The Signatera molecular residual disease test was able to detect patients with stage II to IV colorectal cancer who were at an increased risk for recurrence and predict which patients were most likely to benefit from adjuvant chemotherapy.
The Signatera™ molecular residual disease (MRD) test was able to detect patients with stage II to IV colorectal cancer (CRC) who were at an increased risk for recurrence and predict which patients were most likely to benefit from adjuvant chemotherapy (ACT).1
Results from the GALAXY arm of the ongoing CIRCULATE-Japan trial (UMIN000039205) showed that post-surgical MRD status was predictive for chemotherapy benefit. These new data build on results previously presented at the 2022 ASCO Gastrointestinal Cancers Symposium, with median clinical follow-up extended to 16.74 months and disease-free survival (DFS) assessment at 18 months.
Patients with circulating tumor DNA (ctDNA)–positive, high-risk stage II/III disease 4 weeks after surgery derived significant benefit from ACT (adjusted HR, 6.59; 95% CI, 3.53-12.3; P < .001). This trend was consistent across all pathological stages.
Receipt of ACT was associated with a superior 18-month DFS of 61.6% (95% CI, 49.0-71.9%) for the ACT group vs 22.0% (95% CI, 10.9-35.5%) for the non-ACT group, and the lack of ACT was the strongest negative predictor for outcome for patients with stage II to IV disease (adjusted HR, 5.03; 95% CI, 3.17-8.9; P = .001).
In contrast, investigators saw no statistically significant benefit associated with ACT in ctDNA-negative patients after adjusting for potentially confounding factors (HR, 1.71; 95% CI, 0.80-3.7; P = 0.167).
“Until now, oncologists did not have adequate tools to determine which [patients with] CRC are likely to benefit from adjuvant systemic therapy,” principal study investigator Takayuki Yoshino, MD, PhD, director for the Department of Gastroenterology and Gastrointestinal Oncology and head of the Clinical Research Coordinating Division at the National Cancer Center Hospital East, in Chiba, Japan, said in a news release.2 “This study provides strong evidence that Signatera MRD-positive patients will benefit significantly from adjuvant therapy, while MRD-negative patients may be safely observed, regardless of clinical or pathological stage.”
“This is a practice-changing study for the colorectal cancer community, demonstrating the predictive power of Signatera in the adjuvant setting,” added Minetta Liu, MD, chief medical officer of Natera.
Investigators included 1039 patients in the ctDNA analysis. Four weeks following surgery, 18.0% were ctDNA positive and 82.0% were ctDNA negative. To evaluate ctDNA dynamics from 4 to 12 weeks, patients who experienced recurrence within 12 weeks (n = 45) and who did not have ctDNA status available 12 weeks after surgery (n = 157) were excluded.
Among patients the ctDNA-negative group (n = 852), the median was 69 years (range, 25-93). Men made up 50.8% of the cohort, and 87.3% had an ECOG performance status of 0. Left sided tumors made up 53.2% of cancers, 41.1% appeared on the right side, and 5.7% appeared in the rectum. Eighty-four percent of patients had T3-T4 disease, and 54.7% had pathological stage N0 disease. Pathologic stage III disease was most common (36.0%), followed by stage II (34.1%), stage IV or recurrent (18.8%), and stage I (11.1%).
Almost half of patients had RAS and BRAF wild-type tumors, 41.3% had RAS-mutated disease, and 9.2% had BRAF-mutated disease. Most patients (88.8%) were microsatellite stable (MSS), and 11.2% had microsatellite instable-high (MSI-H) tumors.
In the ctDNA-positive group (n = 187), the median was 67 years (range, 39-88). Men made up 62.6% of the cohort, and 88.2% had an ECOG performance status of 0. Left sided tumors made up 61.1% of cancers, 28.6% appeared on the right side and 10.3% appeared in the rectum. Ninety-five percent of patients had T3-T4 disease, and 75.7% had pathological stage N1-N2 disease. Stage III disease was most common (48.7%), followed by stage IV or recurrent (37.4%), stage II (12.8%), and stage I (1.1%).
Just over half of patients had RAS and BRAF wild-type tumors, 46.5% had RAS-mutated disease and 3.2% had BRAF-mutated disease. Unlike in the ctDNA-negative cohort, almost all patients in this group had MSI-high tumors (97.3%).
Investigators conducted whole exome sequencing and analyzed the results to design a “tumor-informed, personalized ctDNA assay.” They selected 8374 genes for 1039 patients, most often TP53 (25.6%) and APC (17.5%). More than 50% of genes were unique to each patient, which investigators said suggests a large variability in the mutational landscape in CRC outside of the known hotspots.
At the June 8, 2022, data cutoff, 61.4% (n = 115/187) of patients who were ctDNA positive 4 weeks after surgery experienced recurrence compared with 9.5% (n = 81/852) of those who were ctDNA negative (HR, 10.0; 95% CI, 7.7-14.0; P < .0001). Investigators found this trend to be consistent across all pathologic stages.
In contrast, investigators did not observe a significant risk for recurrence associated with presurgical ctDNA status (HR, 0.89; 95% CI, 0.55-1.40; P = .062).
The pre-surgical detection rate was 95.9% for patients with pathologic stage II/III disease and 93.1% for patients with stage II to IV disease. Among patients with stage II/III disease, ctDNA positivity 4 weeks following surgery was the most significant predictor for increased risk for recurrence (HR, 10.82; P < .001). “Of note, all clinicopathological risk factors traditional used for staging and prognostication were insignificant,” investigators wrote.