ESTRO 2022 - Abstract Book

S743

Abstract book

ESTRO 2022

Conclusion There were significant PG volumetric changes at mid-treatment of up to 30-40% in a lot of cases, and these changes were significantly associated with mean dose to the PG. Moreover, the dose to the PG or PGSC region at mid-treatment was strongly associated with patient-reported xerostomia. These findings strongly encourage the use of adaptive planning strategies to implement more robust functional avoidance of the PGSC region during treatment, taking into account the radiation-induced shifts and shrinkage of the glands throughout treatment.

PD-0825 A transcriptomic biomarker predicts response to genotoxic cancer therapy

I. Guix 1 , A. Lazar 2 , J. Mao 3 , M.A. Pujana 4 , M.H. Barcellos-Hoff 1

1 University of California San Francisco (UCSF), Radiation Oncology, San Francisco, USA; 2 University of California San Francisco (UCSF), Division of Biostatistics, San Francisco, USA; 3 Lawrence Berkeley National Laboratory, BioEngineering & BioMedical Sciences, Berkeley, USA; 4 Catalan Institute of Oncology, Bellvitge institute for Biomedical Research (IDIBELL), Barcelona, Spain Purpose or Objective Transforming growth factor β (TGF β ) enforces effective DNA repair by promoting homologous recombination and suppressing the use of less efficient alternative end-joining (alt-EJ). We previously translated this mechanistic relationship into gene expression signatures of chronic TGF β signaling and alt-EJ DNA repair to establish a score, β Alt, that predicts patient outcomes in response to genotoxic cancer therapy with radiation or platinum chemotherapy (doi: 10.1126/scitranslmed.abc4465). Here we sought to verify this biology in live human tumors and to further refine the β Alt biomarker to improve its predictive capacity. Materials and Methods Explants of head and neck squamous cell carcinoma (HNSC) tumors and patient-derived xenographs were immunostained to measure TGF β signaling, indicated by SMAD2 phosphorylation, and unrepaired DNA damage, indicated by persistent 53BP1 foci at 5 hours after 5 Gy irradiation. Each signature gene was then weighted by its association with percent pSMAD2 and 53BP1 positive cells, as well as by its centrality degree within their respective gene coexpression network. These results were used to define a modified score, β Alt w , based on the sum of gene expression levels multiplied by their estimated weights. The β Alt w score was compared to the original β Alt biomarker for association with patients’ response to genotoxic therapies and validated in independent datasets. Results Most TGF β genes were positively correlated with the frequency of pSMAD2 positive cells (37/50) and negatively correlated with 53BP1 positive cells (36/50), whereas most alt-EJ genes were positively correlated with residual DNA damage marked by 53BP1 (30/36) and negatively correlated with pSMAD2 (31/36), supporting that the signatures accurately report TGF β signaling competency and inefficient DNA repair, respectively. As expected, β Alt w was correlated with the surviving fraction after exposure to 2 Gy of NCI-60 pancancer cell lines (Spearman correlation coefficient = -0.36, P = 0.005). β Alt w predicted overall survival in TCGA pancancer patients whose standard of care includes radiotherapy and/or genotoxic chemotherapy based on their cancer type and stage (P<0.001; Figure 1); its performance was significantly superior to the original β Alt (P < 0.001; Figure 1). The association between the β Alt w and survival was significant in three HNSC and ovarian cancer patients data sets: HNSC GSE41613 (P = 0.015; Figure 2B), HNSC TCGA (P = 0.019; Figure 2A), and ovarian cancer GSE41613 (P = 0.036; Figure 2C,D).