SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 153,020 new cases of CRC will be diagnosed in the United States in 2023 and about 52,550 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.
It is estimated that approximately 30% of patients with Stage II or III CRC and 60–70% of patients after oligometastatic resection experience recurrence. Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (Stage III) colon cancer has been the standard of care since the 1990s. However, not all patients with Stage III disease benefit from adjuvant chemotherapy. In the IDEA trial, the absolute Disease Free Survival benefit of adjuvant chemotherapy for the lowest-risk Stage III group and the highest-risk group was 8% and 20%, respectively, suggesting that a substantial number of patients with low-risk Stage III cancer can safely forgo adjuvant chemotherapy or be considered for treatment de-escalation. Even though 80% of patients with Stage II colon cancer are cured with surgery alone, adjuvant chemotherapy is recommended for patients who have Stage II colon cancer with high-risk clinicopathological features, including tumor penetration of the serosa (T4 disease). However, the benefit of adjuvant chemotherapy for patients with Stage II disease remains unclear, with less than 5% of patients benefiting from adjuvant chemotherapy. There is therefore an unmet need for more precise markers to predict risk of recurrence after surgery for resectable colon cancer, other than clinicopathological risk factors, and thus avoid exposure to unnecessary chemotherapy.
Circulating Tumor DNA (ctDNA) refers to DNA molecules that circulate in the bloodstream after cell apoptosis or necrosis, and can be detected in the cell-free component of peripheral blood samples (Liquid Biopsy) in almost all patients with advanced solid tumors including advanced colorectal cancer. ctDNA is a valuable biomarker and is directly evaluated for evidence of Minimal Residual Disease and allows early detection of relapse. Several studies have shown that detectable ctDNA following curative intent surgery for early stage cancers, including those with Stage II colon cancer, is associated with a very high risk of recurrence (more than 80%) without further adjuvant therapy. It has remained unclear whether adjuvant treatment is beneficial for these ctDNA-positive patients who are at high risk for recurrence.
The GALAXY study/cohort is a part of the CIRCULATE-Japan project, and is a large prospective, observational study that monitors ctDNA status for patients with clinical Stage II-IV or recurrent colorectal cancer following curative-intent surgery. In order to prospectively validate and build upon the previously published evidence, the authors conducted this cohort study to demonstrate that postsurgical ctDNA positivity is predictive of disease recurrence in early-stage CRC. In this publication the researchers reported on postsurgical ctDNA positivity and its associations with patient outcomes, as well as its implications for adjuvant chemotherapy selection, and the association between ctDNA dynamics and prognosis.
The GALAXY study/cohort included 1039 patients with clinical Stage II-III colon cancer or surgically resectable clinical Stage IV or recurrent colorectal cancer. Eligible patients had histologically confirmed colorectal adenocarcinoma, and curative resection planned for clinical Stage II or III, and R0 resection planned for relapsed or Stage IV colorectal cancer. The median age was 69 years. Formalin-Fixed, Paraffin-Embedded (FFPE) tumor tissue samples from surgical resection or biopsy were used for Whole Exome Sequencing (WES) to identify up to 16 patient-specific clonal, somatic Single-Nucleotide Variants (SNVs). These SNVs were then used to design personalized multiplex Polymerase Chain Reaction-based Next-Generation Sequencing assays (Signatera, Natera) for each study participant. Cell-free DNA was extracted from patient plasma at a given time point and was used to detect ctDNA. Plasma samples with at least 2 out of 16 tumor-specific variants detected above a predefined threshold were defined as ctDNA positive (tumor-informed ctDNA analysis. Overall, a total of 8,374 genes were selected for the 1,039 patients and the most frequently selected genes were TP53 (25.6%) and APC (17.5%). It was noted that more than 50% of genes were unique to each patient, suggesting large variability in the mutational landscape of colorectal cancer outside of known hotspot regions.
At a median follow-up of 16.74 months, postsurgical ctDNA positivity at 4 weeks after surgery was associated with higher recurrence risk compared to those patients who were ctDNA negative (61.4% versus 9.5%; HR=10.0, P< 0.0001) and the 18-month Disease Free Survival (DFS) was 38.4% versus 90.5%, respectively. This benefit was noted across all pathological stages. There was however no significant difference in recurrence risk by presurgical ctDNA status across all stages. In multivariate analysis for DFS in patients with pathological Stage II–III disease, ctDNA positivity 4 weeks after surgery was the most significant prognostic factor associated with increased risk for recurrence (HR=10.82, P< 0.001). Further, clinicopathological risk factors often used for staging and prognostication were nonsignificant. ctDNA was more valuable than CEA for relapse detection.
The researchers in this analysis examined the outcomes of ctDNA-positive and ctDNA-negative patients stratified by adjuvant chemotherapy status after adjusting for confounding variables such as age, sex, MSI status, pathological stage, and performance status in this analysis.
It was noted that patients with high-risk Stage II or Stage III disease and ctDNA-positive status 4 weeks after surgery derived significant benefit from adjuvant chemotherapy (adjusted HR=6.59; P< 0.001), and this trend was observed across all pathological stages. ctDNA-positive patients with Stage II–IV disease, not receiving adjuvant chemotherapy were noted to be at a higher risk for recurrence (adjusted HR=5.03; P< 0.001). Approximately 75% of ctDNA-positive patients with pathological Stage I or low-risk Stage II disease did not receive adjuvant chemotherapy and experienced recurrence.
Among the high-risk pathological Stage II or Stage III disease patients with ctDNA-negative status 4 weeks after surgery, there was no statistically significant benefit with adjuvant chemotherapy and the 18-month DFS was 94.9% and 91.5% for the adjuvant chemotherapy group and the observation group, respectively.
Among patients with available ctDNA status both 4 weeks and 12 weeks after surgery, there was a significantly higher risk of recurrence among patients who converted from ctDNA negative to positive, compared to those patients who were persistently negative (HR=14.0; P< 0.001).
Among the patients with ctDNA positivity 4 weeks after surgery, adjuvant chemotherapy was associated with a higher incidence of ctDNA clearance by week 24 after surgery compared with those who did not receive adjuvant therapy (68.48% versus 12.2%; adjusted HR=8.50, P< 0.0001). Among those who did not achieve ctDNA clearance, the DFS was inferior (adjusted HR=11; P< 0.0001).
Based on the results of this large and comprehensive prospective analysis of ctDNA in resectable colorectal cancer, the authors concluded that ctDNA status is a superior prognostic biomarker than the currently used high-risk clinicopathological features, and can identify patients who are at increased risk of recurrence and are likely to benefit from adjuvant chemotherapy.
Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer. Kotani D, Oki E, Nakamura Y, et al. Nature Medicine 2023; 29:127–134.
