Minimal Residual Disease in Colorectal Cancer: Are We Finding the Needle in a Haystack?

Abstract

Despite significant advances in the surgical and systemic therapy of colorectal cancer (CRC) in recent decades, recurrence rates remain high. Apart from microsatellite instability status, the decision to offer adjuvant chemotherapy to patients with CRC is solely based on clinicopathologic factors, which offer an inaccurate risk stratification of patients who derive benefit from adjuvant therapy. Owing to the recent improvements of molecular techniques, it has been possible to detect small allelic fractions of circulating tumor DNA (ctDNA), and therefore, to identify patients with minimal residual disease (MRD) after curative-intent therapies. The incorporation of ctDNA identifying MRD in clinical practice may dramatically change the standard of care of CRC, refining the selection of patients who are candidates for escalation and de-escalation of adjuvant chemotherapy, and even for organ-preservation strategies in rectal cancer. In the present review, we describe the current standard of care and the DNA sequencing methodologies and assays, present the data from completed clinical studies and list ongoing potential landmark clinical trials whose results are eagerly awaited, as well as the impact and perspectives for the near future. The discussed data bring optimism for the future of oncologic care through the hope of refined utilization of adjuvant therapies with higher efficacy and safety for patients with both localized and advanced CRC.

Keywords: adjuvant; chemotherapy; circulating tumor DNA; colorectal neoplasms; high-throughput nucleotide sequencing; neoplasm; residual.

Figure 1

Standard of care of adjuvant therapy of colon cancer. The current selection of patients for adjuvant chemotherapy is based on the presence of prognostic clinicopathologic factors, which offer an inaccurate risk stratification in low-risk and high-risk stage II and stage III colon cancer. Created with Biorender.com.

Figure 2

Techniques and assays for detection of ctDNA. The sensitivity of the molecular techniques has increased in recent years for the identification of small allelic fractions of ctDNA. The development of tumor-informed assays and association of epigenomic signatures have allowed detection of allelic fractions lower than 0.01% and with high specificity. Created with Biorender.com. Abbreviations: NGS: next-generation sequencing, PCR: polymerase chain reaction.

Figure 3

Potential ctDNA-guided postoperative management. This figure illustrates a potential therapeutic algorithm for the decision of adjuvant therapy in colon cancer after the advent of molecular techniques for the detection of minimal residual disease. Certain clinicopathologic factors, such as T4 tumors, have demonstrated significant prognostic value, even in ctDNA-negative patients. Based on the available clinical data, even with the improvement of molecular techniques, it is unlikely that the test will reach very high levels of sensitivity in the first postoperative weeks, when the decision to offer adjuvant chemotherapy has to be made. Hence, it is possible that the combination of molecular (ctDNA) and clinical data might be a reasonable strategy to offer a more personalized therapy for patients with localized colon cancer. * De-escalation of adjuvant chemotherapy in high clinical risk ctDNA-negative patients will only be possible after the development of techniques with very high sensitivity. Created with Biorender.com.