Abstract
Treatment personalisation remains an unmet need in oropharynx cancer (OPC). We aimed to determine whether gene expression signatures improved upon clinico-pathological predictors of outcome in OPC. The clinico-pathological predictors, AJCC version 7 (AJCC 7), AJCC 8, and a clinical algorithm, were assessed in 4 public series of OPC (n = 235). Literature review identified 16 mRNA gene expression signatures of radiosensitivity, HPV status, tumour hypoxia, and microsatellite instability. We quality tested signatures using a novel sigQC methodology, and added signatures to clinico-pathological variables as predictors of survival, in univariate and multivariate analyses. AJCC 7 Stage was not predictive of recurrence-free survival (RFS) or overall survival (OS). AJCC 8 significantly predicted RFS and OS. Gene signature quality was highly variable. Among HPV-positive cases, signatures for radiosensitivity, hypoxia, and microsatellite instability revealed significant underlying inter-tumour biological heterogeneity, but did not show prognostic significance when adjusted for clinical covariates. Surprisingly, among HPV-negative cases, a gene signature for HPV status was predictive of survival, even after adjustment for clinical covariates. Across the whole series, several gene signatures representing HPV and microsatellite instability remained significant in multivariate analysis. However, quality control and independent validation remain to be performed to add prognostic information above recently improved clinico-pathological variables.
Highlights
Treatment personalisation remains an unmet need in oropharynx cancer (OPC)
American Joint Committee on Cancer (AJCC) version 7 (AJCC 7) stage did not correlate with recurrence-free survival (RFS) (p = 0.188) or overall survival (OS) (p = 0.158) (Fig. 2A,B)
Cases were more evenly distributed across the four stages (Stage I = 30%, Stage II = 17%, Stage III = 19% and Stage IV = 34%), and AJCC 8 significantly predicted response to treatment (p < 0.0001 for both RFS and OS), noting that these patients were treated under the previous staging paradigm (Table 1, Fig. 2C,D)
Summary
We aimed to determine whether gene expression signatures improved upon clinico-pathological predictors of outcome in OPC. Literature review identified 16 mRNA gene expression signatures of radiosensitivity, HPV status, tumour hypoxia, and microsatellite instability. Among HPV-positive cases, signatures for radiosensitivity, hypoxia, and microsatellite instability revealed significant underlying intertumour biological heterogeneity, but did not show prognostic significance when adjusted for clinical covariates. Given the limitations in histochemical pathologic markers, several gene expression-based signatures of response to radiotherapy have been described. These include a radiosensitivity index (RSI), which has been used to determine a genome-based model for adjusting radiotherapy dose (GARD)[22] and several RSIs derived from the radiation response of NCI-60 cell lines[23,24]. MSI has been associated with prognosis[30] and gene expression signatures have been described[31,32]
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