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Serum and plasma protein biomarkers that predict a pathological complete response to neoadjuvant treatment in rectal cancer: a systematic review
Keywords: biomarker rectal cancer Systematic Review
Researchers: Wouter Zwart Prof. Geke Hospers
Type of project: Stage Wetenschap / Researchproject
Nature of the research: Conducting a systematic reviewer and writing an article together with and under supervision of a PhD-candidate, according to an already written research protocol. Dependant on the outcomes and quality of the work, it is possible to expand this project to another topic (coördinating the analyses of blood samples on a protein biomarker in a laboratory in Upsala) or even an PhD-trajectory within the RAPIDO collaborative.
Fields of study: oncology

Background / introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and rectal cancer comprises over a third of all CRC.(1) The treatment of clinical stage II and III rectal cancer consists of both neo-adjuvant treatment (nAT) and surgery in the majority of patients. One of the purposes of nAT is to eradicate micrometastasis to decrease the incidence of distant metastasis. Another purpose, in the most locally advanced cases, is to achieve downsizing of the tumour to enable radical surgery.(2) However, in a recent meta-analysis of 1210 patients with locally advance rectal cancer, 14,9% of the patients achieved a pathological complete response (pCR, defined as ypT0N0) after chemoradiotherapy and a watch and wait (W&W) strategy, in which surgery is withhold and only preserved to those patients with tumor regrowth, could have been followed.(3) Another meta-analysis of 3579 patients with clinical stage II and III rectal cancer treated with total neo-adjuvant therapy showed a pooled rate of pCR of 22.4% (95% CI 19.4%–25.7%).4 Moreover, the patients with a pCR have the lowest rates of local recurrence, distant metastasis and best survival.(5,6) Tumours that show hardly any or no regression to nAT can be considered as the entire other end of the spectrum, as some literature indicates there are few differences in oncological outcome between a near pCR or no response to nAT, albeit literature is not entirely conclusive.(7,8) This seems counterintuitive, as one would expect that a near pCR is almost as good as a pCR, but these results indicate that dividing pathological response (pR) into more than two (no pCR and pCR) or three categories (i.e. no response, response and pCR) has limited clinical relevance.
Predicting which patients would and wouldn’t respond to nAT, could determine the treatment strategy: [1] to start nAT for pre-treatment predicted responders (and possibly follow a W&W strategy in case of a clinical complete response (cCR), [2] to directly perform surgery (provided it can be done radically) for pre-treatment predicted non-responders, [3] to continue nAT for the predicted responders during the nAT (and possibly follow a W&W strategy in case of a cCR) or [4] to discontinue nAT for predicted non-responders during the nAT and directly perform surgery (provided it can be done radically).
Since it is difficult to make a reliable clinical distinction between responders and non-responders prior to and even during treatment,(9) biomarkers are sought to enable this distinction. In the field of geno-, proteo-, metabolo-, and radiomics a vast amount of biomarkers have been researched and claimed to be of some predictive value, both in tissue and blood. However, currently there are no biomarkers that reliably predict a pCR after nAT, with clinical utility.(10-13)
In the RAPIDO trial blood samples were collected prospectively for metabolomic and proteomic analyses. Analysing a vast number of potential biomarkers is time consuming and expensive and therefore a systematic review of the literature to direct the analyses in a cost-effective way will be performed first. The purpose of this systematic review is to evaluate and summarize the literature on serum and plasma protein biomarkers that predict a pCR to nAT in patients with rectal cancer.

Research question / problem definition
Which serum and plasma protein biomarkers have the ability to predict a pathological complete response to neo-adjuvant treatment in patients with rectal cancer?

Workplan
This systematic review will be performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.(14,15) See research proposal for elaborate workplan: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=323190

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018 Nov;68(6):394-424.

2. Nagtegaal ID, Quirke P. What is the role for the circumferential margin in the modern treatment of rectal cancer? J Clin Oncol 2008 Jan 10;26(2):303-312.

3. Kasi A, Abbasi S, Handa S, Al-Rajabi R, Saeed A, Baranda J, et al. Total Neoadjuvant Therapy vs Standard Therapy in Locally Advanced Rectal Cancer: A Systematic Review and Meta-analysis. JAMA Netw Open 2020 Dec 1;3(12):e2030097.

4. Petrelli F, Trevisan F, Cabiddu M, Sgroi G, Bruschieri L, Rausa E, et al. Total Neoadjuvant Therapy in Rectal Cancer: A Systematic Review and Meta-analysis of Treatment Outcomes. Ann Surg 2020 Mar;271(3):440-448.

5. Maas M, Nelemans PJ, Valentini V, Das P, Rödel C, Kuo LJ, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010 Sep;11(9):835-844.

6. de Campos-Lobato LF, Stocchi L, da Luz Moreira A, Geisler D, Dietz DW, Lavery IC, et al. Pathologic complete response after neoadjuvant treatment for rectal cancer decreases distant recurrence and could eradicate local recurrence. Ann Surg Oncol 2011 Jun;18(6):1590-1598.

7. Swellengrebel HA, Bosch SL, Cats A, Vincent AD, Dewit LG, Verwaal VJ, et al. Tumour regression grading after chemoradiotherapy for locally advanced rectal cancer: a near pathologic complete response does not translate into good clinical outcome. Radiother Oncol 2014 Jul;112(1):44-51.

8. Kim JY, Park IJ, Hong SM, Lee JL, Yoon YS, Kim CW, et al. Is Pathologic Near-Total Regression an Appropriate Indicator of a Good Response to Preoperative Chemoradiotherapy Based on Oncologic Outcome of Disease? Medicine (Baltimore) 2015 Dec;94(50):e2257.

9. de Jong EA, ten Berge JC, Dwarkasing RS, Rijkers AP, van Eijck CH. The accuracy of MRI, endorectal ultrasonography, and computed tomography in predicting the response of locally advanced rectal cancer after preoperative therapy: A metaanalysis. Surgery 2016 Mar;159(3):688-699.

10. Al-Sukhni E, Attwood K, Mattson DM, Gabriel E, Nurkin SJ. Predictors of Pathologic Complete Response Following Neoadjuvant Chemoradiotherapy for Rectal Cancer. Ann Surg Oncol 2016 Apr;23(4):1177-1186.

11. Dayde D, Tanaka I, Jain R, Tai MC, Taguchi A. Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer. Int J Mol Sci 2017 Mar 7;18(3):573. doi: 10.3390/ijms18030573.

12. Ryan JE, Warrier SK, Lynch AC, Ramsay RG, Phillips WA, Heriot AG. Predicting pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer: a systematic review. Colorectal Dis 2016 Mar;18(3):234-246.

13. Fischer J, Eglinton TW, Richards SJ, Frizelle FA. Predicting pathological response to chemoradiotherapy for rectal cancer: a systematic review. Expert Rev Anticancer Ther 2021 May;21(5):489-500.

14. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009 Jul 21;339:b2535.

15. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009 Jul 21;6(7):e1000100.

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