Aptitude Health recently spoke with Tanios Bekaii-Saab, MD, from the Mayo Clinic in Phoenix, AZ, USA, regarding management of colorectal cancer (CRC). Dr Bekaii-Saab is the David F. and Margaret T. Grohne Professor of Novel Therapeutics for Cancer Research I and chair of the Division of Hematology and Medical Oncology at the Mayo Clinic College of Medicine and Science. He conducts clinical and translational research focused on developing anticancer agents for patients with gastrointestinal cancers. His research includes a primary focus on the incorporation of agents that target multiple facets of cancer, including genetic and epigenetic drivers, as well as the feeding microenvironment and the immune milieu. This work includes 2 recent discoveries as co-inventor of a molecule that targets cancer-related cachexia (AR-42) and an anti-programmed cell death protein 1 vaccine (PD1-Vaxx).
Dr Bekaii-Saab has served as a reviewer for many high-impact journals and sits on the editorial board of the prestigious Journal of the National Cancer Institute. He has authored or co-authored more than 500 peer-reviewed publications, abstracts, and book chapters, including papers in journals such as New England Journal of Medicine, Lancet, Lancet Oncology, Journal of Clinical Oncology, Cancer Discovery, JAMA, Journal of the National Cancer Institute, Annals of Oncology, and Clinical Cancer Research.
Here is a recap of our conversation:
What recent advancements in the management of CRC do you consider the most relevant to clinical practice?
Some of the most recent and exciting advancements in the management of colorectal cancer have been the targeted approaches to treatment. We are catching up with lung cancer and breast cancer in terms of subsegmenting colorectal cancer into subgroups. We now understand KRAS mutations as a driving decision piece, essentially as a negative predictive biomarker for the use of EGFR inhibitors. We’ve discovered positive predictive biomarkers such as BRAF V600E mutations and HER2 amplifications, as well as microsatellite instability (MSI)-high, which allows for impressive responses to immune therapy. Furthermore, we’re now subsegmenting KRAS mutations into G12C, G12D, G12V, and others with emerging agents that target these subsegments. Progressing from an era where we only had 1 negative predictive biomarker (KRAS) to multiple positive predictive biomarkers has transformed the landscape quite a bit, mainly in the refractory setting, with potential to move many to first-line use, as many of these agents are currently being studied in the first-line setting. However, it is important to note that this still affects only about 20% of all patients . . . 80% of patients have no positive predictive biomarker, so there remains a significant unmet need.
Would you say that equal advancements have been made in the early stages of colorectal cancer vs the metastatic setting?
Unfortunately, there is not much happening yet with targeted or immune therapies in the earlier stages of the disease. The pending results of the ATOMIC study may help us understand the role of immune therapy in stage III colon cancer with MSI-high disease. In rectal cancer, we’re starting to see quite a bit of excitement around the role of immunotherapy in the neoadjuvant setting with MSI-high disease, including sparing most patients radiation and chemotherapy, but that’s a very small subset of patients. One thing that seems to be advancing care for those patients with early-stage CRC is the assessment of molecular or minimal residual disease (MRD). We’ve learned MRD has a major prognostic role in CRC, while we won’t know its predictive value until we have the readouts from the prospective clinical trials that are underway. If these trials are positive, I think this will revolutionize how we treat patients with colorectal cancer. Consider patients with stage II or III colon cancer. . . . Many of them likely don’t need chemotherapy, and if predictive value is validated, knowledge of MRD (ie, positive or negative) could have implications on treatment decisions for these patients.
How is the role of biomarkers evolving in CRC, and are there disparities in how biomarker-guided treatment approaches are integrated into academic centers vs clinical practice?
Biomarker-guided treatment approaches are becoming of key importance and essentially defining our evolving treatment paradigm, although there remains some disparity in the tests that are performed in colorectal cancer from day 1. For example, an MSI-high result could spare a patient chemotherapy and even offer them the opportunity for a cure with immunotherapy. Having HER2 amplification assessed from day 1 can guide you to HER2-targeted therapy-based trials such as MOUNTAINEER-03, which is ongoing. Also, we recently published data on HER2 amplification as a predictor for lack of activity from EGFR inhibitors, so having that is important. Same for BRAF mutations. . . . There is the BREAKWATER study that is assessing the role of BRAF inhibitors in the first line, and this may become a standard, same for G12C and a lot of others.
While biomarker testing has become common practice in academic settings, that isn’t always the case in community settings. Lost opportunities for treating patients sooner rather than later with a biologic or immunologic are amplified in communities with racial disparities or among underrepresented minorities who may be even less likely to have these tests done sooner—or even at all in some cases—due to lack of affordability, lack of access, etc.
What is the current role of circulating tumor (ct)DNA in CRC, and will it be utilized in clinical practice?
I think ctDNA has revolutionized the way we treat patients with colorectal cancer. In the earlier stages, ctDNA is used to assess for MRD. That certainly continues to be an evolving field, with prognostic and predictive implications. There are 2 platforms: tumor informed and tumor uninformed; tumor informed meaning you have tissue and match the blood to it after you form your assay. This is the preferred platform, since it has increasing utility in the clinical setting with the highest level of sensitivity and great specificity, but its role remains to be fully defined.
For later stages of the disease, ctDNA has been a great asset in our clinics. If a patient comes to my clinic with a first diagnosis of colorectal cancer, I send a ctDNA sample along with a tissue sample. The reason for this is we receive ctDNA results in 6 to 7 days and the concordance rate is over 80%, meaning if you find it in the blood, it will likely also be in tissue. Conversely, there’s a 20% chance it may not be in tissue, which is why we also send the tissue and wait on the results before making treatment decisions. There are also other elements with liquid that are not easy to capture, such as fusions and tumor mutation burden, that we still must rely on tissue for. In my practice, I also use ctDNA at each progression to capture changes in clonality and any emerging alterations that are targetable, but I don’t recommend for this to be done routinely in the community practice unless they have access to clinical trials.
What remains an unmet need, and how do you expect CRC management to evolve in the next 3 to 5 years?
We must continue to expand on the subgrouping of patients and defining groups of patients who can be matched to biologics or immune therapeutics, as well as enhance the sensitivities of ctDNA. I suspect in the next 3 to 5 years that will become a standard of care. . . . Tissue will be optional, and blood will be the main driver that gives us the information we need quickly so we can move forward with treatment.
The other thing I see evolving in the next 3 to 5 years is, like immune therapy, a lot of the biologic options that achieve response in later lines of therapy will start moving toward first-line use. Studies are underway that will not only change the landscape of how we do things in the first line, but also enhance patient survival in very meaningful ways long-term.
Lastly, another area that continues to be incredibly challenging is how to integrate immune therapy options in a microsatellite-stable disease outside the MSI-high. There are opportunities to define better biomarkers such as Immunoscore, and a lot of exciting work happening in cell therapies, especially in the presence of actionable genetic alterations.
