The Problem: who should receive chemotherapy after surgery for colorectal cancer
Adjuvant chemotherapy refers to treatment prescribed after complete surgical resection of a primary cancer. This aims to remove any small remaining cancer lesions to prevent disease relapse in the future. Administration of adjuvant chemotherapy following complete surgery for colorectal cancer has been demonstrated to improve overall survival1.
Identification of patients who will benefit from adjuvant chemotherapy remains controversial after surgery for colorectal cancer. This is particularly evident in stage II disease, a substantial proportion (20-30%) of these patients will experience disease relapse, but the benefits of chemotherapy are modest, offering only a 3-5% reduction in rate of relapse.2 It is also recognised that a subset of those with stage III disease are at low risk of disease relapse, which likely represent a population of patients who are being overtreated.
Circulating tumour DNA: the new kid on the block
Circulating tumour DNA (ctDNA) refers to fragments of DNA shed into the blood by a cancer. Measuring this ctDNA has been proposed as a new method of investigating cancer, and is referred to as a ‘liquid biopsy’. This has been the focus of much attention by the research community in recent years and has a wide range of potential applications.3
Multiple, independent studies have found that patients in whom we can detect ctDNA after surgery for have a much poorer prognosis than in those where ctDNA cannot be found. It is thought this represents detection of ctDNA from microscopic remnants of the cancer not otherwise visible, referred to as ‘Minimal Residual Disease’.4 If left untreated these remaining lesions hold the potential for future disease relapse. Being able to detect this would enable more appropriate management of these patients including influencing selection to chemotherapy.
Bringing it all together
Here, we performed a systematic review, investigating the ability of ctDNA to detect minimal residual disease following curative surgery for colorectal cancer. Searching the literature, we found 37 papers that addressed this question which are described in this review.5
We then went on to combine data from these induvial studies via a meta-analysis, to test if there was a statistical difference between the time to cancer relapse in patients after surgery in those with ctDNA compared to those without when the results from all these studies were pooled together.
On meta-analysis, detection of ctDNA after surgery was associated with a significantly shorter PFS [HR:6.92 CI:4.49-10.64 p<0.00001]. We found this pattern was also true when we looked at subgroups including stages of disease, different methods of measuring ctDNA and based on whether participants had received chemotherapy.
The outstanding questions: What, When, How
Despite the compelling evidence for the prognostic implications of ctDNA detection after surgery, there was much variation in the study design of the included trials.
One of the main differences between studies was the time point ctDNA was tested after surgery. Physiological cell free DNA from normal cells rises following surgery, making ctDNA more difficult to detect if testing if performed too early. However, in colorectal cancer, adjuvant chemotherapy needs to be started within 3 months of surgery in order to be of benefit. Therefore, in order to influence adjuvant chemotherapy prescriptions results would need to be processed before this time.
The studies in this review used a range of different methods for measuring ctDNA in the laboratory. When looking for ctDNA from MRD, a key feature of the techniques are being able to detect very small amount of DNA. Another of the main differences in approaches between the studies was the number of gene defects measured for in ctDNA.
Translational Potential: bringing it into the clinic
The outcomes of this review have huge translational potential and the liquid biopsy could be used to risk stratify patient after surgery for colorectal cancer. The implications of this could be two fold, both identifying patients who are at high risk of disease relapse, and conversely identifying patients in whom chemotherapy would be unnecessary. Risk evaluation of this patient cohort could also be used to determine which chemotherapy agents to use and how long treatment should be given for. In addition, identification of patient at high risk of disease recurrence could be used to guide post-operative monitoring regimes, with closer monitoring in those with detectable ctDNA.
- André, T. et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J. Clin. Oncol. 27, 3109–16 (2009).
- Kannarkatt, J., Joseph, J., Kurniali, P. C., Al-Janadi, A. & Hrinczenko, B. Adjuvant Chemotherapy for Stage II Colon Cancer: A Clinical Dilemma. J. Oncol. Pract. 13, 233–241 (2017).
- Wan, J. C. M. et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat. Rev. Cancer 17, 223–238 (2017).
- Dasari, A., Grothey, A. & Kopetz, S. Circulating tumor DNA–defined minimal residual disease in solid tumors: Opportunities to accelerate the development of adjuvant therapies. J. Clin. Oncol. 36, 3437–3440 (2018).
- Faulkner, L. G., Howells, L. M., Pepper, C., Shaw, J. A. & Thomas, A. L. The utility of ctDNA in detecting minimal residual disease following curative surgery in colorectal cancer: a systematic review and meta-analysis. Br. J. Cancer (2022) doi:10.1038/s41416-022-02017-9.