Genomic predictor of complete response after chemoradiotherapy in rectal cancer

A multimodal approach to locally advanced (cT3, 4 and/or N+) rectal cancer, based on the use of concurrent chemo-radiotherapy followed by radical surgery with total mesorectal excision, has led to a significant improvement in oncologic outcomes (1,2). This therapeutic approach also improves tumor resectability and increases the chance to preserve anal sphincter (3,4). For these reasons, neoadjuvant chemoradiotherapy (nCRT) followed by surgery has become the standard treatment for locally advanced rectal cancer.

However, the response to nCRT varies substantially in each individual patient, which is considered as an important prognostic factor (5-8). Currently, there is no definite method to predict a tumor response to nCRT. Determination of factors predicting tumor regression after nCRT is important, which would permit tailored treatment strategies that include fewer invasive surgical approaches or intensified neoadjuvant treatment in patients with a lower likelihood of responding (9,10).

To date, multiple factors have been suggested as a putative predictive factor for tumor regression. Clinical factors include performance status, tumor stage, tumor mobility and circumference of the rectal wall involved by tumor (11). Treatment factors include radiation dose and time elapsed from radiation to surgery (12,13). Additionally, there are various biologic factors that may be involved in the tumor response process such as specific gene or protein expression and genetic mutation (14).

As a biologic factor, genetic polymorphisms have been investigated to reveal the association with tumor regression after nCRT. In the previous study, patients with specific thymidylate synthase (TS) single nucleotide polymorphism (SNP) showed significantly greater downstage of rectal cancer after nCRT (15). Also, polymorphisms in the EGFR gene have been investigated but the results were not confirmed as predictive markers of response (16).

A recent The Pharmacogenomics Journal paper entitled “EGFR ligands and DNA repair genes: genomic predictors of complete response after capecitabine-based chemoradiotherapy in locally advanced rectal cancer” investigated the association between tumor response to capecitabine-based nCRT and polymorphism in genes involved in the fluoropyrimidine metabolism (TS), the DNA repair (ERCC1, XPD, XRCC1) and the EGFR pathway (EGFR, EGF, AREG and EREG). A total of 84 patients with rectal cancer underwent capecitabine-based nCRT were included. Analyzing SNPs in the selected genes from blood samples by means of genotyping, the associations of pathological response to nCRT with each SNP were investigated. This study showed significant associations of two SNPs with pCR; rs11942466 C>A polymorphism in AREG gene and rs11615 C>T in ERCC1 gene. Authors suggested these SNPs as a potential biomarker for pCR after capecitabine based chemoradiation.

The EGFR pathway and DNA repair mechanism were revealed to involve in the resistance to radiotherapy (17). Several studies have found a relationship between the expression of these genes and tumor response after nCRT in rectal cancer (18). However, limited data are available on the polymorphisms in AREG or ERCC1 genes and the radiotherapy response (19). Furthermore, in the field of specific haplotypes and genetic polymorphisms, the data for SNPs is limited and only a few genes have been the candidate for genotyping such as TS and EGFR. In this context, the result of this study has substantial clinical importance.

Genetic polymorphisms are promising predictive biomarker because drug resistance or severe toxicity might be related to genetic variations in tumor cells and/or to the genetic background of each patient. However, it requires higher levels of evidence before they can be considered clinically useful. Thus retrospective studies on large numbers of samples with detailed clinical data, and prospective pharmacogenetic-guided clinical trials, albeit challenging, are needed. These gene polymorphisms could be candidate markers for such further studies.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. Du CZ, Li J, Cai Y, et al. Effect of multidisciplinary team treatment on outcomes of patients with gastrointestinal malignancy. World J Gastroenterol 2011;17:2013-8. [Crossref] [PubMed]
2. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638-46. [Crossref] [PubMed]
3. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer. N Engl J Med 2004;351:1731-40. [Crossref] [PubMed]
4. Roh MS, Colangelo LH, O'Connell MJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 2009;27:5124-30. [Crossref] [PubMed]
5. Rödel C, Martus P, Papadoupolos T, et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 2005;23:8688-96. [Crossref] [PubMed]
6. Eich HT, Stepien A, Zimmermann C, et al. Neoadjuvant radiochemotherapy and surgery for advanced rectal cancer: prognostic significance of tumor regression. Strahlenther Onkol 2011;187:225-30. [Crossref] [PubMed]
7. Fokas E, Liersch T, Fietkau R, et al. Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: updated results of the CAO/ARO/AIO-94 trial. J Clin Oncol 2014;32:1554-62. [Crossref] [PubMed]
8. Maas M, Nelemans PJ, Valentini V, 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;11:835-44. [Crossref] [PubMed]
9. Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 2004;240:711-7. [PubMed]
10. Smith FM, Waldron D, Winter DC. Rectum-conserving surgery in the era of chemoradiotherapy. Br J Surg 2010;97:1752-64. [Crossref] [PubMed]
11. Janjan NA, Abbruzzese J, Pazdur R, et al. Prognostic implications of response to preoperative infusional chemoradiation in locally advanced rectal cancer. Radiother Oncol 1999;51:153-60. [Crossref] [PubMed]
12. Glimelius B, Isacsson U, Jung B, et al. Radiotherapy in addition to radical surgery in rectal cancer: evidence for a dose-response effect favoring preoperative treatment. Int J Radiat Oncol Biol Phys 1997;37:281-7. [Crossref] [PubMed]
13. Francois Y, Nemoz CJ, Baulieux J, et al. Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90-01 randomized trial. J Clin Oncol 1999;17:2396. [PubMed]
14. Kim NK, Hur H. New Perspectives on Predictive Biomarkers of Tumor Response and Their Clinical Application in Preoperative Chemoradiation Therapy for Rectal Cancer. Yonsei Med J 2015;56:1461-77. [Crossref] [PubMed]
15. Hur H, Kang J, Kim NK, et al. Thymidylate synthase gene polymorphism affects the response to preoperative 5-fluorouracil chemoradiation therapy in patients with rectal cancer. Int J Radiat Oncol Biol Phys 2011;81:669-76. [Crossref] [PubMed]
16. Molinari C, Matteucci F, Caroli P. Biomarkers and Molecular Imaging as Predictors of Response to Neoadjuvant Chemoradiotherapy in Patients With Locally Advanced Rectal Cancer. Clin Colorectal Cancer 2015;14:227-38. [Crossref] [PubMed]
17. Liang K, Ang KK, Milas L, et al. The epidermal growth factor receptor mediates radioresistance. Int J Radiat Oncol Biol Phys 2003;57:246-54. [Crossref] [PubMed]
18. Bertolini F, Bengala C, Losi L, et al. Prognostic and predictive value of baseline and posttreatment molecular marker expression in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Int J Radiat Oncol Biol Phys 2007;68:1455-61. [Crossref] [PubMed]
19. Spindler KL, Nielsen JN, Lindebjerg J, et al. Prediction of response to chemoradiation in rectal cancer by a gene polymorphism in the epidermal growth factor receptor promoter region. Int J Radiat Oncol Biol Phys 2006;66:500-4. [Crossref] [PubMed]