Early Stage Prostate Research Articles

The role of microRNAs in the development of radioresistance of prostate cancer cells (experimental study)

Background. Radiation therapy is one of the leading treatments for early and late stage prostate cancer. Radiation therapy is one of the leading treatments for early and late stage prostate cancer. The significant frequency of prostate cancer progression after radiation therapy makes it relevant to study the molecular mechanisms of the development of radioresistance, to identify prognostic markers of its development.Objective: identification and analysis of the mechanism of action of microRNAs regulating radioresistance of prostate cancer cells on the model of the androgen-independent DU145 cell line.Materials and methods. We used human prostate adenocarcinoma cell lines: DU145-hormone-independent prostate cancer cell line and DU145-RR - its radioresistant variant. Differential microRNA expression was measured in cultured DU145 and DU145-RR cells 1, 8 days after a single gamma irradiation at a dose of 4 Gy. To analyze the differential expression of microRNAs in the initial and radioresistant variants of DU145 cells, the HiSeq 2000 platform (Illumina Inc., USA) was used. The miRBase v.21 database was used to identify microRNAs. The miRTarbase 7.0 and KEGG PATHWAY databases were used for bioinformatic analysisResults. The results of the study showed that the aberrant expression of miR-101-3p, -148a-3p, -21-3p, -532-5p, -92a-3p in DU145-RR cells upregulated compared to that in DU145 cells, and miR-125b-5p, -23a-3p, -424-3p - downregulated. It has been shown that the role of these microRNAs is associated with the provision of functional interaction between DNA methyltransferases, the transcriptional regulator of the proto-oncogenic protein Myc, and PTEN phosphatase in the regulation of the activity of MAPK and PI3K protein kinase signaling cascades. Constitutive activation of these cascades leads to an increase in cell survival, migration, proliferation, and growth.Conclusion. A wide range of target genes and a significant change in the expression profiles of microRNAs in various conditions, including the transition of malignant cells to a radioresistant status, makes microRNAs promising prognostic markers of radioresistance in prostate cancer.

Abstract P26: Re-analyzing randomized trials with incorporation of COVID-19 risk associated with cancer therapy

Abstract Background: Cancer therapy may put patients at risk of mortality from COVID-19. The impact of abbreviated treatment courses on outcomes in the setting of COVID-19 is unknown. We incorporated COVID-19-associated risks in re-analysis of practice-defining randomized trials in oncology that compared different radiation therapy (RT) regimens. Methods: We extracted individual patient level data (IPLD) from published survival curves from randomized trials in rectal cancer (Dutch TME, TROG 01.04), early stage breast cancer (CALGB 9343, OCOG hypofractionation trial, FAST-Forward, NSABP B-39), and localized prostate cancer (CHHiP, HYPO-RT-PC). Trials were simulated with incorporation of varying risk of SARS-CoV-2 infection and mortality associated with receipt of therapy. Results: IPLD from 14,170 patients were re-analyzed. In scenarios with low COVID-19-associated risks (0.5% infection risk per fraction [IRF], 5% case fatality rate [CFR]), fractionation did not significantly affect outcomes. In locally advanced rectal cancer, short-course RT appeared preferable to long-course chemoradiation (TROG 01.04) or RT omission (Dutch TME) in most settings. While moderate hypofractionation in early stage breast cancer (OCOG hypofractionation trial) and prostate cancer (CHHiP) was not associated with survival benefits in the setting of COVID-19, more aggressive hypofractionation (FAST-Forward, HYPO-RT-PC) and accelerated partial breast irradiation (NSABP B-39) were associated with improved survival in higher risk scenarios (≥5% IRF; ≥ 20% CFR). In settings where RT can be omitted, such as favorable early stage breast cancer in the elderly (CALGB 9343), RT was associated with worse survival in higher risk pandemic scenarios (≥5% IRF, ≥ 20% CFR). Conclusions: Our framework, which can be adapted to dynamic changes in COVID-19 risk, provides a flexible, quantitative approach to assess the impact of treatment recommendations across oncology. The magnitude of potential benefit from abbreviated RT courses depends on the degree of hypofractionation and local COVID-19-associated risk. Abbreviated RT courses should be prioritized when possible and are increasingly beneficial in higher risk pandemic settings. With increased understanding and precautions against COVID-19 that can minimize risks for patients, our results support the continued use of evidence-based treatments for cancer patients in the COVID-19 era. Citation Format: Shervin Tabrizi, Lorenzo Trippa, Daniel Cagney, Ayal A. Aizer, Shyam Tanguturi, Steffen Ventz, Geoffrey Fell, Jennifer R. Bellon, Harvey Mamon, Paul Nguyen, Anthony V. D'Amico, Daphne Haas-Kogan, Brian M. Alexander, Rifaquat Rahman. Re-analyzing randomized trials with incorporation of COVID-19 risk associated with cancer therapy [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P26.

Abstract 1759: KDM5 inhibitor regulates growth of early stage and advanced human prostate cancer cells

Abstract Prostate cancer (PCa) remains a leading cause of cancer deaths because many patients ultimately develop an incurable castration-resistant form of metastatic PCa. While chromatin alterations are linked to PCa, the role of histone demethylases in the PCa progression has not been fully elucidated. Members of the Jumonji AT-rich interactive domain 1 (JARID1) or lysine demethylase 5 (KDM5) family of lysine demethylases are known for their ability to demethylate H3K4me3. However, the genes encoding these proteins are amplified in metastatic PCa. Literature suggests members of the KDM5 family enhance expression and function of androgen receptor (AR), a protein that drives growth of human PCa cells. The KDM5 family inhibitor 2-4(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT) has been suggested as a potential lead compound for cancer therapy since it suppresses proliferation of human breast cancer cells. However, to date no studies have tested the effects of PBIT in PCa. The goal of this study was to characterize the effects of PBIT alone and in combination with a PPARγ agonist, 15-Deoxy-Δ-12,14-prostaglandin J2 (15-dPGJ2) on PCa cells. Presto blue analyses were conducted in AR positive, castration-sensitive LNCaP cells and the castration-resistant PC3 cells expressing little to no AR. Our studies revealed that PBIT treatment decreased the proliferation of both LNCaP and PC3 cells in a dose-dependent manner. Significant decreases in cell proliferation were detected when PBIT concentrations were greater than or equal to 5 μM. In addition, 15-dPGJ2 was able to decrease the proliferation of PCa cells. Importantly, the combination of PBIT and 15-dPGJ2 significantly suppressed the growth of PC3 and LNCaP cells. The anti-proliferative effect of the combined inhibition was at least additive, as the combination index was less than 1. Furthermore, PBIT at concentrations ≥ 5 μM also reduced migration of PC3 cells. Together, our data suggest that PBIT and other KDM5 inhibitors can reduce the proliferation and migration of multiple types of PCa cells. Our findings also provide evidence that the combination of KDM5 family inhibitors and PPARγ agonists might serve as an effective therapy for advanced human PCa. Citation Format: Tunde Smith, Zhenbang Chen, LaMonica V. Stewart. KDM5 inhibitor regulates growth of early stage and advanced human prostate cancer cells [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 1759.

Abstract 783: Epigenomic detection of multiple cancers in plasma derived cell free DNA

Abstract Background: Our feasibility study employed a novel genomic detection methodology that enriches 5-hydroxymethylcytosine (5hmC) loci in cell free DNA (cfDNA) from the plasma of cancer patients using click chemistry coupled with sequencing and machine learning based classification methods. These classification methods were developed to detect the presence of disease in the plasma of cancer and control subjects. Cancer and control patient cfDNA cohorts were accrued from multiple sites consisting of 48 breast, 55 lung, 32 prostate and 2 pancreatic datasets consisting of 41 and 53 cancer subjects (Set 1 and 2). In addition, a control cohort of 260 subjects (non-cancer) was employed to match cancer patient demographics (age, sex and smoking status) in a case-control study design. Methods: Machine learning methods, applied to each cancer case cohort individually, with a balancing non-cancer cohort, were able to classify cancer and control samples. Measures of predictive performance using 5-fold cross validation coupled with out-of-fold Area Under the Receiver Operating Characteristic Curve (AUROC) measures were employed. Gene sets selected as part of biomarker discovery were further analyzed for disease relevance using pathway analysis tools (GSEA, mSigDB). Results: 260 controls and 229 cancers from four disease types (breast, lung, pancreas and prostate) were analyzed; more than 60% of cancer patients had early stage disease (I or II). Predictive performance, employing AUROC measures, was established for breast (0.89), lung (0.84), pancreas (set 1 - 0.95 and 2 - 0.93) and prostate (0.83). The genes defining each of these predictive models were enriched for pathways relevant to disease specific etiology, notably in the control of gene regulation in these same pathways. The breast cancer cohort consisted primarily of stage I and II patients including tumors < 2 cm and these samples exhibited a higher prediction probability score. The prostate cancer cohort consisted of both indolent and aggressive disease sample and prediction performance was equally high for both (AUROC for indolent vs aggressive was 0.81 and 0.77, respectively). Conclusions: These findings suggest that 5hmC changes in cfDNA enable non-invasive detection of early stage breast, pancreatic, prostate, and lung cancers. Furthermore, 5hmC profiling in cfDNA may enable the prediction of clinically relevant features such as tumor size in breast adenocarcinoma or indolent disease in prostate cancer. Finally, this study identified a suite of 5hmC biomarkers that may be further validated in larger, and more diverse, patient cohorts. Citation Format: Anna Bergamaschi, Jeremy Ku, Yuhong Ning, Francois Collin, Chris Ellison, Tierney Phillips, Erin McCarthy, Wendy Wang, Michael Antoine, David Haan, Aaron Scott, Paul Lloyd, Gulfem Guler, Alan Ashworth, Stephen Quake, Samuel Levy. Epigenomic detection of multiple cancers in plasma derived cell free DNA [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 783.

Unmet supportive care needs and health behaviors in Hispanic/Latino cancer survivors with cardiometabolic comorbidities.

e24038 Background: Cardiometabolic illness is a leading cause of death among cancer survivors previously treated for early-stage breast, prostate, and colorectal cancer. Despite the fact that Hispanics/Latinos in the U.S. are at a significantly elevated risk for poor cardiometabolic health, there is a paucity of research examining cardiometabolic comorbidities in Hispanic/Latino cancer survivors. The aim of this study was to examine unmet supportive care needs and health behaviors in Hispanic/Latino cancer survivors with and without comorbid peripheral vascular disease and diabetes. Methods: Hispanics/Latinos diagnosed with breast, prostate, or colorectal cancer (N = 288) were assessed using the Charlson Comorbidity Index, Supportive Care Needs Survey, and ACS Lifestyle Behavior Scale within 15 months of treatment completion in an NCI-funded project. Logistic regression analyses were conducted adjusting for sociodemographic and medical covariates. Results: Most survivors had a high school education or less (65.6%) and a household income less than $50,000 (68.4%) and were foreign-born (59.4%) and either monolingual Spanish-speaking (54.2%) or English-Spanish bilingual (26.0%). One-quarter (24.7%) were diagnosed with comorbid diabetes and one-fifth (20.8%) were diagnosed with comorbid peripheral vascular disease. Survivors with peripheral vascular disease were more likely to have unmet health system and information needs (OR 2.29, p = .011) and unmet sexuality needs (OR 2.07, p = .020) and marginally more likely to have unmet psychological care needs (OR 1.71, p = .099) than those without peripheral vascular disease. Survivors with diabetes were more likely to have unmet sexuality needs (OR 2.06, p = .015) than those without diabetes. Survivors reported increasing some positive health behaviors following their diagnosis of cancer, including regular health check-ups (61.5%) and consumption of healthy foods like fruits and vegetables (61.8%). However, attempts to lose weight (45.1%), exercise (40.6%), and avoid alcohol (26.0%) and cigarettes (17.0%) were less common. Health behaviors did not vary between survivors with and without peripheral vascular disease and diabetes (p > .05). Conclusions: Comorbid peripheral vascular disease and diabetes are highly prevalent among Hispanic/Latino cancer survivors and are associated with greater unmet supportive care needs. Targeted efforts are needed to increase exercise and weight loss as well as reduce smoking and alcohol consumption in Hispanic/Latino cancer survivors.

A comparison of sipuleucel-T (sip-T) product parameters from two phase III studies: PROVENT in active surveillance prostate cancer and IMPACT in metastatic castrate-resistant prostate cancer (mCRPC).

321 Background: Sip-T is an FDA approved, autologous cellular immunotherapy for mCRPC, manufactured by activating peripheral blood mononuclear cells collected by apheresis and culturing them with PA2024 (PAP fused to human GM-CSF). Overall survival (OS) in mCRPC is positively correlated with key product parameters of sip-T: CD54 upregulation; CD54+ cell count; and total nucleated cell (TNC) count. Product parameters were amplified in men with earlier stage prostate cancer vs mCRPC, including increased T cell trafficking to the prostate (Fong L, JNCI 2014) and greater CD54 upregulation and larger immune responses (Antonarakis ES, Clin Can Res 2017). Methods: ProVENT (NCT03686683) will evaluate sip-T in men with Gleason grade 1/2 prostate adenocarcinoma receiving active surveillance (target, 450 men; randomized 2:1 to receiving sip-T or not). We evaluated apheresis and final key product parameters (CD54 upregulation; CD54+ cell count; and TNC count) for each infused product as well as cumulative values while also comparing with IMPACT (NCT00065442) study results. Results: This preliminary analysis describes data from the first 184 sip-T men in ProVENT. CD54 upregulation profiles were consistent between IMPACT and ProVent, peaking in week 2 products; however, values at each treatment week, and subsequently cumulative CD54 upregulation, were statistically significantly higher for ProVENT (P<0.001 per comparison; Table). The number of CD54+ cells was significantly greater at each treatment for both incoming apheresis as well as the final product, including cumulative values, in ProVENT compared to IMPACT (P<0.001 per comparison) as was TNC count (P<0.001 per comparison). Conclusions: This preliminary analysis of product parameters in ProVENT suggest sip-T potency is higher in pts undergoing active surveillance. Clinical trial information: NCT03686683. [Table: see text]

Abstract 5210: Darolutamide impairs prostate cancer growth by altering chromatin conformation and transcriptional activity of genes involved in cell proliferation and survival

Abstract Androgen signalling is essential for early and late stage prostate cancer (PCa), as demonstrated by the efficacy of androgen receptor (AR) antagonists. The AR gene and its regulatory element are frequently amplified in castration-resistant tumors for which improved treatments are highly needed. Recent findings underscore that gene regulatory elements play an important role in tumor development due to their impact on chromatin conformation and gene regulation. Here we describe the genome-wide effects of darolutamide, a novel AR antagonist which just completed a pivotal clinical phase III trial, by analyzing AR occupancy and its impact on chromatin looping, histone H3K27 acetylation and downstream gene regulation. Genome-wide RNA-seq and ChIP-seq were used to analyze the androgen-sensitive cell lines VCaP, LAPC4 and LNCaP treated with R1881, or with R1881 and darolutamide. Binding of AR and of the pioneer factor FOXA1, as well as histone H3K27 acetylation were determined. Chromatin conformation was detected using the HiChIP method with an AR-specific antibody. Differential gene expression was analyzed by DESeq2 and Gene Set Enrichment Analyses. ChIP-seq peak identification was done by MACS2. HiChIP analysis was performed with the hichipper pipeline. Darolutamide efficiently blocked AR signalling at the level of transcriptional regulation and altered chromatin landscape interaction. Analysis of transcriptomic data showed a strong reduction of the androgen response, as well as down-regulation of proliferation and cell cycle genes by darolutamide. Concordantly, AR occupancy was decreased genome-wide compared to androgen stimulation. Importantly, no binding cluster was identified which showed increased AR occupancy after darolutamide treatment, as reported for other AR antagonists. Interestingly, we observed in darolutamide-treated samples a parallel reduction of FOXA1 occupancy at AR sites, which argues for a co-dependence between this pioneer factor and the AR. Also, we found that H3K27 acetylation, a histone mark linked to active regions, was markedly down-regulated at specific enhancer and gene regions following darolutamide treatment, further pointing to reduced activity of enhancer regions recognized by the AR. Finally, determination of chromatin looping mediated by the AR between enhancers and gene promoters showed a dense network at genes involved in prostate cancer survival. The loss of AR binding at these regions was in line with the significantly reduced transcriptional response observed following darolutamide treatment. In conclusion, we found that darolutamide strongly prevented genome-wide AR binding in multiple hormone-sensitive cellular PCa models, importantly at genes involved in cell proliferation and survival. We furthermore highlight the cross-talk between the pioneer factor FOXA1 and the AR. Citation Format: Simon J. Baumgart, Ekaterina Nevedomskaya, Ralf Lesche, Bernard Haendler. Darolutamide impairs prostate cancer growth by altering chromatin conformation and transcriptional activity of genes involved in cell proliferation and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5210.

Abstract 4188: Registering cancer recurrence in a population-based registry: The value of pathology data

Abstract INTRODUCTION No population-wide cancer registry systematically records recurrence. It is often requested of U.S. registries, but cannot be provided. To fill this gap, the Georgia Cancer Registry (GCR) has embarked on a five-year project to add recurrence data to the registry for early-stage breast, prostate, colorectal cancer and lymphoma patients. Multiple data streams will be used to provide signals of recurrence, which will then be validated by a Certified Tumor Registrar from the registry staff. Electronic pathology data are submitted in real-time to the GCR and could be a key data stream to signal recurrences. METHODS We created cohorts of early-stage breast and colorectal cancer patients treated at Commission on Cancer (CoC) facilities in Georgia and for whom the CoC facility both reported their pathology data to the GCR electronically and had documented a recurrence in the patient’s record. A randomly selected sample (n = 60) from each cohort was linked to electronic pathology (E-Path) reports in the registry to evaluate a) the proportion of patients with a report available in the GCR within 10 days of the documented recurrence and b) the proportion of patients whose E-Path report included the specific term(s) “recurrent”, or “recurrence(s)”. All pathology reports were manually reviewed to make the above determinations. RESULTS All 60 cases from each cancer site had E-Path reports available for the incident cancer that was diagnosed. Upon manual review, 67% of breast cases and 63% of colorectal cases had reports in the registry within 10 days of the recurrence date reported by the CoC facility. When examining all reports for a given patient, regardless of date, for use of the specific term(s) “recurrent”, or “recurrence(s)”, only 18% of breast cases and 9% of colorectal cases contained these exact terms. CoC facilities also attempt to document the location of the recurrence in addition to the date. For cases with reports available in the registry within 10 days of the recurrence reported by the CoC facility, confirmation of the recurrence location was documented in the pathology report for the majority of patients (78% for breast and 89% for colon). DISCUSSION E-Path reports will be an important source of information to signal recurrences, but the specific use of recurrence terminology was limited in the sample of reports selected for this study. Use of the terms “metastatic” or documentation of other organs as “positive for malignancy” was much more common. Not all recurrences will be signaled by E-Path reports, so the use of additional data streams as planned by this project will be critical and validation of these signals by trained staff will establish the gold standard of true recurrences. This ambitious project is just launching, with the aim of providing the first-ever descriptive data about recurrence rates for four common cancers over up to ten years of follow-up. Citation Format: Leah Moubadder, Audrey Chang, Kevin C. Ward, Timothy L. Lash. Registering cancer recurrence in a population-based registry: The value of pathology data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4188.

Impact of Prior Cancer on Eligibility for Plasma Cell Disorder (PCD) Clinical Trials

▪History of prior cancer is a widespread exclusion criterion in cancer trials. Up to 80% of NCI-sponsored and 80% of industry-sponsored lung cancer trials exclude patients with a prior cancer. We suspect this exclusion is commonly applied in other cancer trials, although no definitive data exist. Prior cancer is especially common among older patients and those with certain cancer types. Among patients >65 years, 15.1% overall have prior cancer. In Multiple Myeloma, the most common plasma cell disorder (PCD), prevalence of prior cancer is as high as 17.4%. Examining the prior cancer exclusion criterion is important because the number of US cancer survivors is large and rapidly growing. Arbitrarily excluding cancer survivors from trials is not evidence-based and exclusion presumably arises from assumptions that higher mortality of patients with prior cancer could hinder study conduct and bias trial outcomes. However, few data exist to support this assumption of higher mortality. In fact, we demonstrated that lung cancer patients with a prior cancer have similar or lower mortality risk, compared to those without prior cancer.In this abstract, we reviewed prior cancer related eligibility criteria in three of the most common PCD (Multiple Myeloma, Amyloidosis and Waldenström Macroglobulinemia) clinical trials sponsored or endorsed by 5 major Co-Operative groups in North America (Table 1). We use descriptive statistics (n, %) and Fisher's exact tests to describe characteristics of trials with and without exclusion criteria. Of 33 trials, 26 (79%) excluded patients with prior cancer as follows - active cancer (12%), within 2-3 years of PCD diagnosis (9%), or within 5 years of PCD diagnosis (55%). Many trials had exceptions to prior cancer exclusion. Specifically, 67% of trials allowed non-melanoma skin cancer, 58% allowed in-situ cervical cancer, 12% allowed early stage prostate cancer.Table 2 shows the association between clinical trial characteristics and prior cancer exclusion. There was no association between prior cancer exclusion and phase of study, transplant studies, or survival end point. Exclusion criteria varied across year of activation (p=0.01); for example, 75% of studies activated 1990-1999 excluded prior cancer, compared to 100% of studies activated after 2010. Type of PCD was marginally associated with exclusion criteria (p=0.08); 74% of Multiple Myeloma trials excluded patients with prior cancer compared to 100% of the Amyloidosis and Waldenström Macroglobulinemia trials.Conclusion:A substantial proportion of potential participants may be excluded from PCD clinical trials because of a history of prior cancer. This practice impacts accrual, generalizability, and fair access to cutting-edge treatments and the highest level of clinical care. As treatment outcomes for other cancers continue to improve, it is likely that the prevalence of multiple primary cancers will increase. This exclusion criterion is applied widely across studies, including more than two-thirds of those with non-survival endpoints. Our study is the first to examine the prevalence and potential impact of prior cancer exclusion in PCD clinical trials. Using population-based cancer registry data, we plan to undertake further research to understand the appropriateness and ramifications of this standard exclusion policy in PCD cancer trials. [Display omitted] DisclosuresCollins:Agios: Research Funding; Bristol Myers Squibb: Research Funding; Celgene Corporation: Research Funding; Arog Pharmaceuticals: Research Funding. Devine:Kiadis Pharma: Consultancy. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy. Anderson:Amgen: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Kumar:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

The impact of physician communication on diabetes management in cancer survivors.

77 Background: As cancer survivors live longer and many die from other comorbidities, it becomes increasingly important to understand factors associated with self-management behaviors for common comorbidities such as diabetes (DM). Provider guidance and inclusive communication have been found to promote self- management behaviors (SMB) in patients with DM. This study aims to explore the impact of provider communication on DM SMB in cancer survivors with DM. Methods: Patients with pre-existing DM who were newly diagnosed with early-stage breast, prostate, colorectal or lung cancer were enrolled. The Summary of Diabetes Self-Care Activities instrument was used to assess patients’ SMBs. The Patient Reaction Assessment scale was used to assess physician communication. Additional survey questions elicited the range of DM self-care recommendations made by patients’ healthcare providers. Mann-Whitney U test was used to assess the association between provider recommendations and communication and SMBs. Results: Of the 74 patients enrolled, the average age was 62 years and 64% were female. Patients who reported their healthcare providers recommended exercise reported more days of specific physical activity (median 5 vs. 0, p = 0.029). Patients who reported that their providers recommended checking their sugar checked their blood sugar more days out of the last 7 days (median 4 vs. 0, p < 0.001). Patients who reported that is hard to talk to their provider about how their treatment is going reported eating more sweets per week (median 2 vs. 1, p = 0.015) and fewer vegetables (median 0 vs. 1, p = 0.043). Conversely, patients who felt that their providers were interested in them as a person reported following a healthful eating plan for more days in a week (median 5.5 vs. 2, p = 0.016) and checked their feet more often (median 6.5 vs. 0, p = 0.008). Conclusions: Cancer survivors with DM whose healthcare providers recommend specific DM SMBs and who report better provider relationships perform DM SMBs more often. Healthcare providers should recognize that supportive recommendations for diet and exercise may improve survivors’ self-management of comorbidities.

Does depression affect illness beliefs in cancer survivors?

156 Background: As cancer survivors live longer and many die from their comorbidities rather than from cancer, it is important to understand how a cancer diagnosis may impact survivors’ perception of their other comorbidities. In addition, cancer is associated with increased risk for depression. We aim to assess the relationship between depressive symptoms and illness beliefs in cancer survivors with diabetes (DM). Methods: We recruited 75 patients with DM who were newly diagnosed with early-stage breast, prostate, lung or colon cancer. Depressive symptoms were assessed with the Center for Epidemiological Studies Depression Scale; illness beliefs were assessed with the Brief Illness Perception Questionnaire. Illness belief questions were dichotomized at the median, and non-parametric analyses were used to assess the relationship between depressive symptom scores and presence of illness beliefs. Results: Seventy-five patients with DM and a new diagnosis of cancer were enrolled. The average age was 61.8 years, 47% were male, 45% had breast cancer, 42% prostate cancer, 8% colon cancer, and 4% had lung cancer. Patients who perceived having more control over their DM had lower depression scores (median 26 vs. 20, p = 0.01). Furthermore, those who did not feel their health depended on their DM medications at present (median score 21 vs. 26, p = 0.007) had lower depression scores. Regarding beliefs about cancer, those who reported being less concerned about cancer had lower depression scores (median 21 vs. 25, p = 0.01). Additionally, patients who did not feel that cancer affected their lives much (median 19 vs. 26, p = 0.001) or who did not report that cancer affected them emotionally (median 19 vs. 26, p = 0.001) had lower depression scores. Patients’ perception of their control over their cancer was not associated with depression scores. Conclusions: Cancer survivors with higher depression scores report being more affected by cancer and simultaneously feel they have less control over DM. It is important to support survivors emotionally while increasing their self-efficacy over their comorbidity management to improve survivors’ health outcomes.

Increase in time to initiating cancer therapy and association with worsened survival in curative settings: A U.S. analysis of common solid tumors.

6557 Background: Increase in time to treatment initiation (TTI) for new cancer diagnoses causes patient distress and may adversely affect outcomes. We investigated trends in TTI for common solid tumors treated with curative intent, determinants of delayed TTI and impact on overall survival. Methods: We utilized population-based, prospective data from the National Cancer Database for newly diagnosed US patients with early-stage breast, prostate, lung, colorectal, renal and pancreas cancers from 2004-13. TTI was defined as days between diagnosis of cancer and first treatment (surgery, systemic or radiation therapy). Negative binomial regression and Cox proportional hazard models were used for analysis. Results: The study population of 3,672,561 patients included breast (N = 1,368,024), prostate (N = 944,246), colorectal (N = 662,094), non-small cell lung (NSCLC)(N = 363,863), renal(N = 262,915) and pancreas (N = 71,419) cancers. Median TTI increased from 21 days in 2004 to 29 days in 2013 (P < 0.0001). Aside from year, determinants of delays included care at academic centers and change in treating facility. Increased TTI was associated with worsened overall survival (OS) for stages I and II breast, lung, renal, and pancreas cancers, and stage II colorectal cancers, with hazard ratios per week of delay ranging from1.005 (1.002-1.008) to 1.030 (1.025-1.035), adjusting for comorbidities and other variables. Prolonged TTI ( > 6 wks) was associated with substantially worsened OS e.g., 5-yr OS for stage I NSCLC was 56% (±0.2) for TTI ≤ 6wks v 43% (±0.2) for TTI > 6 wks and for stage I pancreas was 38% (±0.6) v 29% (±1) respectively (P < 0.0001 for both). Conclusions: TTI has lengthened significantly over recent years, associated with multiple factors. Increase in TTI is associated with substantial increase in mortality ranging from 0.5-3.2% per week of delay in curative settings such as early-stage breast, lung and pancreas cancers. Simplifying access and navigation of complex health systems is essential to diminish this apparently iatrogenic impact on outcomes.

Evaluation of a multimodal strategy to accelerate drug evaluations in early-stage metastatic prostate cancer.

187 Background: The paradigm of first testing systemic treatments in advanced disease followed by development in earlier disease states and finally large-scale trials evaluating whether the approach, in combination with local therapy, can prevent or delay the time-to-event measures of disease progression or death in patients with “high-risk” tumors is no longer practical now that 6 life-prolonging systemic therapies in metastatic castration-resistant prostate cancer are available. New strategies are needed to rapidly evaluate and prioritize regimens for large-scale phase 3 testing. Methods: We conducted a pilot study of twenty men with oligometastatic M1a (extrapelvic nodal disease) or M1b (bone disease) at diagnosis. All sites of disease were treated using a multimodal approach that included androgen deprivation (ADT), radical prostatectomy plus pelvic lymphadenectomy (retroperitoneal lymphadenectomy in the presence of clinically positive retroperitoneal nodes), and stereotactic body radiotherapy to osseous disease and/or the primary site. ADT was discontinued in responding patients. Outcomes of each treatment were assessed sequentially. The primary endpoint of “no evidence of disease” (NED) was defined by an undetectable PSA with noncastrate levels of testosterone at 20 months. Results: Each treatment modality contributed to the outcome: 95% of the cohort achieved an undetectable PSA with multimodal treatment, including 25% of patients after ADT alone and an additional 50% and 20% after surgery and radiotherapy, respectively. Overall, 20% of patients (95% confidence interval 3-38%) achieved the primary endpoint, which persisted for 5, 6, 27+, and 46+ months. All patients meeting the primary endpoint had been classified with M1b disease at presentation. Conclusions: Treatment directed at all sites can eliminate detectable disease in selected patients with metastatic prostate cancer. A multimodal treatment strategy inclusive of the NED endpoint for patients who present with disease that is beyond the limits of curability by any single modality should be considered to enable the evaluation of new approaches in order to prioritize large-scale testing in early stages of advanced disease.

Cancer-related side effects and diabetes self-management.

152 Background: Cancer survivors often experience cancer and treatment-related side effects and may also have comorbidities that may further impact their quality of life. Little is known about how cancer-related side effects and health status impact survivors’ beliefs and management of comorbidities. We undertook this study to assess the relationship between cancer-related side effects and diabetes (DM) self-management behaviors (SMB) and beliefs in cancer survivors with comorbid diabetes. Methods: We recruited diabetes patients recently diagnosed with early-stage breast or prostate cancer who were taking at least one oral hypoglycemic agent. Side effects for prostate cancer survivors were assessed using the Expanded Prostate Cancer Index Composite; side effects for breast cancer survivors were assessed using a standardized questionnaire for hormonal therapy-related side effects. Patients were asked to rate their overall health status and about the perceived impact of cancer treatment on DM. We measured DM medication adherence using the 8-item Morisky Medication Adherence Scale, and DM SMB were evaluated using the Summary of Diabetes Self-Care Activities. Descriptive and univariate analyses were used to assess factors associated with DM SMB. Results: Of the 52 patients recruited, 32 (62%) were male. Twenty-four (46%) patients reported cancer or treatment related side effects, with most (21, 88%) being moderately or severely bothered by these symptoms. Of these patients, 20 (83%) reported non-adherence to their DM medications and 18 (71%) reported checking their fingersticks < 5 times a week. Yet most patients (20, 84%) felt that their diabetes care was at least equally as important as their cancer care. Neither the presence nor severity of side effects was associated with DM SMB. However, patients who reported poorer overall health status were more likely to be worried about the impact of cancer treatment on diabetes management (75% vs. 25%, p < 0.01). Conclusions: Many cancer survivors report moderate to severe treatment-related side effects, although severity of side effects was not found to be associated with DM SMB. Further effort should focus on addressing survivors’ concerns about the impact of cancer treatment on comorbid disease management.

Abstract SY22-02: Exercise and cancer progression: Preclinical evidence

Abstract A major objective of the emerging field of exercise-oncology research is to determine the efficacy of, and biological mechanisms by which, aerobic exercise affects cancer incidence, progression and/or metastasis. There is a strong inverse association between self-reported exercise and the primary incidence of certain forms of cancer, while emerging data suggest that post-diagnosis exercise exposure may improve outcomes for early-stage breast, colorectal, or prostate cancer. Arguably, critical next steps in the development of exercise as a candidate treatment in cancer control require preclinical studies that validate the biological efficacy of exercise, identify the optimal “dose” and pinpoint mechanisms of action. However, as we reviewed the extant literature, we were struck by substantial heterogeneity in the methods and means of analysis across pre-clinical exercise studies. As a result, we were unable to derive any cardinal features of exercise studies that could and should be adhered to. Furthermore, exercise protocols employed in many pre-clinical trials would never translate directly to human studies. At a minimum, we would argue that such studies must be conducted to mirror human studies as closely as possible. We found that mice that voluntarily run on wheels ad libitum exhibit slowed tumor growth compared with sedentary controls. Further, we observed improved perfusion in multiple tumor models. Interestingly, the increases in perfusion are associated with increases in HIF-1 and VEGF. Although upregulation of VEGF is normally associated with reduced vascular maturity, exercise increased vascular maturity, as assessed by association of CD31 (an endothelial cell marker) and desmin, a marker of pericytes was observed with animals that exercised. The improvement in perfusion was associated with concomitant reduction in hypoxia in the primary tumor. This has important clinical implications, as we observed enhanced anti-tumor effects when voluntary exercise was combined with either cyclophosphamide or radiotherapy in the 4T1mouse mammary carcinoma model. We further found that exercise reduced metastatic burden alone and when combined with radiotherapy to the primary tumor site. These are the first pre-clinical studies that have examined the value of exercise combined with chemo / radiotherapy. The results lead us to suggest that exercise intervention in human patients undergoing chemotherapy and/or radiotherapy can enhance local tumor control as well as reducing risk for metastasis. Future pre-clinical studies will identify mechanisms underlying these effects as well as establishing optimal exercise regimens to achieve enhanced treatment response. Work supported by a grant from the NIH/NCI CA40355 Citation Format: Mark W. Dewhirst, Kathleen Ashcraft, Lee Jones. Exercise and cancer progression: Preclinical evidence. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY22-02.

Physical activity communication between oncology providers and patients with early stage breast, colon or prostate cancer.

171 Background: National guidelines recommend that patients with a cancer diagnosis engage in regular physical activity (PA) to reduce cancer-related fatigue, maintain quality of life and physical function, and improve overall prognosis and survival. This study investigates oncology provider communications about PA during routine clinic visits with early stage breast, colon or prostate cancer patients. Methods: Retrospective chart review for documentation of communications (inquiries or recommendations) pertaining to PA in clinician notes and after visit patient summaries. Mixed methods analysis. Results: In a 1-month period, 55 oncology providers had 361 encounters (clinic visits) with early stage cancer patients. Of these encounters, 35% included a provider communication about “physical activity”, “exercise” or “activity”. Encounters with a medical oncologist resulted in a PA communication 55% of the time as compared to 20% of encounters with other clinician specialties (p < 0.0001). Older patients were more likely than younger patients to have a PA communication (p < 0.001). When the encounter was with a patient who was being seen for surveillance, chemotherapy or endocrine treatment, the rate of PA communications was significantly higher (46%, 37%, 58% respectively) as compared to when the visit was during radiation treatment or surgery (6%, 19% respectively) (p < 0.0001). Four PA themes emerged from our analysis of provider communications: (1) level and types of engagement in PA, (2) restrictions on PA either by the provider or perceived by patients, (3) encouragement or recommendations, or (4) relationships between PA and weight, nutrition, pain, and fatigue. There were no significant differences in PA communication rates by clinician gender, clinician training, patient gender, patient race, or disease site. Conclusions: This study shows it is feasible for oncology providers to have PA communications during routine clinic visits; however, the frequency of PA communications varies among providers. Interventions are needed to remind all oncology providers to encourage of their patients with early stage cancer to be physically active.

Impact of stress on diabetes self-management in cancer survivors.

11 Background: Few studies have evaluated the impact of stress on diabetes self- management among cancer survivors. We undertook this study to assess factors associated medication adherence and diabetes self-management in a cohort of diabetic patients with recently-diagnosed early-stage cancer. Methods: We recruited diabetes patients recently diagnosed with early-stage breast, prostate, lung or colorectal cancer on at least one oral hypoglycemic agent and used the Impact of Event Scale (IES) to assess the subjective distress caused by cancer. The 15-item IES consists of 2 subscales assessing avoidant and intrusive feelings about cancer. We measured medication adherence using the 8-item Morisky Medication Adherence Scale, and diabetes self-management behaviors were evaluated using the Summary of Diabetes Self-Care Activities. Participants were surveyed at baseline and after 3 months. Descriptive and univariate analyses were used to assess baseline factors associated with diabetes self-management at 3 months. Results: Of the 36 participants recruited to date, 20 (56%) were male. At baseline, 70% reported adherence to their diabetes medications which dropped to 63% at 3 months. There were no gender differences between IES scores at baseline; however, at 3 months women were more stressed (p = 0.02) and had more intrusive thoughts (p = 0.005) about cancer. Higher baseline total IES scores were associated with lack of a general healthy diet (p = 0.01). Patients who had trouble falling asleep from thoughts about cancer felt more hassled sticking to their diabetes medication treatment at 3 months (p = 0.02). Those who had dreams about cancer (p = 0.007) and those who tried to stay away from reminders about cancer (p = 0.04) were more likely to forget their diabetes medications when travelling. Lastly, patients who felt that the cancer wasn’t real were more likely to have difficulty remembering to take medications (p = 0.03). Conclusions: Cancer survivors with comorbid diabetes who have higher stress are less likely to follow a healthy diet and more likely to report trouble with taking their diabetes medications. Providers should be aware of the impact of stress caused by cancer to better support diabetes self-management among early cancer survivors.

Abstract 223: Generation of single cell-derived normal, benign and cancer mini-prostates from primary patient-derived tissues

Abstract Clinically effective next generation androgen deprivation therapy (ADT) and androgen receptor (AR)-directed therapies have been developed to treat castration-resistant prostate cancer (CRPC). However, disease progression inevitably occurs, and majority of relapsed tumors continue to overexpress AR. AR mutations and constitutively active AR splice variants (AR-Vs) are detected during ADT and may lead to drug resistance. Therefore, there is dire need to develop models that provide a better understanding of AR signaling and determine markers of ADT resistance in prostate cancer patient cells. Mouse models and existing human prostate cancer cell lines have inherent limitations for deciphering mechanisms of therapy resistance. Unlike the recently reported prostate tissue organoids that were derived at a low efficiency from 7/49 metastatic prostate cancer samples, we have developed a novel and exciting technology to generate normal, benign prostatic hyperplasia (BPH) and cancer “mini-prostates” from both early-stage and advanced prostate cancer patient samples. We have successfully rederived mini-prostates from 17 out of 19 primary prostatectomy tissues. We incorporated developmental epithelial and mesenchymal signals, stem-like cells and growth requirements in 3D cultures for maintaining primary normal, BPH and prostate cancer patient-derived cells as stem-like cell-derived organoids. Our preliminary data show the establishment of patient- single cell-derived normal, BPH and cancer mini-prostates comprised of organoids with glandular tissues that have a thick basement membrane, an outer mesenchymal and inner epithelial cells conveying AR signaling, expressing cytokeratins and secreting PSA. RNA sequencing, expression profiling and ADT revealed that mini-prostate cells maintain the genetic, chemoresistance, and growth rate features of the primary prostate. To model tumor heterogeneity, prostate cells from surgical tissues were isolated upon digital imaging and tissue mapping in mirror sections for AMACR, AR, AR-Vs, p63, Ki67, ERG expression and FISH analysis for TMPRSS2-ERG fusion. Living cells from mapped BPH and cancer clones are being utilized to derive single cells into mini-prostates. Our studies generated novel therapy sensitivity and drug discovery models that would allow for precision medicine and coclinical approaches to be enlisted to reveal chemo- or hormonal-resistance profiles in genetically defined mini-prostates, apply combinatory-targeted therapies and study therapy-induced clonal selection processes to ultimately guide future clinical trials. Citation Format: Monica Bartucci, Michele Patrizii, Eric Huselid, Shamila Yussuf, Nitu Bansal, Kathleen Flaherty, Denis Tolkunov, Hua Zhong, Mark N. Stein, Joseph Bertino, Robert DiPaola, Isaac Kim, Hatem E. Sabaawy. Generation of single cell-derived normal, benign and cancer mini-prostates from primary patient-derived tissues. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 223. doi:10.1158/1538-7445.AM2015-223

Abstract 2116: Mapping peptides critical for association of the androgen receptor with Elk1

Abstract Both early stage and advanced prostate tumors are generally dependent on the androgen receptor (AR) for growth. Indeed a major clinical approach in management of the disease is to disrupt the AR signaling in the tumors by androgen ablation and the use of anti-androgen drugs. However, these options present major drawbacks including limited efficacy in advanced disease and many undesirable side effects on non-target tissues. Therefore a more tactical therapy approach would be one that could disrupt a functional arm of AR signaling that is critical for prostate tumor growth but not for the essential physiological roles of AR in normal adult tissues. A considerable amount of evidence suggests that in prostate cancer, androgen/AR signaling is redirected to support tumor growth through the association of AR with critical growth promoting genes via tethering proteins. Our previous studies have identified Elk1, a genetically redundant DNA binding transcription factor, as an AR tethering protein essential for AR-dependent growth in established models of both hormone-dependent prostate cancer and castration recurrent prostate cancer. Elk1 recruits AR to chromatin sites to upregulate a major subset of genes that is strongly and primarily enriched for cell growth functions. Further studies in the lab demonstrate that the A/B domain of the AR alone is capable of co-activation of Elk1, suggesting that Elk1 may also mediate the hormone-independent growth supporting function of AR splice variants. Peptide or small molecule inhibitors of the Elk1-AR interaction may therefore selectively target the growth supporting function of AR in the spectrum of prostate tumors, obviating the need for androgen ablation. Toward this end we undertook to map peptide segment(s) of Elk1and AR that are essential for the Elk1-AR synergy. In this study we used deletional and mutational analysis together with a promotor-reporter assay and a mammalian two-hybrid assay. The results demonstrate that the ability to recruit AR resides largely in the C-terminal activation domain of Elk1 (amino acids 307-428) and that residues within segments 367-428 and 307-337 are essential for this interaction. They also demonstrate that the recruitment of AR by Elk1 does not require Elk1 phosphorylation. Critical sites within the AR-A/B domain required for its association with Elk1 reside in the N-terminal region that is distal to known sites of co-regulator binding. This information will guide the development of peptide inhibitors of Elk1-dependent growth induction by androgen/AR and set the stage for future development of small molecule inhibitors. Citation Format: Rayna Rosati, Mugdha Patki, Venkatesh Chari, Manohar Ratnam. Mapping peptides critical for association of the androgen receptor with Elk1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2116. doi:10.1158/1538-7445.AM2014-2116

Changes in androgen deprivation therapy overuse: Reimbursement response and characteristics of persistent overusers.

5044 Background: Reimbursement cuts driven by the Medicare Modernization Act of 2003 are associated with declining androgen deprivation therapy (ADT) overuse in prostate cancer; yet, 25.7% of men for whom ADT was not recommended still received it in 2005. We examined physician-level prescribing changes and characteristics of persistent overusers among urologists. Understanding characteristics of urologists who persistently overuse ADT can improve quality of care and inform current efforts to limit reimbursement. Methods: We conducted a population-based, retrospective study of 2,138 urologists treating 12,943 men with early stage and lower grade prostate cancer diagnosed between 2000 and 2007. SEER-Medicare data was matched to American Medical Association physician data. Mixed effects regression modeling controlled for patient and provider characteristics. Results: We observed 3 distinct patterns of overuse. Static users (69%) had low levels of ADT overuse in 2000 and maintained infrequent overuse. Decreas...