a role in selecting patients for metastasectomy hepatobiliary surgery, said Michael Choti, MD, Division Chief of Surgery at Banner MD Anderson Cancer Center in Gilbert, Ariz. "There may be signals of molecular characteristics for some patients, but the signals are not reaching us and allowing these molecular characteristics to be used to treat these patients."


A subset of these patients enjoys long-term survival. About 20 percent of patients achieve 5-10 year recurrence-free survival (RFS), but the majority of patients go on to recurrence.


He pointed out differences in the definition of resectability. The definition by the old paradigm includes how many lesions, how large are the lesions, and is there extrahepatic disease. "The old paradigm is mostly oncological. The new paradigm uses technical and biologic/oncologic parameters," he said.


The technical standpoint is used to identify and remove all visible disease, answering the question: Can resection of all known disease be safely achieved? The biologic includes the number of metastases, synchronous or disease-free interval (DFI), presence of extrahepatic disease, and molecular biomarkers. Molecular biomarkers may identify those with more favorable outcomes, he said.


"What is borderline resectable disease? Technically, borderline is all initial disease that can be removed, but with some tricks, including staged resections, preoperative PVE, and resection and ablation. It also is potentially convertible with tumor size reduction," Choti noted.


Oncologically unfavorable tumors are resectable, but have bad biology, with a high tumor number, resectable extrahepatic disease, and possibly synchronous presentation. "Can molecular markers help identify oncological unfavorable disease?" he asked.


Choti noted that traditional clinicopathologic prognostic factors include number of metastases, resection margin status, high preoperative CEA, size of largest tumor, stage of primary tumor, disease-free interval, synchronous disease, extrahepatic disease, periportal node status, and response to chemotherapy. "Can we identify molecular biomarkers which can help characterize biologic behavior and refine our prognostic assessment?" he asked.


The incidence of KRAS and BRAF mutations has prognostic impact on patients undergoing liver surgery for colorectal metastases. There is a subtle sign that KRAS mutations lead to worse prognosis and RFS. Data suggest that liver resection patients do poorly, that wild-type versus mutant KRAS may be prognostic, and right-sided primary tumor versus left-sided liver disease has a different prognostic signal, which suggests different patient biology, he said.


"RAS mutational status predicts survival and patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases," said Choti. Patients with a double mutation of RAS and TP53 have an even worse prognosis.


"Why is biology prognostic? Local recurrence after ablation is higher in RAS-mutated patients. This suggests other factors we don't understand," he said, adding that BRAF may be prognostic, but in small number.


Tumor biology, rather than surgical technique, dictates prognosis in colorectal cancer liver metastases. "We do need better biomarkers to identify which patients derive the greatest benefit from local therapy, such as metastasectomy. We are seeing some early signals that molecular biomarkers have prognostic value in the management of colorectal cancer liver metastases with potentially resectable disease and may provide a useful adjunct for prognostic assessment."


Studies show that the MSKCC Clinical Risk Score is valid and is "an important prognostic signal," he said. The score includes node-positive primary, more than one liver metastases, largest liver metastases more than 5 cm, preoperative CEA more than 200, and primary metastases DFI less than 12 months.


Currently, markers such as RAS are "not ready to replace our existing clinical risk scores for resectable colorectal cancer liver metastases. BRAF may be highly prognostic, but it is uncommon with colorectal cancer liver metastases only," said Choti.


The key question is should prognostic factors determine selection of patients metastectomy. While we may use some factors to affect the timing or sequencing of therapy (e.g., neoadjuvant chemotherapy), "oncologically unfavorable" disease is almost never used to select or exclude patients from a curative-intent paradigm.


Choti stated, "some retrospective studies do suggest prognostic value of some molecular biomarkers (for example, RAS) following resection of liver metastases. No molecular marker has been shown to be better at predicting prognosis than traditional clinicopathologic factors, such as disease-free survival, metastases number, and node status.


"Prognostic factors do not define resectability. The observed differences in survival in RAS mutations should not preclude or impact the recommendation for metastasectomy in a resectable patient. While they may play a role in the selection of a chemotherapeutic regimen or sequencing of chemotherapy and liver resection, molecular biomarkers should not play a role in selecting patients for metastectomy."


Mark L. Fuerst is a contributing writer.