bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence of other multiple primary malignancies in patients with adrenocortical carcinoma.
Authors: Koshiya Hiren , Pandav Vivek , Mosalem Osama M. , Inampudi Jyothik Varun , Patel Jaydeepbhai , Lou Yanyan , Manochakian Rami , Rao Sarika , Zhao Yujie
Published: June 2023

e16621

Background: Adrenocortical carcinoma (ACC) is an exceedingly rare aggressive endocrine malignancy with about 1 new case per million people diagnosed annually in the US. Higher incidence of ACC has been reported in patients (pts) with inherited syndromes such as Lynch syndrome and Li-Fraumeni syndrome. However, the incidence rate of developing multiple primary cancers in this population is unknown. The aim of this study is to investigate the frequency of additional malignancies in ACC patients. Methods: Using the Mayo Clinic Cancer Registry, we identified 63 pts who were treated for ACC from 2010- 2018 with updated follow up data until 01/31/2023. Electronic medical records were reviewed. Results: Among the patient cohort, 22 pts were male. 18/63 (29%) pts were found to have at least one additional malignancy, including basal cell carcinoma (3/18, 17%), melanoma (3/18, 17%), thyroid cancer (3/18, 17%), prostate cancer (3/18, 17%), squamous cell carcinoma of skin (2/18, 11%), renal cell carcinoma (2/18, 11%), breast cancer (2/18, 11%), leukemia (2/18, 11%), lung cancer (1/18, 6%), transitional cell malignant neoplasm of kidney (1/18, 6%), squamous cell carcinoma of tonsil (1/18, 6%), ovarian cancer (1/18, 6%), seminoma (1/18, 6%) and bladder cancer (1/18, 6%). 8/18 (45%) pts had more than one (2-3) non-ACC malignancies. The median age at diagnosis of ACC was 56 years (02-83). The median age at diagnosis of non-ACC malignancies was 54 years (25-72). Most of the patients (13/18) were diagnosed with non-ACC malignancy within 5 years of diagnosis of ACC. Most pts (13/18, 72%) were diagnosed with non-ACC malignancy first. Germline mutation information was not available except for 2 pts with known family history (FH) of Lynch syndrome and 2 pt with a known FH of Li-Fraumeni syndrome. FH was available in 38 pts, out of which 29 pts had FH of cancer identified in first-degree relatives. Among the 18 pts with additional malignancies, 12 pts had FH of cancer in first-degree relatives. All except 2 pts underwent curative treatment for their non-ACC malignancies, and 14 pts had no evidence of disease at death or the time of last follow-up. Conclusions: The rate of other multiple primary malignancies in pts with ACC is high, indicating possible genetic predisposition associated with this disease; Early genetic consultation and evaluation for known and novel germline mutations may need to be considered for these pts to improve long-term outcomes.
Circulating levels of PCSK9, ANGPTL3, and other lipid-related factors in men with high-grade prostate cancer.
Authors: Joncas France-Hélène , Bergeron Ann-Charlotte , Wong Chong Emilie Yan Pin , Robitaille Karine , Fradet Vincent , Bergeron Alain , Calon Frédéric , Seidah Nabil Georges , Gangloff Anne
Published: June 2023

e17001

Background: Cancer cells rely on abundant lipid supplies for growth and metastasis. Previous studies have shown that lipid-lowering drugs provide a protective effect against cancer progression, including prostate cancer. However, the role of hyperlipidemic factors has not yet been extensively studied. Here, we aimed to measure circulating levels of hyperlipidemic factors, such as PCSK9 and ANGPTL3, in a small cohort of men diagnosed with high-grade prostate cancer compared to men without cancer. Methods: Plasma samples and data were obtained from 70 consenting men treated at CHU de Québec-Université Laval. Thirty-five patients with high-grade prostate cancer (cases) were age and BMI-matched to 35 patients without cancer (controls). The circulating levels of various lipids, Apo B and Lp(a) were obtained with a Roche Modular analytical platform, whereas levels of PCSK9, ANGPTL3 and leptin were measured by ELISA. We performed group comparisons and correlations using R version 4.2.1. Results: As expected, Prostate-specific antigen (PSA) levels were significantly higher in the cancer group. The lipid profile as well as Lp(a) and leptin levels did not differ between groups. ANGPTL3 level tended to be lower in patients with prostate cancer without reaching statistical significance (mean 32.2 vs 36.3 ng/mL, p = 0.051). ANGPTL3 level also inversely correlated with leptin among the cases (rho = -0.44, p = 0.008). PCSK9 level was similar in both groups, but inversely correlated with PSA in the cancer group (rho = -0.39, p = 0.022). PSA level correlated with triglycerides, total cholesterol, Apo B, non-HDL-cholesterol and LDL in the control group (p < 0.05). Conclusions: None of the hyperlipidemic factors measured here was significantly different between high-grade prostate cancer patients and controls. However, the trend for lower ANGPTL3 levels in cancer, as well as the inverse correlations between PCSK9 and PSA and between ANGPTL3 and leptin levels in cancer patients, warrant further investigation in larger cohorts.
Comprehension characterization of prostate cancer cell lines identified JAK-STAT3 signaling in lineage-switched non-neuroendocrine cells.
Authors: Cheng Siyuan , Li Lin , Yu Xiuping
Published: June 2023

e17005

Background: Prostate cancer (PCa) is the most diagnosed cancer type among American men. Androgen receptor (AR) targeted therapy as the gold standard of PCa has been challenged by treatment resistance. Lineage plasticity enables PCa cells to transit from prostate luminal epithelia to alternative lineages to bypass their dependency on AR signaling. Previously we established prostatic HOX code to study the prostatic lineage. We found that cells with neuroendocrine (NE) phenotype have a lineage switch. Besides, a subgroup of AR negative, NE negative samples also display lineage switch, among which is DU145, a human PCa cell line. Methods: RNA-seq data of PCa cell lines were obtained from GEO then aligned and quantified using human GRCh38 genome with STAR-Salmon pipeline. Downstream differential expression and enrichment analysis was performed with R. Immunohistochemistry (IHC) was used to assess protein levels on cell line derived xenografts. Results: 45 RNA-seq datasets of 6 prostate adenocarcinoma cell lines (VCaP, LNCaP, C4-2, 22RV1, PC3 and DU145) and 8 RNA-seq datasets of neuroendocrine prostate cancer cell line (H660) passed quality control. Principle component analysis indicates that samples from the same cell line had similar transcriptomes. Differential expression analysis followed by gene function enrichments analysis identified the marker genes and key signaling pathways of each cell line. HOX code analysis confirmed previous conclusion that all PCa cell lines but DU145 and H660 samples maintained prostatic HOX code. IHC staining on cell line-derived xenografts confirmed the protein expression of selected marker genes (TUBB2B for H660, HGF for VCaP and 22RV1, CXCL1 and KRT7 for DU145 and PC3). The three AR-negative PCa cell lines were further characterized in terms of AR/ NE activity scores, transcriptome identities, HOX codes. These analyses demonstrated that PC3 is a prostate progenitor like cell line, H660 is a lineage-switched NE cell line, and DU145 is a lineage-switched non-NE cell line. Further, signaling enrichment analysis revealed that DU145 cells had higher JAK-STAT3 signaling activity compared to other cell lines. IHC staining detected strong p-STAT3 signals on DU145-derived tumors but not on any other cell line-derived tumors. Conclusions: Human PCa cell lines were fully characterized based on their transcriptomes with high sample numbers. PC3 represents cells dedifferentiated into progenitor stage. DU145 and H660 represent cells that further trans-differentiate into alternative lineages. Neuron master regulators drive H660 cells into NE lineage and STAT3 drives DU145 cells into a non-NE lineage. DU145, representing a non-NE PCa class that have lost prostatic lineage, would be a suitable model system to study JAK-STAT targeting therapy.
Hyperinsulinemia and risk of lethal prostate cancer.
Authors: Tanawattanacharoen Veeraya Kate , Mucci Lorelei A , Giovannucci Edward L.
Published: June 2023

e17008

Background: Epidemiologic studies have found that insulin-like growth factor (IGF)-1 causally increases prostate cancer incidence and mortality, but the effect of insulin is less clear. IGF-1 and insulin act as mitogens by binding non-selectively to their receptors. To this end, this study tests the hypothesis that high circulating insulin increases risk for lethal (fatal or metastatic) prostate cancer among men with non-metastatic prostate cancer. Methods: The study population was drawn from two U.S.-based longitudinal cohorts: the Health Professionals Follow-Up Study (HPFS) of 51,529 health professionals and the Physicians’ Health Study (PHS) of 29,067 physicians. Pre-diagnostic plasma concentration of C-peptide was used as a proxy for insulin and measured on blood collected in 1993-1995 (HPFS) or 1982 (PHS) and stratified into quartiles for analysis. The empiric lifestyle index (based on body mass index (BMI), physical activity, and diet) for hyperinsulinemia (ELIH) was calculated from questionnaire data. Covariates of interest (age and fasting status at blood draw, BMI, height, clinical stage, and tumor grade) were attained from questionnaires and medical records. We followed patients for development of metastasis or death (lethal) through 2019 (HPFS) and 2015 (PHS). SAS 9.4 and R Studio were used for analyses. Chi-squared tests and Mann Whitney U tests were used to compare differences between groups, and Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% CI. Results: The sample included 2,812 men with 353 lethal prostate cancer events and a mean follow-up of 164 months from diagnosis to death. The mean time from blood draw to cancer diagnosis was 8.1 years. Compared to men with non-lethal prostate cancer, those with lethal disease had significantly more severe clinical grade and stage at diagnosis, higher BMI (25.1 vs 24.6), older age at blood draw (64.5 vs 61.9 years), and higher ELIH index. There were no differences by other covariates. There was no association between pre-diagnostic c-peptide levels and cancer-specific survival in a multivariable model that included clinical stage and grade (HR, 95% CI for high vs. low quartiles: 1.17, 0.83, 1.67). High ELIH was positively associated with risk of lethal prostate cancer (HR, 95% CI: 2.41, 1.36, 4.28), even when controlling for C-peptide (HR, 95% CI: 2.18, 1.20, 3.96). Conclusions: C-peptide levels measured prior to cancer diagnosis were not associated with increased mortality from prostate cancer. Higher ELIH was associated with increased risk of lethal prostate cancer among those diagnosed with prostate cancer, which could be partly mediated by hyperinsulinemia, but other dietary, physical activity, or BMI mechanisms could contribute.
Defining the prevalence of inherited DNA damage repair genetic variants (DDRv) in men with prostate cancer (PCa) detected by PSMA PET.
Authors: Maldonado Edward , Hope Thomas A. , Aggarwal Rahul Raj , Kwon Daniel H , Zhang Li , Gordon Kelly , Tong Barry , Bailey Adina , Kumar Vipul , de Kouchkovsky Ivan , Koshkin Vadim S , Borno Hala , Chou Jonathan , Bose Rohit , Fong Lawrence , Desai Arpita , Friedlander Terence W. , Small Eric Jay
Published: June 2023

e17010

Background: Approximately 12% of patients (pts) with metastatic PCa (mPCa) identified by conventional imaging harbor DDRv. The increased use of PSMA PET has identified a group of pts with extra-prostatic PCa which is not apparent on conventional imaging and for whom the frequency of germline DDRv testing remains unknown. Methods: A single-institution retrospective analysis of patients with PCa detected by PSMA PET who had also undergone germline genetic testing was undertaken. Data collected included PSA level at time of PSMA PET imaging, stage/Gleason score at diagnosis (dx), rationale for germline testing, castration status, and whether the metastatic disease identified on PSMA PET represented de novo or recurrent mPCa. Germline sequencing results were evaluated for 16 DNA damage repair genes: ATM, ATR, BAP1, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, GEN1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51C, and RAD51D. The frequency of DDRv was evaluated in groups defined by PSMA imaging results: localized (N0M0), Node-Positive (N+M0), metastatic (M+) PCa. Results: Of 795 PCa pts who underwent germline testing and 2101 PCa pts who underwent PSMA PET imaging, 386 had undergone both, and constitute the study cohort. In the study cohort the distribution of PCa extent identified by PSMA PET was: 81/386 (21.0%) N0M0; 76/386 (19.7%) N+M0; 229/386 (59.3%) M+. There were no statistically significant differences in the prevalence of DDRv with regards to age, Gleason score at dx, PSA at time of imaging, castration status at time of imaging, rationale for germline testing, or if metastatic, whether de novo or recurrent. The distribution of DDRv is shown in the table. There were no statistically significant differences between groups. Conclusions: The overall frequency of pathogenic germline DDRv in PCa pts who had undergone PSMA PET imaging was 4.66%, considerably lower than what has been reported in men with mPCa detected with conventional imaging. The presence or absence of extra-prostatic PCa detected by PSMA PET imaging did not appear to affect the frequency of DDRv. Validation of these findings in other cohorts will be important to guide recommendations for germline genetic testing in the growing group of PCa pts undergoing PSMA PET imaging. [Table: see text]
Patterns of recurrence post prostatectomy in the PSMA era: What lessons can we take to daily practice from a high-volume nuclear medicine center?
Authors: Lages Dr. Paulo Sergio , Monteiro do Prado Junior Luciano , Fonseca Monteiro do Prado Leonardo , Barbosa Michelle , Bergerot Paulo Gustavo , Muniz Pamela Carvalho , Lages Luciana , Rosa Diogo Augusto Rodrigues , Dias Mariane Fontes , Resende Cristiano Augusto Andrade de , Pinheiro Maria Fernanda Inocente Messias , Vargas Pivato de Almeida Daniel ,   Latin American Cooperative Oncology Group, LACOG
Published: June 2023

e17013

Background: PSMA has deeply modified the treatment of prostate cancer, mainly in the biochemical recurrence setting, where the therapeutic plan may be changed in up to two thirds of cases. Unfortunately, this diagnostic tool is still not fully available in many places over the world. Growing evidence from high-volume nuclear medicine centers may guide the development of adapted treatment plans based on sites of relapse according to wide available clinical information. Methods: We retrospectively reviewed 648 Ga68-PSMA-PET-CT scans in the biochemical relapse setting in patients initially treated with prostatectomy. Results were classified either as negative or positive if abnormal SUV uptake was detected in the prostate bed, pelvis, or distant organs. We then classified the patients with positive tests based on sites of relapse according to serum PSA level. Results: Among the 648 analyzed patients, there were 60, 63, and 61 recurrences in prostate bed, pelvis, or distant organs, respectively. For those with serum PSA ≤ 1.0 ng/mL, there was a higher chance of locoregional failure (prostate bed or pelvis), with less than 20% presenting distant metastasis. When assessing patients with serum PSA 1.1-2.0 ng/mL, the rate of distant metastasis increased to 22.7%, while it was found in 40.7% of patients with serum PSA between 2 and 5 ng/mL. Conclusions: PSMA-PET-CT scan is clearly modifying the therapeutic landscape of prostate cancer in different scenarios. Although it is not available in many regions due to high financial costs and logistic barriers, the emerging evidence arising from specialized cancer centers matching the clinical information with tests results may help doctors to make better treatment decisions even without PSMA-PET-CT scans. [Table: see text]
Assessing the discordance rate of HER2 expression by immunohistochemistry between primary and secondary prostate cancer biopsies.
Authors: Mabellos Joshua , Gill Puneet , Lap Coen Johannes Gerardus , Zara Rozalen Alexandra , Diao Guoqing , Liu Shanshan , Thomas Shrina , Subrahmanyam Ramesh , Nava Victor , Jain Maneesh Rajiv
Published: June 2023

e17014

Background: Preliminary evidence suggests that human epidermal growth factor receptor 2 (HER2) expression may play a role in tumor cell proliferation in prostate cancer. Minner et al ( Clin Cancer Res, 2010) identified a prevalence of ~ 20% HER2 expression in prostate cancer. The aim of the study is to assess the prevalence and discordance rate of HER2 expression in prostate cancer patients with multiple prostate biopsies using immunohistochemistry (IHC) at a Veterans Affairs hospital. Methods: A single-center, retrospective chart review of at least 30 patients with prostate cancer that had two prostate biopsies based on data collected from the Computerized Patient Record System (CPRS) and Veterans Information Systems and Technology Architecture (VISTA). Demographic and laboratory data including age, race, Gleason score, and stage of cancer were collected under IRB-approved waivers for consent and HIPAA authorization. Formalin-fixed paraffin embedded (FFPE) prostate tumors were evaluated for IHC analysis by the Washington DC Pathology Department. HER2 expression was assessed using the VENTANA anti-HER2/neu (4B5) rabbit monoclonal primary antibody and scored as 0, 1+, 2+, and 3+. HER2 scores of 0 and 1+ to 3+ were categorized as HER2-negative and HER2-positive, respectively. The primary endpoints are the prevalence and discordance rate of HER2 expression in paired prostate samples. Results: In our predominately African American (94%) cohort of 32 patients with a mean age of 60 years, overall HER2 prevalence was 25% (n = 8) and 56% (n = 18) in the primary and secondary biopsies, respectively. The mean time between biopsies was 41 weeks and overall HER2 discordance was 56% (n = 18). Discordance from HER2-negative to HER2-positive was 38% (n = 12), while discordance from HER2-positive to HER2-negative was 6% (n = 2). The remaining discordance were from HER2-low to HER2-positive or vice-versa. The most common variance between primary and secondary biopsies was observed as +1 HER2 scoring category (n = 11). No significant associations were found between HER2 discordance and Gleason score or stage of cancer . Conclusions: In our cohort of patients with prostate cancer, HER2 expression was observed in 25% of initial biopsies and over 50% of secondary biopsies. Discordance of HER2 expression was found in over 50% of patients. A few patients had initial HER2-positive biopsies and subsequent HER2-negative biopsies. The majority of HER2 discordance involved patients who had initial HER2-negative biopsies and secondary HER2-positive biopsies with most showing +1 difference in IHC scores. This study could lead to the consideration of utilizing multiple prostate cancer biopsies to determine the eligibility for anti-HER2 therapy in future trials.
The association of HLA-DR and PD-L1 expression with clinical characteristics in prostate adenocarcinoma.
Authors: Tuerff Daniel , Muller Daniel J. , Lap Coen Johannes Gerardus , Liu Shanshan , Diao Guoqing , Antonio Martha , Nava Victor , Jain Maneesh Rajiv
Published: June 2023

e17017

Background: Prostate adenocarcinoma is the second most commonly occurring cancer in men, yet therapeutic progress in the past decade has stalled. Immune checkpoint inhibitors (ICI) are being successfully used for the treatment of multiple types of cancers and remain an appealing treatment option for patients with prostate adenocarcinoma. Unfortunately, only a small group of patients with prostate cancer appear to benefit from treatment with ICI. Both HLA-DR and PD-L1 have been identified as predictors of response to ICI in other malignancies. We investigated the prevalence of HLA-DR and PD-L1 expression in prostate cancer, and if there is a correlation with clinical characteristics. Methods: For this retrospective cohort study, 40 patients were randomly selected from a database of patients with prostate cancer seen at the Washington DC VA Medical Center between 2000 and 2022; 19 patients (47.5%) with metastatic disease at presentation and 21 patients (52.5%) presenting without metastatic disease. Clinical information was collected and included age at diagnosis, ethnicity, PSA at diagnosis, total Gleason score, and AJCC stage. Tissue samples of the primary tumors were retrieved and immunohistochemistry was performed for HLA-DR and PD-L1. Staining was independently scored by two experienced pathologists who were blinded to clinical information. Results: HLA-DR was found to be expressed in 14 patients (35%) with prostate cancer, whereas PD-L1 positivity was identified in 18 patients (45%). HLA-DR expression was not associated with metastatic disease, PSA at diagnosis, Gleason score, or AJCC stage ( p = 0.816, p = 0.314, p = 0.920, p = 0.458, respectively). In contrast, PD-L1 positivity was significantly associated with metastatic disease ( p = 0.028), a higher PSA at diagnosis ( p = 0.041), Gleason score ( p = 0.026), as well as AJCC stage ( p = 0.0438). No correlation was observed between HLA-DR positivity and positivity for PD-L1 ( p = 0.641). Conclusions: Both HLA-DR and PD-L1 are found to be expressed in tumor tissues of patients with prostate adenocarcinoma. Although HLA-DR expression was not associated with clinical characteristics, we did observe an association between PD-L1 positivity and advanced disease. This observation would be consistent with prior studies that have reported that PD-L1 expression in prostate cancer is correlated with clinic-pathologic features such as advanced stage of disease, castration resistance and poor overall survival. More studies are necessary to evaluate if PD-L1 could serve as prognostic or predictive biomarker in prostate adenocarcinoma.
Development and initial clinical testing of a multiplex assay evaluating histone modifier p300 acetylation in prostate cancer circulating tumor cells.
Authors: Jarrard David Frazier , Filon Mikolaj , Yang Bing , Schehr Jennifer L. , Singh Anupama , Bigarella Marcelo , Denu John M , Lang Joshua Michael
Published: June 2023

e17020

Background: Histone modifying enzymes (HMEs) hold promise as targets for drug discovery in cancer. Histone acetyltransferases and histone deacetylases dictate the presence of acetyl marks, which regulate chromatin and transcriptional activation. We previously developed a novel ‘histone array on a chip’ to measure HME dysregulation associated with the development of castration resistant prostate cancer (CRPC) (ACS Chem Biol 2017). This approach identified decreased SIRT2 expression and increased p300 activity leads to a concerted mechanism of hyperacetylation at specific histone lysine sites (H3K9, H3K14, and H3K18) in CRPC xenografts. These alterations were subsequently validated in castration-resistant tissues (BMC Cancer 2017). The goal of the current study was to determine if circulating tumor cells (CTCs) could be used as a therapeutic biomarker to identify patients with altered p300 acetylation activity. Methods: Blood was collected from 11 CRPC and 3 hormone-sensitive patients with advanced PC under an IRB-approved protocol. PBMCs were isolated with Ficoll-paque PLUS, and lymphocytes were depleted using anti-CD45 magnetic beads. CTCs were then captured with EpCAM labeled coated magnetic beads. Bound cells were isolated with Exclusion-based Sample Preparation (ESP) technology. Bound cells were moved through staining and washing wells prior to imaging at 20x on a fluorescent microscope. Images were analyzed with NIS Elements software. Results: We initially optimized the staining of acetyl-p300, total p300, H3K18ac, and SIRT2 in single cell prostate cancer cell cultures. Exposure to A-485, a selective p300/CBP catalytic inhibitor, reduced levels of p300 and H3K18 acetylation confirming assay specificity. CTCs from patient samples were then captured by EpCAM antibody binding and target staining revealed clear expression of acetyl-p300, acetyl-H3K18, SIRT2, and CK (cytokeratin). No expression of CD45+ cells (lymphocyte exclusion) is noted. Acetyl-p300 displayed a strong positive correlation with its target acetylated H3k18 (Pearson’s r = 0.61), and SIRT2 expression showed robust negative correlation with H3k18 (r = -0.60). A distinct group of 6/11 (55%) of CRPC patients demonstrated altered expression. In one subject with an untreated CSPC sample and subsequent CRPC sample ( > 12mo) a loss of SIRT2 expression, increased p300 activity, and histone H3 hyperacetylation are associated with the transition from hormone-sensitive to CRPC. Conclusions: Acetyl-p300, H3K18ac, and SIRT2 increase in a subset of CTC from patients with CRPC. These biomarkers are associated with increased CBP/p300 activity. This biomarker suite could potentially be used for noninvasive monitoring of outcomes and predicting tumor responses to CBP/p300 acetylation inhibitors in clinical development.
Clinicopathological characteristics and survival outcomes for testicular choriocarcinoma and non-testicular choriocarcinoma: A SEER database analysis.
Authors: Alshwayyat Sakhr Abdulsalam , Ababneh Obada Ehab , Alshwayyat Tala Abdulsalam , Qaddoura Marwa Thaker , Soudi Maen Suliman
Published: June 2023

e17026

Background: Primary Choriocarcinoma (CC) is a rare germ cell tumor that can occur in males. The most common primary site in men is the testis. It can occur in extragonadal sites such as the mediastinum, retroperitoneum, lungs or brain. The clinical and prognostic differences between testicular CC and non-testicular CC are unclear. We aim to study the differences in clinical features, prognostic factors, and outcomes between the two subtypes of CC. Methods: We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with pure CC between 2000 and 2018. Patients with a previous history of cancer or with other concurrent malignancies were excluded. These patients were divided into two groups: testicular and non-testicular CC. The clinicopathological features of each group were compared using chi-square tests. Kaplan-Meier estimator, log-rank tests, and Cox proportional hazard regression were used to identify prognostic factors over overall survival (OS) and cancer-specific survival (CSS). Results: The study included 363 patients, with 270 (74.4%) patients classified as having testicular CC and 93 (25.6%) as having non-testicular CC. The results showed that testicular CC was more likely to occur in white patients, be bilateral in distribution, have a smaller size, and be in more advanced SEER stages compared to non-testicular CC. Additionally, testicular CC patients were more likely to undergo surgical treatment, but not radiation. Testicular CC patients had a better OS and CSS (HR = 0.52, 95% CI: 0.38-0.71 and HR = 0.52, 95% CI: 0.37-0.71, respectively) compared with non-testicular CC. Our Cox multivariate analyses for OS and CSS identified the following independent prognostic factors for testicular CC: localized stage, surgery, tumor size ≥ 4cm, radiotherapy, and chemotherapy. Interestingly, the use of radiotherapy was actually associated with poor OS and CSS (HR = 1.8, 95% CI: 1.17-2.85 and HR = 1.7, 95% CI: 1.05-2.73, respectively). For non-testicular CC, the independent prognostic factors for OS and CSS were age ≥ 30 years, non-paired site, regional stage, surgery, and chemotherapy. Conclusions: Our study provides important insights into the differences between testicular and non-testicular CC. The use of radiotherapy is generally not recommended in testicular CC which might explain its bad prognostic effect as these patients might be naturally at higher risk of dying. However, the bad poor prognosis of patients using radiotherapy persisted even after controlling for other important prognostic factors. Further studies with larger sample sizes are needed to validate and build upon these findings, but our results provide a starting point for a better understanding of such rare cancer.
Doxorubicin, paclitaxel, and cisplatin (ATP) for refractory germ cell tumors.
Authors: Xiang Jenny Jing , Campbell Matthew T , Tu Shi-Ming , Araujo John C. , Nieto Yago , Lin John Kent , Xiao Lianchun , Shah Amishi Yogesh , Wang Jianbo
Published: June 2023

e17028

Background: Patients with refractory germ cell tumor (GCT) have limited treatment options and poor prognosis. We describe our institutional experience with doxorubicin, paclitaxel, and cisplatin (ATP) as an outpatient chemotherapy regimen for patients with refractory GCT. Methods: We performed a retrospective chart review of all patients who received ATP at our institution between August 2017 and August 2022. ATP consisted of doxorubicin 30 mg/m2, paclitaxel 100 mg/m2 over one hour, and cisplatin 30 mg/m2 every 2-3 weeks. We reviewed patient and disease characteristics including staging, histology, prior therapies, tumor marker and imaging responses. Progression free survival (PFS) and overall survival (OS) were respectively calculated from the first ATP dose date to disease progression/death and to death/last follow up. Results: A total of 39 patients with refractory GCT received ATP. Patients were 95% male, 54% white, with a mean age of 30 years (range 18-63). Prior to ATP administration, 92% of GCTs had elevated tumor markers, including 54% with elevated AFP, 56% with elevated HCG, and 18% with elevated both tumor markers. 8% of GCTs did not have elevated tumor markers at baseline. Further disease characteristics are described in table 1. Patients received a median of 2 lines of prior systemic therapies (range 1-6), including 97% with prior cisplatin-based regimens and 21% with prior high dose chemotherapy with stem cell rescue transplant. Patients received a median of 3 doses of ATP (range 1-8) with 31% for palliative intent and the rest as a bridge to transplant or other therapies. After ATP administration, 77% patients had decreased tumor markers, including 18% with tumor marker normalization. Of the 19 patients with imaging post-ATP, 53% had complete or partial response, 16% had stable disease, and 32% had disease progression. By December 2022, 79% patients had progression or death, with a median PFS of 3.8 months (95% CI: 1.94, 7.16) and median OS of 10.7 months (95% CI: 6.37, 32.69). 18% of patients experienced toxicities requiring admissions. Conclusions: Based on our retrospective single institution experience, ATP has clinical activity in refractory GCT and is associated with decreased tumor markers and imaging response in most patients. ATP is a convenient and feasible outpatient regimen and can be used in the salvage setting and as a bridge to other therapies. [Table: see text]
Bone metastasis in patients with germ-cell tumors: Analysis of survival outcomes and prognostic factors.
Authors: Hassoun Rebecca , King Jennifer , Althouse Sandra K. , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil
Published: June 2023

e17029

Background: Bone metastasis (BM) is uncommon in patients with germ-cell tumor (GCT). There is lack of data regarding optimal treatment approach. We report the outcomes and prognostic factors in 99 pts with BM treated at our institution. Methods: We identified 99 pts with GCT and BM treated at Indiana University between year 1986-2021. Kaplan-Meier methods were used for progression free survival (PFS) and overall survival (OS) analysis. Results: Median age was 31.5 (range, 13.1-58.8). Primary tumor histology was non-seminoma in 77 and pure seminoma in 22. Predominant histology was seminoma in 26, yolk sac tumor 23, mixed 16, embryonal ca 12, teratoma 10, choriocarcinoma 9. Other mets sites included lungs in 68, RP LNs in 63, liver in 34, brain in 19. BM location was spine in 73, pelvic bones in 22, humerus/femur in 14, ribs in 10, sternum/clavicle in 7. Median pre-chemo AFP was 438 (range, 1-75,414) and hCG 80 (range, 0.7-1,700,000). 1L chemo was BEP x4 in 46, VIPx4 in 10, BEP x3 + EP x1 in 8, EP x4 in 8, BEP x3 in 7, VIPx3 in 1, and other in 19. Histology of BM resection for those who underwent surgery was viable non-teratoma GCT in 6, teratoma in 1, malignant transformation of teratoma in 3, and necrosis in 3. 28 had radiotherapy to symptomatic BM. 80 (82.5%) pts progressed after 1L chemo and 46 (53.5%) progressed after 2L chemo. With median f/u from diagnosis of 5.7 years, 5 yr PFS was 17.8% (95% CI 10.3-27.0) and 5 yr OS was 59.9% (95% CI 47.9-70.0). For pts with pure seminoma, 5 yr PFS was 29.8% (95% CI 12.4-49.5) and 5 yr OS 83.1% (95% CI 55.7-94.3). For non-seminoma: 5 yr PFS was 14.6% (95% CI 6.9-25.1) and 5 yr OS 52.2% (95% CI 38.4-64.2). Multivariable analysis indicated that pts with concurrent liver and/or brain mets had worse OS. Conclusions: Outcomes of pts with GCT and BM are inferior than what is expected based on IGCCCG risk categories. Pts with concurrent liver and/or brain mets have particularly worse OS outcomes. [Table: see text]
Real world utilization and outcomes of immunotherapy regimens in metastatic castration resistant prostate cancer (mCRPC).
Authors: Ganta Teja , Anker Jonathan Forrest , Miller Eric James , Tsao Kai , Oh William K.
Published: June 2023

e17038

Background: While immune checkpoint inhibitors (ICIs) have shifted the treatment paradigm in many cancers, their efficacy in mCRPC is limited. Ongoing research suggests distinct subpopulations of mCRPC may derive benefit or that combinatorial regimens including ICIs may overcome treatment resistance. This single-center retrospective study aims to describe real-world utilization patterns of ICIs for patients with mCRPC and assess the treatment effects. Methods: The EHR database was queried for patients with PC who were treated with an ICI outside of a clinical trial. Additional data were obtained from chart review and the cancer registry. Patients were excluded if ICI was given for another cancer type, non-metastatic disease, or as a component of small-cell lung cancer regimens. Kaplan-Meier curves were used to estimate time to events. Results: 31 patients are included in the study. From years 2016 to 2022, 13 patients received ICI alone. Starting in 2019, 18 patients received ICI combined with cabozantinib (C). ICI+C had PSA response rate (RR) of 50%, median duration of treatment (DOT) of 5.5 months, and median overall survival (OS) of 8 months (Table 1). 3 of these patients received therapy for ≥ 12 months. ICI alone had a RR of 0%. 94% of patients who received ICI+C were not a candidate for CONTACT-2 (NCT04446117). Conclusions: Oncologists continue to use ICI for mCRPC. While noncomparative, ICI+C demonstrated favorable activity over a historical cohort of ICI alone. Ongoing clinical trial participation is vital for patients with mCRPC; however, off-label prescribing may provide additional access to treatment options. [Table: see text]
Dual inhibition of PARP and ATR induces homologous recombination repair deficiency and leads to synthetic lethality in prostate cancer with CDK12 alteration.
Authors: Akamatsu Shusuke , Kamiyama Yuki , Sunada Takuro , Hikami Kensuke , Fukui Tomohiro , Mizuno Kei , Sumiyoshi Takayuki , Goto Takayuki , Kobayashi Takashi , Sasanuma Hiroyuki
Published: June 2023

e17042

Background: CDK12 is considered as a gene involved in homologous recombination repair (HRR); however, recent clinical trials have shown poor benefit of poly(ADP-ribose) polymerase(PARP) inhibitors in prostate cancer (PCa) patients with CDK12 alterations. Since CDK12 is the third most commonly altered gene in the HRR pathway in PCa, development of a new treatment strategy is urgently needed. Methods: To understand the biological consequence of CDK12 alteration, CDK12 was knocked out in LNCaP using CRISPR-Cas9 system to generate CDK12KO cells. Cell growth and cell cycle were evaluated as well as HRR efficiency. Downstream genes were evaluated by RT-PCR and western blots. Combination therapy by a PARP inhibitor and ATR inhibitors were tested using two lines of patient derived xenografts (PDX) established from tissues of patients with deleterious CDK12 variants. Three different ATR inhibitors were tested to confirm reproducibility. Results: In LNCaP, CDK12 knockout enhanced cell cycle progression until the M phase, however, cell cycle was stalled at the M phase with accumulation chromosomal aberration, suggesting that rapidly progressive CDK12 altered tumors clinically encountered harbor a mechanism of escaping the M phase checkpoint without DNA repair. γH2AX was accumulated in CDK12KO after treatment with CPT11, consistent with impaired HRR in CDK12 KO cells. Analysis of HRR associated genes showed that in PCa, CDK12 knockout leads to transcriptional downregulation of ATM but not the other HRR associated genes. Expression patterns of downstream genes after double strand break (DSB) induction in CDK12 and ATM knockout cells suggested that in PCa, CDK12 regulates HRR through regulation of ATM. Since synthetic lethality of PARP and ATR inhibition has been reported in ATM deficient PCa, 2 PDX lines with CDK12 alterations were administered the combination therapy. Tumor growth suppression and accumulation of γH2AX in tumor tissue was observed when treated by the combination therapy, but not with either drug alone. Either drug alone or in combination did not affect the growth of a PDX established from a tissue of a patient with wild-type CDK12. Conclusions: In PCa, CDK12 acts through transcriptional regulation of ATM, and combination treatment with PARP inhibitor and ATR inhibitor could be a potential treatment strategy in PCa with CDK12 alteration.
Real-world data for predictors of PSA response to Lu177-PSMA-617 in metastatic castration resistant prostate cancer.
Authors: Hassoun Rebecca , Tann Mark , Sims Justin , Auxier Ashleigh , Althouse Sandra K. , King Jennifer , Adra Nabil
Published: June 2023

e17044

Background: Lu177-PSMA-617 (Lu177) therapy is effective in a subgroup of patients with metastatic castration resistant prostate cancer (mCRPC). We evaluated PSA responses in subgroups of pts with mCRPC. Methods: Pts with mCRPC who progressed after androgen receptor pathway inhibitor (ARPI) and taxane chemotherapy (or who have refused chemotherapy) were treated with Lu177. Pts with ≥6 weeks follow-up after start of Lu177 therapy were included. Baseline clinical/molecular characteristics and PSMA PET parameters were analyzed and association with PSA30 response was evaluated. Results: 45 pts were included. Median age 71.7 (range, 58-90). At baseline PSMA PET: 37 pts had PSMA + disease in bone, 28 lymph nodes, 5 lungs, 4 liver, and 1 brain. 14 pts had 1 prior ARPI, 31 pts had ≥2 prior ARPI. 5 pts had no prior taxane regimen, 18 had 1 prior taxane, 14 had 2 prior taxanes and 8 had ≥3 taxane regimens. 10 pts had prior PARP inhibitor. With a median follow-up of 2.8 months (1.4-6.1) from starting Lu177 therapy, 21 (46.7%) pts achieved a PSA30 response, and 18 (40.0%) pts achieved a PSA50 response. 24 (53.3%) pts achieved any confirmed PSA response. Grade≥3 toxicity occurred in 3 pts. Conclusions: There is a trend with higher PSA30 and PSA50 response to Lu177 with higher SUVmean, less prior taxane exposure, and in pts with homologous recombination repair mutations (HRR). [Table: see text]
Integration analysis of single-cell multi-omics in the prostate cancer ecosystem.
Authors: Bian Xiaojie , Wang Wenfeng , Abudurexiti Mierxiati , Yao Zhu , Zhang Min , Ye Ding-Wei , Wang Jianhua
Published: June 2023

e17046

Background: Prostate cancer (PCa) is characterized as a extensive heterogeneous disease with the complex cellular ecosystem in the tumor microenvironment (TME). However, the content of how heterogeneity is shaped by tumors and stromal cells or vice versa remains poorly understood. Methods: Single-cell RNA sequencing, spatial transcriptomics and bulk ATAC-sequence from a series of human PCa and normal control were integrated. Results: We identified a stemness subset of club cells marked with SOX9highARlow expression, which enriched significantly after neoadjuvant androgen-deprivation therapy (ADT). Furthermore, a subset of CD8+CXCR6+ T cell, functioned as effector T cell, was observed to be markedly reduced in the malignant PCa patients. Notably, immunosuppressive microenvironment in advanced PCa was associated with infiltration of regulatory T cells (Tregs), which is potentially induced by FAP+ fibroblasts (cancer-associated fibroblasts, CAFs subset). Moreover, for spatial transcriptome analysis, we comprehensively utilized machine learning and computational intelligence to identify cellular diversity of prostate and cell-cell communication with each other in situ.Importantly, we also depicted macrophage and neutrophil state transition under different biological conditions in vivo. Conclusions: We delineate the cellular heterogeneity in the stage-specific PCa microenvironment at single-cell resolution, uncover their reciprocal crosstalk with disease progression and these results will be helpful in exploring potential target for PCa therapy.
Phenotypic differences related to homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) treated in routine care settings in the United States (US).
Authors: Sillah Arthur , Adeboyeje Gboyega , Lee Liam , Gart Mike , Saunders William M. , Wang Brandon , Dave Poras , English Sandy , Blanc Simon
Published: June 2023

e17047

Background: Recent evidence suggests mutations in HRR genes predict clinical benefit from treatment with PARP inhibitors in patients (pts) with mCRPC. Little is known about the prevalence, clinical and prognostic phenotypes associated with HRR-mutated (HRRm) mCRPC pts receiving routine oncology care in the US. We assessed HRRm positivity rate and described difference in phenotypic factors between HRRm+ and HRRm- mCRPC patients receiving routine care in community oncology settings. Methods: In this retrospective cohort study, we identified biologically male pts with mCRPC, ≥18 years, who received HRRm testing and on systemic anti-cancer treatment from 5/1, 2020 – 3/31, 2022, from the Integra Connect database, an electronic medical record (EMR) and claims database of US cancer pts in community oncology. We defined 2 cohorts based on their HRRm status (defined by the presence of an alteration in at least 1 of the following genes: BRCA1/2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L). We described age and race (at diagnosis), cancer stage and Gleason score (at staging), and line of therapy (LOT), Eastern Cooperative Oncology Group (ECOG) performance status, prostate-specific antigen (PSA) values and microsatellite instability (MSI) status using values closest to mCRPC diagnosis. HRR tests were stratified by germline, ctDNA, and solid tumor. Results: The study cohort comprised 376 HRRm-tested pts: by ctDNA only – 29%, germline only – 16.2%, solid tissue only – 18.4% and > 2 testing types – 33.5%. 96 had HRRm+ mCRPC (25.5%). Median (IQR) age at diagnosis for both cohorts was 67 (43-89) years and there were no statistically significant differences in age, race, stage, Gleason score, PSA value, LOT or ECOG by HRRm status. HRRm+ rates by ctDNA, germline, and solid tissue testing were 26.6%, 13.1% and 21.7%, respectively. Of the 126 patients with > 2 testing types, HRRm+ rate was 30.9%. A higher, but not statistically significant, proportion of HRRm+ pts had Gleason scores 9-10 compared to HRRm- pts (54.8% vs 48.6%). Of HRRm- pts, 10.2% had MSI-H status compared to 6.5% in HRRm+ pts. Conclusions: In this real-world cohort of HRR gene-tested pts with mCRPC, we observed a 25.5% HRRm+ rate, which suggests the prevalence for HRR mutation is significant enough to warrant testing for all pts with mCRPC. Further research is needed to examine the impact of these findings on overall survival and other clinical outcomes.
Lu-PSMA-617 in combination with third-line therapy for castration-resistant prostate cancer: A systemic review and meta-analysis.
Authors: Akbar Usman Ali , Ali Fatima , Vikash Sindhu , Khalid Saad , Farooqui Sabeeh , Aman Aleena , Qazi Shaheryar , Muhibullah - , Qadeer Abdul , Rehman Mohammad Ebad Ur , Zubair Rameesha , Ashraf Muhammad Aizaz , Shabbir Muhammad Asad , Ahmed Muhammad Ihsan , Khalid Alina
Published: June 2023

e17051

Background: Prostate cancer is the second most common cancer and the sixth leading cause of cancer death among men worldwide. Lu-177 viptriplet, also known as lutetium-177-PSMA-617, is a highly targeted form of radioligand therapy that aims to shrink prostate cancer tumors and slow their progression. It is also recommended as a treatment option by the American Society of Clinical Oncology (ASCO) for patients with prostate-specific membrane antigen (PSMA) positive PET/CT-positive castration resistant prostate cancer (CRPC) who have progressed on at least one prior line of androgen receptor pathway inhibitors (ARPI) and at least one prior line of chemotherapy. However, the evidence on its effectiveness with third-line chemotherapy is scarce. We aim to evaluate the efficacy of Luma-PSMA plus third-line chemotherapy in CRPC. Methods: We conducted a comprehensive literature search in PubMed, PMC, Scopus, and Embase using relevant keywords to identify articles related to Luma-PSMA and third line chemotherapy for prostate cancer from inception to Jan 30, 2023. Three independent reviewers screened the articles for eligibility and extracted data on outcomes such as overall survival (OS), PSA decline > 50%, and partial remission. We used Raveman 5 software to perform a statistical analysis and calculated the odds ratio with a 95% confidence interval for each outcome. Results: A total of 11 studies were included in our analysis with 787 patients. Pooled analysis of studies demonstrated an overall survival after Lu-PSMA-617 therapy plus third line chemotherapy as compared to standalone chemotherapy in castration resistant prostate cancer to be 13.15 months (95% CI = 10.66 – 15.65, P = < 0.001, I2= 69.93%). Pooled prevalence of prostate specific antigen (PSA) decline > 50% was determined to be 49.5% (95% CI = 44.2 – 54.7, P = 0.162 I2= 33.27%) and partial remission was observed in 39.7% patients (95% CI = 28.5 – 50.9, P = 0.952 I2= 0%). Conclusions: Our meta-analysis suggests that Lu-PSMA-617 therapy plus third-line chemotherapy may improve overall survival and PSA response in patients with CRPC compared to chemotherapy alone. However, the quality of evidence is limited by heterogeneity and risk of bias. More high-quality randomized trials are needed to confirm the efficacy and safety of this combination therapy. [Table: see text]