1. Fuerst, Mark L.

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CHICAGO-Patients with metastatic colorectal cancer originating on the left side of the colon survive longer than those whose cancer originates on the right side, according to a new study.

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A retrospective analysis of data from a large clinical trial found that the location of the primary tumor within the colon predicts survival and may help inform optimal treatment selection for patients with metastatic colorectal cancer.


The study (Abstract 3504) was featured in a press briefing and was presented at the 2016 American Society of Clinical Oncology Annual Meeting.


"Overall survival in patients with stage 4 metastatic colorectal cancer is 14 months greater with left-sided versus right-sided primary tumor. Cetuximab added to first-line chemotherapy in KRAS wild-type patients is associated with more favorable progression-free survival (PFS) than with left-sided primary tumor.


Cetuximab appears to add more than bevacizumab to chemotherapy in KRAS wild-type patients with left-sided primary tumors. Patients with right-sided primary tumors appear to benefit more from bevacizumab than cetuximab," said lead author Alan P. Venook, MD, Professor of Medicine at the University of California, San Francisco.


The data show that patients whose primary tumors originate on the left side of the colon (the descending colon, sigmoid colon, and rectum) survive significantly longer than those whose tumors originate on the right side (the cecum and ascending colon).


"We should not be surprised. Different tissues originate from different parts of the embryo, the right side of the colon from the midgut and the left side from the hindgut," Venook said.


He noted that previous studies had suggested that tumor location may impact clinical colorectal cancer outcomes, but "the effect we observed in this analysis appears to be far greater than we expected. These findings will likely change the way we approach colorectal cancer treatment and research, even as we seek to more deeply understand the biology driving the difference in outcomes between right- and left-sided cancers."


Examining Colon Cancer

Venook presented data from a retrospective evaluation from the phase III 80405 clinical trial, which was designed to compare bevacizumab and cetuximab in combination with chemotherapy as initial therapy for metastatic colorectal cancer. Two years ago at the ASCO annual meeting, researchers presented data from the primary analysis of the trial. Those results showed that chemotherapy plus cetuximab led to similar overall survival (29.9 months) as chemotherapy plus bevacizumab (29 months).


The new analysis looked at 293 patients with right-sided primary tumors and 732 patients with left-sided primary tumors. This analysis included only patients without a mutated KRAS gene, which is a known biomarker of response to certain colorectal cancer therapies. Cetuximab is approved only for treating KRAS wild-type tumors.


In this patient population, those with left-sided tumors had longer median overall survival (33.3 months) as compared to those with right-side tumors (19.4 months). In subsets by treatment, for patients who received cetuximab, those with left-sided tumors lived 36 months, while those with right-sided tumors lived 16.7 months. Similar trends were observed among patients receiving bevacizumab, with overall survival of 31.4 months for patients with left-sided tumors and 24.2 months for those with right-sided tumors. PFS results were similar, he said.


These findings are "dramatic" and "surprising," said Venook, given the previous understanding that sidedness is not likely to make a difference.


Because the trial was initiated before KRAS mutation status was known to be an important factor in use of cetuximab, there was a smaller population of patients who had KRAS mutations. In a separate analysis, researchers found that those patients with left-sided tumors also lived longer (median overall survival of 30.3 months) as compared to patients with right-sided tumors (median overall survival of 23.1 months).


Venook said "large clinical trials may uncover results that are not apparent in smaller studies. Molecular analysis of tissues from patients on study should explain the biology. Until this can be sorted out, colon cancer originating on the right side should be treated differently than colon cancer on the left side. Although retrospective, this data and other findings suggest patients with right-sided primary metastatic colorectal cancer get little to no benefit from cetuximab."


Molecular Testing

Forthcoming molecular analyses of primary tumors may provide a biological explanation. Researchers are in the process of examining the molecular biology that presumably underlies these findings. "We are completing analysis on 44,000 biological specimens, both colon cancer tumors and normal tissue," said Venook. "We think we will find that sidedness is a surrogate marker for biology that explains the outcome. Molecular features may predict outcome."


Previous analyses have found four potential subsets with features of unique RNA. "We think we will be able to define different versions of colon cancer based on these features," he said. Tumor mutations, including BRAF and RAS mutation, may predict efficacy of agents. Researchers now recognize multiple colon cancer sub-types based on genetic patterns, he noted.


Venook believes the data are "practice changing." Other presentations at the ASCO meeting support the importance of sidedness in colon cancer.


"Ultimately, we will find that right-sidedness is a marker for criteria of biological features for why these patients do not respond as well to cetuximb," he said. "We still need to define mutational status of colon cancer. Six months from now, sidedness may be a surrogate for a crisp biological testing for personalized care."


ASCO President Julie M. Vose, MD, MBA and Professor of Internal Medicine, Division of Oncology & Hematology at the University of Nebraska Medical Center in Omaha, commented: "This is the largest study to date of tumor location in colorectal cancer, and it strongly suggests that this unexpected factor could answer some long-standing questions about why certain patients do better than others. It is also an important reminder, in this exciting era of precision medicine, that genomics is not the only source of insight into how cancers should be studied and treated."


Mark L. Fuerst is a contributing writer.