ctDNA Testing Shows Promise for Influencing Colorectal Cancer Treatment

SAN FRANCISCO — Circulating tumor DNA (ctDNA) measurements showed promise for identifying patients with early colorectal cancer (CRC) most likely to benefit from adjuvant therapy, analyses of two large clinical trials suggested.

Patients who had positive ctDNA tests after surgery were almost twice as likely to be alive at 3 years if they received adjuvant celecoxib in addition to chemotherapy, whereas the addition of the COX2 inhibitor to chemotherapy was not associated with better disease-free survival (DFS) in ctDNA-negative patients. This insight came from a randomized trial that showed no benefit of celecoxib overall in a population not determined by ctDNA status.

A second study also showed that only ctDNA-positive patients benefited from adjuvant chemotherapy and that ctDNA clearance within 3 or 6 months predicted better DFS. Serial testing was associated with a high rate of potentially curative therapy for oligometastatic disease.

Both studies were reported at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.

The two studies added to mounting evidence that “ctDNA is a powerful tool poised to revolutionize oncology practice,” according to invited discussant Richard Kim, MD, of the Moffitt Cancer Center in Tampa, Florida.

“However, I think that at this time the science has outpaced the clinical data, creating some uncertainty for oncologists and payers,” said Kim. “I think there’s really strong observational data supporting ctDNA as a predictive and prognostic marker, and we’re still awaiting results from ongoing phase III trials to solidify its role in clinical practice.”

Status of ctDNA is prognostic for recurrence both during molecular residual disease (MRD) and surveillance windows, he continued. “It is potentially predictive for adjuvant therapy in stage II and III colon cancer. However, details of stratification and the adjuvant regimen and duration remain to be determined. Early and intensive surveillance could potentially increase curative-intent interventions, highlighting an area that warrants further investigation.”

In the meantime, carcinoembryonic antigen assessment remains the cost-effective standard and aligns with current clinical guidelines, said Kim.

Negative Trial With ctDNA Upside

The CALGB/SWOG 80702 trial evaluated the addition of celecoxib to standard adjuvant chemotherapy in stage III CRC. The trial failed to show an improvement in DFS among patients who received the COX2 inhibitor. However, separation of the Kaplan-Meier survival curves and a final hazard ratio of 0.89 suggested a potential benefit in subgroups of patients, said Jonathan A Nowak, MD, PhD, of Dana-Farber Cancer Institute in Boston.

About 1,750 of the 2,526 patients in the trial consented to specimen collection. In a separate study, investigators generated whole-exome sequencing data for about 1,200 patients. Subsequently, 940 patients had sufficient plasma, collected after surgery but before the start of adjuvant therapy, for ctDNA testing by means of the Signatera assay. Results showed that 18.4% of the specimens were ctDNA positive.

Consistent with previous studies, ctDNA status predicted 3-year DFS, which was 86.5% in patients with ctDNA-negative tests and 33.7% among patients with positive results (PP=0.0013).

An analysis of overall survival (OS) yielded similar results: ctDNA-positive patients who received celecoxib in addition to chemotherapy had a statistically significant 37% reduction in the hazard ratio, whereas patients with negative ctDNA test results had a nonsignificant 16% reduction in the hazard.

“In a subset of patients enrolled in CALGB/SWOG 80702, ctDNA status after surgery and prior to starting adjuvant therapy was highly prognostic of DFS and OS,” said Nowak. “ctDNA status also appeared predictive of benefit of adjuvant celecoxib. Studies on the predictive value of ctDNA for 3 versus 6 months of adjuvant [chemotherapy] are underway.”

Positive Trial With ctDNA Upside

Postoperative ctDNA testing for patients with stage II-III CRC led to a change in adjuvant therapy in 16% of cases, and 84% of oncologists who did not change treatment plans nonetheless said the test results made them feel more comfortable with planned treatment, the multicenter BESPOKE CRC study showed.

“The current standard of care for surgically resected, high-risk stage II and all stage III CRC patients is adjuvant chemotherapy for 3 to 6 months,” said presenter Purvi Shah, MD, of the Virginia Cancer Institute in Richmond. “Yet, we know that adjuvant chemotherapy benefits only a subset of these patients, unnecessarily exposing them to the toxicities of chemotherapy.

“In the BESPOKE CRC study, we used a commercial personalized ctDNA test … to assess the impact of ctDNA testing on adjuvant treatment decisions, evaluate recurrence rates in stage II and III colorectal cancer, and [secondarily] study molecular residual disease clearance, impact on survival, and patient quality of life.”

The study involved 1,780 patients with resectable stage II-III CRC, 1,166 of whom were included in the analysis of ctDNA testing. The analyses included 694 patients who received adjuvant chemotherapy and 472 who did not.

The results showed that 7.54% of patients with stage II disease had positive ctDNA tests after surgery, as did 28.35% of those with stage III CRC. Confirming the strong association between ctDNA test results and DFS, stage II patients with a negative ctDNA test had a 2-year DFS of 91.8% versus 45.9% among those with positive results. In the stage III cohort, a negative test was associated with a 2-year DFS of 87.4% versus 35.5% for patients with positive results.

An analysis of postoperative surveillance of MRD status showed that recurrence at the first MRD assessment was associated with a DFS hazard ratio of 20.63 (PP

Clearance of ctDNA after adjuvant therapy was associated with improved DFS, including clearance within 3 months (HR 0.43, 95% CI 0.29-0.64, PP

Overall, 188 patients had disease recurrence, including 26 (14%) who were ctDNA-negative within 24 weeks and 162 (86%) who were ctDNA-positive. Subsequently, 48 (30%) patients received metastasis-directed therapy (MDT), primarily surgery (n=47) but also ablative therapy, radiotherapy, and radionuclide therapy.

“This underscores the value of following ctDNA serially, not only in the surveillance setting, not only as a prognostic marker, but for its potential ability to be associated with a higher rate of MDT compared to historical data, potentially giving these patients a shot at a cure,” said Shah.

An analysis of ctDNA testing for early detection of recurrence showed that test had high sensitivity across multiple sites of recurrence, including liver (96%), lymph nodes (89%), abdominopelvic (86%), peritoneum (79%), and lung (76%), as well as all four cases of bone recurrence and all three abdominal-wall recurrences.

Finally, ctDNA-MRD testing proved to be predictive of benefit from adjuvant chemotherapy in ctDNA-positive patients. Those who received adjuvant therapy had a 2-year postoperative DFS 40.3% versus 24.7% for those who were observed. Median DFS was 17.7 months with adjuvant therapy and 7.1 months without.

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