Cancer Stem Cells and Androgen Receptor Signaling: Partners in Disease Progression (preprint)

The cancer stem cell hypothesis suggests that neoplastic cells with stem characteristics hierarchically regulate tumor generation and its high cellular heterogeneity. These cells have been detected in all cancer types, and specific signaling pathways give the regulation of self-renewal and differentiation. In prostate cancer, androgen receptor signaling has been extensively studied, and in non-stem cells, it promotes cell proliferation and tumor progression, but in the cancer stem cell population, it negatively regulates processes such as self-renewal. However, in other types of cancer, such as breast and glioblastoma, the androgen receptor seems to favor the maintenance of cancer stem cells, suggesting that androgen signaling has different effects depending on the tumor context. This review discusses the role of androgen receptor in maintaining cancer stem cells by regulating proliferation, self-renewal, and differentiation, as well as the possible signaling pathways involved in these processes.

Nuclear Medicine and Cancer Theragnostics (preprint)

Cancer theragnostics is a novel approach that combines diagnostic imaging and radionuclide therapy. It is based on the use of a pair of radiopharmaceuticals, one optimized for positron emission tomography imaging, through linkage to a proper radionuclide, and the other bearing a beta-emitter isotope that can induce significant damage to cancer cells. In recent years, the use of theragnostics in nuclear medicine clinical practice has increased considerably, and thus investigation has focused on the identification of novel radionuclides that can bind to molecular targets which are typically dysregulated in different cancers. The major advantages of the theragnostic approach include elimination of multi-step procedures, reduced adverse effects to normal tissues, early diagnosis, better predicting responses and personalized patient care. This review aims to discuss emerging theragnostic molecules that have been investigated in a series of human malignancies, including gliomas, thyroid cancer, neuroendocrine tumors, cholangiocarcinoma and prostate cancer, as well as potent and recently introduced molecular targets, like cell-surface receptors, kinases, and cell adhesion proteins. Furthermore, special reference has been made to copper radionuclides as theragnostic agents, and their radiopharmaceutical applications since they present promising alternatives to the well-studied gallium-68 and lutetium-177.

De Novo Metastatic Prostate Cancer: Are We Moving towards a Personalized Treatment? (preprint)

De novo metastatic hormone-sensitive PC (mHSPC) accounts for 5-10% of all prostate cancer (PC) diagnoses but it is responsible for nearly 50% of PC-related deaths. Since 2015, the prognosis of mHSPC has slightly improved thanks to the introduction of new hormonal agents and chemotherapy combined with androgen deprivation therapy from the first-line setting. This review describes the current therapeutic opportunities in de novo mHSPC, focusing on potential molecular biomarkers identified in the main clinical trials that have changed the standard of care, the genomic features of de novo mHSPC, and the principal ongoing trials that are investigating new therapeutic approaches and the efficacy of a biomarker-guided treatment in this setting. The road towards a personalized treatment for de novo mHSPC is still long considering that the randomized clinical trials, which have furnished the basis of the current therapeutic options, stratified patients according to clinical criteria that not necessarily reflect the biological rationale of the chosen therapy. The role of transcriptomic profiling of mHSPC as predictive biomarker requires further validation, as well as it remains to ascertain how the genomic alterations detected in mHSPC, that are considered predictive in the castration-resistant disease, can be exploited in the mHSPC setting.

Targeting Key Players of Neuroendocrine Differentiation in Prostate Cancer (preprint)

Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer (PC) that commonly emerges through a transdifferentiation process from prostate adenocarcinoma and evades conventional therapies. Extensive molecular research has revealed factors that drive lineage plasticity, uncovering novel therapeutic targets to be explored. A diverse array of targeting agents is currently under evaluation in pre-clinical and clinical studies with promising results in suppressing or reversing the neuroendocrine phenotype and inhibiting tumor growth and metastasis. This new knowledge has the potential to contribute to development of novel therapeutic approaches that may enhance clinical management and prognosis of this lethal disease.

The Impact of the UK COVID-19 Lockdown on the Screening, Diagnostics and Incidence of Breast, Colorectal, Lung and Prostate Cancer in the UK: a Population-Based Cohort Study (preprint)

Objectives: This study aimed to assess the impact of the COVID-19 lockdown on the screening and diagnosis of breast, colorectal, lung, and prostate cancer. The study also investigated whether the rates returned to pre-pandemic levels by December 2021. Design: Cohort study. Setting: Electronic health records from UK primary care Clinical Practice Research Datalink (CPRD) GOLD database. Participants: The study included individuals registered with CPRD GOLD between January 2017 and December 2021, with at least 365 days of prior observation. Main outcome measures: The study focused on screening, diagnostic tests, referrals and diagnoses of first-ever breast, colorectal, lung, and prostate cancer. Incidence rates (IR) were stratified by age, sex and region, and incidence rate ratios (IRR) were calculated to compare rates during and after lockdown with the reference period before lockdown. Forecasted rates were estimated using negative binomial regression models. Results: Among 5,191,650 eligible participants, the initial lockdown resulted in reduced screening and diagnostic tests for all cancers, which remained dramatically reduced across the whole observation period for almost all tests investigated. For cancer incidence rates, there were significant IRR reductions in breast (0.69), colorectal (0.74), and prostate (0.71) cancers. However, the reduction in lung cancer incidence (0.92) was non-significant. Extrapolating to the entire UK population, an estimated 18,000 breast, 13,000 colorectal, 10,000 lung, and 21,000 prostate cancer diagnoses were missed from March 2020 to December 2021. Conclusion: The national COVID-19 lockdown in the UK had a substantial impact on cancer screening, diagnostic tests, referrals and diagnoses. Although incidence rates started to recover after the lockdown, they remained significantly lower than pre-pandemic levels for breast and prostate cancers and associated tests. Delays in diagnosis are likely to have adverse consequences on cancer stage, treatment initiation, mortality rates, and years of life lost. Urgent strategies are needed to identify undiagnosed cases and address the long-term implications of delayed diagnoses.

Effects of estradiol on fat in men undergoing androgen deprivation therapy: a randomized trial.

OBJECTIVE: Indirect evidence suggests that the effects of testosterone on fat mass in men are dependent on aromatization to estradiol (E2). However, no controlled study has assessed the effects of E2 in the absence of testosterone. DESIGN: Six-month randomized, placebo-controlled trial with the hypothesis that men randomized to E2 would reduce their fat mass. METHODS: Seventy-eight participants receiving androgen deprivation therapy for prostate cancer were randomized to 0.9 mg of 0.1% E2 gel per day, or matched placebo. Dual x-ray absorptiometry body composition was measured at baseline, month 3, and month 6. The primary outcome was total fat mass. RESULTS: Serum E2 increased in the estradiol group over 6 months compared to placebo, and mean-adjusted difference (MAD) was 207 pmol/L (95% CI: 123-292), P < 0.001. E2 treatment changed total fat mass, MAD 1007 g (95% CI: 124-1891), but not significantly, so P = 0.09. There were other consistent non-significant trends toward increased proportional fat mass, MAD 0.8% (95% CI: 0.0-1.6), P= 0.15; gynoid fat, MAD 147 g (95% CI: 2-293), P = 0.08; visceral fat, 53 g (95% CI: 1-105) P = 0.13; and subcutaneous fat, MAD 65 g (95% CI: 5-125), P = 0.11. Android fat increased, MAD 164 g (95% CI: 41-286), P = 0.04. CONCLUSION: Contrary to our hypothesis, we provide suggestive evidence that E2 acting in the absence of testosterone, may increase total and regional fat mass in men. Given the premature closure of clinical trials due to the COVID pandemic, this potentially important observation should encourage additional studies to confirm or refute whether E2 promotes fat expansion in the absence of testosterone.

Implementation of a Telehealth Genetic Testing Station to Deliver Germline Testing for Men With Prostate Cancer.

PURPOSE: Germline testing for men with prostate cancer (PCa) poses numerous implementation barriers. Alternative models of care delivery are emerging, but implementation outcomes are understudied. We evaluated implementation outcomes of a hybrid oncologist- and genetic counselor-delivered model called the genetic testing station (GTS) created to streamline testing and increase access. METHODS: A prospective, single-institution, cohort study of men with PCa referred to the GTS from October 14, 2019, to October 14, 2021, was conducted. Using the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework, we described patients referred to GTS (Reach), the association of GTS with germline testing completion rates within 60 days of a new oncology appointment in a pre- versus post-GTS multivariable logistic regression (Effectiveness), Adoption, Implementation, and Maintenance. Because GTS transitioned from an on-site to remote service during the COVID-19 pandemic, we also compared outcomes for embedded versus remote GTS. RESULTS: Overall, 713 patients were referred to and eligible for GTS, and 592 (83%) patients completed germline testing. Seventy-six (13%) patients had ≥ 1 pathogenic variant. Post-GTS was independently associated with higher odds of completing testing within 60 days than pre-GTS (odds ratio, 8.97; 95% CI, 2.71 to 29.75; P < .001). Black race was independently associated with lower odds of testing completion compared with White race (odds ratio, 0.35; 95% CI, 0.13 to 0.96; P = .042). There was no difference in test completion rates or patient-reported decisional conflict for embedded versus remote GTS. GTS has been adopted by 31 oncology providers across four clinics, and implementation fidelity was high with low patient loss to follow-up, but staffing costs are a sustainability concern. CONCLUSION: GTS is a feasible, effective model for high-volume germline testing in men with PCa, both in person and using telehealth. GTS does not eliminate racial disparities in germline testing access.

Measuring cancer burden in prostatic needle core biopsies: simplified assessments outperform complex measurements in assessing outcome: evidence to assist pathologist efficiency and minimize datasets.

AIMS: The optimal method of measuring cancer extent in prostate cancer (PCa) biopsies is unknown. METHODS AND RESULTS: Nine hundred eighty-one men with clinically localised PCa managed conservatively were reviewed with follow up. The number of positive cores (NPC), the Maximum Cancer Length in a core (MCL), Total Cancer Length (TCL), and percentage of positive cores (%+cores) was calculated and univariate and multivariate analysis performed using prostate-specific antigen (PSA), T-stage, and Gleason score. The presence of stromal gaps (SG) was recorded. Univariate models were run where SG made a difference to the MCL. All variables showed significant association with PCa death in univariate models. In multivariate models, incorporating PSA, T-stage, and Gleason score, only %+cores was a significant predictor of outcome, with a 10% increase in %+cores resulting in a hazard ratio (HR) of 1.07 (likelihood-ratio test P > Χ2  = 0.01). There were 120 patients where SG made a difference to the MCL and a total of 20 events in this group. Including SG, on univariate analysis the median MCL was 10 mm and HR was 1.16 (P = 0.007), not including SG, the median MCL was 6 mm and HR was 1.23 (P = 6.3 × 10-4 ). Inclusion or exclusion of SG made no significant difference to TCL as a predictor of outcome. CONCLUSION: Cancer extent is a strong predictor of PCa death but only %+cores added to the multivariate model. Expressed as a fraction of NPC/total number of cores, this is the simplest method of assessment, which we favour over more complicated methods in nontargeted biopsies.

Nurse-led virtual prostate cancer clinic for survivorship care: Qualitative study of healthcare professional experiences and needs (preprint)

Background: Approximately one in eight Canadian males will be diagnosed with prostate cancer. Longer survivorship horizons and resource constraints are leading to increasing strain on current models of specialist-led follow-up care delivery. Nurse-led digital health innovations can reduce demand on specialists if co-designed with health care professionals (HCPs). Methods: Using human-centred design, the purpose of this exploratory qualitative study with ten HCPs was to characterize their experiences with prostate cancer (PCa) follow-up and virtual care to optimally situate a nurse-led clinic within this ecosystem. Results: HCPs highlight how current follow-up care can be fragmented, so the scope of a nurse-led clinic should focus on the management of care with referral as needed. Despite an ambivalence for telemedicine arising from its implementation during the COVID-19 pandemic, HCPs see potential for improved care through digital health but note several concerns. Burn-out, weakened patient-provider relationships, and creeping scope of responsibilities were identified as pain points. We provide a health ecosystem readiness checklist to improve odds of acceptability, appropriateness, and feasibility synthesized from six HCP-defined facilitators mapped onto Proctor’s outcomes. Facilitators include: functionality testing (acceptability), technical support and usability (adoption), expectation management (appropriateness), resource allocation (cost), staff readiness (feasibility), and staff training (penetration). Conclusion: Intentional and empathetic co-design with HCPs during the development of digital health innovations, such as digital therapeutics, is necessary to ensure that HCPs can benefit from, instead of being burdened from, the rising tide of digital health in their clinical responsibilities.

Home-based exercise improves quality of life in breast and prostate cancer survivors: A meta-analysis.

BACKGROUND: Breast (BCa) and prostate (PCa) cancer are two of the most common but survivable cancers. One important component of survivorship that is impacted by treatment long term is diminished quality of life (QoL). Supervised exercise improves QoL and subsequent outcomes but is not accessible for all survivors. Additionally, many factors influence QoL including physical activity (PA), cardiorespiratory fitness (CRF), physical function, and fatigue. However, the COVID-19 pandemic has highlighted the need to increase access to exercise beyond supervised exercise facilities. Home-based exercise may provide a feasible alternative for cancer survivors especially for those living in rural communities. OBJECTIVES: The primary aim is to investigate the effects of home-based exercise training (Pre-training vs. Post-training) on QoL in BCa/PCa. A secondary aim is to investigate PA, CRF, physical function, and fatigue and potential moderators (age, cancer-type, intervention duration and type). Home-based exercise trials (randomized crossover or quasi-experimental design) with adults (aged 18 years and over) breast or prostate cancer survivors (not currently undergoing chemotherapy or radiation treatment) were eligible for inclusion. DATA SOURCES: Electronic databases were searched (inception-December 2022) for studies which included adult BCa or PCa survivors (not currently on chemotherapy/radiation), at least measured QoL, and undergoing unsupervised, home-based exercise training. APPRAISAL AND SYNTHESIS METHODS: Initially, 819 studies were identified, from which 17 studies (20 effects) involving 692 participants were extracted. Effect sizes were calculated as standardized mean differences (SMD). Data were pooled using a 3-level model with restricted maximum likelihood estimation. Pooled SMD was used to assess the magnitude of effect, where <0.2, 0.2, 0.5, and 0.8 was defined as trivial, small, moderate, and large respectively. RESULTS: Home-based exercise resulted in small improvements in QoL (SMD = 0.30, 95% CI 0.01, 0.60, p = 0.042), PA (SMD = 0.49, 95% CI 0.26, 0.75, p<0.001) and CRF (SMD = 0.45, 95% CI -0.01, 0.91, p = 0.056). Physical function (SMD = 0.00, 95% CI -0.21, 0.21, p = 1.000) and fatigue (SMD = -0.61, 95%CI -1.53, 0.32, p = 0.198) did not change. CONCLUSIONS: Home-based exercise results in small improves QoL in BCa/PCa survivors, independent of cancer type, intervention duration and type, or age. Home-based exercise also improves PA and CRF enhancing survivorship. Therefore, home-based exercise is an efficacious alternative option to improve QoL for BCa and PCa survivors especially for those who live in rural communities or lack access to exercise facilities.

Linitis plastica of the rectum secondary to prostate carcinoma.

Linitis plastica is an intramural carcinoma that may occur in any hollow organ. Rectal linitis plastica (RLP) is a morphological variant cancer that may occur as a primary form of cancer or secondary as a metastasis of a primary malignancy. We report the case of a man in his 70s with RLP secondary to prostate carcinoma who was initially suspected to have an obstructing rectal adenocarcinoma. During colonoscopy a segment of cobblestone mucosa was seen in the distal rectum. Subsequent imaging showed enhancement of all wall-layers of the rectum and diffuse retroperitoneal fat infiltration with traction on both ureters. A prostate-specific membrane antigen scan confirmed RLP secondary to a prostate carcinoma mimicking the clinical and radiological signs of an obstructing rectal carcinoma with retroperitoneal fibrosis.This case emphasises the possible pitfalls in the diagnosis of RLP and the importance of advanced imaging techniques, such as MRI, as well as appropriate histological samples. The patient underwent androgen deprivation therapy to which RLP responded well and neither systemic chemotherapy or surgery was necessary.

ICD-11 adjustment disorder following diagnostic procedures of prostate cancer: A 12-month follow-up study.

OBJECTIVE: The medical procedures in diagnosing or treating prostate cancer may impair adjustment and quality of life. The current prospective study aimed to evaluate the trajectories of symptoms of ICD-11 adjustment disorder in patients diagnosed vs. non-diagnosed with prostate cancer before (T1), after diagnostic procedures (T2), and at 12-month follow-up (3). METHODS: In total, 96 male patients were recruited before prostate cancer diagnostic procedures. The mean age of the study participants at baseline was 63.5 (SD = 8.4), ranging from 47 to 80 years; 64% were diagnosed with prostate cancer. Adjustment disorder symptoms were measured using the Brief Adjustment Disorder Measure (ADNM-8). RESULTS: The prevalence of ICD-11 adjustment disorder was 15% at T1, 13% at T2, and 3% at T3. The effect of cancer diagnosis was not significant on adjustment disorder. A medium main effect for time was detected on adjustment symptom severity, F(2, 134) = 19.26, p < .001, partial η2 = 0.223, with symptoms significantly lower at 12-month follow-up, compared to T1 and T2, p < .001. CONCLUSIONS: The study's findings reveal the increased levels of adjustment difficulties in males undergoing the diagnostic process of prostate cancer.

Impact of COVID-19 pandemic on prostate cancer outcomes at an uro-oncology referral center.

INTRODUCTION: To evaluate the possible effects of the coronavirus disease 2019 (COVID-19) pandemic on the oncologic results of patients with prostate cancer regarding clinical staging, presence of adverse pathological outcomes, and perioperative complications. MATERIALS AND METHODS: This retrospective study included patients who underwent radical prostatectomy. The time between biopsy and surgery, staging tests, final histopathological evaluation after surgery, lymphadenectomy rate, postoperative complications, and prostatic specific antigen (PSA) levels (initial and 30 days after surgery) were analyzed and compared in a group of patients before and during the pandemic period. RESULTS: We included 226 patients: 88 in the pre-pandemic period and 138 during the pandemic period. There was no statistically significant difference in mean age, body mass index, ASA, pathological locally advanced disease, the proportion of patients who underwent lymphadenectomy, and ISUP grade in the biopsy between the groups. Positive surgical margins, prostatic extracapsular extension, and PSA levels at 30 days were also similar between the groups. The mean time between medical consultation and surgery was longer in the pandemic period than in the pre-pandemic (124 vs. 107 days, p<0.001), and the mean time between biopsy and medical consultation (69.5 days vs. 114 days, p<0.001) and between biopsy and surgery (198.5 days vs. 228 days, p=0.013) was shorter during the pandemic. The incidence of severe early and late perioperative complications was similar between the periods. CONCLUSIONS: There was no delay between diagnosis and treatment at our institution during the COVID-19 pandemic period. No worsening of the prostate cancer features was observed.

Cancer stage and time from cancer diagnosis to first treatment during the COVID-19 pandemic.

The 2019 coronavirus disease (COVID-19) pandemic has impacted cancer care and the diagnosis of new cases of cancer. We analyzed the impact of the COVID-19 pandemic on patients with cancer by comparing the number of newly diagnosed cases, cancer stage, and time to treatment in 2020 with those in 2018, 2019, and 2021. A retrospective cohort of all cancer cases treated at A.C. Camargo Cancer Center in 2018-2021, identified from the Hospital Cancer Registry, was studied. We analyzed single and multiple primary cancer case and patient characteristics-by year and by clinical stage (early v advanced). Times from diagnosis to treatment were compared according to the most frequent tumor sites between 2020 and the other study years. Between 2018 and 2021, a total of 29,796 new cases were treated at the center including 24,891 with a single tumor and 4,905 with multiple tumors, including nonmelanoma skin cancer. The number of new cases decreased by 25% between 2018 and 2020 and 22% between 2019 and 2020, followed by an increase of about 22% in 2021. Clinical stages differed across years, with the number of new advanced cases decreasing from 17.8% in 2018 to 15.2% in 2020. Diagnoses of advanced-stage for lung and kidney cancer decreased between 2018 and 2020, while the number of thyroid and prostate cancer cases diagnosed in advanced-stages increased from 2019 to 2020. The time from diagnosis to treatment decreased between 2018 and 2020 for breast (55.5 v 48 days), prostate (87 v 64 days), cervical/uterine (78 v 55 days) and oropharyngeal (50 v 28 days) cancers. The COVID-19 pandemic affected the numbers of single and multiple cancers diagnosed in 2020. An increase in the number of advanced-stage cases diagnosed was observed only for thyroid and prostate cancer. This pattern may change in coming years due to the possibility that a significant number of cases went undiagnosed in 2020.

Evaluation of Trends in Treatment of Metastatic Hormone Sensitive Prostate Cancer (mHSPC) Across Canada During the COVID-19 Pandemic.

BACKGROUND: In metastatic hormone sensitive prostate cancer (mHSPC), treatment intensification with either docetaxel or an androgen-receptor-axis targeted therapy (ARAT), added to androgen deprivation therapy (ADT) is the new standard of care. To better understand patterns of treatment intensification in Canada and specifically how it has been influenced by the COVID-19 pandemic, we conducted a national survey of genitourinary medical oncologists from across Canada. METHODS: Using SurveyMonkey, we conducted an online survey of 119 medical oncologists in Canada from January 15 to January 27, 2021. The survey consisted of 16 questions, including demographics, and asked specifically about their approach to managing mHSPC before and during the pandemic. RESULTS: Overall there were 50/119 (42%) respondents. Most were male (65%), from Ontario (35%), practicing in academic centers (71%), with 45% reporting their practices focused primarily on genitourinary malignancies and one other tumor site. The majority were in practice 1 to 5 years (34%). Overall 65% indicated their practice patterns had changed since the pandemic, with 51% offering more ARATs and less docetaxel chemotherapy. In low volume mHSPC, the use of ARATs increased from 73% to 79%, while the use of docetaxel remained unaltered at 2%. In high volume disease, the use of ARATs increased from 63% to 84%, while the use of docetaxel decreased from 37% to 14%. Use of granulocyte colony stimulating factor (G-CSF) with docetaxel chemotherapy increased by 35%. Post-pandemic, 45% reported they intend to maintain these changes. Only 18% reported they had prostate cancer patients test positive for COVID-19, and all patients recovered. CONCLUSION: Management of patients with mHSPC in Canada has changed during the pandemic, with increased uptake of ARATs and reduced use of docetaxel, a trend expected to continue beyond the pandemic. How this trend will impact uptake of triplet therapy (ADT + ARAT + Docetaxel), downstream treatment choices and overall outcomes remains to be seen.

18F-Fluciclovine-Avid Axillary Lymph Nodes After COVID-19 Vaccination on PET/CT for Suspected Recurrence of Prostate Cancer.

Abnormally increased 18F-FDG avidity of axillary lymph nodes has become a frequent diagnostic dilemma on PET/CT in the current climate of global vaccinations directed against severe acute respiratory syndrome coronavirus 2. This avidity is due to the inflammatory response evoked by vaccines and the nonspecific nature of 18F-FDG uptake, which is increased in both malignant and inflammatory processes. Similarly, 18F-fluciclovine, an amino acid analog indicated for the assessment of biochemical recurrence of prostate cancer, may also demonstrate nonspecific inflammatory uptake. We report a case of 18F-fluciclovine PET/CT obtained for concern about prostate cancer. In this case, isolated avid lymph nodes were seen in the left axilla. A screening questionnaire revealed that the patient had recently received the second dose of the Pfizer-BioNTech coronavirus disease 2019 vaccine in his left shoulder, and hence, the uptake was determined to be reactive.