ctDNA Proven to Guide Adjuvant Chemotherapy in Colorectal Cancer – MediaMedic

Dr: Kasi: shared early findings from the BESPOKE CRC trial, which evaluates ctDNA-based MRD to inform adjuvant chemotherapy for stage II/III CRC patients. This trial builds on retrospective analyses suggesting MRD’s utility in guiding treatment decisions.

The study analyzed plasma samples from 350 patients (154 stage II, 196 stage III) using tumor-informed ctDNA detection and quantification. Following curative tumor resection, 232 patients received adjuvant chemotherapy while 118 were observed. Median follow-up was 24.8 months.

Overall, we observed a 15.6% ctDNA positivity rate in the initial dataset, with more stage III than stage II patients testing positive (22% vs. 7%). Regardless of stage, ctDNA-positive patients had over 20 times the recurrence risk compared to ctDNA-negative patients, noted Dr. Kasi.

The trial also assessed ctDNA’s predictive value for survival outcomes. MRD-positive patients receiving adjuvant chemotherapy had a median disease-free survival (DFS) of 18.7 months, compared to 6.7 months for the observation group (HR 3.9, 95% CI [1.3, 11.5]; P = 0.01).

Interestingly, in ctDNA-negative patients, DFS did not significantly differ with or without chemotherapy (HR 1.1, 95% CI [0.3, 3.9]; P = 0.89). Dr. Kasi suggests two possibilities for ctDNA-negative patients: either they are cured, or ctDNA levels are too low for current detection methods to capture.

ctDNA is a dynamic variable that changes over time and is influenced by treatment, Dr. Kasi explained. Currently, clinician’s base adjuvant chemotherapy decisions on at least a dozen factors, including patient age, tumor size, lymph node involvement, and tumor budding. In previous trials like DYNAMIC, ctDNA-guided adjuvant therapy proved non-inferior to standard treatment in stage II colon cancer.

Dr. Alberto Puccini from IRCCS Humanitas Research Hospital in Milan commended the BESPOKE CRC data, especially for stage III CRC patients with an MRD positivity rate around 20-25%. “These findings validate ctDNA’s prognostic impact in CRC patient’s post-resection, confirming the lack of adjuvant chemotherapy benefits in MRD-negative patients and significant advantages for MRD-positive ones,” Dr. Puccini stated.

The study highlights ctDNA clearance’s importance, showing that MRD-cleared patients enjoy longer DFS than those who remain MRD-positive.

ctDNA in Guiding Adjuvant Chemotherapy for Rectal Cancer

Dr. Tie and colleagues conducted the phase II AGITG DYNAMIC-Rectal trial to assess ctDNA’s role in LARC adjuvant chemotherapy guidance. “Given the modest benefits of adjuvant chemotherapy for LARC, we examined whether a ctDNA blood test could reduce the number of patients needing chemotherapy,” Dr. Tie said.

Eligible patients had LARC (cT3-4 and/or cN+) treated with neoadjuvant chemoradiotherapy and total mesorectal excision. Patients were randomized 2:1 to ctDNA-guided therapy or standard management. Post-surgery, ctDNA-positive patients at weeks 4 and/or 7 received four months of oxaliplatin or fluoropyrimidine chemotherapy, while ctDNA-negative patients with node-negative status skipped chemotherapy unless clinicians deemed it necessary.

Though the study ended early due to COVID-19 and increased uptake of total neoadjuvant therapy, the authors showed that ctDNA-guided adjuvant therapy was linked to lower chemotherapy use.

The ctDNA positivity rate was 28%. Only 46% of patients in the ctDNA-guided group received adjuvant chemotherapy, compared to 77% in the standard management group. Moreover, 28% of ctDNA-guided patients received oxaliplatin-based doublet therapy versus 25% in the standard group. Three-year DFS was 76% for ctDNA-guided management and 82% for standard treatment.

For LARC patients with post-surgery ctDNA positivity, recurrence risk remained high despite adjuvant chemotherapy—more than double that of ctDNA-negative patients not receiving chemotherapy (38% vs. 17%), underscoring their need for more effective treatment, Dr. Tie explained.

The study noted that most (80%) ctDNA-negative patients who relapsed developed lung-only metastases. This intriguing observation suggests that micro-metastatic lung disease may not shed enough ctDNA into circulation for detection, Dr. Tie remarked.

Dr. Tie emphasized key points for patients with post-surgery ctDNA positivity, new therapies might be more appropriate than reusing the same chemotherapy used in neoadjuvant treatment. For ctDNA-negative patients, omitting chemotherapy may be viable, though it depends on clinicians’ tolerance for minor false negatives.

Looking Ahead: The Future of ctDNA in Clinical Practice

These trials represent early results of randomized studies on ctDNA-guided disease management for rectal cancer, similar to findings from the colon cancer DYNAMIC trial. Fewer patients received chemotherapy overall, but ctDNA-positive patients were more likely to receive doublet therapy with oxaliplatin, given their poorer prognosis.

Based on these findings, Dr. Puccini remains optimistic about ctDNA’s clinical utility in oncology centers soon, helping to personalize treatment for CRC patients.”

For more posts like this visit oncodaily.com.