Deep learning-based whole-body PSMA PET/CT attenuation correction utilizing Pix-2-Pix GAN.

PURPOSE: Sequential PET/CT studies oncology patients can undergo during their treatment follow-up course is limited by radiation dosage. We propose an artificial intelligence (AI) tool to produce attenuation-corrected PET (AC-PET) images from non-attenuation-corrected PET (NAC-PET) images to reduce need for low-dose CT scans. METHODS: A deep learning algorithm based on 2D Pix-2-Pix generative adversarial network (GAN) architecture was developed from paired AC-PET and NAC-PET images. 18F-DCFPyL PSMA PET-CT studies from 302 prostate cancer patients, split into training, validation, and testing cohorts (n = 183, 60, 59, respectively). Models were trained with two normalization strategies: Standard Uptake Value (SUV)-based and SUV-Nyul-based. Scan-level performance was evaluated by normalized mean square error (NMSE), mean absolute error (MAE), structural similarity index (SSIM), and peak signal-to-noise ratio (PSNR). Lesion-level analysis was performed in regions-of-interest prospectively from nuclear medicine physicians. SUV metrics were evaluated using intraclass correlation coefficient (ICC), repeatability coefficient (RC), and linear mixed-effects modeling. RESULTS: Median NMSE, MAE, SSIM, and PSNR were 13.26%, 3.59%, 0.891, and 26.82, respectively, in the independent test cohort. ICC for SUVmax and SUVmean were 0.88 and 0.89, which indicated a high correlation between original and AI-generated quantitative imaging markers. Lesion location, density (Hounsfield units), and lesion uptake were all shown to impact relative error in generated SUV metrics (all p < 0.05). CONCLUSION: The Pix-2-Pix GAN model for generating AC-PET demonstrates SUV metrics that highly correlate with original images. AI-generated PET images show clinical potential for reducing the need for CT scans for attenuation correction while preserving quantitative markers and image quality.

Stem cell dynamics and cellular heterogeneity across lineage subtypes of castrate resistant prostate cancer.

To resist lineage-dependent therapies such as androgen receptor inhibition, prostate luminal epithelial adenocarcinoma cells often adopt a stem-like state resulting in lineage-plasticity and phenotypic heterogeneity. Castrate resistant prostate adenocarcinoma can transition to neuroendocrine and occasionally to amphicrine, co-expressed luminal and neuroendocrine, phenotypes. We developed CRPC patient-derived organoid models that preserve heterogeneity of the originating tumor, including an amphicrine model displaying a range of luminal and neuroendocrine phenotypes. To gain biological insight and to identify potential treatment targets within heterogeneous tumor cell populations, we assessed the lineage hierarchy and molecular characteristics of various CRPC tumor subpopulations. Transcriptionally similar stem/progenitor cells were identified for all lineage populations. Lineage tracing in amphicrine CRPC showed that heterogeneity originated from distinct subclones of infrequent stem/progenitor cells that produced mainly quiescent differentiated amphicrine progeny. By contrast, adenocarcinoma CRPC progeny originated from stem/progenitor cells and self-renewing differentiated luminal cells. NEPC was composed almost exclusively of self-renewing stem/progenitor cells. Amphicrine subpopulations were enriched for secretory luminal, mesenchymal, and enzalutamide treatment persistent signatures that characterize clinical progression. Finally, the amphicrine stem/progenitor subpopulation was specifically depleted with an AURKA inhibitor, which blocked tumor growth. These data illuminate distinct stem cell characteristics for subtype-specific CRPC in addition to demonstrating a context for targeting differentiation-competent prostate stem cells.

Localized high-risk prostate cancer harbors an androgen receptor low subpopulation susceptible to HER2 inhibition.

Patients diagnosed with localized high-risk prostate cancer have higher rates of recurrence, and the introduction of neoadjuvant intensive hormonal therapies seeks to treat occult micrometastatic disease by their addition to definitive treatment. Sufficient profiling of baseline disease has remained a challenge in enabling the in-depth assessment of phenotypes associated with exceptional vs. poor pathologic responses after treatment. In this study, we report comprehensive and integrative gene expression profiling of 37 locally advanced prostate tumors prior to six months of androgen deprivation therapy (ADT) plus the androgen receptor (AR) inhibitor enzalutamide prior to radical prostatectomy. A robust transcriptional program associated with HER2 activity was positively associated with poor outcome and opposed AR activity, even after adjusting for common genomic alterations in prostate cancer including PTEN loss and expression of the TMPRSS2:ERG fusion. Patients experiencing exceptional pathologic responses demonstrated lower levels of HER2 and phospho-HER2 by immunohistochemistry of biopsy tissues. The inverse correlation of AR and HER2 activity was found to be a universal feature of all aggressive prostate tumors, validated by transcriptional profiling an external cohort of 121 patients and immunostaining of tumors from 84 additional patients. Importantly, the AR activity-low, HER2 activity-high cells that resist ADT are a pre-existing subset of cells that can be targeted by HER2 inhibition alone or in combination with enzalutamide. In summary, we show that prostate tumors adopt an AR activity-low prior to antiandrogen exposure that can be exploited by treatment with HER2 inhibitors.

Deep Learning-Based Detection and Classification of Bone Lesions on Staging Computed Tomography in Prostate Cancer: A Development Study.

RATIONALE AND OBJECTIVES: Efficiently detecting and characterizing metastatic bone lesions on staging CT is crucial for prostate cancer (PCa) care. However, it demands significant expert time and additional imaging such as PET/CT. We aimed to develop an ensemble of two automated deep learning AI models for 1) bone lesion detection and segmentation and 2) benign vs. metastatic lesion classification on staging CTs and to compare its performance with radiologists. MATERIALS AND METHODS: This retrospective study developed two AI models using 297 staging CT scans (81 metastatic) with 4601 benign and 1911 metastatic lesions in PCa patients. Metastases were validated by follow-up scans, bone biopsy, or PET/CT. Segmentation AI (3DAISeg) was developed using the lesion contours delineated by a radiologist. 3DAISeg performance was evaluated with the Dice similarity coefficient, and classification AI (3DAIClass) performance on AI and radiologist contours was assessed with F1-score and accuracy. Training/validation/testing data partitions of 70:15:15 were used. A multi-reader study was performed with two junior and two senior radiologists within a subset of the testing dataset (n = 36). RESULTS: In 45 unseen staging CT scans (12 metastatic PCa) with 669 benign and 364 metastatic lesions, 3DAISeg detected 73.1% of metastatic (266/364) and 72.4% of benign lesions (484/669). Each scan averaged 12 extra segmentations (range: 1-31). All metastatic scans had at least one detected metastatic lesion, achieving a 100% patient-level detection. The mean Dice score for 3DAISeg was 0.53 (median: 0.59, range: 0-0.87). The F1 for 3DAIClass was 94.8% (radiologist contours) and 92.4% (3DAISeg contours), with a median false positive of 0 (range: 0-3). Using radiologist contours, 3DAIClass had PPV and NPV rates comparable to junior and senior radiologists: PPV (semi-automated approach AI 40.0% vs. Juniors 32.0% vs. Seniors 50.0%) and NPV (AI 96.2% vs. Juniors 95.7% vs. Seniors 91.9%). When using 3DAISeg, 3DAIClass mimicked junior radiologists in PPV (pure-AI 20.0% vs. Juniors 32.0% vs. Seniors 50.0%) but surpassed seniors in NPV (pure-AI 93.8% vs. Juniors 95.7% vs. Seniors 91.9%). CONCLUSION: Our lesion detection and classification AI model performs on par with junior and senior radiologists in discerning benign and metastatic lesions on staging CTs obtained for PCa.

American Cancer Society's report on the status of cancer disparities in the United States, 2023.

In 2021, the American Cancer Society published its first biennial report on the status of cancer disparities in the United States. In this second report, the authors provide updated data on racial, ethnic, socioeconomic (educational attainment as a marker), and geographic (metropolitan status) disparities in cancer occurrence and outcomes and contributing factors to these disparities in the country. The authors also review programs that have reduced cancer disparities and provide policy recommendations to further mitigate these inequalities. There are substantial variations in risk factors, stage at diagnosis, receipt of care, survival, and mortality for many cancers by race/ethnicity, educational attainment, and metropolitan status. During 2016 through 2020, Black and American Indian/Alaska Native people continued to bear a disproportionately higher burden of cancer deaths, both overall and from major cancers. By educational attainment, overall cancer mortality rates were about 1.6-2.8 times higher in individuals with ≤12 years of education than in those with ≥16 years of education among Black and White men and women. These disparities by educational attainment within each race were considerably larger than the Black-White disparities in overall cancer mortality within each educational attainment, ranging from 1.03 to 1.5 times higher among Black people, suggesting a major role for socioeconomic status disparities in racial disparities in cancer mortality given the disproportionally larger representation of Black people in lower socioeconomic status groups. Of note, the largest Black-White disparities in overall cancer mortality were among those who had ≥16 years of education. By area of residence, mortality from all cancer and from leading causes of cancer death were substantially higher in nonmetropolitan areas than in large metropolitan areas. For colorectal cancer, for example, mortality rates in nonmetropolitan areas versus large metropolitan areas were 23% higher among males and 21% higher among females. By age group, the racial and geographic disparities in cancer mortality were greater among individuals younger than 65 years than among those aged 65 years and older. Many of the observed racial, socioeconomic, and geographic disparities in cancer mortality align with disparities in exposure to risk factors and access to cancer prevention, early detection, and treatment, which are largely rooted in fundamental inequities in social determinants of health. Equitable policies at all levels of government, broad interdisciplinary engagement to address these inequities, and equitable implementation of evidence-based interventions, such as increasing health insurance coverage, are needed to reduce cancer disparities.

Screening for lung cancer: 2023 guideline update from the American Cancer Society.

Lung cancer is the leading cause of mortality and person-years of life lost from cancer among US men and women. Early detection has been shown to be associated with reduced lung cancer mortality. Our objective was to update the American Cancer Society (ACS) 2013 lung cancer screening (LCS) guideline for adults at high risk for lung cancer. The guideline is intended to provide guidance for screening to health care providers and their patients who are at high risk for lung cancer due to a history of smoking. The ACS Guideline Development Group (GDG) utilized a systematic review of the LCS literature commissioned for the US Preventive Services Task Force 2021 LCS recommendation update; a second systematic review of lung cancer risk associated with years since quitting smoking (YSQ); literature published since 2021; two Cancer Intervention and Surveillance Modeling Network-validated lung cancer models to assess the benefits and harms of screening; an epidemiologic and modeling analysis examining the effect of YSQ and aging on lung cancer risk; and an updated analysis of benefit-to-radiation-risk ratios from LCS and follow-up examinations. The GDG also examined disease burden data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Formulation of recommendations was based on the quality of the evidence and judgment (incorporating values and preferences) about the balance of benefits and harms. The GDG judged that the overall evidence was moderate and sufficient to support a strong recommendation for screening individuals who meet the eligibility criteria. LCS in men and women aged 50-80 years is associated with a reduction in lung cancer deaths across a range of study designs, and inferential evidence supports LCS for men and women older than 80 years who are in good health. The ACS recommends annual LCS with low-dose computed tomography for asymptomatic individuals aged 50-80 years who currently smoke or formerly smoked and have a ≥20 pack-year smoking history (strong recommendation, moderate quality of evidence). Before the decision is made to initiate LCS, individuals should engage in a shared decision-making discussion with a qualified health professional. For individuals who formerly smoked, the number of YSQ is not an eligibility criterion to begin or to stop screening. Individuals who currently smoke should receive counseling to quit and be connected to cessation resources. Individuals with comorbid conditions that substantially limit life expectancy should not be screened. These recommendations should be considered by health care providers and adults at high risk for lung cancer in discussions about LCS. If fully implemented, these recommendations have a high likelihood of significantly reducing death and suffering from lung cancer in the United States.

Health diplomacy in action: The cancer legacy of the Good Friday Agreement.

2023 marks the 25th anniversary of the Good Friday Agreement, which led peace in Northern Ireland. As well as its impact on peace and reconciliation, the Good Friday Agreement has also had a lasting positive impact on cancer research and cancer care across the island of Ireland. Pursuant to the Good Friday Agreement, a Memorandum of Understanding (MOU) was signed between the respective Departments of Health in Ireland, Northern Ireland and the US National Cancer Institute (NCI), giving rise to the Ireland - Northern Ireland - National Cancer Institute Cancer Consortium, an unparalleled tripartite agreement designed to nurture and develop linkages between cancer researchers, physicians and allied healthcare professionals across Ireland, Northern Ireland and the US, delivering world class research and better care for cancer patients on the island of Ireland and driving research and innovation in the US.

Quantitative Analysis of Serial Positron Emission Tomography Imaging in Men with Metastatic Castration-resistant Prostate Cancer Treated with Enzalutamide.

BACKGROUND: The emergence of positron emission tomography (PET) in prostate cancer is impacting clinical practice, but little is known about PET imaging as a tool to determine treatment failure in metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE: To evaluate PET imaging dynamics in mCRPC patients on enzalutamide with stable computed tomography (CT) and technetium-99m (Tc99) bone scans. DESIGN, SETTING, AND PARTICIPANTS: All patients were on treatment with enzalutamide for first-line mCRPC in a clinical trial at the National Cancer Institute (Bethesda, MD, USA). A volunteer sample had serial 18F-sodium fluoride (NaF) PET in parallel with CT and Tc99. Regions of interest (ROIs) on NaF were analyzed quantitatively for response. INTERVENTION: Patients were randomized to enzalutamide with/without a cancer immunotherapy, Prostvac. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A post hoc, descriptive analysis was performed comparing the changes seen on CT and Tc99 as per RECIST 1.1 with NaF PET scans including the use of a quantitative analysis. RESULTS AND LIMITATIONS: Eighteen mCRPC patients had 67 NaF scans. A total of 233 ROIs resolved after treatment, 52 (22%) of which eventually retuned while on therapy. In all, 394 new ROIs were seen, but 112(28%) resolved subsequently. Of 18 patients, 14 had new ROIs that ultimately resolved after appearing. Many patients experienced progression in a minority of lesions, and one patient with radiation intervention to oligoprogression had a remarkable response. This study is limited by its small number of patients and post hoc nature. CONCLUSIONS: These data highlight the dynamic nature of NaF PET in mCRPC patients treated with enzalutamide, where not all new findings were ultimately related to disease progression. This analysis also provides a potential strategy to identify and intervene in oligoprogression in prostate cancer. PATIENT SUMMARY: In this small analysis of patients with prostate cancer on enzalutamide, changes on 18F-sodium fluoride positron emission tomography (PET) imaging were not always associated with treatment failure. Caution may be indicated when using PET imaging to determine whether new therapy is needed.

A tripartite approach toward ending cancer as we know it, for everyone: An American Cancer Society perspective.

Gaps in the cancer care continuum are vast, both in the United States and globally. The American Cancer Society orchestrates an integrated, tripartite approach toward improving the lives of cancer patients and their families through research, advocacy, and patient support. With a focus on eradicating cancer disparities, the American Cancer Society aims to scale and deploy best practices worldwide through partnerships, to ensure everyone has an opportunity to prevent, detect, treat, and survive cancer.

Flutamide With or Without PROSTVAC in Non-metastatic Castration Resistant (M0) Prostate Cancer.

BACKGROUND: Before 2018, there was no standard of care for non-metastatic (M0) castration resistant prostate cancer nmCRPC. Androgen receptor antagonists (ARAs) were commonly used sequentially nmCRPC. METHODS: This was a multicenter, randomized clinical trial comparing the ARA flutamide+/-PROSTVAC, a pox viral vaccine targeting PSA that includes T-cell co-stimulatory molecules. Eligible men had negative CT and Tc99 bone scans, and rising PSA on ADT. Previous treatment with ARA was a stratification factor. Patients were also evaluated for antigen-specific immune responses using intracellular cytokine staining. RESULTS: Thirty-three patients randomized to flutamide and 31 to flutamide+vaccine. The median age was 71.8 and 69.8 years, respectively. The median time to treatment failure after a median potential follow-up of 46.7 months was, 4.5 months (range 2-70) for flutamide alone vs. 6.9 months (2.5-40; P = .38) with flutamide+vaccine. Seven patients in each arm had a >50% PSA response. Antigen-specific responses were similar in both arms (58% of patients in flutamide alone and 56% in flutamide+vaccine). The treatments were well tolerated. The most common side effect > grade 2 was injection site reaction seen in 29/31 vaccine patients which were self-limiting. CONCLUSION: The combination of flutamide+PROSTVAC did not improve outcomes in men with nmCRPC compared with flutamide alone. (ClinicalTrials.gov Identifier: NCT00450463).

Avelumab in Men With Metastatic Castration-Resistant Prostate Cancer, Enriched for Patients Treated Previously With a Therapeutic Cancer Vaccine.

Therapeutic cancer vaccines including sipuleucel- T , a prostatic acid phosphatase (PAP) targeted vaccine that improves survival in metastatic castration-resistant prostate cancer (mCRPC), can produce immune responses that translate to clinical benefit. The effects of sequential checkpoint inhibitors after therapeutic vaccine on immune responses are unknown. Avelumab is an anti-programmed death ligand-1 monoclonal antibody evaluated in patients with mCRPC in the JAVELIN solid tumor phase 1 trial expansion cohort, enriched for patients with a previous therapeutic prostate cancer-targeted vaccine. mCRPC patients received intravenous avelumab 10 mg/kg every 2 weeks with imaging every 6 weeks. Peripheral blood T-cell responses to PAP and to PA2024, the peptide containing PAP utilized by the vaccine, were evaluated pre and posttreatment. Eighteen patients enrolled, and previous treatments included abiraterone or enzalutamide in 14 (78%), therapeutic cancer vaccine in 14 (78%), and chemotherapy in 4 (22%). Avelumab had a manageable safety profile. There were no sustained prostate specific antigen decreases. Of 17 patients evaluable for best overall response by RECISTv1.1, 12 had stable disease (SD) and 5 had progressive disease. Seven patients had SD for >24 weeks posttreatment. Fourteen patients had previously received therapeutic cancer vaccines. Eleven (79%) had SD as the best overall response. Of these 14 patients, 9 had previously received sipuleucel T . Analysis of antigen-specific T-cell responses pre and postavelumab treatment did not demonstrate changes in interferon-γ production or proliferation in response to PAP or PA2024. This unplanned analysis does not support the use of sequential therapeutic cancer vaccine therapy followed by programmed death ligand-1 inhibition in mCRPC.

A Phase 2, Double-blind, Randomized Controlled Trial of PROSTVAC in Prostate Cancer Patients on Active Surveillance.

BACKGROUND: There is an unmet clinical need for interventions to prevent disease progression in patients with localized prostate cancer on active surveillance (AS). OBJECTIVE: To determine the immunologic response to the PROSTVAC vaccine and the clinical indicators of disease progression in patients with localized prostate cancer on AS. DESIGN, SETTING, AND PARTICIPANTS: This was a phase 2, double-blind, randomized controlled trial in 154 men with low- or intermediate-risk prostate cancer on AS. INTERVENTION: Participants were randomized (2:1) to receive seven doses of subcutaneous PROSTVAC, a vaccinia/fowlpox viral vector-based immunotherapy containing a prostate-specific antigen (PSA) transgene and three T-cell co-stimulatory molecules, or an empty fowlpox vector (EV) over 140 d. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the change from baseline in CD4 and CD8 T-cell infiltration in biopsy tumor tissue. Key secondary outcomes were safety and changes in prostate biopsy tumor pathology, peripheral antigen-specific T cells, and serum PSA. Continuous variables were compared using nonparametric tests. Categorical variables were compared using Fisher's exact test. RESULTS AND LIMITATIONS: The PROSTVAC/EV vaccination was well tolerated. All except one participant completed the vaccination series. Changes in CD4 or CD8 density in biopsy tumor tissue did not differ between the PROSTVAC and EV arms. The proportions of patients with Gleason upgrading to grade group 3 after treatment was similar between the arms. There were no differences in postvaccination peripheral T-cell responses or the PSA change from baseline to 6-mo post-treatment follow-up between the groups. CONCLUSIONS: In this first-of-kind trial of immunotherapy in patients on AS for prostate cancer, PROSTVAC did not elicit more favorable prostate tissue or peripheral T-cell responses than the EV. There was no difference between the arms in clinicopathologic effects. Despite the null findings, this is the first study reporting the feasibility and acceptability of an immunotherapy intervention in the AS setting. PATIENT SUMMARY: We looked at responses after an experimental prostate cancer vaccine in patients with prostate cancer on active surveillance (AS). Participants who received the vaccine did not show more favorable outcomes than those receiving the control. Despite these findings, this is the first report showing the feasibility and acceptability of immunotherapy for prostate cancer in patients on AS.

Clinically oriented prediction of patient response to targeted and immunotherapies from the tumor transcriptome.

BACKGROUND: Precision oncology is gradually advancing into mainstream clinical practice, demonstrating significant survival benefits. However, eligibility and response rates remain limited in many cases, calling for better predictive biomarkers. METHODS: We present ENLIGHT, a transcriptomics-based computational approach that identifies clinically relevant genetic interactions and uses them to predict a patient's response to a variety of therapies in multiple cancer types without training on previous treatment response data. We study ENLIGHT in two translationally oriented scenarios: personalized oncology (PO), aimed at prioritizing treatments for a single patient, and clinical trial design (CTD), selecting the most likely responders in a patient cohort. FINDINGS: Evaluating ENLIGHT's performance on 21 blinded clinical trial datasets in the PO setting, we show that it can effectively predict a patient's treatment response across multiple therapies and cancer types. Its prediction accuracy is better than previously published transcriptomics-based signatures and is comparable with that of supervised predictors developed for specific indications and drugs. In combination with the interferon-γ signature, ENLIGHT achieves an odds ratio larger than 4 in predicting response to immune checkpoint therapy. In the CTD scenario, ENLIGHT can potentially enhance clinical trial success for immunotherapies and other monoclonal antibodies by excluding non-responders while overall achieving more than 90% of the response rate attainable under an optimal exclusion strategy. CONCLUSIONS: ENLIGHT demonstrably enhances the ability to predict therapeutic response across multiple cancer types from the bulk tumor transcriptome. FUNDING: This research was supported in part by the Intramural Research Program, NIH and by the Israeli Innovation Authority.

Disparities and Trends in Genitourinary Cancer Incidence and Mortality in the USA.

BACKGROUND: Previous studies have reported on incidence and mortality patterns for individual genitourinary cancers in the USA. However, these studies addressed individual cancer types rather than genitourinary cancers overall. OBJECTIVE: To comprehensively examine disparities and trends in the incidence and mortality for the four major genitourinary cancers (bladder, kidney, prostate, and testis) in the USA. DESIGN, SETTING, AND PARTICIPANTS: We obtained incidence data from the National Cancer Institute 22-registry Surveillance, Epidemiology and End Results (SEER) database and the US Cancer Statistics database (Centers for Disease Control and Prevention) and mortality data from the National Center for Health Statistics to examine cross-sectional and temporal trends in incidence and death rates stratified by sex, race/ethnicity, and county. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Age-adjusted incidence and death rates were calculated using SEER*Stat software. Temporal trends were analyzed using Joinpoint regression for a two-sided significance level of p < 0.05. RESULTS AND LIMITATIONS: Incidence and mortality rates for bladder and kidney cancers were two to four times higher for men than for women. Among non-Hispanic White individuals, the highest incidence rates were found in the Northeast for bladder cancer and in Appalachia for kidney cancer, whereas the highest death rates for prostate cancer were found in the West. Incidence rates increased for cancers of the kidney and testis and for advanced-stage prostate cancer in almost all racial/ethnic populations and for bladder cancer in the American Indian/Alaska Native population. Death rates increased for testicular cancer in the Hispanic population and stabilized for prostate cancer among White and Asian American/Pacific Islander men after a steady decline since the early 1990s. Study limitations include misclassification of race/ethnicity on medical records and death certificates. CONCLUSIONS: We found persistent sociodemographic disparities and unfavorable trends in incidence or mortality for all four major genitourinary cancers. Future studies should elucidate the reasons for these patterns. PATIENT SUMMARY: In the USA, rates of cancer cases are increasing for kidney, testis, and advanced-stage prostate cancers in the overall population, and for bladder cancer in the American Indian/Alaska Native population. Differences in the rates by sex and race/ethnicity remain.

Predicting Outcomes of Indeterminate Bone Lesions on 18F-DCFPyL PSMA PET/CT Scans in the Setting of High-Risk Primary or Recurrent Prostate Cancer.

Indeterminate bone lesions (IBLs) on prostate-specific membrane antigen (PSMA) PET/CT are common. This study aimed to define variables that predict whether such lesions are likely malignant or benign using features on PSMA PET/CT. Methods: 18F-DCFPyL PET/CT imaging was performed on 243 consecutive patients with high-risk primary or biochemically recurrent prostate cancer. IBLs identified on PSMA PET/CT could not definitively be interpreted as benign or malignant. Medical records of patients with IBLs were reviewed to determine the ultimate status of each lesion. IBLs were deemed malignant or benign on the basis of evidence of progression or stability at follow-up, respectively, or by biopsy results; IBLs were deemed equivocal when insufficient or unclear evidence existed. Post hoc patient, lesion, and scan variables accounting for clustered data were evaluated using Wilcoxon rank-sum and χ2 tests to determine features that favored benign or malignant interpretation. Results: Overall, 98 IBLs within 267 bone lesions (36.7%) were identified in 48 of 243 patients (19.8%). Thirty-seven of 98 IBLs were deemed benign, and 42 were deemed malignant, of which 8 had histologic verification; 19 remained equivocal. Location and SUVmax categorical variables were predictive of IBL interpretation (P = 0.0201 and P = 0.0230, respectively). For IBLs with new interpretations, 34 of 37 (91.9%) considered benign showed an SUVmax of less than 5 or exhibited focal uptake without coexisting bone metastases; 37 of 42 (88.1%) deemed malignant demonstrated an SUVmax of at least 5 or were present with coexisting bone metastases. Logistic regression predicted IBLs with a high SUVmax (univariable: odds ratio [OR], 9.29 [P = 0.0016]; multivariable: OR, 13.87 [P = 0.0089]) or present with other bone metastases (univariable: OR, 9.87 [P = 0.0112]; multivariable: OR, 11.35 [P = 0.003]) to be malignant. Conclusion: IBLs on PSMA PET/CT are concerning; however, characterizing their location, SUV, and additional scan findings can aid interpretation. IBLs displaying an SUVmax of at least 5 or present with other bone metastases favor malignancy. IBLs without accompanying bone metastases that exhibit an SUVmax of less than 5 and are observed only in atypical locations favor benign processes. These guidelines may assist in the interpretation of IBLs on PSMA PET/CT.

Assessment of Androgen Receptor Splice Variant-7 as a Biomarker of Clinical Response in Castration-Sensitive Prostate Cancer.

PURPOSE: Therapies targeting the androgen receptor (AR) have improved the outcome for patients with castration-sensitive prostate cancer (CSPC). Expression of the constitutively active AR splice variant-7 (AR-V7) has shown clinical utility as a predictive biomarker of AR-targeted therapy resistance in castration-resistant prostate cancer (CRPC), but its importance in CSPC remains understudied. EXPERIMENTAL DESIGN: We assessed different approaches to quantify AR-V7 mRNA and protein in prostate cancer cell lines, patient-derived xenograft (PDX) models, publicly available cohorts, and independent institutional clinical cohorts, to identify reliable approaches for detecting AR-V7 mRNA and protein and its association with clinical outcome. RESULTS: In CSPC and CRPC cohorts, AR-V7 mRNA was much less abundant when detected using reads across splice boundaries than when considering isoform-specific exonic reads. The RM7 AR-V7 antibody had increased sensitivity and specificity for AR-V7 protein detection by immunohistochemistry (IHC) in CRPC cohorts but rarely identified AR-V7 protein reactivity in CSPC cohorts, when compared with the EPR15656 AR-V7 antibody. Using multiple CRPC PDX models, we demonstrated that AR-V7 expression was exquisitely sensitive to hormonal manipulation. In CSPC institutional cohorts, AR-V7 protein quantification by either assay was associated neither with time to development of castration resistance nor with overall survival, and intense neoadjuvant androgen-deprivation therapy did not lead to significant AR-V7 mRNA or staining following treatment. Neither pre- nor posttreatment AR-V7 levels were associated with volumes of residual disease after therapy. CONCLUSIONS: This study demonstrates that further analytical validation and clinical qualification are required before AR-V7 can be considered for clinical use in CSPC as a predictive biomarker.

A Single-arm Phase II Study Combining NLG207, a Nanoparticle Camptothecin, with Enzalutamide in Advanced Metastatic Castration-resistant Prostate Cancer Post-Enzalutamide.

BACKGROUND: Despite the clinical efficacy of enzalutamide monotherapy in patients with advanced prostate cancer, therapeutic resistance and disease progression are inevitable. We proposed a study to evaluate NLG207, a nanoparticle-drug conjugate (NDC) of the potent topoisomerase I inhibitor camptothecin, in combination with enzalutamide, in patients with metastatic castration-resistant prostate cancer (mCRPC) following progression on enzalutamide. METHODS: This was a single-arm, optimal two-stage, phase II study to evaluate the efficacy of NLG207 in combination with enzalutamide in patients with mCRPC who received prior enzalutamide. A lead-in dose escalation evaluated the recommended phase 2 dose of NLG207 in combination with enzalutamide. Patients received NLG207 via IV infusion every 2 weeks and enzalutamide 160 mg orally once daily. RESULTS: Between March 2019 and June 2021, four patients were accrued to the lead-in dose escalation. Two of the four patients were evaluable and both experienced DLTs at the NLG207 12 mg/m2 dose level; one DLT was related to a dose delay for noninfective cystitis and myelosuppression, the other a grade 3 noninfective cystitis. Further evaluation of NLG207 in combination with enzalutamide was halted and the study was ultimately terminated. PSA declines from baseline were observed in two patients. CONCLUSION: NLG207 12 mg/m2 in combination with enzalutamide was not well tolerated in patients with mCRPC following several lines of the standard of care therapy. CLINICALTRIALS.GOV IDENTIFIER: NCT03531827.

Assessment of Aortoiliac Atherosclerotic Plaque on CT in Prostate Cancer Patients Undergoing Treatment.

Traditionally, atherosclerotic risk factors for cardiovascular disease and cancer are assessed using coronary artery calcium scoring. However, this neglects the impact of atherosclerotic disease more proximal to the cancer site. This study assesses whether aortoiliac atherosclerotic plaque is associated with prostate cancer. The dataset consisted of abdominopelvic CT of 93 patients with prostate cancer and 186 asymptomatic patients who underwent CT colonography as an age- and gender-matched control group. Agatston scores were measured in the abdominal aorta, common iliac, and internal iliac arteries. The scores were evaluated for associations with age, Framingham risk score, and prostate cancer-related biomarkers, including prostate-specific antigen, Gleason score, tumor location, prostatectomy, androgen deprivation therapy, mortality, and bone metastasis. The atherosclerotic plaque of prostate cancer patients did not differ from the control group (p = 0.22) and was not correlated with any of the prostate cancer-related biomarkers (p > 0.05). However, Agatston scores of abdominal plaques correlated well with age (p < 0.001) and Framingham risk scores (p = 0.002).