Multi-omic profiling and radiotherapy response in rectal cancer biopsies of COPERNICUS trial: results from SCORT (Stratification in COloRecTal cancer)


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Enric Domingo1,Andrew Blake1,Susan Richman2,Peter Stewart3,Alessandro Barberis1,Syed Haider1,Wei-Chen Cheng1,Philip Dunne3,Francesca Buffa1,Simon Gollins4,Tim Maughan1
1University of Oxford,2Leeds Institute of Cancer and Pathology,3Queens University,4North Wales Cancer Treatment Centre

Abstract

Background

Neoadjuvant radiotherapy is commonly used to treat rectal cancer. However, patients have different levels of response and/or toxic effects. Potentially, molecular stratifiers for radiotherapy could be identified by multi-omic profiling of pre-treatment biopsies but comprehensive analyses on such limited pieces of tumour tissue are challenging.

Method

As part of the Stratification in COloRecTal cancer (S-CORT) programme, we performed a feasibility study of multi-omic profiling of rectal biopsies from the COPERNICUS trial. Then three hypothesis-driven expression signatures were tested as stratifiers for radiotherapy response: Consensus Molecular Subtype (CMS), DNA Damage Response Deficiency (DDRD) and a new Hypoxia Signature (HS) we specifically derived for colorectal cancer.

Results

Profiling of 52 rectal biopsies was successful for RNA arrays, targeted DNA sequencing and DNA methylation arrays in 44(85%), 17(33%) and 0 paraffin blocks respectively. Lack of DNA profiling was due to insufficient DNA yield after successful RNA extraction. Interestingly, most genes in our newly derived HS had never been identified in any of 32 previous HS mainly derived from pancancer analyses, suggesting hypoxia modulation might be tissue specific. The expression signatures tested seemed to carry information for prediction of response and survival albeit not significant in our relatively small cohort. For example, CMS4 was borderline associated with poor response (OR=7.06; 95%CI=0.79-63.18; p=0.081) and poor relapse-free survival (HR=4.53, 95%CI=0.91-22.51; p=0.064). Exploratory analyses suggested putative stratifiers of radiotherapy response from molecular data. These were able to correctly classify patients as responders/non-responders in ~70% of patients.

Conclusion

We concluded that multi-omic profiling of rectal biopsies is not feasible with standard protocols but molecular biomarkers may be able to provide information for radiotherapy stratification. Accordingly, we have set up new protocols for low-input DNA sequencing and methylation profiling and we are currently screening 250 rectal biopsies across all three ‘omic’ platforms as part of S-CORT.