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  • TMB is an emerging predictive

    2019-09-03

    TMB is an emerging predictive biomarker for responses to immune checkpoint blockades (ICBs) in patients with NSCLC. The phase III trial evaluating combinations of the programmed cell death protein 1 (PD-1) inhibitor nivolumab, the CTLA4 inhibitor ipilimumab, and chemotherapy as first-line treatments in newly diagnosed advanced NSCLC, revealed that the two drugs were more effective than chemotherapy in patients with a high TMB, suggesting that TMB could be used as a predictive biomarker in patients who receive upfront immunotherapy [36]. It may be tempting to consider that the findings of this study, which revealed increased TMB in patients exposed to high-radon levels, might indicate that ICBs could be more effective in these patients. However, the effective immunogenicity of mutations needs to be assessed [37], and the absolute cutoff of high TMB remains to be established. NOTCH2 germline mutations were exclusively identified in radon-high tumors, present in 8 of 20 patients (40%). Notch signaling pathways play a key role in the development of cancer, as they target stem cell populations, organ morphogenesis and Elafibranor (GFT505) [38]. Crosstalk between the Notch and p53 pathways have been reported, in which Notch signaling regulates p53 activity, which in turn, also regulates Notch, in positive or negative feedback loops. Although NOTCH somatic mutations have been reported in various cancers, the role of germline NOTCH2 mutations remains unclear. Regarding the cut-off dose of radon exposure, we adopted the median value (48 Bq/m [3]) in our cohort in defining radon-high vs. radon-low groups. Different studies have adopted different cut-offs of defining radon-high group. Choi et al. divided subjects into two groups with the cutoff value of 100 Bq/m3(5), and Elio, et al. used the reference value of 200 Bq/m3 in defining lung cancer risk [39]. However, as there is no absolute safe level of radon exposure, and low radon concentration may also cause adverse effects, future large-scaled studies are necessary to more accurately define radon-related lung cancer risks. A few limitations, mainly associated with the small study sample size, should be considered when interpreting the results of this study. The small sample size makes it difficult to generalize the results and likely contributed to the large standard errors, leading to the wide CIs and high P-values. Additionally, it would be difficult to conduct a prospective validation study based on our results in patients. In vivo studies may enhance our understanding of the effects of radon on lung cancer development and the mutational landscape. Another limitation is the inclusion criteria of at least 2 years of residence where the radon was measured. Previous literature suggested that it takes at least 5 years to observe a change of lung cancer risk due to Elafibranor (GFT505) radon exposure [40]. Even though the inclusion criteria was a minimum of 2 years in our study, the median duration of residence was 13 years (range 3–38 years) and we adopted a more accurate measurement method of indoor radon by assessing the residence, the environment around residence, and lifestyles of the residents [41].
    Acknowledgement
    Introduction The preferred treatment for patients with Stage II non-small cell lung cancer (NSCLC) is definitive surgical resection [1,2]. However, a minority of patients do not undergo surgery because of comorbidities that render them unsuitable surgical candidates, and some operable patients may prefer not to undergo surgery. There is a rising role for stereotactic body radiation therapy (SBRT) in early stage, typically Stage I NSCLC, delivering ablative doses of highly conformal radiation in a limited number of fractions. In one study, a survey of radiation oncologists in the United States concluded that lung was the most common disease site treated with SBRT [3]. SBRT has been demonstrated to provide high rate of local tumor control in inoperable early stage NSCLC measuring < 5 cm [4]. With the increasing use of SBRT, the STARS and ROSEL trials, as well as RTOG 0618, aimed to evaluate the role of SBRT in operable Stage I NSCLC [5,6]. The National Comprehensive Cancer Network (NCCN) and the American College of Chest Physicians recommend definitive radiotherapy with SBRT treatment for inoperable T 1-2 node-negative NSCLC [1,2]. However, its use in treating Stage II NSCLC with larger primaries and node-positive disease is not as well studied.