Jeremy C. Jones, MD, vice chair, assistant professor, medical oncologist, hematologist, Division of Hematology and Oncology, Mayo Clinic, discusses the applications of circulating tumor DNA (ctDNA) testing in colorectal cancer (CRC).

ctDNA tests are typically engineered to achieve a high level of specificity, Jones begins. When such a test yields a positive result, it strongly suggests the presence of residual disease, specifically molecular residual disease, he highlights, adding that these tests excel in this regard. However, the development of such tests involves a balance between sensitivity and specificity. Specificity pertains to the likelihood of disease presence when the test is positive; a positive test result is generally trusted to signify the presence of disease, Jones emphasizes. To achieve this level of trust, there may be a trade-off with sensitivity, and a negative test result may not effectively rule out the presence of residual cancer, he adds. 

Understanding this dynamic in these testing platforms is essential for determining how to integrate these tests effectively into clinical practice, Jones expands. For example, in stage II CRC, there hasn't been a definitive prospective adjuvant trial demonstrating a universal benefit of ctDNA testing, therefore, oncologists often rely on post hoc analyses to identify high-risk features, such as lymphovascular invasion, perineural invasion, or primary tumor disruption, to guide adjuvant chemotherapy decisions, Jones explains. However, if a patient with stage II disease were to test positive for ctDNA, a strong indicator of high risk, even without these established high-risk features, the positive result would warrant a discussion about the potential benefits and risks of adjuvant chemotherapy, Jones says. Furthermore, Jones emphasizes the current lack of conclusive data in all stage II CRC cases within this landscape.

Conversely, for stage III colon cancer, where robust randomized data support the use of adjuvant chemotherapy, it would be unwise to withhold chemotherapy solely based on a ctDNAtest result, he continues. These tests are reliable when positive, but in isolation, a negative result may not provide sufficient information, Jones says. In practice, these considerations inform how these tests are used. They may serve as tools to enhance post-adjuvant treatment monitoring in stage III cases, although the precise effect on patient outcomes remains uncertain, he adds. Furthermore, ctDNA test results can be a valuable entry point for clinical trial enrollment, enriching the trial population with patients at the highest risk for unfavorableoutcomes, Jones concludes.

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Jeremy C. Jones, MD, discusses the applications of circulating tumor DNA testing in colorectal cancer.


Dr Jones on the Application of ctDNA Testing in CRC

Jeremy C. Jones, MD, hematologist/oncologist, Mayo Clinic, discusses key lessons learned from the phase 3 KEYNOTE-177 trial (NCT02563002), which examined the use of the checkpoint inhibitor pembrolizumab (Keytruda) in patients with microsatellite instability–high or mismatch repair deficient stage IV colorectal cancer. 

Approximately 40% of the patients who were enrolled to the phase 3 trial had not received treatment with immune checkpoint inhibitors at any time point during their disease course, which is not best practice, according to Jones. It has been shown that even patients with a high disease burden or marginal performance status can achieve responses to immune checkpoint inhibitors and experience improved outcomes, Jones notes. As such, it is important to utilize immune checkpoint inhibitors in the treatment of this patient population, preferably in the first-line setting, Jones concludes.

Jeremy C. Jones, MD, discusses key lessons learned from the phase 3 KEYNOTE-177 trial.

Dr. Jones on the Importance of Immune Checkpoint Inhibitors in CRC

Jeremy C. Jones, MD, hematologist and oncologist, Mayo Clinic, discusses targeting HER2 alterations in colorectal cancer (CRC).

HER2 amplification occurs in approximately 3% of patients with metastatic CRC, Jones explains. However, these alterations are not identifiable without genetic testing, Jones says. Cell-free DNA–based testing can identify copy number variance or HER2-amplification status; however, immunohistochemistry testing with reflex fluorescence in situ hybridization is the most effective way to test for HER2 positivity, Jones says.

A number of clinical trials evaluating HER2 positivity in CRC led to drug development for this patient subgroup, Jones explains. Most trials studied therapeutic options for patients with HER2-positive breast cancer, Jones adds. For example, the ongoing phase 2 DESTINY-CRC02 trial (NCT04744831) is evaluating the efficacy of the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with HER2-overexpressing locally advanced, unresectable, or metastatic CRC.

Previous findings from the phase 2 DESTINY-CRC01 trial (NCT03384940) reported a confirmed overall response rate of 45.3% with trastuzumab deruxtecan in patients with HER2-overexpressing metastatic CRC. The median progression-free survival was 6.9 months, and the disease control rate was 83%, concludes Jones.

Jeremy C. Jones, MD, discusses targeting HER2 alterations in colorectal cancer.  

Dr. Jones on Targeting HER2 Alterations in CRC

Jeremy C. Jones, MD, hematologist/oncologist, Mayo Clinic, discusses the risk of interstitial lung disease (ILD) with fam-trastuzumab deruxtecan-nxki (Enhertu) in colorectal cancer (CRC).

Initial findings from the phase 2 DESTINY-CRC01 trial demonstrated a 45.3% confirmed objective response rate with trastuzumab deruxtecan in patients with HER2-positive metastatic CRC. Regarding safety, 6% (n = 5) of patients developed ILD; 2 of these cases were grade 5. 

As such, close monitoring for ILD is required when using trastuzumab deruxtecan for patients with CRC. Moreover, early intervention with steroids could mitigate the toxicity, Jones explains. In gastrointestinal cancers, ILD is not a common adverse effect associated with available therapies, Jones says. However, the promising efficacy observed with trastuzumab deruxtecan in HER2-positive CRC will likely outweigh the ILD-associated risks of the agent, concludes Jones.

Jeremy C. Jones, MD, discusses the risk of interstitial lung disease with fam-trastuzumab deruxtecan-nxki in colorectal cancer.



Dr. Jones on the Risk of Interstitial Lung Disease With Trastuzumab Deruxtecan in CRC 

Jeremy C. Jones, MD, hematologist/oncologist, Mayo Clinic, discusses the clinical utility of pembrolizumab (Keytruda) in microsatellite instability–high (MSI-H) colorectal cancer (CRC).

Prior to the June 2020 FDA approval of pembrolizumab for the frontline treatment of patients with unresectable or metastatic MSI-H or mismatch repair deficient (dMMR) CRC, the agent was widely utilized off-label for this patient population, says Jones. Since the FDA approval, the agent is now a standard of care treatment for patients with MSI-H or dMMR CRC, Jones adds.

Moreover, checkpoint inhibitors in combination with TKIs have been evaluated for patients with microsatellite stable disease, but did not demonstrate significant efficacy, Jones concludes.

Jeremy C. Jones, MD, discusses the clinical utility of pembrolizumab in microsatellite instability–high colorectal cancer.


Dr. Jones on the Clinical Utility of Pembrolizumab in MSI-H CRC 

Jeremy C. Jones, MD, hematologist/oncologist, Mayo Clinic, discusses the importance of testing for microsatellite instability high (MSI-H) in colorectal cancer (CRC). 

All patients with CRC, including those without metastatic disease, should undergo molecular testing to determine MSI-H status, says Jones. Testing is commonly performed by immunohistochemistry or polymerase chain reaction assays, Jones adds. 

Although MSI-H tumors account for approximately 5% of all CRC, this patient subgroup has demonstrated dramatic response rates with checkpoint inhibitor therapy, Jones explains. As such, it is critical to ensure patients with MSI-H CRC are appropriately identified and treated with checkpoint inhibitors, such as pembrolizumab (Keytruda), concludes Jones. 

Jeremy C. Jones, MD, discusses the importance of testing for microsatellite instability high in colorectal cancer. 



Jeremy C. Jones, MD

Articles

Dr Jones on the Application of ctDNA Testing in CRC

Dr. Jones on the Importance of Immune Checkpoint Inhibitors in CRC

Dr. Jones on Targeting HER2 Alterations in CRC

Dr. Jones on the Risk of Interstitial Lung Disease With Trastuzumab Deruxtecan in CRC

Dr. Jones on the Clinical Utility of Pembrolizumab in MSI-H CRC

Dr. Jones on the Importance of Testing for Microsatellite Instability in CRC