On-treatment measurements of circulating tumor DNA during FOLFOX therapy in patients with colorectal cancer

Abstract

We addressed a significant unknown feature of circulating tumor DNA (ctDNA), i.e., how ctDNA levels change during chemotherapy, by serially monitoring ctDNA in patients with colorectal cancer during the 48-h application of FOLFOX. Surprisingly, we did not observe a spike in ctDNA as a sign of a responsive tumor, but instead ctDNA levels initially decreased and remained low in patients with stable disease or partial response. Our observations reveal further insights into cell destruction during chemotherapy with important implications for the management of patients.

Blood, Toil, and Taxoteres: Biological Determinants of Treatment-Induced ctDNA Dynamics for Interpreting Tumor Response

“…This observation is consistent with increased tumor cell sensitivity to cytotoxic agents compared to healthy tissue. Contrary to these findings, however, CRC patients receiving FOLFOX did not exhibit a spike in ctDNA at any point within the first 48 h of treatment, despite high-resolution sampling at 3, 9, 18, 23, 26, 42, and 47 h ( 90 ). Another study involving metastatic CRC patients receiving FOLFIRI looked at ctDNA levels before and 7 days after each of the first two treatment cycles and again at progression ( 91 ).…”

“…Very early changes (1–3 h) in ctDNA levels have been hypothesized to reflect treatment response as well, but this appears to be less generalizable. For example, we might expect effective chemotherapy to induce ctDNA shedding immediately, and early, high-frequency sampling to detect it, yet observations between NSCLC, CRC and prostate cancer patients sampled within 1–3 h of chemotherapy were inconsistent ( 89 , 90 , 117 ). Unfortunately, there are a lack of studies sampling within this timeframe.…”

Monitoring and adapting cancer treatment using circulating tumor DNA kinetics: Current research, opportunities, and challenges

“…The most consistent finding regarding ctDNA kinetics in chemotherapy is that ctDNA levels decline within the first few days of treatment regardless of clinical response ( 4 , 94 ), and a greater decline is often associated with improved outcomes ( 4 , 55 , 95 – 97 ). Less consistent, however, is the observation of transient ctDNA peaks after chemotherapy being noted by some ( 4 , 96 ), while others show an immediate decrease after treatment ( 55 , 95 ). Some studies have suggested that such peaks may predict eventual radiological response.…”

Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer

“…Lastly, in advanced-stage tumors (including CRC), the amount of ctDNA is dependent on tumor type and dynamics of tumor size, but variables including physical exercise, time of the day, and recent meal do not significantly influence ctDNA content [158]. In mCRC patients on systemic therapy, it should be noted that ctDNA dynamics can be rapid with rapid decreases in MAFs as early as the first 48 h of FOLFOX infusion with potential correlation between ctDNA MAFs that remain low and tumor response (stable disease or partial response) [133]. ctDNA shedding and therefore detection in plasma has also been shown to be affected by site of metastases in mCRC, with the liver being among the sites of highest ctDNA shedding, while higher ctDNA content increases with CRC tumor stage [18,159].…”

“…Interestingly, ctDNA assayed within the first 48 h of FOLFOX infusion in mCRC patients saw rapid decreases in MAFs within the first 24 h of chemotherapy. ctDNA MAFs that remained low at the time the of last blood collection (hour 52 from chemotherapy) were associated with response (stable disease or partial response) [ 133 ].…”