Shifting the Risk-Benefit Ratio in CRC With Molecular Subtyping

Oncology Live®August 2015
Volume 16
Issue 8

Recent evidence has shed some light on the prognostic value of microsatellite instability and the potential benefit of checkpoint inhibition in colorectal cancer.

John L. Marshall, MD

Knowledge gained regarding molecular subtyping has led to an increased understanding of the diversity in colorectal cancer (CRC) tumors and the need for more nuanced treatment options. Recent evidence has shed some light on the prognostic value of microsatellite instability (MSI) and the potential benefit of checkpoint inhibition in CRC.

In addition, new evidence in the salvage setting has shown promise in extending survival.

However, knowing the best course of treatment in heavily pretreated patients with advanced CRC remains challenging. Treatment considerations in this population were the topic of discussion among a panel of experts during a recent OncLive Peer Exchange led by moderator John L. Marshall, MD.

Microsatellite Instability

Microsatellite instability (MSI) is caused by the loss of DNA mismatch repair (MMR) activity and is present in approximately 15% of all CRCs.1 Evidence has shown that tumors with a greater degree of genetic instability—MSI-high tumors—have a better prognosis and respond differently to chemotherapeutics than do tumors without MSI.1

Howard S. Hochster, MD

The consensus is that MMR status is prognostic in stage II disease, Marshall noted, and that 5-fluorouracil (5-FU)—based therapy seems to be harmful in that setting. A retrospective analysis of data from the PETACC8 and NCCTG N0147 trials, however, showed that MMR was not prognostic in stage III patients.2 This analysis, presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, was conducted in patients treated with FOLFOX, with or without cetuximab. The panel agreed that questions remain as to the utility of MMR status in stage III patients, but that it is still worthwhile to perform MSI tests on primary tumors.

Retrospective data are helpful in this setting, given that there is a paucity of prospective data on MSI in stage III CRC, stated Howard S. Hochster, MD.

“If [retrospective data] tells us that we need to treat the MMR mismatch repair enzyme-deficient patients in stage III with the same treatment and [that] they have the same benefit, that’s already reasonable information,” Hochster said. “It’s an area where we’ve wondered what to do, so I feel more reassured when I see a patient like that that we’re making a good recommendation based on real data.”

The incidence of MMR enzyme deficiency lessens in later stages; Hochster approximated it at 15% in stage II, 7% to 8% in stage III, and 4% in stage IV. At his institution, regardless of the stage of cancer, “every colon resection is reflexively tested for MMR deficiency by immunohistochemical staining.” There are other confounding factors influencing prognosis, such as Lynch syndrome and RAF mutations. Studies have suggested that chromosomal aberrations may be different in stage II and stage III, and this may help explain why 5-FU is associated with poorer outcomes in stage II disease, stated Richard M. Goldberg, MD. “As we [understand] the importance of immune checkpoints, it may be that part of that explanation is that we’re killing the wrong cells,” Goldberg said. “We’re killing those lymphocytes that are helping to contain micrometastatic disease.” He added that he often prefers FOLFOX to 5-FU in MSI-high patients.

Richard M. Goldberg, MD

Checkpoint Inhibitors

Checkpoint inhibition has shown promise in traditional immunologically active cancers, such as kidney cancer and melanoma. More recently, agents targeting immune checkpoints such as programmed death-1 (PD-1) and its ligand, PD-L1, have demonstrated efficacy in lung cancer and bladder cancer.

Although immune infiltrate of a primary colon cancer has been a “very strong predictor of outcome,” until recently no assay existed in colon cancer, Marshall noted. Marshall referred to a late-breaking abstract from ASCO 2015 of a phase II trial that tested whether MMR defects would be susceptible to immune checkpoint blockade.3 Investigators evaluated the clinical activity of the PD-1 inhibitor pembrolizumab in 41 patients with previously treated, progressive, metastatic disease (Table).3

Goldberg called the findings a “game-changer” for colon cancer. He has treated patients with pembrolizumab, which has demonstrated “remarkable results in patients with MSI-high tumors.” It is also well tolerated; the main side effects are related to activation of the immune system, he remarked. “So even though it’s a small percentage of patients, only 4% of people with metastatic disease [are MMR-deficient], it is I think, equivalent to the finding of the ALK mutations,” said Goldberg, referring to the lung cancer aberration.

Table. Prognostic Value of Mismatch Repair Status in PD-1 Blockade3

CRC indicates colorectal cancer; irORR, immune-related objective response rate; irPFS, immune-related progression-free survival; MMR, mismatch repair.

Compared with their efficacy in other cancer types, checkpoint inhibitors “have been notoriously disappointing in colorectal cancer,” stated Fadi Braiteh, MD, adding that these new data are encouraging in that a certain subset of patients appears to benefit greatly from PD-1 inhibition. The next areas to explore will be around combination therapies with checkpoint inhibitors, according to Braiteh. “I believe personally that we need to combine with other cytotoxic and angiogenic [agents] to have really meaningful [responses] and, of course, to find the magic marker predictor of who would respond,” he added.

Later-Line Therapies

Management of advanced-stage CRC often involves multiple lines of therapy. Several agents have shown promise in patients who are refractory to two or more standard therapies. These include regorafenib and TAS-102.


Regorafenib is a multitargeted tyrosine kinase inhibitor. The phase III CORRECT trial, the results of which were published in 2013, randomized 760 patients with metastatic CRC who had progressed following standard therapy to receive regorafenib or placebo plus best supportive care.4 Median overall survival (OS) was 6.4 months in the regorafenib arm versus 5.0 months in the placebo arm (P <.0052).4

Adverse events included hand-foot syndrome, fatigue, hypertension, and diarrhea.4 Toxicities associated with the drug have been a major barrier to its use, Marshall stated. A recent analysis of the CORRECT study, presented at ASCO 2015, examined molecular subtypes to better understand who benefited most from treatment with the study drug.5 Although a similar OS benefit was seen across the six subtypes, a greater progression-free survival benefit was seen with regorafenib in patients in the high-risk subgroups.5

Although these high-risk groups made up a small percentage of the total population, “that population seemed to benefit quite a bit.” It is worthwhile to examine molecular subtypes so that the drug is given to those who will benefit most, Hochster stated. “If we could really kind of shift the risk—benefit ratio a little bit, that would probably make the drug a lot more useful in clinical practice,” he said.

Fadi Braiteh, MD

Finding biomarkers and directing therapy to the subset of patients who are most likely to benefit protects patients from unnecessary toxicities and also makes the therapy rank higher on the value-based decision-making front, according to Goldberg. “I do think it really enriches your value for a drug if you can avoid treating a percentage of patients that have no likelihood of benefiting and have a likelihood of toxicity,” Goldberg said.

Patients taking regorafenib require frequent monitoring, dose adjustments, and treatment holidays. Careful management can dramatically improve tolerability, Goldberg noted. Hochster agreed, adding, “You can’t just say, take the pills, come back next month. That’s not going to work. So, you need to really see the patients, be in touch with them, and modify their doses.”


Another agent being studied as a salvage therapy in clinical trials is TAS-102, which is approved in Japan. Compassionate use and participation in clinical trials has allowed some patients in the United States access. The drug is an antimetabolite composed of trifluorothymidine and a metabolic inhibitor, stated Hochster, and is similar to 5-FU.

The phase III RECOURSE trial examined TAS-102 or placebo plus best supportive care in 800 patients who had received at least two prior lines of treatment.6 Median OS was 7.1 months with TAS-102 and 5.3 months with placebo (HR, 0.68; P <.001).6 The most common adverse events were neutropenia and leukopenia.6 The drug is well-tolerated, Hochster said, adding that the “benefit seems to be very similar to what we’ve seen with other single agents in this kind of lastline setting.”

The data are promising, noted Goldberg. “The basic science data look very encouraging in that it does work in cell lines that are refractory to 5-FU,” he said. Ongoing studies are examining the agent in combination with other therapies in earlier-line settings.


  1. Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010; 138(6): 2073-2087.e3.
  2. Zaanan A, Shi Q, Taieb J, et al. Analysis of DNA mismatch repair (MMR) and clinical outcome in stage III colon cancers from patients (pts) treated with adjuvant FOLFOX +/- cetuximab in the PETACC8 and NCCTG N0147 adjuvant trials. J Clin Oncol. 2015(suppl; abstr 3506).
  3. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch repair deficiency. J Clin Oncol. 2015;33(suppl; abstr LBA100).
  4. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international multicenter, randomized, placebo-controlled, phase 3 trial [published online November 22, 2012]. Lancet. 2013;381(9863):303-312.
  5. Teufel M, Schwenke S, Seidel H, et al. Molecular subtypes and outcomes in regorafenib-treated patients with metastatic colorectal cancer (mCRC) enrolled in the CORRECT trial. J Clin Oncol. 2015;33(suppl; abstr 3558).
  6. Mayer RJ, Van Custem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909-1919.

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