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    • Petrovics et al demonstrated that

    2018-10-30

    Petrovics et al. demonstrated that the statistical power can be improved by combining and integrating different data types including whole genome sequencing (WGS), FISH assays and SNP array data. Despite the initial discovery was based on only 7 CA and 7 AA tumor/normal pairs of WGS data, the findings of GDC-0994 were further replicated in 1) TCGA SNP array data for 279 CA and 41 AA patients; and 2) FISH assay data for 59 CA and 42 AA. Even larger sample size, especially for the discovery phase, could possibly lead to additional novel findings highlighting differences in prostate tumors between CA and AA patients.
    Late radiation-induced side effects are a major concern for both clinicians and patients, owing to their frequent irreversibility and possibly permanent detrimental effect on quality of life. Despite technological refinements simply unimaginable less than 10–15years ago, a significant fraction of patients still experience severe long-term sequelae after radiotherapy. It is surprising to observe how in some cohorts of subjects treated on the same anatomical site, with identical radiation doses and techniques and with comparable doses unavoidably delivered to healthy tissues surrounding the tumor, only a minority of subjects occasionally develop dramatic late sequelae, while all the others pass through irradiation with no, or only minimal, negative consequences. Such a phenomenon is explainable only by hypothesizing the existence of individual radiosensitivity. In their elegant paper in this issue of , Azria et al. report on the first prospective, multi-Institute trial investigating the role of Radiation Induced Lymphocyte Apoptosis (RILA) as a predictor of breast fibrosis after adjuvant radiotherapy following breast conservative surgery (). RILA, defined as the percentage of peripheral blood lymphocyte (PBL) death induced by a certain radiation dose minus the spontaneous cell death (), is a versatile, rapid and reproducible assay of radiosensitivity on PBL (). In general, radiobiological normal tissue assays are technically more convenient and feasible than tumor tissue assays (). Lymphocytes, in particular, appear to be the ideal candidates for such analyses, owing to both their accessibility and high concentrations in peripheral blood (). As previously reported, though only in a retrospective manner or in prospective single-Institute studies () an inverse relationship between the percentage of apoptosis in irradiated lymphocytes and late toxicity emerged also in this report (). The mechanism of this inverse association is not completely clear, being possibly related to the delay of cells in recognizing the radiation-induced cell damage and initiating apoptosis, with a consequently increased risk of toxicity and, theoretically, of cancer radioresistance and reduced tumor control. In particular, a decreased incidence of Grade≥2 breast fibrosis was observed by Azria et al. for increasing values of RILA, while no Grade 3 breast fibrosis was observed in patients with RILA >12%, with a negative predictive value of 91% for RILA ≥20%. The positive predictive value was, on the contrary, much lower (22% for RILA ≤12%) (). This finding, far from weakening or reducing the translational significance of this trial, simply suggests that, as appropriately highlighted by the Authors (), a biological assay is not, in itself, sufficient to predict the risk of late effects. In the French multicentric study, treatment-related and behavioural factors (namely, adjuvant hormonal therapy and tobacco smoking) also emerged as strong predictors of complication-relapse-free-survival (CRFS) (). On the contrary, and as previously described (), no correlation emerged between RILA and acute toxicity, leading the Authors to postulate that mechanisms other than DNA repair are represented by the RILA assay (). No predictive value emerged for RILA with respect to oncological outcome. This is not surprising, given the overall favorable prognosis of the analyzed cohort, in which clinical relapses and deaths occurred in only 2.6% and 1.1%, respectively, of the cases. As emphasized in the paper, breast cancer is of course not the most appropriate cancer in which to evaluate the possible prognostic significance of RILA, which has been demonstrated, on the contrary, in more aggressive neoplasms such as cervical () and prostate carcinoma (), though not confirmed in a prospective Swiss study on 399 patients with miscellaneous cancers (). Undoubtedly, the possible association between the radiosensitivity of normal tissues and clinical outcome deserves further thorough investigation ().