Steven J. Cohen, MD
Josep Tabernero, MD, PhD
STEVEN J. COHEN, MD, Director of the Rosenfeld Cancer Center at Jefferson Health/Abington Hospital, Abington, Pennsylvania, and Vice Chair of Medical Oncology at Sidney Kimmel Cancer Center at Jefferson, and Josep Tabernero, MD, PhD, Head of Medical Oncology and the Gastrointestinal Tumors and Department at the Vall d’Hebron University Hospital and Institute of Oncology (VHIO) in Barcelona, discussed these papers at the 2017 ASCO Annual Meeting.
Dr. Cohen noted that “side matters” in metastatic colon cancer, but its importance in early disease remains unclear. Referring to the analysis of the PETACC-8 trial in patients with stage III colon cancer, he noted that side did not matter until after recurrence, where the data became “striking.”
“You don’t recur more with right- vs left-sided tumors, but if you do recur, right-sided tumors do much worse,” he said. The findings regarding differences based on mutation status “also are interesting and need to be more fully explored,” he added.
‘Food for Thought’
Dr. Cohen also commented on the novel observation from NSABP/ NRG C-07 regarding the enterocyte subtype and sidedness. In stage III patients with enterocyte subtype, oxaliplatin had more benefit on left-sided tumors (hazard ratio [HR] = 0.122; P < .001) than on right-sided ones (HR = 0.672; P = .312). This difference was not observed among other subtypes.
Meanwhile, he cautioned, “we should not make current adjuvant decisions based on side,” though the data presented at the ASCO meeting offer “food for thought” about having discussions with stage III (and even stage II) patients regarding the potential value of more aggressive treatment of right-sided tumors, he said.
“Data after recurrence support the impact of side on outcomes, and maybe this has implications for our discussions with patients,” Dr. Cohen commented.
In his discussion, Dr. Tabernero said the data from CALGB/SWOG 80405 fit with data from his own institution, Vall d’Hebron University, on 618 molecularly profiled metastatic tumors. “Our comparison between right and left side is consistent with 80405. Right-sided disease is always a poor-prognostic factor,” he noted.
By molecular profile, BRAF mutations are associated with a worse prognosis, whereas triple– or quadruple–wild-type tumors have a much better prognosis in the metastatic setting. Similar to 80405, as well, his institution’s study identified no important clinical characteristics, but he said other clinical parameters (ie, not typically analyzed) could emerge as important at some point.
Continuum of Changes
It seems evident that molecular differences may be playing a role, he agreed, pointing to “some interesting differences in tumors, according to the signatures that are upregulated.” In right-sided tumors, upregulation of BRAF signatures and the HER family of receptors is observed, along with microsatellite instability (MSI) and a serrated pattern of lesions. On the left side, there is upregulation of canonical pathways.
But these patterns are not “black and white,” he added. “Right vs left is not a dichotomic transition, but a continuum of changes moving from cecum to sigmoid…. Are the known molecular markers (RAS, BRAF, MSI, consensus molecular subtypes [CMS]) unequally distributed throughout the colon, and does this completely explain the poor outcome of right-sided tumors in the metastatic setting? The answer is no,” he said. ■
DISCLOSURE: Dr. Cohen has had a consulting or advisory role for Bayer, Celgene, Genentech, and Taiho Pharmaceuticals. Dr. Tabernero has had a consulting or advisory role for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho, and Takeda.
“Further work is needed to determine the mechanism by which sidedness remains an independent prognostic variable.”— Alan P. Venook, MD
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TUMOR “SIDEDNESS” in colon cancer has become a topic of great interest, after right-sided tumors were shown to...!-->!-->