Triple-negative breast cancer (TNBC) occurs in 10–15% of all breast cancer patients, yet it accounts for about half of all breast cancer deaths. There is an urgent need to identify new antitumor targets to provide additional treatment options for patients afflicted with this aggressive disease. Preclinical evidence suggests a critical role for insulin-like growth factor-2 (IGF2) and androgen receptor (AR) in regulating TNBC progression. To advance this work, a panel of TNBC cell lines was investigated with all cell lines showing significant expression of IGF2. Treatment with IGF2 stimulated cell proliferation in vitro (p < 0.05). Importantly, combination treatments with IGF1R inhibitors BMS-754807 and NVP-AEW541 elicited significant inhibition of TNBC cell proliferation (p < 0.001). Based on Annexin-V binding assays, BMS-754807, NVP-AEW541 and enzalutamide induced TNBC cell death (p < 0.005). Additionally, combination of enzalutamide with BMS-754807 or NVP-AEW541 exerted significant reductions in TNBC proliferation even in cells with low AR expression (p < 0.001). Notably, NVP-AEW541 and BMS-754807 reduced AR levels in BT549 TNBC cells. These results provide evidence that IGF2 promotes TNBC cell viability and proliferation, while inhibition of IGF1R/IR and AR pathways contribute to blockade of TNBC proliferation and promotion of apoptosis in vitro.
Radiation therapy remains at the center of head and neck cancer treatment. With improvements in treatment delivery, radiation therapy has become an affective ablative modality for head and neck cancers. Immune checkpoint inhibitors are now also playing a more active role both in the locally advanced and metastatic setting. With improved systemic options, local noninvasive modalities including radiation therapy are playing a critical role in overcoming resistance in head and neck cancer. The aim of this review is to describe the role of radiation therapy in modulating the tumor microenvironment and how radiation dose, fractionation and treatment field can impact the immune system and potentially effect outcomes when combined with immunotherapy. The review will encompass several common scenarios where radiation is used to improve outcomes and overcome potential resistance that may develop with immunotherapy in head and neck squamous cell carcinoma (HNSCC), including upfront locally advanced disease receiving definitive radiation and recurrent disease undergoing re-irradiation. Lastly, we will review the potential toxicities of combined therapy and future directions of their role in the management of HNSCC.
Objective The purpose of this study was to evaluate overall survival (OS) outcomes by race, stratified by country of origin in patients diagnosed with NSCLC in California. Methods We performed a retrospective analysis of nonsmall cell lung cancer (NSCLC) patients diagnosed between 2000 and 2012. Race/ethnicity was defined as White (W), Black (B), Hispanic (H), and Asian (A) and stratified by country of origin (US vs. non‐US [NUS]) creating the following patient cohorts: W‐US, W‐NUS, B‐US, B‐NUS, H‐US, H‐NUS, A‐US, and A‐NUS. Three multivariate models were created: model 1 adjusted for age, gender, stage, year of diagnosis and histology; model 2 included model 1 plus treatment modalities; and model 3 included model 2 with the addition of socioeconomic status, marital status, and insurance. Results A total of 68,232 patients were included. Median OS from highest to lowest were: A‐NUS (15 months), W‐NUS (14 months), A‐US (13 months), B‐NUS (13 months), H‐US (11 months), W‐US (11 months), H‐NUS (10 months), and B‐US (10 months) (p < 0.001). In model 1, B‐US had worse OS, whereas A‐US, W‐NUS, B‐NUS, H‐NUS, and A‐NUS had better OS when compared to W‐US. In model 2 after adjusting for receipt of treatment, there was no difference in OS for B‐US when compared to W‐US. After adjusting for all variables (model 3), all race/ethnicity profiles had better OS when compared to W‐US; B‐NUS patients had similar OS to W‐US. Conclusion Foreign‐born patients with NSCLC have decreased risk of mortality when compared to native‐born patients in California after accounting for treatments received and socioeconomic differences.
Tyrosine kinase inhibitor (TKI) therapy is the recommended first-line treatment for metastatic non-small-cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) gene mutation. However, most individuals treated with TKI therapy for EGFR-mutant NSCLC will develop tumor resistance to TKI therapy. Therapeutic strategies to overcome TKI resistance are the topic of several ongoing clinical trials. One potential strategy, which has been explored in numerous trials, is the treatment of progressive sites of disease with stereotactic body radiation treatment (SBRT) or stereotactic radiosurgery (SRS). We sought to review the literature pertaining to the use of local ablative radiation therapy in the setting of acquired resistance to TKI therapy and to discuss stereotactic radiation therapy as a strategy to overcome TKI resistance.
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