Predictive ctDNA Testing Opens the Door for Increasingly Personalized Care in Colon Cancer

Liquid biopsy, particularly circulating tumor DNA (ctDNA) testing, is leading to increased accuracy and efficiency in how treatments are determined and delivered for patients with colon cancer, according to Ben Ho Park, MD, PhD.

At the 2022 ASCO Annual Meeting, data from the phase 2 DYNAMIC trial showed that, at a median follow-up of 37 months, 15.3% of patients with resected stage II colon cancer in the ctDNA-guided arm received chemotherapy vs 27.9% in the standard-of-care (SOC) arm.¹ Park said those results showed that ctDNA could identify which patients were most likely to benefit from chemotherapy. Additionally, the CHiRP study used ctDNA testing to detect minimal residual disease (MRD) in 100% of distant recurrence cases in patients with hormone receptor (HR)–positive, HER2-negative breast cancer.²

Moreover, the phase 3 VOYAGER trial (NCT03465722) demonstrated that identification of KIT mutations via ctDNA sequencing negatively correlated with avapritinib (Ayvakit) activity in patients with pretreated gastrointestinal stromal tumors (GISTs).³ Finally, the plasma biomarker analysis of the phase 1/2 CodeBreaK 100 trial (NCT03600883) used ctDNA testing to identify mechanisms of resistance to sotorasib (Lumakras) in patients with KRAS G12C–mutated non–small cell lung cancer and colorectal cancer (CRC).⁴

“All those data presented together were amazing,” Park said. “I’ve been in this field for well over a decade, and to see it grow from where we started off to these huge international studies and to start to see clinical benefit is encouraging and has been phenomenal to see. I was excited and blessed to be asked to discuss this setting [at ASCO].”

In an interview with OncLive^®, Park, the Donna S. Hall Professor of Medicine in the Division of Hematology and Oncology, the diversity liaison, and the director of the Vanderbilt-Ingram Cancer Center at the Vanderbilt University Medical Center, summarized exciting data regarding ctDNA testing that were presented at ASCO. He emphasized the ability of ctDNA testing to determine the benefits of adjuvant chemotherapy in individual patients, the successful preliminary use of this testing to detect cancer prior to recurrence, and how this testing may help detect mutations that can better guide future therapies.

OncLive^®: What background information is important to know about the development of ctDNA testing?

Park: This is an exciting time to be in oncology. Particularly, what my research team [at Vanderbilt University Medical Center] and others have been working on is the concept of liquid biopsy. There are many forms of liquid biopsy, but specifically, we’re now working with ctDNA. That’s the notion that all our cells, both cancer and normal, will shed free-floating DNA molecules into the bloodstream. We now have technologies to take that blood out and sequence it to see what the tumor makeup is in a given patient.

What data regarding ctDNA testing were highlighted at the 2022 ASCO meeting?

The session that I presented in [consisted of] 4 separate talks. Some of [the data covered pertained to] how we are best utilizing this new technology and information to guide cancer care for patients.

One of the bigger stories that came out [at ASCO] was findings from the DYNAMIC trial, which evaluated whether we could use ctDNA to decide who might benefit from additional chemotherapies after surgery for stage II colon cancer. [These additional therapies were] compared with a control arm where [patients were treated with] the SOC. The results were encouraging because they showed us that we could reduce the amount of chemotherapy that would traditionally be given by about half. This is akin to the Oncotype [DX test] in breast cancer, where now we can spare many patients from chemotherapy because it doesn’t benefit them.

The other encouraging aspect of the DYNAMIC study was that there was no difference in outcomes in the ctDNA-guided arm vs the SOC arm in terms of number of relapses, meaning [ctDNA is] not going to compromise care. That’s important and, critically, it allows us to, going forward, design further, bigger trials using this technology for this group of patients.

Other trials were similar in the MRD landscape. We’re looking for patients who still have cancer cells in their blood that we can’t currently detect. In breast cancer, this is a real conundrum for HR-positive disease, where many women are on endocrine therapies for a decade. A minority of them are going to recur and when that happens, it’s no longer a curable disease because it’s metastatic.

In the CHiRP study, led by investigators at the Dana-Farber Cancer Institute and published in the Journal of Clinical Oncology, the investigators used long-term follow-up and serial blood draws [to determine whether they could] detect cancer before it recurred in these individuals. The answer was, yes. The sample size was small, but it speaks to us because in all the patients who recurred, investigators detected that possibility in their blood beforehand. That opens up the opportunity to intervene and give these patients additional therapies that might cure them. That’s exciting news.

The last 2 studies were more about the qualitative aspects of ctDNA, asking: Can we find certain mutations that lead to resistance to targeted therapies and act upon that? [The ctDNA analysis of the phase 3 VOYAGER trial, which] was from Spain, looked at GISTs. There are certain targeted therapies that are trying to hit the molecular alterations that drive [GIST] tumors. But eventually, resistance occurs.

By looking at liquid biopsies and finding what mutations occur, the VOYAGER group showed nicely that some resistance mutations should probably not get a certain type of second-line therapy but would rather benefit from a different line of therapy. That’s exciting, because even though [this trial is] retrospective right now, it sets the stage for prospective studies that we can use to show that getting liquid biopsies dictates which is a patient’s best therapy.

The last study, [a plasma biomarker analysis of CodeBreaK 100], was from Memorial Sloan Kettering Cancer Center, where my colleagues were looking at resistance mechanisms to a relatively new inhibitor, a targeted therapy called sotorasib. Sotorasib is specifically for [KRAS G12C–mutant] cancers, and [in this analysis, was studied in KRAS G12C–mutant] CRC and lung cancer. Sotorasib, as a mutation-specific drug, is new and different in our field.

Unfortunately, many patients [with KRAS G12C mutations] will develop resistance. This group looked at liquid biopsies to figure out the mechanisms. What they found was that there are many different mechanisms, but they all seem to be in certain types of pathways, many of which we have drugs for. This sets the stage and provides a greater opportunity to now do additional trials, which are underway, looking at combining therapies or giving them sequentially with the new drug, sotorasib, and existing drugs, to prevent the emergence of resistance.

What study showed the greatest clinical implications in terms of applying ctDNA to practice?

All these studies helped move the needle forward. The one that probably gets us closest to clinical utility, is the [DYNAMIC] study, which was a collaborative effort from a group in Australia, the Peter MacCallum Cancer Centre, and the Johns Hopkins University School of Medicine. That study brings to bear that we’re close to using ctDNA for many of our patients and making decisions based upon liquid biopsies to determine who [will and won’t] benefit from chemotherapy.

Many of these tests are now available, but I can envision that [ctDNA testing] is going to become a routine practice for our patients. It’s going to spare many patients chemotherapy toxicity who don’t have any chance of benefit, and importantly, it will also identify patients who aren’t getting chemotherapy or additional therapies who would benefit. It also provides a whole new platform for how we can [develop] newer drugs faster to cure more patients going forward. This is an exciting time and a wave of the future. The ASCO presentation session was aptly named, “ctDNA: Dawn of a New Era.”

How will ctDNA testing fit into the treatment paradigm moving forward?

We should all be careful to make sure we have the highest possible level of evidence that shows that these tests are as good as we hope and think they are, and that they are going to meaningfully affect outcomes in a positive way. That takes time, and it takes more than validation studies. It takes utility studies to show that doing these tests, incorporating them into both early-stage and late-stage [treatment, is effective].

[We need to look at] both the quantitative aspects, like [whether the mutations are there], and the qualitative aspects, like what new genes can mediate resistance. All of that has a tremendous opportunity to be integrated into all stages of cancer therapy. That’s the exciting part. But to get there, [we still need to conduct many studies and do a lot of work]. Unfortunately, in some ways, none of us are going to be out of a job anytime soon.

What additional ongoing ctDNA research are you excited about?

When I think about ctDNA analysis and how to guide therapies, heretofore, most of the studies have been focused on the qualitative aspects. We see a mutation and we have a drug [for it] or we see a new mutation that pops up as a resistance mediator [and we want to find] a drug for that.

The opportunities that haven’t been leveraged are the quantitative aspects, [and not just measuring MRD]. The paradigm in metastatic disease is usually to start a new drug, wait 2, 3, or even 4 months, take another computed tomography [CT] scan, and go from there. You [as the care provider] feel bad, as does the patient, if you’ve spent 3 to 4 months administering a drug, and the next staging CT scan shows that it didn’t work.

[We want to know if we can] do better. [If a patient has a lot of] CT data and blood before they start their new therapy for metastatic disease, and after a week or 2, [those data] go up, that probably means [the therapy is] not working. However, if they go down, that probably means it is working.

We’re doing a study right now looking at whether we can use that quantitative aspect to get to a newer drug faster than we can if we wait 3 months [to discover the new therapy] doesn’t work and see that the disease is now bigger than it was 2 or 3 months ago. We’re hopeful that this approach will lead to a paradigm shift in how we think about treating metastatic disease and getting drugs earlier to patients when they need them.

What main message about these ctDNA studies would you like to impart to colleagues?

This is hugely exciting. Over the next 5 to 10 years as a field, [we may experience a change in] how we think about using liquid biopsies to guide therapy. However, I want to end on a note of caution. We can’t just leapfrog ahead and skip all the steps that we need to prove how sensitive and how predictive these tests are or are not. We’ve learned time and time again, the hard way, that if you do that, you probably end up causing more harm than good.

[I’d like to] quote 1 of my heroes in this field, Daniel F. Hayes, [MD, of the University of Michigan Comprehensive Cancer Center], a past president of ASCO and 1 of the godfathers of biomarker development. He said that a bad test can be just as dangerous as a bad drug. I believe that philosophy. We must take all the necessary and oftentimes slow steps to get these tests to the level where we trust them and where they can be used reliably.

References

1. Tie J, Cohen J, Lahouel K, et al. Adjuvant chemotherapy guided by circulating tumor DNA analysis in stage II colon cancer: the randomized DYNAMIC trial. J Clin Oncol. 2022;40 (suppl 17):LBA100. doi:10.1200/JCO.2022.40.17_suppl.LBA100
2. Lipsyc-Sharf M, De Bruin EC, Santos K, et al. Circulating tumor DNA (ctDNA) and late recurrence in high-risk, hormone receptor–positive, HER2-negative breast cancer (CHiRP). J Clin Oncol. 2022;40(suppl 16):103. doi:10.1200.JCO.2022.40.16_suppl.103
3. Serrano C, Bauer S, Gómez-Peregrina D, et al. Circulating tumor DNA (ctDNA) analyses of the phase III VOYAGER trial: KIT mutational landscape and outcomes in patients with advanced gastrointestinal stromal tumor (GIST). J Clin Oncol. 2022;40(suppl 16):101. doi:10.1200.JCO.2022.40.16_suppl.101
4. Li BT, Velcheti V, Price TJ, et al. Largest evaluation of acquired resistance to sotorasib in KRAS p.G12C-mutated non–small cell lung cancer (NSCLC) and colorectal cancer (CRC): plasma biomarker analysis of CodeBreaK100. J Clin Oncol. 2022;40(suppl 16):102. doi:10.1200/JCO.2022.40.16_suppl.102