Liquid Biopsy Can Determine the Need for Chemotherapy After Colon Cancer Surgery

Stage 2 colon (large bowel) cancer involves a tumor affecting all layers and the lining of the large bowel, but without spread to nearby lymph nodes or distant organs. The main treatment for these patients is surgical removal of the tumor through colon cancer surgery. However, postoperative chemotherapy to reduce the risk of recurrence is known to benefit only a small proportion of patients with stage 2 colon cancer, and until now we have had little concrete information about which patients benefit from adjuvant (preventive) chemotherapy.

According to a study presented at the ASCO 2022 annual meeting, for people with stage 2 colon cancer after surgery, a new test detecting circulating tumor DNA in the blood (ctDNA) is a new liquid (fluid) biopsy that helps identify patients most likely to benefit from adjuvant chemotherapy, identifies those unlikely to benefit, and allows them to avoid this chemotherapy.

Liquid biopsy, the detection of tumor-related DNA in the blood, is currently the best technological tool available for improving clinical decision-making in precision oncology. Liquid biopsy currently has sufficient evidence and clinical validity for mapping the tumor’s genetic makeup in already diagnosed advanced cancers to predict the benefit of molecularly targeted drugs. However, measuring circulating tumor DNA (ctDNA) to detect cancer early or identify patients at high risk of recurrence after surgery has not yet received FDA (US Food and Drug Administration) approval. This new study highlights residual disease after primary treatment and recurrence (relapse) risk as areas in which using liquid biopsy holds great potential for prediction.

The Phase 2 DYNAMIC Study

The New England Journal of Medicine published the study results simultaneously with their presentation at the ASCO 2022 annual meeting by medical oncologist Dr. Jeanne Tie from the University of Melbourne, Australia. Dr. Tie said, “The strategy of using ctDNA results to guide treatment after surgery nearly halved the number of patients receiving chemotherapy, from 28% to 15%.”

Dr. Tie said that the overall proportion of patients alive and free of cancer 3 years after ctDNA-guided treatment was 92%, the same as among patients receiving standard treatment.

The probabilities of survival and being cancer-free were 86.4% and 92.5%, respectively, in ct-DNA-negative patients who did not receive chemotherapy and ctDNA-positive patients who received adjuvant chemotherapy. In contrast, ctDNA-positive patients had a risk of disease recurrence without treatment of more than 80%.

Tie said the study supports adding a ctDNA-guided approach to treatment in this group of patients and also addresses a clinical dilemma: surgery can cure more than 80% of stage 2 patients, but few will benefit from postoperative chemotherapy – fewer than 1 in 20 patients. Without a tool such as liquid biopsy, however, we cannot predict which patients will benefit. Even if the proportion benefiting from chemotherapy is small, identifying them is very important.

Patients whose blood is ct-DNA positive after surgery may need more than standard chemotherapy. For example, adjuvant immunotherapy, EGFR-targeted adjuvant treatment, or other treatments in metastatic disease that we have shown to be beneficial should be considered for the group of ct-DNA-positive patients.

Study Details

Tie and colleagues enrolled patients with resected stage 2 colon cancer from multiple centers in the DYNAMIC study between August 2015 and August 2019, totaling 445 patients.

Of these, 302 were randomized (assigned to groups at random) to receive ctDNA-guided chemotherapy, and 153 received standard treatment based on conventional criteria, including tumor stage, the number of lymph nodes assessed, whether the tumor had penetrated the bowel wall, and other factors.

The experimental group used a personalized ctDNA test called Safe-SewS to detect ctDNA. Patients with a positive ctDNA result 4 or 7 weeks after surgery received oksaliplatin-based or floropirimidin chemotherapy; those with negative ctDNA were observed during follow-up.

As expected, fewer patients overall received adjuvant chemotherapy in the ctDNA-guided group than in the standard treatment group (15.3% versus 27.9%).

Two-year relapse-free survival in the ctDNA-guided treatment group was not lower than in the standard treatment group (92.4% versus 93.5%).

Three-year relapse-free survival was 86.4% in ctDNA-positive patients who received chemotherapy, 92.5% in ctDNA-negative patients who did not receive chemotherapy, and 96.7% in a clinically low-risk subgroup.

Thanks to the results of these studies, we can now better identify which stage 2 colon cancer patients will benefit from postoperative chemotherapy and which can avoid additional treatment without compromising recurrence-free survival.

The Next Stage of the Study

The authors state that a randomized study is being considered that would include ctDNA-positive and ctDNA-negative patients randomized to treatment or no treatment. According to the press release, this could provide more definitive evidence of the effect of treatment or withholding treatment in each patient subgroup.

The New England Journal of Medicine published an editorial by Clara Montagut and Joana Vidal, who wrote that, considering the novelty of the approach used in this study and the potential clinical implications of the results, “The authors should be congratulated”.

This study, across all solid-organ cancers, may allow the need for adjuvant treatment to be determined more clearly.

This study also raises important questions, including whether selected patients with high-risk pathological factors and ctDNA-negative disease will benefit from chemotherapy, whether chemotherapy prevents recurrence or merely delays it, which subgroup of ctDNA-positive patients may truly benefit from chemotherapy, and which chemotherapy regimen should be used.

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The uses and approval status of liquid biopsies in cancer can be seen below: