Highly aneuploid non-small cell lung cancer shows enhanced responsiveness to concurrent radiation and immune checkpoint blockade.

Over 500 clinical trials are investigating combination radiotherapy and immune checkpoint blockade (ICB) as cancer treatments; however, the majority of trials have found no positive interaction. Here we perform a comprehensive molecular analysis of a randomized phase I clinical trial of patients with non-small cell lung cancer (NSCLC) treated with concurrent or sequential ablative radiotherapy and ICB. We show that concurrent treatment is superior to sequential treatment in augmenting local and distant tumor responses and in improving overall survival in a subset of patients with immunologically cold, highly aneuploid tumors, but not in those with less aneuploid tumors. In addition, radiotherapy alone decreases intratumoral cytotoxic T cell and adaptive immune signatures, whereas radiotherapy and ICB upregulates key immune pathways. Our findings challenge the prevailing paradigm that local ablative radiotherapy beneficially stimulates the immune response. We propose the use of tumor aneuploidy as a biomarker and therapeutic target in personalizing treatment approaches for patients with NSCLC treated with radiotherapy and ICB.

Determining the Organ at Risk for Lymphedema After Regional Nodal Irradiation in Breast Cancer.

PURPOSE: Lymphedema after regional nodal irradiation is a severe complication that could be minimized without significantly compromising nodal coverage if the anatomic region(s) associated with lymphedema were better defined. This study sought to correlate dose-volume relationships within subregions of the axilla with lymphedema outcomes to generate treatment planning guidelines for reducing lymphedema risk. METHODS AND MATERIALS: Women with stage II-III breast cancer who underwent breast surgery with axillary assessment and regional nodal irradiation were identified. Nodal targets were prospectively contoured per Radiation Therapy Oncology Group guidelines for field design. The axilla was divided into 8 distinct subregions that were retrospectively contoured. Lymphedema outcomes were assessed by arm circumferences. Multivariate Cox proportional hazards regression assessed patient, surgical, and dosimetric predictors of lymphedema outcomes. RESULTS: Treatment planning computed tomography scans for 265 women treated between 2013 and 2017 were identified. Median post-radiation therapy follow-up was 3 years (interquartile range [IQR], 1.9-3.6). Dose to the axillary-lateral thoracic vessel juncture (ALTJ; superior to level I) was most associated with lymphedema risk (maximally selected rank statistic = 6.3, P < .001). The optimal metric was ALTJ minimum dose (Dmin) <38.6 Gy (3-year lymphedema rate 5.7% vs 37.4%, P <.001), although multiple parameters relating to sparing of the ALTJ were highly correlated. Multivariate analysis confirmed ALTJ Dmin <38.6 Gy (hazard ratio [HR], 0.13; P < .001), body mass index (HR, 1.06/unit; P = .002), and number of lymph nodes removed (HR, 1.08/node; P < .001) as significant predictors. Women with ALTJ Dmin <38.6 Gy maintained median V45Gy of 99% in the supraclavicular (IQR, 94-100%), 100% in level III (IQR, 97%-100%), 98% in level II (IQR, 86%-100%), and 91% in level I (IQR, 75%-98%) nodal basins. CONCLUSIONS: Anatomic studies suggest the ALTJ region is typically traversed by arm lymphatics and appears to be an organ at risk in breast radiation therapy. Ideally, avoidance of the ALTJ may be feasible while simultaneously encompassing breast-draining nodal basins. Confirmation of this finding in future prospective studies is needed.