The mitochondrial DNA constitution shaping T-cell immunity in patients with rectal cancer at high risk of metastatic progression.

PURPOSE: A significant percentage of colorectal cancer patients proceeds to metastatic disease. We hypothesised that mitochondrial DNA (mtDNA) polymorphisms, generated by the high mtDNA mutation rate of energy-demanding clonal immune cell expansions and assessable in peripheral blood, reflect how efficiently systemic immunity impedes metastasis. PATIENTS AND METHODS: We studied 44 rectal cancer patients from a population-based prospective biomarker study, given curative-intent neoadjuvant radiation and radical surgery for high-risk tumour stage and followed for metastatic failure. Blood specimens were sampled at the time of diagnosis and analysed for the full-length mtDNA sequence, composition of immune cell subpopulations and damaged serum mtDNA. RESULTS: Whole blood total mtDNA variant number above the median value for the study cohort, coexisting with an mtDNA non-H haplogroup, was representative for the mtDNA of circulating immune cells and associated with low risk of a metastatic event. Abundant mtDNA variants correlated with proliferating helper T cells and cytotoxic effector T cells in the circulation. Patients without metastatic progression had high relative levels of circulating tumour-targeting effector T cells and, of note, the naïve (LAG-3+) helper T-cell population, with the proportion of LAG-3+ cells inversely correlating with cell-free damaged mtDNA in serum known to cause antagonising inflammation. CONCLUSION: Numerous mtDNA polymorphisms in peripheral blood reflected clonal expansion of circulating helper and cytotoxic T-cell populations in patients without metastatic failure. The statistical associations suggested that patient's constitutional mtDNA manifests the helper T-cell capacity to mount immunity that controls metastatic susceptibility. TRIAL REGISTRATION: ClinicalTrials.gov NCT01816607; registration date: 22 March 2013.

Personalized radiotherapy: concepts, biomarkers and trial design.

In the past decade, and pointing onwards to the immediate future, clinical radiotherapy has undergone considerable developments, essentially including technological advances to sculpt radiation delivery, the demonstration of the benefit of adding concomitant cytotoxic agents to radiotherapy for a range of tumour types and, intriguingly, the increasing integration of targeted therapeutics for biological optimization of radiation effects. Recent molecular and imaging insights into radiobiology will provide a unique opportunity for rational patient treatment, enabling the parallel design of next-generation trials that formally examine the therapeutic outcome of adding targeted drugs to radiation, together with the critically important assessment of radiation volume and dose-limiting treatment toxicities. In considering the use of systemic agents with presumed radiosensitizing activity, this may also include the identification of molecular, metabolic and imaging markers of treatment response and tolerability, and will need particular attention on patient eligibility. In addition to providing an overview of clinical biomarker studies relevant for personalized radiotherapy, this communication will highlight principles in addressing clinical evaluation of combined-modality-targeted therapeutics and radiation. The increasing number of translational studies that bridge large-scale omics sciences with quality-assured phenomics end points-given the imperative development of open-source data repositories to allow investigators the access to the complex data sets-will enable radiation oncology to continue to position itself with the highest level of evidence within existing clinical practice.

MRI volumetry for prediction of tumour response to neoadjuvant chemotherapy followed by chemoradiotherapy in locally advanced rectal cancer.

OBJECTIVE: To investigate if MRI-assessed tumour volumetry correlates with histological tumour response to neoadjuvant chemotherapy (NACT) and subsequent chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC). METHODS: Data from 69 prospectively enrolled patients with LARC receiving NACT followed by CRT and radical surgery were analysed. Whole-tumour volumes were contoured in T2 weighted MR images obtained pre-treatment (VPRE), after NACT (VNACT) and after the full course of NACT followed by CRT (VCRT). VPRE, VNACT and tumour volume changes relative to VPRE, ΔVNACT and ΔVCRT were calculated and correlated to histological tumour regression grade (TRG). RESULTS: 61% of good histological responders (TRG 1-2) to NACT followed by CRT were correctly predicted by combining VPRE < 10.5 cm(3), ΔVNACT > -78.2% and VNACT < 3.3 cm(3). The highest accuracy was found for VNACT, with 55.1% sensitivity given 100% specificity. The volume regression after completed NACT and CRT (VCRT) was not significantly different between good and poor responders (TRG 1-2 vs TRG 3-5). CONCLUSION: MRI-assessed small tumour volumes after NACT correlated with good histological tumour response (TRG 1-2) to the completed course of NACT and CRT. Furthermore, by combining tumour volume measurements before, during and after NACT, more good responders were identified. ADVANCES IN KNOWLEDGE: MRI volumetry may be a tool for early identification of good and poor responders to NACT followed by CRT and surgery in LARC in order to aid more individualized, multimodal treatment.