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Purpose: Emerging data suggest that metastasis-directed therapy (MDT) improves outcomes in patients with oligometastatic castration-sensitive prostate cancer (omCSPC). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) can detect occult metastatic disease, and PSMA response has been proposed as a biomarker for treatment response. Herein, we identify and validate a PSMA-PET biomarker for metastasis-free survival (MFS) following MDT in omCSPC. Methods and Materials: We performed an international multi-institutional retrospective study of patients with omCSPC, defined as ≤3 lesions, treated with metastasis-directed stereotactic ablative radiation who underwent PSMA-PET/computed tomography (CT) before and after (median, 6.2 months; range, 2.4-10.9 months) treatment. Pre- and post-MDT PSMA-PET/CT maximum standardized uptake value (SUVmax) was measured for all lesions, and PSMA response was defined as the percent change in SUVmax of the least responsive lesion. PSMA response was both evaluated as a continuous variable and dichotomized into PSMA responders, with a complete/partial response (at least a 30% reduction in SUVmax), and PSMA nonresponders, with stable/progressive disease (less than a 30% reduction in SUVmax). PSMA response was correlated with conventional imaging-defined metastasis-free survival (MFS) via Kaplan-Meier and Cox regression analysis. Results: A total of 131 patients with 261 treated metastases were included in the analysis, with a median follow-up of 29 months (IQR, 18.5-41.3 months). After stereotactic ablative radiation, 70.2% of patients were classified as PSMA responders. Multivariable analysis demonstrated that PSMA response as a continuous variable was associated with a significantly worse MFS (hazard ratio = 1.003; 95% CI, 1.001-1.006; P = .016). Patients classified as PSMA responders were found to have a significantly improved median MFS of 39.9 versus 12 months (P = .001) compared with PSMA nonresponders. Our study is limited as it is a retrospective review of a heterogenous population. Conclusions: After stereotactic ablative radiation, PSMA-PET response appears to be a radiographic biomarker that correlates with MFS in omCSPC. This approach holds promise for guiding clinical management of omCSPC and should be validated in a prospective setting.

Abstract Background Survivorship care plans (SCPs) communicate cancer‐related information from oncology providers to patients and primary care providers. SCPs may limit overuse testing by specifying necessary follow‐up care. From a randomized, controlled trial of SCP delivery, we examined whether cancer‐related tests not specified in SCPs, but conducted after SCP receipt, were appropriate or consistent with overuse. Methods Survivors of breast, colorectal, or prostate cancer treated at urban‐academic or rural‐community health systems were randomized to one of three SCP delivery arms. Tests during 18 months after SCP receipt were classified as consistent with overuse if they were (1) not included in SCPs and (2) on a guideline‐based predetermined list of “not recommended surveillance.” After chart abstraction, physicians performed review and adjudication of potential overuse. Descriptive analyses were conducted of tests consistent with overuse. Negative binomial regression models determined if testing consistent with overuse differed across study arms. Results Among 316 patients (137 breast, 67 colorectal, 112 prostate), 140 individual tests were identified as potential overuse. Upon review, 98 were deemed to be consistent with overuse: 78 tumor markers and 20 imaging tests. The majority of overuse testing was breast cancer‐related (95%). Across sites, 27 patients (9%) received ≥1 test consistent with overuse; most were breast cancer patients (22/27). Exploratory analyses of overuse test frequency by study arm showed no significant difference. Conclusions This analysis identified practice patterns consistent with overuse of surveillance testing and can inform efforts to improve guideline‐concordant care. Future interventions may include individual practice patterns and provider education.

Abstract Prostate cancer is the most frequent cancer in men and a leading cause of cancer death. Determining a patient’s optimal therapy is a challenge, where oncologists must select a therapy with the highest likelihood of success and the lowest likelihood of toxicity. International standards for prognostication rely on non-specific and semi-quantitative tools, commonly leading to over- and under-treatment. Tissue-based molecular biomarkers have attempted to address this, but most have limited validation in prospective randomized trials and expensive processing costs, posing substantial barriers to widespread adoption. There remains a significant need for accurate and scalable tools to support therapy personalization. Here we demonstrate prostate cancer therapy personalization by predicting long-term, clinically relevant outcomes using a multimodal deep learning architecture and train models using clinical data and digital histopathology from prostate biopsies. We train and validate models using five phase III randomized trials conducted across hundreds of clinical centers. Histopathological data was available for 5654 of 7764 randomized patients (71%) with a median follow-up of 11.4 years. Compared to the most common risk-stratification tool—risk groups developed by the National Cancer Center Network (NCCN)—our models have superior discriminatory performance across all endpoints, ranging from 9.2% to 14.6% relative improvement in a held-out validation set. This artificial intelligence-based tool improves prognostication over standard tools and allows oncologists to computationally predict the likeliest outcomes of specific patients to determine optimal treatment. Outfitted with digital scanners and internet access, any clinic could offer such capabilities, enabling global access to therapy personalization.

Abstract Background Metastasis directed therapy (MDT) for patients with oligometastatic disease is associated with improvements in progression free survival (PFS) and overall survival (OS) compared to systemic therapy alone. Additionally, within a prostate-cancer-specific cohort, MDT is able to forestall initiation of androgen deprivation therapy (ADT) in men with hormone-sensitive, oligometastatic prostate cancer (HSOPCa) compared to observation. While MDT appears to be safe and effective in HSOPCa, a large percentage of men will eventually have disease recurrence. Patterns of failure in HSOPCa demonstrate patients tend to have recurrence in the bone following MDT, raising the question of sub-clinically-apparent osseous disease. Radium-223 dichloride is a radiopharmaceutical with structural similarity to calcium, allowing it to be taken up by bone where it emits alpha particles, and therefore might have utility in the treatment of micrometastatic osseous disease. Therefore, the primary goal of the phase II RAVENS trial is to evaluate the efficacy of MDT + radium-223 dichloride in prolonging progression free survival in men with HSOPCa. Methods Patients with HSOPCa and 3 or less metastases with at least 1 bone metastasis will be randomized 1:1 to stereotactic ablative radiation (SABR, also known as stereotactic body radiation therapy (SBRT)) alone vs SABR + radium-223 dichloride with a minimization algorithm to balance assignment by institution, primary intervention, prior hormonal therapy, and PSA doubling time. SABR is delivered in one to five fractions and patients in the SABR + radium-223 dichloride arm will receive six infusions of radium-223 dichloride at four-week intervals. The primary end point is progression free survival. The secondary clinical endpoints include toxicity and quality of life assessments, local control at 12 months, locoregional progression, time to distant progression, time to new metastasis, and duration of response. Discussion The RAVENS trial will be the first described phase II, non-blinded, randomized study to compare SABR +/− radium-223 dichloride in patients with HSOPCa and 3 or less metastases with at least one bone metastasis. The primary hypothesis is that SABR + radium-223 dichloride will increase median progression-free survival from 10 months in the SABR arm to 20 months in the SABR + radium-223 dichloride arm. Trial registrations Clinicaltrials.gov. Identifier: NCT04037358 . Date of Registration: July 30, 2019. Date of First Participant Enrolled: August 9, 2019. Date of Last Approved Amendment: October 16, 2019. Protocol Version: Version 5.

Purpose: Stereotactic ablative radiation therapy (SABR) for oligometastatic prostate cancer (OMPC) may improve clinical outcomes, but current challenges in intrafraction tracking of multiple small targets limits treatment accuracy. A biology-guided radiation therapy (BgRT) delivery system incorporating positron emission tomography (PET) detectors is being developed to use radiotracer uptake as a biologic fiducial for intrafraction tumor tracking to improve geometric accuracy. This study simulates prostate-specific membrane antigen (PSMA)-directed BgRT using a cohort from our phase II randomized trial of SABR in men with recurrent hormone sensitive OMPC and compares dose distributions to clinical SABR (CSABR). Methods and Materials: A research treatment planning system (RTPS) was used to replan 15 patients imaged with PSMA-targeted 18F-DCFPyL PET/computed tomography and previously treated with CSABR using conventional linear accelerators (linacs). The RTPS models a prototype ring-mounted linac incorporating PET and kilo-voltage computed tomography imaging subsystems and can be used to optimize BgRT plans, as well as research SABR (RSABR) plans, which use the prototype linac without radiotracer guidance. CSABR, RSABR, and BgRT plans were compared in terms of maximum planning target volume (PTV) dose (Dmax), mean dose to proximal organs at risk (DOAR), conformity index, as well as voxel-wise correlation of dose with PET specific uptake values to investigate possible dose-painting effects. Results: RSABR and BgRT plans resulted in mean ± standard deviation increases in Dmax of 4 ± 11% (P = .21) and 18 ± 15% (P < .001) and reductions in DOAR of –20 ± 19% (P

Abstract Background In men with a rising PSA following radical prostatectomy, salvage radiation therapy (SRT) offers a second chance for cure. Hormonal therapy can be combined with SRT in order to increase prostate tumor control, albeit with associated higher rates of treatment side effects. This trial studies the effectiveness of SRT combined with hormonal therapy using a more potent anti-androgen with a favorable side effect profile. Enzalutamide, a next generation selective androgen receptor antagonist, is approved by the Food and Drug Administration for the treatment of metastatic castrate-resistant prostate cancer (CRPC) where it has been shown to improve overall survival in combination with androgen deprivation therapy. The primary objective of this study is to evaluate the efficacy of combination SRT and enzalutamide for freedom-from-PSA-progression. Secondary objectives include time to local recurrence within the radiation field, metastasis-free survival and safety as determined by frequency and severity of adverse events. Methods/design This is a randomized, double-blind, phase II, prospective, multicenter study in adult males with biochemically recurrent prostate cancer following radical prostatectomy. Following registration, enzalutamide 160 mg or placebo by mouth (PO) once daily will be administered for 6 months. Following two months of study drug, external beam radiotherapy to 66.6–70.2 Gray (Gy) will be administered to the prostate bed over 7–8 weeks while continuing daily placebo/enzalutamide. This is followed by two additional months of placebo/enzalutamide. Discussion The SALV-ENZA trial is the first phase II placebo-controlled double-blinded randomized study to test SRT in combination with a next generation androgen receptor antagonist in men with high-risk recurrent prostate cancer after radical prostatectomy. The primary hypothesis of this study is that clinical outcomes will be improved by the addition of enzalutamide compared to standard-of-care SRT alone and pave the path for phase III evaluation of this combination. Trial registrations ClinicaltTrials.gov Identifier: NCT02203695 Date of Registration: 06/16/2014. Date of First Participant Enrollment: 04/16/2015.

Despite extraordinary advances that have been achieved in the last few decades, cancer continues to represent a leading cause of mortality worldwide. Lethal cancer types ultimately become refractory to standard of care approaches; thus, novel effective treatment options are desperately needed. Tumor Treating Fields (TTFields) are an innovative non-invasive regional anti-mitotic treatment modality with minimal systemic toxicity. TTFields are low intensity (1–3 V/cm), intermediate frequency (100–300 kHz) alternating electric fields delivered to cancer cells. In patients, TTFields are applied using FDA-approved transducer arrays, orthogonally positioned on the area surrounding the tumor region, with side effects mostly limited to the skin. The precise molecular mechanism of the anti-tumor effects of TTFields is not well-understood, but preclinical research on TTFields suggests it may act during two phases of mitosis: at metaphase, by disrupting the formation of the mitotic spindle, and at cytokinesis, by dielectrophoretic dislocation of intracellular organelles leading to cell death. This review describes the mechanism of action of TTFields and provides an overview of the most important in vitro studies that investigate the disruptive effects of TTFields in different cancer cells, focusing mainly on anti-mitotic roles. Lastly, we summarize completed and ongoing TTFields clinical trials on a variety of solid tumors.

Abstract Radiotherapy (RT) has been a fundamental component of the anti-cancer armamentarium for over a century. Approximately half of all cancer patients are treated with radiotherapy during their disease course. Over the two past decades, there has been a growing body of preclinical evidence supporting the immunomodulatory effects of radiotherapy, particularly when combined with immunotherapy, but only anecdotal clinical examples existed until recently. The renaissance of immunotherapy and the recent U.S. Food and Drug Administration (FDA) approval of several immune checkpoint inhibitors (ICIs) and other immuno-oncology (IO) agents in multiple cancers provides the opportunity to investigate how localized radiotherapy can induce systemic immune responses. Early clinical experiences have demonstrated feasibility of this approach but additional preclinical and clinical investigation is needed to understand how RT and immunotherapy can be optimally combined. To address questions that are critical to successful incorporation of radiation oncology into immunotherapy, the American Society for Radiation Oncology (ASTRO), the Society for Immunotherapy of Cancer (SITC) and the National Cancer Institute (NCI) organized a collaborative scientific workshop, Incorporating Radiation Oncology into Immunotherapy, that convened on June 15 and 16 of 2017 at the Natcher Building, NIH Campus in Bethesda, Maryland. This report summarizes key data and highlights from each session.

Abstract Background We describe a randomized, non-blinded Phase II interventional study to assess the safety and efficacy of stereotactic ablative radiotherapy (SABR) for hormone-sensitive oligometastatic prostate adenocarcinoma, and to describe the biology of the oligometastatic state using immunologic, cellular, molecular, and functional imaging correlates. 54 men with oligometastatic prostate adenocarcinoma will be accrued. The primary clinical endpoint will be progression at 6 months from randomization with the hypothesis that SABR to all metastases will forestall progression by disrupting the metastatic process. Secondary clinical endpoints will include local control at 6 months post-SABR, toxicity and quality of life, and androgen deprivation therapy (ADT)-free survival (ADT-FS). Further fundamental analysis of the oligometastatic state with be achieved through correlation with investigational 18F–DCFPyL PET/CT imaging and measurement of circulating tumor cells, circulating tumor DNA, and circulating T-cell receptor repertoires, facilitating an unprecedented opportunity to characterize, in isolation, the effects of SABR on the dynamics of and immunologic response to oligometastatic disease. Methods/design Patients will be randomized 2:1 to SABR or observation with minimization to balance assignment by primary intervention, prior hormonal therapy, and PSA doubling time. Progression after 6 months will be compared using Fisher’s exact test. Hazard ratios and Kaplan-Meier estimates of progression free survival (PFS), ADT free survival (ADT-FS), time to locoregional progression (TTLP) and time to distant progression (TTDP) will be calculated based on an intention-to-treat. Local control will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Withdrawal from the study prior to 6 months will be counted as progression. Adverse events will be summarized by type and grade. Quality of life pre- and post- SABR will be measured by Brief Pain Inventory. Discussion The ORIOLE trial is the first randomized, non-blinded Phase II interventional study in the North America evaluating the safety and efficacy of SABR in oligometastatic hormone-sensitive prostate cancer. Leading-edge laboratory and imaging correlates will provide unique insight into the effects of SABR on the oligometastatic state. Trial registrations ClinicalTrials.gov Identifier: NCT02680587. URL of Registry: https://clinicaltrials.gov/show/NCT02680587 Date of Registration: 02/08/2016. Date of First Participant Enrollment: 05/23/2016.

We have uncovered that epithelial plasticity programs metabolically reprogram epithelial lung cells by increasing expression of genes (e.g., glutamine-fructose-6-phosphate transaminase 2 – GFPT2 and UDP-N-acetylglucosamine pyrophosphorylase 1 – UAP1) critical for the hexosamine biosynthetic pathway (HBP) and elevating global protein O-GlcNAcylation – a specific type of glycosylation. We found that increased O-GlcNAcylation could suppress oncogene-induced senescence tumor suppressor pathways that ultimately led to accelerated KrasG12D-driven lung tumorigenesis.

Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade.

The TWIST1 gene has diverse roles in development and pathologic diseases such as cancer. TWIST1 is a dimeric basic helix-loop-helix (bHLH) transcription factor existing as TWIST1-TWIST1 or TWIST1-E12/47. TWIST1 partner choice and DNA binding can be influenced during development by phosphorylation of Thr125 and Ser127 of the Thr-Gln-Ser (TQS) motif within the bHLH of TWIST1. The significance of these TWIST1 phosphorylation sites for metastasis is unknown. We created stable isogenic prostate cancer cell lines overexpressing TWIST1 wild-type, phospho-mutants, and tethered versions. We assessed these isogenic lines using assays that mimic stages of cancer metastasis. In vitro assays suggested the phospho-mimetic Twist1-DQD mutation could confer cellular properties associated with pro-metastatic behavior. The hypo-phosphorylation mimic Twist1-AQA mutation displayed reduced pro-metastatic activity compared to wild-type TWIST1 in vitro, suggesting that phosphorylation of the TWIST1 TQS motif was necessary for pro-metastatic functions. In vivo analysis demonstrates that the Twist1-AQA mutation exhibits reduced capacity to contribute to metastasis, whereas the expression of the Twist1-DQD mutation exhibits proficient metastatic potential. Tethered TWIST1-E12 heterodimers phenocopied the Twist1-DQD mutation for many in vitro assays, suggesting that TWIST1 phosphorylation may result in heterodimerization in prostate cancer cells. Lastly, the dual phosphatidylinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitor BEZ235 strongly attenuated TWIST1-induced migration that was dependent on the TQS motif. TWIST1 TQS phosphorylation state determines the intensity of TWIST1-induced pro-metastatic ability in prostate cancer cells, which may be partly explained mechanistically by TWIST1 dimeric partner choice.

Background Glioblastoma (GBM) is a poorly immunogenic neoplasm treated with focused radiation. Immunotherapy has demonstrated synergistic survival effects with stereotactic radiosurgery (SRS) in murine GBM. GITR is a co-stimulatory molecule expressed constitutively on regulatory T-cells and by effector T-cells upon activation. We tested the hypothesis that anti-GITR monoclonal antibody (mAb) and SRS together would confer an immune-mediated survival benefit in glioma using the orthotopic GL261 glioma model.Methods Mice received SRS and anti-GITR 10 days after implantation. The anti-GITR mAbs tested were formatted as mouse IgG1 D265A (anti-GITR (1)) and IgG2a (anti-GITR (2a)) isotypes. Mice were randomized to four treatment groups: (1) control; (2) SRS; (3) anti-GITR; (4) anti-GITR/SRS. SRS was delivered to the tumor in one fraction, and mice were treated with mAb thrice. Mice were euthanized on day 21 to analyze the immunologic profile of tumor, spleen, and tumor draining lymph nodes.Results Anti-GITR (1)/SRS significantly improved survival over either treatment alone (p

Metastasis is a major cause of cancer mortality. We generated an autochthonous transgenic mouse model whereby conditional expression of MYC and Twist1 enables hepatocellular carcinoma (HCC) to metastasize in >90% of mice. MYC and Twist1 cooperate and their sustained expression is required to elicit a transcriptional program associated with the activation of innate immunity, through secretion of a cytokinome that elicits recruitment and polarization of tumor associated macrophages (TAMs). Systemic treatment with Ccl2 and Il13 induced MYC-HCCs to metastasize; whereas, blockade of Ccl2 and Il13 abrogated MYC/Twist1-HCC metastasis. Further, in 33 human cancers (n = 9502) MYC and TWIST1 predict poor survival (p=4.3×10−10), CCL2/IL13 expression (p