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Introduction: To assess the role of the 21-gene recurrence score (RS) assay on decision-making of postoperative radiotherapy (RT) following breast-conserving surgery (BCS) in elderly women with early-stage breast cancer.Methods: The 21-gene RS for elderly (≥65 years) women with stage T1–2N0M0 estrogen receptor-positive breast cancer who underwent BCS from 2004 to 2015 was obtained from the Surveillance, Epidemiology, and End Results program. We estimated the association of 21-gene RS and adjuvant RT related to breast cancer-specific survival (BCSS) using propensity score matching (PSM).Results: We identified 18,456 patients, of which 15,326 (83.0%) received postoperative RT. Of identified patients, 58.9, 34.0, and 7.1% of patients had a low-, intermediate-, and high-risk RS, respectively. Receipt of postoperative RT was not related to the year of diagnosis according to the 21-gene RS groups. Multivariate analysis suggested that receipt of postoperative RT was an independent predictor of better BCSS before (hazard ratio [HR] 0.587, 95% confidence interval [CI] 0.426–0.809, P = 0.001) and after (HR 0.613, 95%CI 0.390–0.963, P = 0.034) PSM. However, subgroups analyses indicated that receipt of postoperative RT was related to better BCSS in women with intermediate-risk RS before (HR 0.467, 95%CI 0.283–0.772, P = 0.003) and after (HR 0.389, 95%CI 0.179–0.846, P = 0.017) PSM, but not in women with low- and high-risk RS groups before and after PSM.Conclusions: Although causation cannot be implied, adjuvant RT in elderly women was associated with a greater effect size in patients with an intermediate-risk RS.

We have demonstrated that subclones carrying driver mutations are more prone to release DNA. We have also demonstrated the quantitative ability of capture-based sequencing, paving its way for routine utilization in clinical settings.

Rationale: Ferroptosis, a newly identified form of regulated cell death, can be induced following the inhibition of cystine-glutamate antiporter system X C - because of the impaired uptake of cystine. However, the outcome following the accumulation of endogenous glutamate in lung adenocarcinoma (LUAD) has not yet been determined. Yes-associated protein (YAP) is sustained by the hexosamine biosynthesis pathway (HBP)-dependent O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation), and glutamine-fructose-6-phosphate transaminase (GFPT1), the rate-limiting enzyme of the HBP, can be phosphorylated and inhibited by adenylyl cyclase (ADCY)-mediated activation of protein kinase A (PKA). However, whether accumulated endogenous glutamate determines ferroptosis sensitivity by influencing the ADCY/PKA/HBP/YAP axis in LUAD cells is not understood. Methods: Cell viability, cell death and the generation of lipid reactive oxygen species (ROS) and malondialdehyde (MDA) were measured to evaluate the responses to the induction of ferroptosis following the inhibition of system X C - . Tandem mass tags (TMTs) were employed to explore potential factors critical for the ferroptosis sensitivity of LUAD cells. Immunoblotting (IB) and quantitative RT-PCR (qPCR) were used to analyze protein and mRNA expression. Co-immunoprecipitation (co-IP) assays were performed to identify protein-protein interactions and posttranslational modifications. Metabolite levels were measured using the appropriate kits. Transcriptional regulation was evaluated using a luciferase reporter assay, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA). Drug administration and limiting dilution cell transplantation were performed with cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. The associations among clinical outcome, drug efficacy and ADCY10 expression were determined based on data from patients who underwent curative surgery and evaluated with patient-derived primary LUAD cells and tissues. Results: The accumulation of endogenous glutamate following system X C - inhibition has been shown to determine ferroptosis sensitivity by suppressing YAP in LUAD cells. YAP O-GlcNAcylation and expression cannot be sustained in LUAD cells upon impairment of GFPT1. Thus, Hippo pathway-like phosphorylation and ubiquitination of YAP are enhanced. ADCY10 acts as a key downstream target and diversifies the effects of glutamate on the PKA-dependent suppression of GFPT1. We also discovered that the protumorigenic and proferroptotic effects of ADCY10 are mediated separately. Advanced-stage LUADs with high ADCY10 expression are sensitive to ferroptosis. Moreover, LUAD cells with acquired therapy resistance are also prone to higher ADCY10 expression and are more likely to respond to ferroptosis. Finally, a varying degree of secondary labile iron ...