Weiye Deng

RAD50 expression is associated with poor clinical outcomes after radiotherapy for resected non-small cell lung cancer

Purpose: Although postoperative radiotherapy is often used to maintain local control after surgical resection and chemotherapy for locally advanced non–small cell lung cancer (NSCLC), both locoregional failure and distant metastasis remain problematic. The mechanisms of therapeutic resistance remain poorly understood. Experimental Design: We used reverse-phase protein arrays (RPPA) to profile the baseline expression of 170 total and phosphorylated proteins in 70 NSCLC cell lines to categorize pathways that may contribute to radiation resistance. Significant markers identified by RPPA were further analyzed in tissue microarrays (TMA) of specimens from 127 patients with NSCLC who had received surgery before receiving postoperative radiotherapy. Cox regression analysis and log-rank tests were used to identify potential predictive factors. We then validated the biological function of the markers in NSCLC cell lines in vitro. Results: Of the 170 proteins or phospho-proteins profiled, a subset of 12 proteins was found to correlate with radiation response parameters. TMA analysis of the 12 proteins showing the greatest differences in expression in the RPPA analysis demonstrated that RAD50 had the strongest correlation with distant relapse-free survival, locoregional relapse-free survival, and disease-free survival in patients with NSCLC. We confirmed that knockdown of RAD50 sensitized NSCLC cells to radiation and that upregulation of RAD50 increased radioresistance in in vitro experiments. Conclusions: Upregulated RAD50 may be a predictor of radioresistance in patients with lung cancer who received radiotherapy. Clin Cancer Res; 24(2); 341–50. ©2017 AACR.

Combining Immunotherapy and Radiotherapy for Cancer Treatment: Current Challenges and Future Directions

Since the approval of anti-CTLA4 therapy (ipilimumab) for late-stage melanoma in 2011, the development of anticancer immunotherapy agents has thrived. The success of many immune-checkpoint inhibitors has drastically changed the landscape of cancer treatment. For some types of cancer, monotherapy for targeting immune checkpoint pathways has proven more effective than traditional therapies, and combining immunotherapy with current treatment strategies may yield even better outcomes. Numerous preclinical studies have suggested that combining immunotherapy with radiotherapy could be a promising strategy for synergistic enhancement of treatment efficacy. Radiation delivered to the tumor site affects both tumor cells and surrounding stromal cells. Radiation-induced cancer cell damage exposes tumor-specific antigens that make them visible to immune surveillance and promotes the priming and activation of cytotoxic T cells. Radiation-induced modulation of the tumor microenvironment may also facilitate the recruitment and infiltration of immune cells. This unique relationship is the rationale for combining radiation with immune checkpoint blockade. Enhanced tumor recognition and immune cell targeting with checkpoint blockade may unleash the immune system to eliminate the cancer cells. However, challenges remain to be addressed to maximize the efficacy of this promising combination. Here we summarize the mechanisms of radiation and immune system interaction, and we discuss current challenges in radiation and immune checkpoint blockade therapy and possible future approaches to boost this combination.

Log odds of positive lymph nodes may predict survival benefit in patients with node-positive non-small cell lung cancer

OBJECTIVES The number of positive lymph nodes (npLNs) and the lymph node ratio [LNR; npLNs/number of resected LNs] are useful for predicting survival among patients with non-small cell lung cancer (NSCLC). Here we compared the relative effectiveness of npLNs, LNR, and the log odds of positive lymph nodes (LODDS) to predict overall survival (OS) and cancer-specific survival (CSS) among patients with node-positive NSCLC. MATERIALS AND METHODS We identified 5289 patients with NSCLC and lymph node involvement who had lobectomy or pneumonectomy in 2010-2013 from the Surveillance Epidemiology and End Results (SEER) database. Potential associations between npLNs, LNR, and LODDS with overall survival (OS) and cancer-specific survival (CSS) were assessed with Cox regression analysis. The goodness of fit of npLNs, LNR, and LODDS was compared with the -2 log-likelihood ratio (-2LLR) and by differences in Akaikes information criterion scores (ΔAIC). Tree-based recursive partitioning was applied to split ratio-based variables (LNR and LODDS) into low- and high-risk groups. Kaplan-Meier actuarial estimates of OS and CSS in the various npLNs, LNR, and LODDS subgroups were compared with log-rank tests. RESULTS AND CONCLUSION Of 5289 patients, 2297 (43.3%) had <10 LNs retrieved and 2992 (56.6%) had ≥10 LNs harvested. Multivariate Cox analysis adjusted for significant factors indicated that LODDS, npLNs, and LNR were independent risk factors for OS and CSS. A LODDS model had the best fit compared with LNR or npLN models in predicting OS and CSS (P < 0.001, ΔAIC = 0). LODDS was slightly superior to LNR for patients with <10 resected LNs, and LNR was slightly superior to LODDS for patients with ≥10 resected LNs (P < 0.001). Higher LODDS was associated with worse OS and worse CSS (log-rank P for both <0.001). LODDS and LNR staging schemes outperformed those of npLNs for predicting OS and CSS.

Survival Patterns for Patients with Resected N2 Non-Small Cell Lung Cancer and Postoperative Radiotherapy: A Prognostic Scoring Model and Heat Map Approach.

Introduction: The positive‐to‐resected lymph node ratio (LNR) predicts survival in many cancers, but little information is available on its value for patients with N2 NSCLC who receive postoperative radiotherapy (PORT) after resection. We tested the applicability of prognostic scoring models and heat mapping to predict overall survival (OS) and cancer‐specific survival (CSS) in patients with resected N2 NSCLC and PORT. Methods: Our test cohort comprised patients identified from the Surveillance, Epidemiology, and End Results database with N2 NSCLC who received resection and PORT in 2000–2014. Prognostic scoring models were developed to predict OS and CSS using Cox regression; heat maps were constructed with corresponding survival probabilities. Recursive partitioning analysis was applied to the Surveillance, Epidemiology, and End Results data to identify the optimal LNR cutoff point. Models and cutoff points were further tested in 183 similar patients treated at The University of Texas M. D. Anderson Cancer Center in 2000–2015. Results: Multivariate analyses revealed that low LNR independently predicted better OS and CSS in patients with resected N2 NSCLC who received PORT. Conclusions: LNR can be used to predict survival of patients with resected N2 NSCLC followed by PORT. This approach, which to our knowledge is the first application of heat mapping of positive and negative lymph nodes, was effective in estimating 3‐, 5‐, and 10‐year OS probabilities.

Mutant LKB1 Confers Enhanced Radiosensitization in Combination with Trametinib in KRAS-Mutant Non–Small Cell Lung Cancer

Purpose: The MEK inhibitor trametinib radiosensitizes KRAS-mutant non–small cell lung cancer (NSCLC) and is being tested clinically with chemoradiation. However, variability in response to trametinib suggests that additional pathways are involved. The mechanism of resistance to trametinib radiosensitization is still unknown. Experimental Design: We used a panel of KRAS-mutant NSCLC cells and tested the radiosensitization effects of trametinib by clonogenic survival assay. Then, we investigated the mechanisms underlying the resistance to the combination therapy through several knockout and overexpression systems. Finally, we validated our findings in syngeneic mouse models in a treatment setting that mimicked the standard of care in the clinic. Results: Radiosensitization by trametinib was effective only in KRAS-LKB1–mutated cells with wild-type (WT) p53, and we found that restoring LKB1 expression in those cells blocked that sensitization. Trametinib and radiotherapy both induced senescence in a p53-dependent manner, but in WT LKB1 cells, the combination also activated the AMPK-autophagy pathway to rescue damaged cells from senescence. LKB1-knockout or autophagy inhibition in WT LKB1 cells potentiated trametinib radiosensitization. In syngeneic animal models of Kras-mutant lung tumors, Lkb1-knockout tumors were resistant to trametinib and chemoradiation given separately, but the combination greatly controlled tumor growth and prolonged survival. Conclusions: The LKB1 mutation in KRAS-mutant NSCLC conferred enhanced radiosensitization in combination with trametinib. The WT LKB1 could activate autophagy through AMPK pathway to induce resistance to the combination of trametinib and radiation. The KRAS-LKB1 mutation could potentially be a biomarker to select patients for trametinib and radiotherapy combination therapy. Clin Cancer Res; 24(22); 5744–56. ©2018 AACR.

Dosimetric comparison of the helical tomotherapy, volumetric-modulated arc therapy and fixed-field intensity-modulated radiotherapy for stage IIB-IIIB non-small cell lung cancer

The study aimed to compare the dosimetric parameters to target dose coverage and the critical structures in the treatment planning of helical tomotherapy (TOMO), volumetric-modulated arc therapy (VMAT), and fixed-field intensity-modulated radiotherapy (IMRT) for NSCLC delivering conventionally fractionated radiotherapy. Thirty patients with pathologically confirmed NSCLC were included. Three radiation treatment plans were designed for each patient. All patients received the uniform prescription dose of 60 Gy to the planning target volume. The conformity index (CI), heterogeneity index (HI), and parameters of critical structures were calculated. A significantly superior mean CI was observed in VMAT than in TOMO or IMRT (P = 0.013, 0.001). Mean HI was also better using VAMT or IMRT than TOMO (P = 0.002, 0.003). Mean lung V20 and V30 were significantly reduced by TOMO compared to IMRT (P = 0.019, 0.029). The heart was spared by IMRT compared to TOMO in terms of mean heart dose, V5, V10, and V20 (P < 0.05). In larger tumor, VMAT provided the optimal dose distribution and sparing to heart. Compared to TOMO and IMRT, VMAT achieved better target dose distribution and similar sparing of critical structures. VMAT seemed to be the optimal technique for NSCLC.

Association Between LGALS3 Gene Polymorphisms and Survival in Non–Small Cell Lung Cancer Patients Treated With Definitive Radiation Therapy

associated with a worse FFP (8.2 months vs 14.4 months, HRZ2.26 [1.1, 4.72] PZ.028). Conclusion: The primary tumor is the most common site of progression in patients with metastatic EGFR-mt NSCLC on a TKI. In 15% of patients, progression was limited to the primary site in the lung. Interestingly, patients with liver metastases have a higher incidence of primary site progression, warranting further evaluation. Additionally, FFP is improved in patients who have undergone upfront treatment to the primary site, regardless of modality, although this finding may be affected by selection bias. These findings will help inform treatment paradigms investigating local therapy in metastatic EGFR-mt NSCLC, including patients presenting with stage IV disease who ordinarily might not have definitive treatment to the primary site. Author Disclosure: D.M. Guttmann: Employee; Childrens Hospital of the University of Pennsylvania. A. Doucette: None. P.E. Gabriel: Employee; Penn Medicine. J.J. Morrissette: None. J. Kucharczuk: None. W.P. Levin: None. C.B. Simone: Employee; Nemours Alfred I. duPont Hospital for Children. E. Alley: None. C. Ciunci: None. J. Bauml: None. C. Langer: Research Grant; Bristol-Myers Squibb Company, ImClone Systems Incorporated, Pfizer, Eli Lilly and Companry, Genentech, OSI Pharmaceuticals, GlaxoSmithKline, Clovis, Merck, Nektar, Advantagene, Inovio, Ariad. C. Aggarwal: None. R. Cohen: Advisory Board; Takeda, Kolltan, Cerulean. T.L. Evans: None. A.T. Berman: None.

Prospective Study of Marginal Recurrence in Patients with Non–Small Cell Lung Cancer After Proton or Photon Chemoradiation Therapy

Prospective Study of Marginal Recurrence in Patients with NoneSmall Cell Lung Cancer After Proton or Photon Chemoradiation Therapy P. Yang, Z. Liao, D.R. Gomez, T. Xu, L.B. Levy, W. Deng, J. Yang, and R. Mohan; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, Hunan Cancer Hospital, Changsha, China, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, The University of Texas MD Anderson Cancer Center, Division of Radiation Oncology, Houston, TX, University of Texas M.D. Anderson Cancer Center, Houston, TX Purpose/Objective(s): The dose distribution of proton therapy is better than photon therapy to reduce the toxicities to the normal tissues due to the marginal dose decreasing. This study is to investigate whether there is a difference in marginal local recurrence (LR) adjacent to the GTV between proton and photon. The primary hypothesis is that the proton group has more marginal LR than the photon group. Materials/Methods: Patients were enrolled in a prospective randomized trial comparing IMRT and PSPT from 2009 to 2014. Total 64 patients with local recurrence were included in the current analysis. The average images of simulated 4DCT were set as the baseline; then we export DICOM PETCT images when the local recurrence occurred in regular exam after treatment and register these two images rigidly by focusing on the primary and recurrence tumor site via Velocity. We expanded 10 mm to the margin of GTVand contoured the recurrence site where SUV > 5 on PET-CT, then we calculated the volume of recurrence tumor (GTVr), which was located in the overlap space between GTV and GTV 10 mm expansion 3-dimensionally. The original and log-transformation data were utilized in an independent sample t-test model to analyze the difference in overlapped contour between the proton and photon groups. Factors that might impact the outcome were analyzed using multivariate linear regression model. Results: No significant differences were found between the proton and photon groups whether using the original volume data (PZ.372) or the log-transformation volume data (PZ.745) in the independent sample T-test. Twenty-two patients with LR tumor outside the overlap zone were excluded after log-transforming. In multivariable linear regression, no factors were related to the GTVr (P>.05). Conclusion: There is no difference in marginal local recurrence between proton and photon therapy. Author Disclosure: P. Yang: None. Z. Liao: None. D.R. Gomez: None. T. Xu: None. L.B. Levy: None. W. Deng: None. J. Yang: None. R. Mohan: None.