Serial ctDNA Monitoring to Predict Response to Systemic Therapy in Metastatic Gastrointestinal Cancers

Abstract

Purpose: ctDNA offers a promising, noninvasive approach to monitor therapeutic efficacy in real-time. We explored whether the quantitative percent change in ctDNA early after therapy initiation can predict treatment response and progression-free survival (PFS) in patients with metastatic gastrointestinal cancer. Experimental Design: A total of 138 patients with metastatic gastrointestinal cancers and tumor profiling by next-generation sequencing had serial blood draws pretreatment and at scheduled intervals during therapy. ctDNA was assessed using individualized droplet digital PCR measuring the mutant allele fraction in plasma of mutations identified in tumor biopsies. ctDNA changes were correlated with tumor markers and radiographic response. Results: A total of 138 patients enrolled. A total of 101 patients were evaluable for ctDNA and 68 for tumor markers at 4 weeks. Percent change of ctDNA by 4 weeks predicted partial response (PR, P < 0.0001) and clinical benefit [CB: PR and stable disease (SD), P < 0.0001]. ctDNA decreased by 98% (median) and >30% for all PR patients. ctDNA change at 8 weeks, but not 2 weeks, also predicted CB (P < 0.0001). Four-week change in tumor markers also predicted response (P ¼ 0.0026) and CB (P ¼ 0.022). However, at a clinically relevant specificity threshold of 90%, 4-week ctDNA change more effectively predicted CB versus tumor markers, with a sensitivity of 60% versus 24%, respectively (P ¼ 0.0109). Patients whose 4-week ctDNA decreased beyond this threshold (≥30% decrease) had a median PFS of 175 days versus 59.5 days (HR, 3.29; 95% CI, 1.55-7.00; P < 0.0001). Conclusions: Serial ctDNA monitoring may provide early indication of response to systemic therapy in patients with metastatic gastrointestinal cancer prior to radiographic assessments and may outperform standard tumor markers, warranting further evaluation.

Favorable Outcomes in FGFR Fusion-Positive Cholangiocarcinomas and Evolution on Treatment Noted on Circulating Tumor DNA Liquid Biopsies

“…The diagnosis of cancer and its treatments already result in significant financial toxicity. Finally, the value of "repeat genomic testing" (whether tissue and preferably liquid first) merits attention following progression on targeted therapies as is illustrated in some of the recent studies [17]. It brings up an intriguing question about carefully revisiting locoregional treatments for the right patient following exposure to targeted therapies.…”

Patient specific circulating tumor DNA fingerprints to monitor treatment response across multiple tumors

“…These properties make ctDNA a promising tool to monitor tumor progression and treatment response [ 4 – 6 ]. Several studies have demonstrated that ctDNA had higher sensitivity and specificity than the traditional methods such as radiological imaging and blood protein biomarkers under some conditions [ 7 , 8 ]. In metastatic colorectal cancer (CRC), the different patterns of ctDNA level change correlated with tumor responses in patients [ 9 , 10 ].…”

Multiplex detection of ctDNA mutations in plasma of colorectal cancer patients by PCR/SERS assay

“…We also followed patient #61 during treatment and after 4 months of chemotherapy, we observed ten-fold reduced ctDNA levels for the BRAF mutant allele, consistent with good treatment response. It has been reported that serial monitoring of BRAF V600E levels in ctDNA at baseline and on treatment may be a clinically useful marker for tumor response, with greater reduction in ctDNA mutant alleles in responding patients compared to those with stable or progressive disease 43 - 45 . These results demonstrate that the PCR/SERS ctDNA detection strategy holds great potential for rapid liquid biopsy mutation detection, tracking treatment responses, monitoring tumor progression, and assessing residual disease.…”