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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.

This study aimed to understand baseline knowledge of basic principles of radiation therapy for lung cancer among medical oncology, thoracic surgery, and pulmonology trainees and practicing physicians and also assess whether a didactic lecture will improve objective knowledge and perceived comfort level in making appropriate referrals to radiation oncology (RO). Radiation oncologists at 8 academic institutions offered a presentation covering indications, logistics, efficacy, and toxicity of thoracic radiation. Participants completed a survey to assess their prior exposures to RO and perceived value of the lecture, and objective knowledge gained based on pre/post-lecture questions. Among 121 attendees, 76 completed the pre-test, and 25 the post-test (response rates 62.8% and 20.7%, respectively). Fifty-seven (75.0%) had never previously experienced a RO didactic about lung cancer, 62 (81.6%) had never seen a linear accelerator, and 65 (85.5%) had never rotated in a RO department. The mean pre-test score was 53.5% (SD 17.6%), with a trend (p = 0.066) towards thoracic surgeons (61.5%) performing better than medical oncologists (55.5%) or pulmonologists (48.3%). Level of training (p = 0.130), and prior RO exposures (p = 0.240), did not significantly impact pre-test scores. The mean post-test score of 75.1% (SD 3.6%) was significantly higher than mean pre-test score (p 0.001). After the lecture, 25 participants (100%) felt more knowledgeable about RO, and 24 (96%) felt more comfortable making appropriate referrals to RO. A didactic lecture about RO for trainees and physicians who treat lung cancer at 8 academic institutions was feasible, filled a gap in exposure, and improved knowledge.

PURPOSE Molecular factors predicting relapse in early-stage non–small-cell lung cancer (ES-NSCLC) are poorly understood, especially in inoperable patients receiving radiotherapy (RT). In this study, we compared the genomic profiles of inoperable and operable ES-NSCLC. MATERIALS AND METHODS This retrospective study included 53 patients with nonsquamous ES-NSCLC (stage I-II) treated at a single institution (University of Chicago) with surgery (ie, operable; n = 30) or RT (ie, inoperable; n = 23) who underwent tumor genomic profiling. A second cohort of ES-NSCLC treated with RT (Stanford, n = 39) was included to power clinical analyses. Prognostic gene alterations were identified and correlated with clinical variables. The primary clinical end point was the correlation of prognostic genes with the cumulative incidence of relapse, disease-free survival, and overall survival (OS) in a pooled RT cohort from the two institutions (N = 62). RESULTS Although the surgery cohort exhibited lower rates of relapse, the RT cohort was highly enriched for somatic STK11 mutations (43% v 6.7%). Receiving supplemental oxygen (odds ratio [OR] = 5.5), 20+ pack-years of tobacco smoking (OR = 6.1), and Black race (OR = 4.3) were associated with increased frequency of STK11 mutations. In the pooled RT cohort (N = 62), STK11 mutation was strongly associated with inferior oncologic outcomes: 2-year incidence of relapse was 62% versus 20% and 2-year OS was 52% versus 85%, remaining independently prognostic on multivariable analyses (relapse: subdistribution hazard ratio = 4.0, P = .0041; disease-free survival: hazard ratio, 6.8, P = .0002; OS: hazard ratio, 6.0, P = .022). STK11 mutations were predominantly associated with distant failure, rather than local. CONCLUSION In this cohort of ES-NSCLC, STK11 inactivation was associated with poor oncologic outcomes after RT and demonstrated a novel association with clinical hypoxia, which may underlie its correlation with medical inoperability. Further validation in larger cohorts and investigation of effective adjuvant systemic therapies may be warranted.

Purpose Interprofessional education (IPE) is gaining recognition as a means of improving health care delivery and patient outcomes. A primary goal of IPE is improved interprofessional collaboration (IPC). The multidisciplinary team in the radiation oncology clinic requires effective IPC for optimal delivery of radiation therapy. However, there are limited data on IPE and IPC in radiation oncology. This qualitative study aims to characterize IPC in radiation oncology. Methods and Materials Semistructured phone interviews were performed from June to August 2019 with radiation oncologists, nurses, dosimetrists, radiation therapists, medical physicists, and medical students across a single academic medical center and affiliated network sites. Interviews were recorded, de-identified, and transcribed verbatim. Resulting transcripts were analyzed using thematic analysis. Results Seventeen interviews were performed with 4 radiation oncologists, 2 nurses, 2 dosimetrists, 4 radiation therapists, 2 medical physicists, and 3 medical students. Thematic analysis identified 4 themes: (1) management of the radiation oncology clinic, (2) potential impact of interprofessional training in radiation oncology, (3) current climate of interprofessional education in radiation oncology, and (4) creating an interprofessional training program in radiation oncology. Each theme elicited between 2 and 7 subthemes. Conclusions From the analytical themes that emerged, it is hypothesized that misunderstanding professionals’ roles can lead to communication breakdown, which creates less efficient clinic management and disorganized patient care. Although other medical professionals shadow physicians during their training, physicians are not learning about other professions in the same way. Interviewees from each professional category recommend a formal shadowing program for radiation oncology trainees at the medical student or resident level. Having structured opportunities for IPE is important given competing demands of learners during medical student rotations and residency. This study suggests an unmet need for exposure of radiation oncology medical trainees to IPE with the ultimate goal of improving IPC in the radiation oncology clinic.

Cancer metastasis is the leading cause of cancer-related mortality, and most patients with metastases from solid tumors have historically been considered incurable. Here, we discuss the evolution of our understanding of the oligometastatic state with an emphasis on the view that cancer metastasis represents a spectrum of disease. We highlight several recently published prospective clinical trials demonstrating improvements in cancer-specific outcomes with the utilization of metastasis-directed local therapies. We discuss biological aspects of oligometastases, including genetic, epigenetic, and immune determinants of the metastatic spectrum. Finally, we propose future considerations regarding clinical trial design for patients with oligometastatic disease.

In this review, we discuss the oligometastatic state, with a focus on its current and future relevance within the field of radiation therapy. We first outline the scope of the problem and the evolving understanding of metastatic disease existing along a spectrum. We then transition to a discussion of the clinical data that led to the formulation of the oligometastatic hypothesis, delving in some detail into the clinical factors associated with improved outcomes in the setting of local therapy-whether surgical or radiotherapeutic. In particular, we highlight the marked limitations of using clinical criteria alone to determine the absence or presence of true extracranial oligometastatic disease. After this, we briefly discuss the radiation therapy literature that has recently demonstrated benefits in cancer-specific outcomes with ablative treatment of oligometastatic disease. We emphasize data in the setting of non-small cell lung cancer and prostate cancer and briefly discuss the importance of our enhanced ability to detect occult metastatic disease with improved imaging technologies. After noting that resulted and ongoing prospective trials of ablative radiation therapy use the most rudimentary of oligometastatic classifiers-number of metastases-as their inclusion criteria, we transition to our core argument: a growing body of preclinical and translational work aims to refine the definition of oligometastatic disease using molecular features. We address genomic, epigenetic, and immunologic features that have, across histology, demonstrated an improved ability to prognosticate when combined with classic clinical correlates of oligometastatic disease. We also discuss studies that suggest particular molecular targets which, when manipulated for therapeutic purposes, have the potential to revert the polymetastatic phenotype to the oligometastatic one. We conclude with what we believe are the repercussions of this work for radiation therapy trials and clinical practice, and the importance of enriching and supporting these inquiries for the future of our field.

In the era of cancer immunotherapy, there is significant interest in combining conventional cancer therapies, such as radiotherapy, with drugs that stimulate the immune system. The observation that ionizing radiation applied to murine tumors delays the growth of distant tumors (“abscopal effect”) and that this effect is potentiated by immunostimulatory drugs, led to clinical trials in which often only one lesion is irradiated in combination with immunotherapy drugs. The results of these initial clinical trials combining radio therapy and immunotherapy show that a meaningful abscopal effect is still infrequent. Recent preclinical data suggest that preexistent intratumoral T cells can survive radiation and contribute to its therapeutic effect. In this review, we discuss possible mechanisms underlying the preclinical/clinical discrepancies regarding the abscopal effect, and we propose the irradiation of multiple or all tumor sites in combination with systemic immunotherapy as a possible avenue to increase the efficacy of radio-immunotherapy.

Background Several studies have suggested that antiplatelet (AP) or anticoagulant (AC) therapy may improve outcome in men with prostate cancer. We evaluated the effects of AP/AC therapy and tested the hypothesis that platelet count may also be associated with outcomes. Methods A total of 482 patients received primary radiotherapy (median dose 72 Gy) for nonmetastatic prostate cancer; 49% received androgen deprivation therapy. NCCN risk was low/intermediate/high risk in 39%/39%/22%. AP/AC therapy and platelet counts were analyzed with respect to freedom from biochemical failure (FFBF, nadir+2), distant metastasis (FFDM), and cause specific survival (CSS). Results After a median follow‐up of 103 months, 10‐year FFBF, FFDM, and CSS were 77%, 92%, and 96%, respectively. The 10‐year cumulative incidence of BF and DM (with death as a competing event) was 19% and 7.0%, respectively. The 32% of men on AP/AC therapy had a lower incidence of 10‐year BF (P = .016) and a trend toward a lower incidence of DM (P = .084) and CSS (P = .091). In the entire cohort, lowest platelet quartile (platelet count, 482 men received primary radiotherapy for non‐metastatic prostate cancer and those men with pre‐treatment platelet count in the lowest quartile experienced worse 10‐year freedom from biochemical failure (61% vs 81%, P

This review outlines the history of the oligometastatic state from its first proposal to the current formulation. The article discusses the accumulating evidence for the biology of oligometastases, including clinical parameters, such as number and rate of progression, as well as ongoing molecular profiling efforts. The authors then discuss the current state of prospective clinical trials. They review the early site-specific as well as subsite agnostic studies using stereotactic body radiation therapy. Moreover, the article makes the case for why phase II trials should not be practice changing, and highlights the pivotal importance of accruing to phase III clinical trials.

Immune checkpoint blockade (ICB) improves outcomes in non-small cell lung cancer (NSCLC) though most patients progress. There are limited data regarding molecular predictors of progression. In particular, there is controversy regarding the role of CDKN2A loss-of-function (LOF) in ICB resistance. We analyzed 139 consecutive patients with advanced NSCLC who underwent NGS prior to ICB initiation to explore the association of CDKN2A LOF with clinical outcomes. 73% were PD-L1 positive (≥ 1%). 48% exhibited high TMB (≥ 10 mutations/megabase). CDKN2A LOF was present in 26% of patients and was associated with inferior PFS (multivariate hazard ratio [MVA-HR] 1.66, 95% CI 1.02–2.63, p = 0.041) and OS (MVA-HR 2.08, 95% CI 1.21–3.49, p = 0.0087) when compared to wild-type (WT) patients. These findings held in patients with high TMB (median OS, LOF vs. WT 10.5 vs. 22.3 months; p = 0.069) and PD-L1 ≥ 50% (median OS, LOF vs. WT 11.1 vs. 24.2 months; p = 0.020), as well as in an independent dataset. CDKN2A LOF vs. WT tumors were twice as likely to experience disease progression following ICB (46% vs. 21%; p = 0.021). CDKN2A LOF negatively impacts clinical outcomes in advanced NSCLC treated with ICB, even in high PD-L1 and high TMB tumors. This novel finding should be prospectively validated and presents a potential therapeutic target.

In this review, we outline the clinical and biologic evidence supporting the existence of an oligometastatic state. We first discuss the surgical and radiotherapeutic data that demonstrate clear benefits to cancer-specific outcomes with local ablative therapy in subsets of patients with metastatic disease. We then delve into the evolving preclinical and translational studies already beginning to define the biology of oligometastasis, with a specific focus on the genetics, epigenetics, and immunologic aspects of oligometastatic disease. We conclude by highlighting the importance of focusing significant effort as a research community on developing an integrated clinical-molecular classification of metastatic disease to personalize treatment for patients with potentially curable oligometastatic disease.

Background Given similarities in the mediators of medication allergy (MA) and tissue response to radiotherapy, we assessed whether outcomes following prostate radiotherapy differ in patients with MAs. Methods A total 587 men with known MA history and nonmetastatic prostate cancer underwent radiotherapy from 1989 to 2006. Clinicopathologic and treatment variables were analyzed for association with freedom from biochemical failure (FFBF) and late treatment–related, physician-defined Radiation Therapy Oncology Group gastrointestinal (GI) and genitourinary (GU) toxicity. Covariates identified on univariate analysis for toxicity and disease control were examined on multivariable analysis. All statistical tests were 2-sided, and a P less than .05 was considered statistically significant. Results A total of 155 of 587 men (26.4%) had 1 or more MAs, most commonly to penicillin (n = 71), sulfa (n = 35), and aspirin or nonsteroidal antiinflammatory drugs (n = 28). On univariate analysis, men with MAs had superior 10-y FFBF (71.5% vs 63.5%, P = .02) and higher incidence of late GI grade 2 or higher (G2+; 20.6% vs 13.2%, P = .04) and grade 3 or higher (G3+; 7.5% vs 3.9%, P = .08) as well as late GU G2+ (42.5% vs 33.2%, P = .04) and G3+ (7.5% vs 3.0%, P = .02) toxicity than men without MAs. On multivariable analysis, MA history remained a statistically significant predictor of FFBF (hazard ratio [HR] = 0.64, 95% confidence interval [CI] = 0.43 to 0.93, P = .02), late G2+ GI (HR = 1.76, 95% CI = 1.06 to 2.90, P=.03), and G3+ GU (HR = 2.69, 95% CI = 1.16 to 6.27, P = .02) toxicity after controlling for corresponding covariates in each model. Conclusions Men with MAs had improved FFBF and increased treatment-related toxicity following radiotherapy for prostate cancer. MA history could be a relevant consideration in the management of men with localized prostate cancer.

Combinatorial strategies are needed to overcome the resistance of pancreatic cancer to immune checkpoint blockade (ICB). DNA damage activates the innate immune response and improves ICB efficacy. Since ATM is an apical kinase in the radiation-induced DNA damage response, we investigated the effects of ATM inhibition and radiation on pancreatic tumor immunogenicity. ATM was inhibited through pharmacologic and genetic strategies in human and murine pancreatic cancer models both in vitro and in vivo. Tumor immunogenicity was evaluated after ATM inhibition alone and in combination with radiation by assessing TBK1 and Type I Interferon (T1IFN) signaling as well as tumor growth following PD-L1/PD-1 checkpoint inhibition. Inhibition of ATM increased tumoral T1IFN expression in a cGAS/STING-independent, but TBK1 and SRC-dependent manner. The combination of ATM inhibition with radiation further enhanced TBK1 activity, T1IFN production, and antigen presentation. Furthermore, ATM silencing increased PD-L1 expression and increased the sensitivity of pancreatic tumors to PD-L1 blocking antibody in association with increased tumoral CD8(+) T cells and established immune memory. In patient pancreatic tumors, low ATM expression inversely correlated with PD-L1 expression. Taken together, these results demonstrate that the efficacy of ICB in pancreatic cancer is enhanced by ATM inhibition and further potentiated by radiation as a function of increased tumoral immunogenicity, underscoring the potential of ATM inhibition in combination with ICB and radiation as an efficacious treatment strategy for pancreatic cancer.

Purpose: Immune checkpoint blockade (ICB) has improved outcomes for patients with non-small cell lung cancer (NSCLC). However, most patients experience disease progression. There is limited data regarding molecular predictors of progression, particularly in those patients predicted to respond most favorably. We used a next-generation sequencing (NGS) platform to identify genomic aberrations associated with clinical outcomes following ICB in NSCLC. Methods: We retrospectively reviewed stage III/IV NSCLC patients who received radiotherapy (RT) in our department and underwent NGS with OncoPlus, a 1212-gene hybrid capture genomic sequencing assay. We characterized tumor mutations and insertions/deletions for patients who received ICB as well as other systemic therapies and investigated their associations with clinical outcome. Results: 149 patients with stage III/IV NSCLC received RT from 2011-2019 and underwent OncoPlus. Median age was 65, median ECOG was 1, and 125 had a smoking history. 87% had adenocarcinoma. AJCC 8th edition staging: IIIA (n=24), IIIB (n=14), IIIC (n=3), IVA (n=16), and IVB (n=92). 79% had PD-L1 staining: 0% in 45 patients (38%), 1-49% in 34 (29%), and ≥50% in 38 (32%). All received RT to a median of 2 lesions (range 1-15); 48% received palliative RT and 52% received ≥1 course of definitive RT (conventional or ablative). The majority received systemic therapy: 68% (n=102) received chemotherapy, 55% (n=82) received ICB, and 30% (n=44) received targeted therapies. Median follow-up was 18 months (range 1-95); most experienced isolated distant failure (n=64, 43%) or regional/distant failure (n=35, 23%) following their first RT course. The most frequent pathogenic mutations/indels were TP53 (68%, n=101), KRAS (31%, n=45), CDKN2A (27%, n=40), STK11 (26%, n=39), EGFR (19%, n=28), and TP53/KRAS co-mutation (17%, n=26). We found CDKN2A mutation (25%)/deletion (75%) was associated with inferior median recurrence-free survival (RFS; 3 vs. 6 mo., p=0.013) and more markedly median OS (13 vs. 38 mo., p=0.015) compared to wild-type tumors. On multivariate Cox proportional hazards analysis including stage, ECOG, PD-L1 %, TMB, type of RT, and # of RT sites, CDKN2A loss was independently associated with 2.5-fold risk of progression (p=0.018) and 3.3-fold risk of death (p=0.05). In high TMB (top 25th%; n=21) or high PD-L1 (>50%; n=30) NSCLCs, CDKN2A loss was negatively associated with RFS (TMB p=0.005; PD-L1 p=0.034) and in the high PD-L1 cohort with a trend towards inferior OS (p=0.08). Conclusions: In a large cohort of stage III/IV NSCLC patients treated with systemic therapy and RT, NGS identified CDKN2A mutation/deletion as a predictor of ICB resistance and poor outcome. In the context of recent evidence for sensitivity to CDK4/6 inhibition of CDKN2A-deficient tumors, our findings raise the possibility of utilizing currently available targeted agents in the treatment of CDKN2A-deficient NSCLC patients progressing on ICB. Citation Format: Stanley I. Gutiontov, Sean Pitroda. CDKN2A mutation predicts immunotherapy resistance in stage III/IV NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 799.