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ObjectiveTo estimate the risk of death from lung cancer in patients treated for breast cancer (BC) in relation to the general population.MethodsBC data, covering 2000 to 2015, were extracted from the Surveillance, Epidemiology and End Results-18 (SEER-18) cancer registry database. A comparison of lung cancer attributed mortality between BC patients and the general population was performed using standardized mortality ratios (SMRs) and SMRs conditional on survival length (cSMRs). Prognostic factors of lung cancer mortality were identified using flexible parametric modelling. Our model adjusts the effect of downstream (histopathological BC tumor grade and hormone receptor status) and upstream (age at diagnosis, ethnicity, and marital status) factors.ResultsThe median follow-up was 6.4 years (interquartile range, 3.0–10.3 years). BC cases who received only radiotherapy (cSMR = 0.93; 95%CI: 0.77–1.13), only chemotherapy (cSMR = 0.91; 0.62–1.33), and radio-and chemotherapy (cSMR = 1.04; 0.77–1.39) had no evidence of increased lung cancer mortality relative to the general population. The adjusted model identified that lung cancer mortality was higher for women who were older at diagnosis compared to those

Summary: Inhibition of the ATR kinase has emerged as a therapeutically attractive means to target cancer since the development of potent inhibitors, which are now in clinical testing. We investigated a potential link between ATR inhibition and the autophagy process in esophageal cancer cells using four ATR inhibitors including two in clinical testing. The response to pharmacological ATR inhibitors was compared with genetic systems to investigate the ATR dependence of the effects observed. The ATR inhibitor, VX-970, was found to lead to an accumulation of p62 and LC3-II indicative of a blocked autophagy. This increase in p62 occurred post-transcriptionally and in all the cell lines tested. However, our data indicate that the accumulation of p62 occurred in an ATR-independent manner and was instead an off-target response to the ATR inhibitor. This study has important implications for the clinical response to pharmacological ATR inhibition, which in some cases includes the blockage of autophagy.

BACKGROUND:Currently, the role of adjuvant irradiation in head and neck cancer (HNC) patients with N1-lymph node status is not clarified. OBJECTIVES:To assess the population-based effect of recent developments in radiotherapy such as intensity-modulated radiotherapy (IMRT) in relation to overall survival (OS) together with surgery in N1 HNC patients. MATERIALS AND METHODS:We used 9,318 HNC cases with pT1/2 N0/1 disease from German cancer registries. Time of diagnosis ranged from January 2000 to December 2014, which we divided into three periods: (low [LIA] vs intermediate [IA] vs high [HIA] IMRT availability period) based on usage of IMRT in Germany. For each period, we examined a possible association between treatment (surgery vs. surgery and radiotherapy) in terms of OS. Statistical analyses included Kaplan-Meier and multivariate Cox regression (models adjusted for HPV-related cancer site). RESULTS:Temporal analysis revealed increasing usage of IMRT in Germany. In patients with N1 tumours, a comparison of patients treated with and without radiotherapy during the HIA period showed a superiority of the combined treatment as opposed to surgery alone (HR 0.54, 95%CI: 0.35-0.85, p = 0.003). The survival analyses related to treatments in terms of period underlined the superiority of surgery plus radiotherapy between periods IA and HIA (p = 0.03). CONCLUSION:The advent of IMRT, additional radiotherapy may present a survival advantage in patients with N1 HNC when combined with surgery.

Hypoxia mediates resistance to radio(chemo)therapy (RT) by stimulating the synthesis of hypoxia-related genes, such as osteopontin (OPN) and stress proteins, including the major stress-inducible heat shock protein 70 (Hsp70). Apart from its intracellular localization, Hsp70 is also present on the plasma membrane of viable tumor cells that actively release it in lipid vesicles with biophysical characteristics of exosomes. Exosomal Hsp70 contributes to radioresistance while Hsp70 derived from dying tumor cells can serve as a stimulator of immune cells. Given these opposing traits of extracellular Hsp70 and the unsatisfactory outcome of locally advanced lung tumors, we investigated the role of Hsp70 in the plasma of patients with advanced, non-metastasized non-small-cell lung cancer (NSCLC) before (T1) and 4–6 weeks after RT (T2) in relation to OPN as potential biomarkers for clinical response. Plasma levels of Hsp70 correlate with those of OPN at T1, and high OPN levels are significantly associated with a decreased overall survival (OS). Due to a therapy-induced reduction in viable tumor mass after RT Hsp70 plasma levels dropped significantly at T2 (p = 0.016). However, with respect to the immunostimulatory capacity of Hsp70 derived from dying tumor cells, patients with higher post-therapeutic Hsp70 levels showed a significantly better response to RT (p = 0.034) than those with lower levels at T2. In summary, high OPN plasma levels at T1 are indicative for poor OS, whereas elevated post-therapeutic Hsp70 plasma levels together with a drop of Hsp70 between T1 and T2, successfully predict favorable responses to RT. Monitoring the dynamics of Hsp70 in NSCLC patients before and after RT can provide additional predictive information for clinical outcome and therefore might allow a more rapid therapy adaptation.