Search

Simple Summary: There are currently limited means by which radiotherapy treatment can be tailored to individual patient needs based on their tumour biology. Published studies of biomarkers aiming to predict tumour sensitivity to radiotherapy treatment for the clinic were reviewed. No gene expression signature biomarkers of sensitivity to radiotherapy are in routine clinical use, have been tested in advanced trials or are recommended for use in clinical guidelines. A pathway for future biomarker development that would enable tools for personalised clinical decision-making is proposed. This focusses on the need to improve the biological understanding of variation in sensitivity to radiotherapy, develop cost-effective assays and conduct large radiotherapy randomised controlled trials. Modern advanced radiotherapy techniques have improved the precision and accuracy of radiotherapy delivery, with resulting plans being highly personalised based on individual anatomy. Adaptation for individual tumour biology remains elusive. There is an unmet need for biomarkers of intrinsic radiosensitivity that can predict tumour response to radiation to facilitate individualised decision-making, dosing and treatment planning. Over the last few decades, the use of high throughput molecular biology technologies has led to an explosion of newly discovered cancer biomarkers. Gene expression signatures are now used routinely in clinic to aid decision-making regarding adjuvant systemic therapy. They have great potential as radiotherapy biomarkers. A previous systematic review published in 2015 reported only five studies of signatures evaluated for their ability to predict radiotherapy benefits in clinical cohorts. This updated systematic review encompasses the expanded number of studies reported in the last decade. An additional 27 studies were identified. In total, 22 distinct signatures were recognised (5 pre-2015, 17 post-2015). Seventeen signatures were 'radiosensitivity' signatures and five were breast cancer prognostic signatures aiming to identify patients at an increased risk of local recurrence and therefore were more likely to benefit from adjuvant radiation. Most signatures (15/22) had not progressed beyond the discovery phase of development, with no suitable validated clinical-grade assay for application. Very few signatures (4/17 'radiosensitivity' signatures) had undergone any laboratory-based biological validation of their ability to predict tumour radiosensitivity. No signatures have been assessed prospectively in a phase III biomarker-led trial to date and none are recommended for routine use in clinical guidelines. A phase III prospective evaluation is ongoing for two breast cancer prognostic signatures. The most promising radiosensitivity signature remains the radiosensitivity index (RSI), which is used to calculate a genomic adjusted radiation dose (GARD). There is an ongoing phase II prospective biomarker-led study of RSI/GARD in triple negative breast cancer. The results of these trials are eagerly anticipated over the coming years. Future work in this area should focus on (1) robust biological validation; (2) building biobanks alongside large radiotherapy randomised controlled trials with dose variance (to demonstrate an interaction between radiosensitivity signature and dose); (3) a validation of clinical-grade cost-effective assays that are deliverable within current healthcare infrastructure; and (4) an integration with biomarkers of other determinants of radiation response. [ABSTRACT FROM AUTHOR]

Simple Summary: The poor prognosis outcome of patients with KRAS mutations (KRASmut) was correlated with an immunosuppressive tumor microenvironment (TME). At the gene expression level and pathway analysis, KRASmut tumor activates TGFβ signaling to reduced proinflammatory and cytokine gene signatures. Spatial profiling in the TME region of KRASmut, classified as consensus molecular subtype 3 (CMS3), showed an up-regulation of genes CD40, CTLA4, ARG1, STAT3, IDO, and CD274, associated with immunosuppression in TME. Colorectal cancers (CRC) with KRAS mutations (KRASmut) are frequently included in consensus molecular subtype 3 (CMS3) with profound metabolic deregulation. We explored the transcriptomic impact of KRASmut, focusing on the tumor microenvironment (TME) and pathways beyond metabolic deregulation. The status of KRASmut in patients with CRC was investigated and overall survival (OS) was compared with wild-type KRAS (KRASwt). Next, we identified CMS, and further investigated differentially expressed genes (DEG) of KRASmut and distinctive pathways. Lastly, we used spatially resolved gene expression profiling to define the effect of KRASmut in the TME regions of CMS3-classified CRC tissues. CRC patients with KRASmut were mainly enriched in CMS3. Their specific enrichments of immune gene signatures in immunosuppressive TME were associated with worse OS. Activation of TGFβ signaling by KRASmut was related to reduced pro-inflammatory and cytokine gene signatures, leading to suppression of immune infiltration. Digital spatial profiling in TME regions of KRASmut CMS3-classified tissues suggested up-regulated genes, CD40, CTLA4, ARG1, STAT3, IDO, and CD274, that could be characteristic of immune suppression in TME. This study may help to depict the complex transcriptomic profile of KRASmut in immunosuppressive TME. Future studies and clinical trials in CRC patients with KRASmut should consider these transcriptional landscapes. [ABSTRACT FROM AUTHOR]

Simple Summary: Precision medicine is needed for muscle-invasive bladder cancer to improve survival rates due to high rates of tumour recurrence and poor patient outcomes. Hypoxia and an immunosuppressive tumour microenvironment are both independent poor prognostic factors that are targetable by hypoxia-modification and immune checkpoint inhibitors (ICIs), respectively. CD8 T cell counts are showing promise as a predictive biomarker for a durable response to ICIs. However, there is currently no biomarker to stratify patients to either hypoxia-targeting or immune-targeting therapies. Using data from a phase III trial where patients were randomised to radiotherapy +/− hypoxia-modifying therapy, we demonstrate that low CD8 T cell counts predict benefit from hypoxia-modifying therapy and associate with high hypoxia. These results inform the design of a clinical trial using CD8 T cell count as a biomarker for stratification to receive either radiotherapy with hypoxia-modifying therapy (low CD8 counts) or standard-of-care alone or with an ICI (high CD8 counts). Background: As hypoxia can drive an immunosuppressive tumour microenvironment and inhibit CD8+ T cells, we investigated if patients with low tumour CD8+ T cells benefitted from hypoxia-modifying therapy. Methods: BCON was a phase III trial that randomised patients with muscle-invasive bladder cancer (MIBC) to radiotherapy alone or with hypoxia-modifying carbogen plus nicotinamide (CON). Tissue microarrays of diagnostic biopsies from 116 BCON patients were stained using multiplex immunohistochemistry (IHC) with the markers CD8, CD4, FOXP3, CD68 and PD-L1, plus DAPI. Hypoxia was assessed using CA9 IHC (n = 111). Linked transcriptomic data (n = 80) identified molecular subtype. Relationships with overall survival (OS) were investigated using Cox proportional hazard models. Results: High (upper quartile) vs. low CD8 T cell counts associated with a better OS across the whole cohort at 16 years (n = 116; HR 0.47, 95% CI 0.28–0.78, p = 0.003) and also in the radiotherapy alone group (n = 61; HR 0.39, 95% CI 0.19–0.76, p = 0.005). Patients with low CD8+ T cells benefited from CON (n = 87; HR 0.63, 95% CI 0.4–1.0, p = 0.05), but those with high CD8 T cells did not (n = 27; p = 0.95). CA9 positive tumours had fewer CD8+ T cells (p = 0.03). Prognostic significance of low CD8+ T cells in the whole cohort remained after adjusting for clinicopathologic variables. Basal vs. luminal subtype had more CD8+ cells (p = 0.02) but was not prognostic (n = 80; p = 0.26). Exploratory analyses with other immune markers did not improve on findings obtained with CD8 counts. Conclusions: MIBC with low CD8+ T cell counts may benefit from hypoxia-modifying treatment. [ABSTRACT FROM AUTHOR]