Approximately 15% of patients show no response to neoadjuvant chemoradiotherapy for the treatment of locally advanced rectal cancer before surgery. August’s Paper of the Month looks at a systematic review aiming to identify biomarkers of innate radioresistant rectal cancer.
Predictive biomarkers in radioresistant rectal cancer: a systematic review
Slipsager A, Henrichsen SN, Falkmer UG, Dybkaer, Belting M, Poulsen LO.
Critical Reviews in Oncology/Hematology 186 (2023) 103991. Available online 13 April 2023.
What is known about the subject?
The yearly incidence of rectal cancer in Europe is 15-25 cases/100000 population with a 5-year survival of approximately 60% [1]. Before only patients with locally advanced cancer received neoadjuvant treatment either radiotherapy alone or a combination of radiosensitizing chemotherapy and radiotherapy. Recently, radiotherapy is often combined with systemic chemotherapy to improve survival [2]. In addition, ongoing trials are investigating whether radiotherapy alone could be used for non-advanced rectal cancer, thereby avoiding resectional surgery [3]. While these treatment regimens are aimed at patients with a good response, at the other end of the scale there are reports of up to 15% of patients with no response or even progression on treatment [4]. Patients with a priori radioresistant tumours may suffer unnecessary toxicity and delays in curative surgery. Therefore, biomarkers of radioresistance would be of paramount importance in identifying patients who should be spared neoadjuvant radiotherapy but require immediate surgery and those who are likely to have a response with potentially curative intent.
What does the study add?
A systematic literature search was performed according to PROSPERO guideline using databases PubMed, Embase, Cochrane, and Web of Science including 159 articles. Only English written peer-reviewed full text articles including rectal cancer patients treated with curative intended neoadjuvant radiotherapy (either radiobiological effect of 25 Gy in 5 fractions per week or above 42 Gy given in fraction doses of 1.8–2 Gy +/- concurrent chemotherapy were included. The CEA biomarker and clinical markers e.g., clinicopathological and radiological variables were investigated in this study. The authors summarized and evaluated statistically significant innate radioresistant biomarkers reported at least once or with a low or moderate risk of bias.
Four radioresistant biomarkers, COASY, HMGCS2, RAD23B, and REG4, and one radiosensitive biomarker, NPTX2, were identified along the above-mentioned criteria.
However, only COASY was reported in more than one publication and showed a low risk of bias.
Implications for colorectal practice
In this systematic review, potential radioresistant biomarkers in patients with rectal cancer were compiled. However, when it comes to implementation in everyday clinical practice, the authors acknowledge that some fundamental differences were found in the original studies. Firstly, the studies showed differences in clinical characteristics (dose of radiotherapy, addition of chemotherapy combinations, timing of surgery, number of samples and cohorts selected for discovery and validation); secondly, there are differences in histopathological (grading of response, grouping of different responders, fresh frozen vs FFPE material) and molecular biological characteristics (different methods and cut-offs for RNA and protein expression). Thirdly, and finally, the bioinformatic tools used in the studies were also different. All these factors increase the risk of bias which is why the authors of this systematic review also have some understanding of why clinical application of the findings is difficult.
Indeed, this review highlights biomarkers and genetic signatures that seem promising and worthy of further investigation. Future scientific research should focus on further exploring and validating genetic and biomarkers of resistance using a prospective study design with well-defined clinical parameters defined in advance to ensure a low risk of bias.
References
- Glynne-Jones R et al. Rectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 28(suppl 4):iv22-iv40. doi:10.1093/annonc/mdx220
- Bahadoer RR et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy TME and optional adjuvant chemotherapy in locally advance rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol 2021:22:29-42. doi: 10.1016/S1470-2045(20)30555-6.
- Bach SP et al. Can we Save the rectum by watchful waiting or TransAnal surgery following (chemo)Radiotherapy versus Total mesorectal excision for early Rectal Cancer (STAR-TREC)? Protocol for the international, multicentre, rolling phase II/III partially randomized patient preference trail evaluating long-course concurrent chemoradiotherapy versus short-course radiotherapy organ preservation approaches. Colorectal Dis 2022;24:639-51. doi: 10.1111/codi.16056.
- Poynter L et al. Network mapping of molecular biomarkers influencing radiation response in rectal cancer. Clin Colorectal Cancer 2019;18:e210–e222. doi:10.1016/j.clcc.2019.01.004.
