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GI GICS 2019: CRC
My Take on the Latest Developments in Colorectal Cancer at the 2019 Gastrointestinal Cancers Symposium

Released: February 07, 2019

Expiration: February 06, 2020

John L. Marshall
John L. Marshall, MD
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The 2019 Gastrointestinal Cancers Symposium featured the latest clinical data on the management of colorectal cancer (CRC). Below, I highlight my key takeaways on molecular testing and profiling, optimizing current practice, and novel immunotherapy strategies.

Molecular Testing and Profiling
I considered the most clinically relevant study at the meeting to be that presented by Tsai and colleagues on the utility of measuring circulating tumor cells to noninvasively assess CRC burden. In this prospective study of patients undergoing routine CRC screening, circulating tumor cell counts effectively differentiated between healthy individuals vs those with adenomas or CRC. There was a significant association between the number of circulating tumor cells and stage of adenoma-carcinoma progression (likelihood ratio P < .0001). Other reports indicate that circulating tumor DNA predicts relapse after primary surgery, and this study further supports using this noninvasive strategy to determine which patients will need adjuvant therapy.

Another interesting study in the adjuvant setting focused on Immunoscore Colon, an in vitro diagnostic that predicts relapse risk based on immune response at the tumor site. In a subanalysis of untreated patients with stage II CRC from the Immunoscore internal validation study, the investigators reported that high-risk patients with a high Immunoscore—indicating a strong immune response—exhibited a recurrence risk comparable to that of low-risk patients. Furthermore, the recurrence rate did not markedly differ when the high-risk, high-Immunoscore patients received adjuvant chemotherapy. This is consistent with the logic behind immunotherapy: If a tumor is stimulating the immune system to recognize and infiltrate it, then the patient will have a better risk profile because the immune system is eliminating microscopic metastatic disease.

Regarding molecular profiling, a consensus emerged across discussions and presentations at the meeting that profiling should be done in all CRC cases, particularly those with metastatic disease. Molecular profiling should include testing for microsatellite instability, RAS (not just KRAS), BRAF, and HER2. Although it is debatable whether HER2 should be tested with IHC or genetic profiling, we know that approximately 5% of our patients with CRC have HER2 alterations, and these patients show improved outcomes with HER2-targeting strategies (eg, trastuzumab plus lapatinib). Similarly, approximately 10% of patients with CRC have BRAF alterations, and we have guideline‑supported therapeutic interventions for BRAF‑mutated CRC. Given the benefits we can now offer to specific populations, molecular profiling must be done for all patients with CRC.

Optimizing Current Practice
There has long been debate over whether we could shorten the duration of radiation in neoadjuvant therapy for rectal cancer from multiple weeks to 5 days. In a retrospective cohort study of patients who received neoadjuvant therapy and total mesorectal excision for stage II-III rectal cancer, short-course radiation was associated with comparable rates of recurrence and pathologic CR vs a longer course. Compared with European clinicians, the United States has been slower to adopt short-course radiation, which is less expensive and less toxic while still offering good outcomes, as this study shows.

Another study addressed optimal use of regorafenib and TAS-102 in patients with refractory metastatic CRC. Sonbol and colleagues performed a meta-analysis of 6 clinical trials evaluating regorafenib started at full dose and standard-dose TAS-102 in the setting of refractory metastatic CRC. Compared with best supportive care, each agent significantly improved both PFS and OS. There was no significant difference between regorafenib and TAS-102. Of interest, when patients started regorafenib at 80 mg/day and escalated as tolerated, their outcomes were even better compared with best supportive care. This analysis supports adopting this strategy of starting patients at a low dose of regorafenib and escalating up to full dose as tolerated.

Novel Immunotherapies
In the arena of immunotherapy, we saw disappointing results for microsatellite‑stable CRC. LICC was a phase II study comparing adjuvant immunotherapy with tecemotide (L-BLP25), a vaccine targeting mucin 1, vs placebo in patients with metastatic CRC who had undergone resections of liver metastases. We do not have an established treatment approach for this setting. Unfortunately, LICC reported negative results that suggested the vaccine arm had worse outcomes, with an estimated 3-year OS rate of 69.1% vs 79.1% with placebo. It is unclear why administering a vaccine after surgery might worsen outcomes.

The other immunotherapy study that I want to note was a relatively large phase II trial, CCTG CO.26, which randomized patients with advanced refractory CRC not selected for microsatellite status to the PD-L1 inhibitor durvalumab plus the CTLA-4 inhibitor tremelimumab vs best supportive care. There were modestly but significantly improved outcomes in the immunotherapy group, even though they were all microsatellite stable. The median OS was 6.6 months with immunotherapy vs 4.1 months with best supportive care (HR: 0.72; 90% CI: 0.54-0.97), and the disease control rate was 22.7% vs 6.6%, respectively (P = .006). I have reservations about this combination immunotherapy approach because it is very expensive and the magnitude of benefit was not like what we see in microsatellite‑instable cancers. Currently, I would not recommend single-agent or combination immunotherapy off label or outside of a clinical trial in microsatellite‑stable CRC.

Your Thoughts?
Which studies presented at 2019 Gastrointestinal Cancers Symposium will have the greatest impact on your clinical practice? Please share your thoughts in the comments box!

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In your current practice, what molecular profiling are you routinely ordering on your patients with metastatic CRC? (Please select all that apply)
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