The Impact of Immunotherapy Use in Stage IIIA (T1-2N2) NSCLC: A Nationwide Analysis.

Introduction: Multiple clinical trials have revealed the benefit of immunotherapy (IO) for NSCLC, including unresectable stage III disease. Our aim was to investigate the impact of IO use on treatment and outcomes of potentially resectable stage IIIA NSCLC in a broader nationwide patient cohort. Methods: We queried the National Cancer Database (2004-2019) for patients with stage IIIA (T1-2N2) NSCLC. Treatment and survival were evaluated with descriptive statistics, logistic regression, Kaplan-Meier analysis, and Cox proportional hazards modeling. Results: Overall, 5.5% (3777 of 68,335) of patients received IO. IO use was uncommon until 2017, but by 2019, it was given to 40.1% (1544 of 2308) of stage IIIA patients. The increased use of IO after 2017 was associated with increased definitive chemoradiation treatment (54.2% [6800 of 12,535] from years 2017 to 2019 versus 46.9% [26,251 of 55,914] from 2004 to 2016, p < 0.001) and less use of surgery (18.1% [2266 of 12,535] from years 2017 to 2019 versus 22.0% [12,300 of 55,914] from 2004 to 2016, p < 0.001). IO treatment was associated with significantly better 5-year survival in the entire cohort (36.9% versus 23.4%, p < 0.001) and the subsets of patients treated with chemoradiation (37.2% versus 22.7%, p < 0.001) and surgery (48.6% versus 44.3%, p < 0.001). Pneumonectomy use decreased with increased IO treatment (5.1% of surgical patients [116 of 2266] from years 2017 to 2019 versus 9.2% [1127 of 12,300] from 2004 to 2016, p < 0.001). Conclusions: Increased use of IO was associated with a change in treatment patterns and improved survival for patients with stage IIIA(N2) NSCLC.

Predicting Depression Risk in Patients With Cancer Using Multimodal Data: Algorithm Development Study.

BACKGROUND: Patients with cancer starting systemic treatment programs, such as chemotherapy, often develop depression. A prediction model may assist physicians and health care workers in the early identification of these vulnerable patients. OBJECTIVE: This study aimed to develop a prediction model for depression risk within the first month of cancer treatment. METHODS: We included 16,159 patients diagnosed with cancer starting chemo- or radiotherapy treatment between 2008 and 2021. Machine learning models (eg, least absolute shrinkage and selection operator [LASSO] logistic regression) and natural language processing models (Bidirectional Encoder Representations from Transformers [BERT]) were used to develop multimodal prediction models using both electronic health record data and unstructured text (patient emails and clinician notes). Model performance was assessed in an independent test set (n=5387, 33%) using area under the receiver operating characteristic curve (AUROC), calibration curves, and decision curve analysis to assess initial clinical impact use. RESULTS: Among 16,159 patients, 437 (2.7%) received a depression diagnosis within the first month of treatment. The LASSO logistic regression models based on the structured data (AUROC 0.74, 95% CI 0.71-0.78) and structured data with email classification scores (AUROC 0.74, 95% CI 0.71-0.78) had the best discriminative performance. The BERT models based on clinician notes and structured data with email classification scores had AUROCs around 0.71. The logistic regression model based on email classification scores alone performed poorly (AUROC 0.54, 95% CI 0.52-0.56), and the model based solely on clinician notes had the worst performance (AUROC 0.50, 95% CI 0.49-0.52). Calibration was good for the logistic regression models, whereas the BERT models produced overly extreme risk estimates even after recalibration. There was a small range of decision thresholds for which the best-performing model showed promising clinical effectiveness use. The risks were underestimated for female and Black patients. CONCLUSIONS: The results demonstrated the potential and limitations of machine learning and multimodal models for predicting depression risk in patients with cancer. Future research is needed to further validate these models, refine the outcome label and predictors related to mental health, and address biases across subgroups.

Patient Selection and Outcomes for Hypofractionated Accelerated Radiation and Concurrent Chemotherapy for Non-Small-Cell Lung Cancer.

PURPOSE/OBJECTIVES: Adoption of hypofractionated accelerated radiation therapy (HART) with concurrent chemotherapy has been limited by toxicity concerns. We aimed to describe outcomes of patients treated with HART and concurrent chemotherapy and to evaluate dosimetry to organs at risk to guide patient selection. MATERIALS/METHODS: We evaluated a retrospective cohort of NSCLC patients treated with concurrent chemotherapy with HART (>2.2 Gy per fraction) or standard fractionated radiation therapy (SFRT; 2-2.2 Gy fractions). Dosimetric parameters to key organs at risk were compared, and toxicity, patterns of recurrence and survival were calculated for the cohorts. RESULTS: Fifty-three patients treated with HART were compared with 100 patients treated with SFRT. Median dose per fraction for the HART cohort was 2.75 Gy (range 2.4-3 Gy). HART patients had significantly lower doses to the lung, heart, and esophagus due to patient selection. The HART group and had rates of grade 2+ pneumonitis (9.4 vs. 19%, P = .16) and grade 2+ esophagitis (20.8 vs. 45%, P < .01) that compared favorably to SFRT. Cumulative incidence of in-field recurrence trended lower in the HART cohort (7.6% vs. 23.1%, P = .058). Among the HART group, 88.7% (47/53) met the newly proposed lung constraints based on the degree of hypofractionation CONCLUSION: In select patients with favorable dosimetry to organs at risk, definitive HART with concurrent chemotherapy achieved excellent local control with low toxicity. These results are being used to inform a prospective study on the safety and efficacy of HART with concurrent chemotherapy for select NSCLC patients.

Patient-reported distress at a cancer center during the COVID-19 pandemic.

Assessments of health-related quality of life (HRQOL) are conducted by health systems to improve patient-centered care. Studies have shown that the COVID-19 pandemic poses unique stressors for patients with cancer. This study investigates change in self-reported global health scores in patients with cancer before and during the COVID-19 pandemic. In this single-institution retrospective cohort study, patients who completed the Patient-Reported Outcomes Measurement Information System (PROMIS) at a comprehensive cancer center before and during the COVID-19 pandemic were identified. Surveys were analyzed to assess change in the global mental health (GMH) and global physical health (GPH) scores at different time periods (pre-COVID: 3/1/5/2019-3/15/2020, surge1: 6/17/2020-9/7/2020, valley1: 9/8/2020-11/16/2020, surge2: 11/17/2020-3/2/2021, and valley2: 3/3/2021-6/15/2021). A total of 25,192 surveys among 7209 patients were included in the study. Mean GMH score for patients before the COVID-19 pandemic (50.57) was similar to those during various periods during the pandemic: surge1 (48.82), valley1 (48.93), surge2 (48.68), valley2 (49.19). Mean GPH score was significantly higher pre-COVID (42.46) than during surge1 (36.88), valley1 (36.90), surge2 (37.33) and valley2 (37.14). During the pandemic, mean GMH (49.00) and GPH (37.37) scores obtained through in-person were similar to mean GMH (48.53) and GPH (36.94) scores obtained through telehealth. At this comprehensive cancer center, patients with cancer reported stable mental health and deteriorating physical health during the COVID-19 pandemic as indicated by the PROMIS survey. Modality of the survey (in-person versus telehealth) did not affect scores.

Predicting Depression Risk in Patients with Cancer Using Multimodal Data.

When patients with cancer develop depression, it is often left untreated. We developed a prediction model for depression risk within the first month after starting cancer treatment using machine learning and Natural Language Processing (NLP) models. The LASSO logistic regression model based on structured data performed well, whereas the NLP model based on only clinician notes did poorly. After further validation, prediction models for depression risk could lead to earlier identification and treatment of vulnerable patients, ultimately improving cancer care and treatment adherence.

Use of Machine Learning and Lay Care Coaches to Increase Advance Care Planning Conversations for Patients With Metastatic Cancer.

PURPOSE: Patients with metastatic cancer benefit from advance care planning (ACP) conversations. We aimed to improve ACP using a computer model to select high-risk patients, with shorter predicted survival, for conversations with providers and lay care coaches. Outcomes included ACP documentation frequency and end-of-life quality measures. METHODS: In this study of a quality improvement initiative, providers in four medical oncology clinics received Serious Illness Care Program training. Two clinics (thoracic/genitourinary) participated in an intervention, and two (cutaneous/sarcoma) served as controls. ACP conversations were documented in a centralized form in the electronic medical record. In the intervention, providers and care coaches received weekly e-mails highlighting upcoming clinic patients with < 2 year computer-predicted survival and no prior prognosis documentation. Care coaches contacted these patients for an ACP conversation (excluding prognosis). Providers were asked to discuss and document prognosis. RESULTS: In the four clinics, 4,968 clinic visits by 1,251 patients met inclusion criteria (metastatic cancer with no prognosis previously documented). In their first visit, 28% of patients were high-risk (< 2 year predicted survival). Preintervention, 3% of both intervention and control clinic patients had ACP documentation during a visit. By intervention end (February 2021), 35% of intervention clinic patients had ACP documentation compared with 3% of control clinic patients. Providers' prognosis documentation rate also increased in intervention clinics after the intervention (2%-27% in intervention clinics, P < .0001; 0%-1% in control clinics). End-of-life care intensity was similar in intervention versus control clinics, but patients with ≥ 1 provider ACP edit met fewer high-intensity care measures (P = .04). CONCLUSION: Combining a computer prognosis model with care coaches increased ACP documentation.

A brief report on the mutational landscape in non-small cell lung cancer of South Asian patients: Comparison at a US and an Indian Institution.

Background: Various molecular underpinnings of lung cancer have been noted in Asian populations, especially with targetable oncogenic drivers such as EGFR mutations and ALK rearrangements, although they have been lesser described in South Asian/Indian patients. Methods: Tumour molecular testing results from non-small cell lung cancer (NSCLC) patients with a name of South Asian origin and diagnosed from 2005 to 2019 at the Stanford Cancer Center in the United States were retrospectively reviewed and compared to the results of molecular testing from PGIMER in Chandigarh, India, from the patients diagnosed from 2011 to 2019. Results: We identified 72 patients of South Asian (largely Indian) origin, of whom 64 patients (51% female) had mutational testing at Stanford. Of the tested patients, 33% of cases harboured either an EGFR exon 19 deletion or exon 21 L858R mutation, and 12.5% had ALK rearrangements. At PGIMER, a larger sample of 1,264 patients was identified (33% female), with 22.5% of patients having two main EGFR activating mutations, and 9.5% harbouring an ALK rearrangement. Conclusions: South Asian, largely Indian, patients with NSCLC appear to have a higher chance of harbouring EGFR mutations and ALK translocation as compared to Caucasians. The percentage of South Asian patients with these molecular abnormalities was largely similar in two different geographical locations. These findings corroborate prior single-institution findings and emphasise the importance of molecular testing.

Characterization of Metastatic Non-Small Cell Lung Cancer and Oligometastatic Incidence in an Era of Changing Treatment Paradigms.

PURPOSE: Because of the limitations of current staging systems and evolving definitions, there are limited data on oligometastatic non-small cell lung cancer (NSCLC) epidemiology. The purpose of this study was to evaluate metastatic disease burden and the incidence of oligometastatic disease using recent clinical trial eligibility criteria. METHODS AND MATERIALS: A cohort of patients with metastatic NSCLC, diagnosed from 2016 to 2019, were randomly sampled from a curated tumor registry. Definitions for oligometastatic disease were obtained from relevant clinical trials. The Stanford Cancer Institute Research Database was used to identify baseline patient factors, systemic and local therapy, extent and location of metastatic lesions, and survival outcomes. RESULTS: Among 120 patients presenting with metastatic NSCLC, the majority had de novo metastatic disease (75%) with a median of 4 metastatic lesions involving 3 organ systems. Of these, 37.5% would have been eligible for at least 1 oligometastatic trial, with 28.3% meeting criteria for the MD Anderson Cancer Center trial, 20.0% for NRG-LU002, 6.7% for SINDAS, and 16.7% for SABR-COMET. By adding malignant pleural effusions and early progression as exclusionary criteria, only 54.1% of patients with ≤3 synchronous metastases were eligible for consideration of local therapy. Early progression on systemic therapy was associated with worse survival (10.0 vs 42.4 months; P < .001), whereas presence of malignant pleural effusions was not. Of those tumors identified as oligometastatic, 44.4% received local therapy and 28.9% underwent ablative therapy to all sites. There was a trend toward greater overall survival (44.4 vs 24.9 months; P = .055) and progression-free survival (8.0 vs 5.4 months; P = .06) in patients meeting eligibility for at least 1 oligometastatic trial. CONCLUSIONS: Around 48% of patients with metastatic NSCLC had ≤3 metastases at presentation and 28% met clinical trial criteria for oligometastatic disease. Future research is needed to better define the oligometastatic state and identify patients most likely to benefit from local therapy.

Patient-reported outcome measurement implementation in cancer survivors: a systematic review.

PURPOSE: Patient-reported outcome measurements (PROMs) are increasingly used for cancer patients receiving active treatment, but little is known about the implementation and usefulness of PROMs in cancer survivorship care. This systematic review evaluates how cancer survivors and healthcare providers (HCPs) perceive PROM implementation in survivorship care, and how PROM implementation impacts cancer survivors' health outcomes. METHODS: We systematically searched PubMed/MEDLINE, Embase, CINAHL, Web of Science, and Cochrane Database of Systematic Reviews from database inception to February 2022 to identify randomized and nonrandomized studies of PROM implementation in cancer survivors. RESULTS: Based on prespecified eligibility criteria, we included 29 studies that reported on 26 unique PROMs. The studies were heterogeneous in study design, PROM instrument, patient demographics, and outcomes. Several studies found that cancer survivors and HCPs had favorable impressions of the utility of PROMs, and a few studies demonstrated that PROM implementation led to improvements in patient quality of life (QoL), with small to moderate effect sizes. CONCLUSIONS: We found implementation of PROMs in cancer survivorship care improved health outcomes for select patient populations. Future research is needed to assess the real-world utility of PROM integration into clinical workflows and the impact of PROMs on measurable health outcomes. IMPLICATIONS FOR CANCER SURVIVORS: Cancer survivors accepted PROMs. When successfully implemented, PROMs can improve health outcomes after completion of active treatment. We identify multiple avenues to strengthen PROM implementation to support cancer survivors.

Implementing Patient-Directed Cancer Education Materials Across Nigeria.

PURPOSE: As access to cancer care expands in low-income countries, developing tools to educate patients is paramount. We took a picture booklet, which was initially developed by the nonprofit Global Oncology for Malawi and Rwanda, and adapted it for use in Nigeria. The primary goal was to assess acceptability and provide education. The secondary goals were (1) to describe the collaboration, (2) to assess knowledge gained from the intervention, (3) to assess patient understanding of their therapy intent, and (4) to explore patient's experiences via qualitative analysis. METHODS: We piloted the original English booklet at a single site and requested feedback from patients and providers. The booklet was updated; translated into Hausa, Yoruba, Igbo, and Pidgin English; and used at three additional sites. For the three-site cohort, we collected basic demographics, pretest and post-test assessing content in the booklet, and performed a qualitative analysis. RESULTS: The original booklet was widely acceptable and recommended by patients at site one (n = 31) and by providers (N = 26) representing all four sites. In the three-site cohort (n = 103), 94% of patients recommended the booklet. An immediate post-test focusing on when patients should present to care showed a statistically significant improvement in one of the seven questions. Fifty-one percent of the patients (n = 103) knew their treatment intent (curative v palliative). Qualitative analysis highlighted that the patient's thoughts on cancer are dominated by negative associations, although curability and modern therapy are also frequently cited. CONCLUSION: We adapted an educational booklet to a novel context and had it delivered by local partners. The booklet was widely recommended to future patients. The booklet had an impact on patient's knowledge of cancer treatment, potentially allowing for decreased abandonment.

Implementation of a cloud-based electronic patient-reported outcome (ePRO) platform in patients with advanced cancer.

BACKGROUND: Patient reported outcomes (PROs) have been associated with improved symptom management and quality of life in patients with cancer. However, the implementation of PROs in an academic clinical practice has not been thoroughly described. Here we report on the execution, feasibility and healthcare utilization outcomes of an electronic PRO (ePRO) application for cancer patients at an academic medical center. METHODS: We conducted a randomized trial comparing an experimental ePRO arm to standard of care in patients with advanced cancer in the thoracic, gastrointestinal, and genitourinary oncology groups at Stanford Cancer Center from March 2018 to November 2019. We describe the pre-implementation, implementation, and post-implementation phases of the ePRO arm, technological barriers, electronic health record (EHR) integration, clinician burden, and patient data privacy and security. Feasibility was pre-specified to be at least 70% completion of all questionnaires. Acceptability was based on patient and clinician feedback. Ambulatory healthcare utilization was assessed by reviewing numbers of phone messages, electronic portal messages, and referrals for supportive care. RESULTS: Of 617 ePRO questionnaires sent to 72 patients, 445 (72%) were completed. Most clinicians (87.5%) and patients (93%) felt neutral or positive about the ePRO tool's ease of use. Exposure to ePRO did not cause a measurable change in ambulatory healthcare utilization, with a median of less than two phone messages and supportive care referrals, and 5-6 portal messages. CONCLUSIONS: Web-based ePRO tools for patients with advanced cancer are feasible and acceptable without increasing clinical burden. Key lessons include the importance of pilot testing, engagement of stakeholders at all levels, and the need for customization by disease group. Future directions for this work include completion of EHR integration, expansion to other centers, and development of integrated workflows for routine clinical practice.

Limited English Proficiency and Disparities in Health Care Engagement Among Patients With Breast Cancer.

PURPOSE: Race and ethnicity have been shown to affect quality of cancer care, and patients with low English proficiency (LEP) have increased risk for serious adverse events. We sought to assess the impact of primary language on health care engagement as indicated by clinical trial screening and engagement, use of genetic counseling, and communication via an electronic patient portal. METHODS: Clinical and demographic data on patients with breast cancer diagnosed and treated from 2013 to 2018 within the Stanford University Health Care system were compiled via linkage of electronic health records, an internal clinical trial database, and the California Cancer Registry. Logistic and linear regression models were used to evaluate for association of clinical trial engagement and patient portal message rates with primary language group. RESULTS: Patients with LEP had significantly lower rates of clinical trial engagement compared with their English-speaking counterparts (adjusted odds ratio [OR], 0.29; 95% CI, 0.16 to 0.51). Use of genetic counseling was similar between language groups. Rates of patient portal messaging did not differ between English-speaking and LEP groups on multivariable analysis; however, patients with LEP were less likely to have a portal account (adjusted OR, 0.89; 95% CI, 0.83 to 0.96). Among LEP subgroups, Spanish speakers were significantly less likely to engage with the patient portal compared with English speakers (estimated difference in monthly rate: OR, 0.43; 95% CI, 0.24 to 0.77). CONCLUSION: We found that patients with LEP had lower rates of clinical trial engagement and odds of electronic patient portal enrollment. Interventions designed to overcome language and cultural barriers are essential to optimize the experience of patients with LEP.

Distress Screening Through Patient-Reported Outcomes Measurement Information System (PROMIS) at an Academic Cancer Center and Network Site: Implementation of a Hybrid Model.

PURPOSE: Cancer care guidelines recommend regular distress screening of patients, with approximately one in three patients with cancer experiencing significant distress. However, the implementation of such programs is variable and inconsistent. We sought to assess the feasibility of implementing a hybrid electronic and paper screening tool for distress in all patients coming to a large academic cancer center and an associated integrated network site. METHODS: Patients at an academic cancer center (Stanford Cancer Center) and its associated integrated network site received either an electronic or on-paper modified Patient-Reported Outcomes Measurement Information System-Global Health questionnaire, to assess overall health and distress. We used the Reach, Effectiveness, Adoption, Implementation, and Maintenance implementation framework to test and report on the feasibility of using this questionnaire. Iterative workflow changes were made to implement the questionnaire throughout the healthcare system, including processes to integrate with existing electronic health records. RESULTS: From June 2015 to December 2017, 53,954 questionnaires representing 26,242 patients were collected. Approximately 30% of the questionnaires were completed before the visit on an electronic patient portal. The number of patients meeting the positive screen threshold remained around 40% throughout the study period. Following assessment, there were 3,763 referrals to cancer supportive services. Of note, those with a positive screen were more likely to have a referral to supportive care (odds ratio, 6.4; 95% CI, 5.8 to 6.9; P < .0001). CONCLUSION: The hybrid electronic and on-paper use of a commonly available patient-reported outcome tool, Patient-Reported Outcomes Measurement Information System-Global Health, as a large-scale distress screening method, is feasible at a large integrated cancer center.

From metrics to practice: identifying preventable emergency department visits for patients with cancer.

BACKGROUND: Oncology patients disproportionately utilize the emergency department (ED) for symptom management. At our institution, approximately 1 in 4 visits to the ED by oncology patients led to discharge. We hypothesized that many of the visits leading to ED discharge would be potentially preventable (PP). METHODS: We retrospectively characterized ED discharges of oncology patients. Visits were classified by presenting symptom, type of cancer, and time of ED visit. Chart reviewers were additionally asked whether each case could have been safely managed as an outpatient. RESULTS: We analyzed 100 ED discharges in a 4-month period in 2016 and 2017. Gastrointestinal (GI) complaints, pain, and fever were the most common presenting symptoms for these visits. We rated 44 of 100 ED discharges as potentially preventable. Given we analyzed only ED discharges which comprise about 25% of ED visits for patients with cancer, overall about 10% of all ED visits by these patients may be preventable. We also found that ED visits without a clinic appointment or phone call to the clinic on the day of ED presentation were more likely to be preventable (51% vs 27%, OR 2.9, p = 0.026). CONCLUSIONS: Many ED visits by oncology patients may be preventable and occur for symptoms which can be managed as an outpatient. More of these visits also appear to occur in those who do not reach a clinic member prior to the visit. These findings suggest that improved access to clinics and standardized outpatient symptom management are next steps to consider in preventing ED visits in this vulnerable population.

Symptom relief and palliative care in gynecologic oncology.

PURPOSE OF REVIEW: Patients with gynecologic malignancies experience varied and often difficult-to-manage symptoms through their disease course, along with decisions surrounding preferences for advance care planning. This review focuses on evidence-based symptom management for these patients and offers a framework for conversations regarding goals of therapy. RECENT FINDINGS: There is increasing literature on palliative care specifically in gynecologic oncology, including barriers and possible solutions for early palliative care use, along with updated guidelines on postoperative pain management and tools for communication. SUMMARY: Integration of early palliative care and focus on symptom management is an important and multidisciplinary approach to help patients with gynecologic malignancies.

Communicating environmental exposure results and health information in a community-based participatory research study.

BACKGROUND: Communicating results to participants is a fundamental component of community-based participatory research (CBPR). However, in environmental exposure studies this is not always practiced, partly due to ethical concerns of communicating results that have unknown clinical significance. METHODS: Growing Up Healthy was a community-based participatory research study that sought to understand the relationship between environmental exposures to phthalates and early puberty in young girls. After in-depth consultation with a Community Advisory Board, study investigators provided group summary results of phthalate exposures and related health information to the parents of study participants. Parents' comprehension and knowledge of the health information provided was then assessed through questionnaires. RESULTS: After receiving the information from the research team, responders were able to correctly answer comprehension questions about phthalate exposures in their community, were able to identify ways to reduce exposure to phthalates, and indicated plans to do so. Questionnaires revealed that parents wanted more information on phthalates, and that children's environmental health was an important concern. CONCLUSIONS: We conclude that effective communication of exposure results of unknown clinical significance to participants in environmental health studies can be achieved by providing group summary results and actionable health information. Results suggest that there was an improvement in knowledge of environmental health and in risk reduction behaviors in our study population.

Statins and prostate cancer: role of cholesterol inhibition vs. prevention of small GTP-binding proteins.

Prostate cancer (PCa) is initially regulated by androgens, such as testosterone and dihydrotestosterone, which regulates cell proliferation and survival by activating the androgen receptor (AR), but later progresses to an aggressive, metastatic, androgen-independent stage for which, currently, there is no cure. Here, we argue that prevention of PCa progression is a better strategy compared to trying to cure the disease once it has already progressed. Statins inhibit the mevalonate pathway, thus preventing the synthesis of cholesterol, geranylgeranyl pyrophosphate and farnesyl pyrophosphate. Multiple clinical studies have shown an inverse relationship between statin use and PCa risk, especially the risk for developing advanced metastatic cancer. Biochemical investigations have largely corroborated the positive effect of statins on PCa risk, showing that statins inhibited cell proliferation, induced apoptosis, and decreased cell migration and invasion in PCa cells in vitro. However, investigations of the biochemical mechanism of statin action in preventing advanced/high risk PCa remains inconclusive, as statins can act through cholesterol, geranylgeranyl, or farnesyl mediated signals. This review discusses the current clinical and biochemical findings on the use of statins in preventing PCa. Evidence of statin action through cholesterol as well as geranylgeranylation and farnesylation has been discussed. As cholesterol is a precursor of androgen production, it can reduce PCa risk by decreasing the levels of circulating testosterone, which in turn reduces the levels of interprostatic dihydrotestosterone, a strong ligand for the AR. Cholesterol was also shown to accumulate in lipid rafts and regulate the activation of the phosphatidylinositol 3-kinase/Akt pathway. However, clinical evidence from multiple studies also point to the existence of cholesterol-independent pathways mediating statin action in PCa patients. In particular, ligand-activated AR activation is seen in early stage PCa and activation of the cholesterol pathway did not indicate an effect on metastasis. Cell migration and invasion, on the other hand, is regulated strongly by members of the Ras superfamily of small GTPases, especially the Rho family, which is geranylgeranylated. This review, therefore, also compares the effects of statins on both cholesterol and geranylgeranylated and farnesylated small GTPases regulating tumor progression and metastasis in biochemical and clinical studies.

Androgen Receptor regulation of Vitamin D receptor in response of castration-resistant prostate cancer cells to 1α-Hydroxyvitamin D5 - a calcitriol analog.

Calcitriol (1,25(OH)(2)D3) is cytostatic for prostate cancer (CaP), but had limited therapeutic utility due to hypercalcemia-related toxicities, leading to the development of low-calcemic calcitriol analogs. We show that one analog, 1-α-Hydroxyvitamin-D5 (1α(OH)D5), induced apoptosis in castration-sensitive LNCaP prostate cancer cells, but unlike calcitriol, did not increase androgen receptor (AR) transcriptional activity. LNCaP-AI, a castrate-resistant (CRCaP) LNCaP subline, was resistant to 1α(OH)D5 in the presence of androgens; however, androgen withdrawal (AWD), although ineffective by itself, sensitized LNCaP-AI cells to 1α(OH)D5. Investigation of the mechanism revealed that the vitamin D receptor (VDR), which mediates the effects of 1α(OH)D5, is downregulated in LNCaP-AI cells compared to LNCaP in the presence of androgens, whereas AWD restored VDR expression. Since LNCaP-AI cells expressed higher AR compared to LNCaP and AWD decreased AR, this indicated an inverse relationship between VDR and AR. Further, AR stimulation (by increased androgen) suppressed VDR, while AR downregulation (by ARsiRNA) stimulated VDR levels and sensitized LNCaP-AI cells to 1α(OH)D5 similar to AWD. Another cell line, pRNS-1-1, although isolated from a normal prostate, had lost AR expression in culture and adapted to androgen-independent growth. These cells expressed the VDR and were sensitive to 1α(OH)D5, but restoration of AR expression suppressed VDR levels and induced resistance to 1α(OH)D5 treatment. Taken together, these results demonstrate negative regulation of VDR by AR in CRCaP cells. This effect is likely mediated by prohibitin (PHB), which was inhibited by AR transcriptional activity and stimulated VDR in CRCaP, but not castrate-sensitive cells. Therefore, in castration sensitive cells, although the AR negatively regulates PHB, this does not affect VDR expression, whereas in CRCaP cells, negative regulation of PHB by the AR results in concomitant negative regulation of the VDR by the AR. These data demonstrate a novel mechanism by which 1α(OH)D5 prolong the effectiveness of AWD in CaP cells.