Stratification to Neoadjuvant Radiotherapy in Rectal Cancer by Regimen and Transcriptional Signatures

Author:

Mahmood Umair1ORCID,Blake Andrew1ORCID,Rathee Sanjay1ORCID,Samuel Leslie2ORCID,Murray Graeme2ORCID,Sebag-Montefiore David3ORCID,Gollins Simon45ORCID,West Nicholas P.3ORCID,Begum Rubina6ORCID,Bach Simon P.7ORCID,Richman Susan D.3ORCID,Quirke Phil3ORCID,Redmond Keara L.8ORCID,Salto-Tellez Manuel8ORCID,Koelzer Viktor H.910ORCID,Leedham Simon J.11ORCID,Tomlinson Ian1ORCID,Dunne Philip D.8ORCID,Buffa Francesca M.112ORCID, ,Maughan Tim S.113ORCID,Domingo Enric114ORCID

Affiliation:

1. Department of Oncology, Medical Science Division, University of Oxford, Oxford, United Kingdom. 1

2. School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, United Kingdom. 2

3. Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom. 3

4. North Wales Cancer Treatment Centre, Besti Cadwaladr University Health Board, Bodelwyddan, United Kingdom. 4

5. Lingen Davies Cancer Centre, Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, United Kingdom. 5

6. Cancer Research & University College London Clinical Trial Unit, London, United Kingdom. 6

7. Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom. 7

8. The Patrick G Johnston Centre for Cancer Research, Queens University Belfast, Belfast, United Kingdom. 8

9. Department of Pathology and Molecular Pathology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. 9

10. Department of Oncology and Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. 10

11. Wellcome Trust Centre for Human genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. 11

12. Department of Computing Sciences, Bocconi University, and Bocconi Institute for Data Science and Analytics (BIDSA), Milano, Italy. 12

13. Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. 13

14. Cancer Research UK Scotland Centre, Edinburgh, United Kingdom. 14

Abstract

Abstract Response to neoadjuvant radiotherapy (RT) in rectal cancer has been associated with immune and stromal features that are captured by transcriptional signatures. However, how such associations perform across different chemoradiotherapy regimens and within individual consensus molecular subtypes (CMS) and how they affect survival remain unclear. In this study, gene expression and clinical data of pretreatment biopsies from nine cohorts of primary rectal tumors were combined (N = 826). Exploratory analyses were done with transcriptomic signatures for the endpoint of pathologic complete response (pCR), considering treatment regimen or CMS subtype. Relevant findings were tested for overall survival and recurrence-free survival. Immune and stromal signatures were strongly associated with pCR and lack of pCR, respectively, in RT and capecitabine (Cap)/5-fluorouracil (5FU)–treated patients (N = 387), in which the radiosensitivity signature (RSS) showed the strongest association. Upon addition of oxaliplatin (Ox; N = 123), stromal signatures switched direction and showed higher chances to achieve pCR than without Ox (p for interaction 0.02). Among Cap/5FU patients, most signatures performed similarly across CMS subtypes, except cytotoxic lymphocytes that were associated with pCR in CMS1 and CMS4 cases compared with other CMS subtypes (p for interaction 0.04). The only variables associated with survival were pCR and RSS. Although the frequency of pCR across different chemoradiation regimens is relatively similar, our data suggest that response rates may differ depending on the biological landscape of rectal cancer. Response to neoadjuvant RT in stroma-rich tumors may potentially be improved by the addition of Ox. RSS in preoperative biopsies provides predictive information for response specifically to neoadjuvant RT with 5FU. Significance: Rectal cancers with stromal features may respond better to RT and 5FU/Cap with the addition of Ox. Within patients not treated with Ox, high levels of cytotoxic lymphocytes associate with response only in immune and stromal tumors. Our analyses provide biological insights about the outcome by different radiotherapy regimens in rectal cancer.

Publisher

American Association for Cancer Research (AACR)

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