SEATTLE – Research in colorectal cancer should focus on part on a handful of high-priority needs for prognostic and predictive biomarkers, according to Dr. William M. Grady, an oncologist at the Fred Hutchinson Cancer Research Center and section chief of gastroenterology at the University of Washington, Seattle.
“These needs are in the selection of optimal agents for the stage II and III cancers, the ones for which we add adjuvant therapy,” he told attendees of a joint meeting by the Global Biomarkers Consortium and the World Cutaneous Malignancies Congress. Additionally, “in the clinic, the main issue is selecting stage II patients who are at high risk for recurrence who may benefit from adjuvant therapy, and then stage III patients who will not benefit from therapy.”
Dr. William M. Grady
There are some high-priority needs in the metastatic setting as well. “For stage IV disease, really the issue is selecting candidates for conventional chemotherapy, and here we are trying to balance toxicity versus survival and quality of life. Also, there is the issue of identifying people who will be optimal responders to some of the targeted therapies,” Dr. Grady elaborated.
The quest for biomarkers has been aided by increasing recognition of the molecular heterogeneity of colorectal cancer. Research has thus far identified three predominant molecular groups – a microsatellite unstable group, a microsatellite stable group, and a CIMP (CpG island methylator phenotype) group – having alterations of different signaling pathways. “This is clearly an oversimplification, and where I think we are going is that we will continue to parse out hopefully finer and finer groups that will be used for directing clinical care based on the response to agents that are being developed,” he said.
Microsatellite instability
Microsatellite instability is already used clinically to screen colorectal cancers in patients younger than 50 for hereditary Lynch syndrome, as recommended in national guidelines, according to Dr. Grady.
It can also be used to assess the prognosis of stage II and III disease, as patients with tumors showing microsatellite instability have better survival (J Clin Oncol. 2005;23[3]:609-18). But studies have been mixed on whether this biomarker is predictive for the response to adjuvant 5-fluorouracil–based chemotherapy (Nat Rev Clin Oncol. 2010;7[4]:197-208).
“Right now, the consensus is that for stage II disease, if there is microsatellite instability, that correlates with a very low-risk group and there doesn’t appear to be any benefit from adding adjuvant therapy; in fact, one study even suggested harm,” he noted. “For stage III disease [with microsatellite instability], there is no change … indicated at this time for 5-[fluorouracil]-based therapy; potentially, some people even argue that you might want to avoid this therapy, although I don’t think that’s the general opinion. And there may be a benefit in these tumors from the use of oxaliplatin, which one study last year suggested.”
In patients with stage IV disease, recent data suggest microsatellite instability may be a marker for benefit from therapies that target the programmed death–1 (PD1) pathway such as pembrolizumab (Keytruda) (N Engl J Med. 2015;372[26]:2509-20). “The challenge here is that only about 2% to 3% of metastatic colon cancers have microsatellite instability, so unfortunately it’s a small group that will benefit,” Dr. Grady commented.
Multigene signatures
A pair of clinically available multigene signatures, Oncotype DX–Colon and ColoPrint, are being used to estimate prognosis in patients with early disease. However, differences between adjacent assay-defined risk strata are fairly small, on the order of an absolute 10% or so. “This raises a question about what the clinical utility of these scores is,” he said.
“The real question we want to know, though, is can we use [these signatures] to choose people who will get adjuvant therapy for stage II disease,” he commented. At present, the answer appears to be a qualified yes for Oncotype DX, with some data suggesting that the survival benefit of chemotherapy may be greatest in patients with early disease who fall into the assay-defined high-risk category (J Clin Oncol. 2013;31[36]:4512-9)
“Where the ColoPrint assay seems to potentially have the highest benefit is in identifying a low- and high-risk group in the patients who have T3N0 disease but that’s microsatellite-stable. It doesn’t add much to those who have tumors that are already identified as being microsatellite-unstable or who have large [T4N0] disease that is microsatellite-stable,” he noted (Oncologist. 2015;20[2]:127-33).
Ultimately, use of Oncotype DX and ColoPrint should be individualized, according to Dr. Grady. “They certainly can be used, but they really need to be discussed on a case-by-case basis with the patient and physician because they have unclear clinical utility,” he said.