Small Cell Prostate Research Articles

Lurbinectedin in prostatic small cell and neuroendocrine carcinoma.

164 Background: Lurbinectedin (L) is a novel inhibitor of oncogenic transcription that was granted accelerated approval by the Food and Drug Administration in June 2020 for the treatment of metastatic small cell lung cancer (SCLC) following disease progression on or after platinum-based chemotherapy (PBC). Prostatic small cell or neuroendocrine carcinoma (SC/NEPC) is a high-grade, invasive malignancy that accounts for < 1% of all prostate cancers. SC/NEPC is distinct from prostatic adenocarcinoma and behaves similar to SCLC. NCCN guidelines for SC/NEPC recommend following the SCLC treatment guidelines. Using these guidelines, L may be used as a second-line treatment in patients (pts) with SC/NEPC who progress on or after PBC. We aimed to characterize the baseline characteristics, clinical course and therapeutic outcomes of pts treated with L for SC/NEPC. Methods: After IRB approval, 18 cases were gathered from 4 academic oncology centers. Baseline patient data, prior treatments and L treatment outcomes, including best radiographic and serologic responses, overall survival (OS), progression-free survival (PFS) and treatment toxicity were assessed. The Kaplan-Meier method was used to calculate OS and PFS from the L start date. Clinical benefit rate (CBR) included pts with complete response (CR), partial response (PR) and stable disease (SD) on imaging. Results: At the time of first L dose, all had metastatic disease with 2-6 distinct sites of metastases, most commonly bone (14/18, 77.8%), lymph nodes (14/18, 77.8%) and liver (13/18, 72.2%); median age was 63.5 (Range: 53-84); 11 pts (61.1%) had an ECOG 0-1; 4 pts (22.2%) had an ECOG of 2-3. The median total number of systemic therapies administered prior to L was 4 (Range: 2-7). All pts received PBC prior to L. The most common dose of L prescribed was 3.2 mg/m2 every 21 days (15/18, 83.3%). Androgen deprivation therapy was administered in conjunction with L in 9 pts (50%). The median number of cycles of L was 5 (Range: 1-10). L was discontinued due to toxicity in 1 patient (5.6%), disease progression in 10 pts (55.6%), transition to hospice in 2 pts (11.1%), 3 pts (16.7%) died while receiving treatment (not due to L toxicity), and 2 pts (11.1%) remained on L at the time of data reporting. The median OS and PFS from date of first L dose was 6.01 months (0.23 – 16.69) and 3.35 months (0.16 – 7.79), respectively. CBR was 9/16 (56.3%) with partial response in 5 pts (31.3%), stable disease in 4 pts (25%), and progressive disease in 7 pts (43.8%). Two pts did not have post-treatment imaging available to assess response. There were no hospitalizations for L treatment related adverse events (tRAE). The most common tRAE were grade I and II fatigue and anemia; 9 pts (50%) experienced no tRAE. The only grade IV toxicity was neutropenia in 3 pts (16.7%). Conclusions: L is a well-tolerated and active treatment option for patients with SC/NEPC. Prospective studies are needed to determine the role of L in the treatment of SC/NEPC.

Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation

Trans-differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy resistance in multiple cancer types. To gain insight into the underlying molecular events of the trans-differentiation, we perform a multi-omics time course analysis of a pan-small cell neuroendocrine cancer model (termed PARCB), a forward genetic transformation using human prostate basal cells and identify a shared developmental, arc-like, and entropy-high trajectory among all transformation model replicates. Further mapping with single cell resolution reveals two distinct lineages defined by mutually exclusive expression of ASCL1 or ASCL2. Temporal regulation by groups of transcription factors across developmental stages reveals that cellular reprogramming precedes the induction of neuronal programs. TFAP4 and ASCL1/2 feedback are identified as potential regulators of ASCL1 and ASCL2 expression. Our study provides temporal transcriptional patterns and uncovers pan-tissue parallels between prostate and lung cancers, as well as connections to normal neuroendocrine cell states.

A bibliometric study of the top 100 most-cited papers in neuroendocrine prostate cancer.

This study used bibliometrics to define and analyze the characteristics of the first 100 most cited papers on the topic of neuroendocrine prostate cancer (NEPC). We explored the Web of Science Core Collection database, and screened the top 100 most frequently cited articles and reviews with the title NEPC or small cell prostate cancer (SCPC). We conducted bibliometrics research on the screening results to identify the most influential journals and authors in the field of NEPC. The first 100 most cited papers have been cited a total of 14,795 times, from 73 to 833 times (mean ± standard deviation, 147.95 ± 101.68). All top 100 most cited papers were published from 1984 to 2019, and the total number of citations for papers published in 2016 was significantly higher than that for papers published in other years. The journal with the largest number of published papers is "Prostate" (n=8). "Neuroendocrine differentiation" has become the most frequently used author keyword. "Oncology" is the most popular topic in the field of NEPC. We analyzed the first 100 most cited papers in the NEPC field by collecting detailed information, which provide guiding opinions for finding the most influential journals and authors in NEPC-related fields. We hope to help researchers and readers in this field improve their understanding of NEPC research trends and provide ideas for future research from a unique perspective.

Radiographic-pathologic concordance in the workup of locally radiorecurrent prostate cancer.

313 Background: Advanced molecular PET/CT (mPET) studies are increasingly being utilized in conjunction with multiparametric MRI (mpMRI) to evaluate the burden of radiorecurrent disease in men who develop a biochemical recurrence following definitive radiotherapy (RT) for prostate cancer (PCa). However, radiographic concordance with pathologic confirmation of radiorecurrent disease in this setting is poorly described. We sought to conduct a patient-level analysis comparing concordance of radiographic and pathologic findings between mpMRI and mPET. Methods: Men who had previously undergone definitive RT for PCa and subsequently experienced treatment failure defined by the Phoenix definition were enrolled in a prospective registry study wherein radiographically identified local PCa recurrences were biopsied using mpMRI or mPET fusion (Artemis) with real-time ultrasound. Prior to biopsy, men underwent diagnostic imaging with mpMRI, advanced mPET (68Ga-PSMA-11 or 18F-FACBC), or both in order to identify a biopsy target. At least one imaging modality had to reveal a recurrent lesion based on PIRADS or PROMISE imaging classifications in order to prompt biopsy. Radiographic and pathologic findings were classified as either “treatment effect” or “recurrent disease”. Using biopsy as the reference standard, positive predictive value (PPV) was evaluated for mpMRI and mPET modalities separately. Results: Of 28 patients with radiographic recurrence on mpMRI or mPET, 10/28 (35.7%) exhibited treatment effect without evidence of active cancer on biopsy confirmation. Prostate adenocarcinoma was identified in 17/28 patient biopsies, whereas small cell prostate cancer was present in 1 patient. All 28 men underwent mpMRI prior to biopsy and 23/28 (82.1%) additionally underwent mPET; 19/23 (82.6%) underwent 68Ga-PSMA-11 and 4/23 (17.4%) were imaged with 18F-FACBC. Concordance in the assessment of recurrent disease between mpMRI and mPET was achieved in 12/23 (52.2%) men who underwent both imaging modalities. Among the 28 men who underwent mpMRI, PPV was 0.84, whereas PPV for the 23 men who underwent mPET was 0.70. Conclusions: In patients for whom clinical suspicion of radiorecurrence was high enough to warrant a biopsy, pre-biopsy mpMRI outperforms mPET in terms of PPV for detecting pathologically confirmed locally radiorecurrent PCa. Used in tandem, mpMRI and mPET might better select appropriate candidates for biopsy than either radiographic modality alone. While advanced mPET remains promising for detecting distant recurrences at the time of RT failure, biopsy confirmation following radiographic detection of local radiorecurrence remains essential for evaluating the true burden of local recurrence.

Lineage plasticity in prostate cancer: Looking beyond intrinsic alterations

Emergence of small cell prostate cancer is linked to the plasticity of tumour cells and avoidance of environmental pressures. This process is thought to be reversable, however to-date evidence of this has been demonstrated in small-cell prostate cancer. To study the plasticity of prostate tumours, we look to clinical cohorts of patients covering the spectra of malignancy subtypes and utilise in vitro and in vivo models of disease progression. Current models have assisted in the understanding of the extremities of this plasticity, elucidating internal mechanisms and adaptations to stressors through transition to altered cell states. By interrogating the tumour microenvironment and earlier time points, we are beginning to form a deeper understanding of the full spectra of tumour plasticity. It could be proffered that this deeper understanding will lead to better patient outcome, with earlier interventions more likely to reverse plasticity and prevent trans-differentiation to the aggressive, small cell phenotype.

Online scaffolds: A constructivist approach to oncology fellow learning.

11010 Background: Oncology is a vast and fast-paced field. Fellows must expend significant effort to learn and stay updated. Up-to-date learning tools covering core oncology content in a digestible manner are lacking. Additionally, passive lectures are common in oncology, while constructivist approaches that may improve learning are rare. Therefore, we piloted updatable online modules (“scaffolds”) as a learning tool for oncology fellows. Methods: Author SB, a University of California, San Francisco (UCSF) solid-tumor oncologist, designed 12 scaffolds (breast, non-small cell lung, small cell lung, head/neck, salivary/thyroid, upper gastrointestinal, lower gastrointestinal, germ cell, bladder/renal/adrenal, prostate, melanoma, and sarcoma) using Google Slides between 12/2018 and 6/2019. The scaffolds included bullet points and tables/figures synthesized from the ASCO self-evaluation program textbook’s solid tumor chapters and the National Comprehensive Cancer Network (NCCN) guidelines. We emailed scaffold links to all UCSF and Stanford oncology fellows in 2019-2020, including instructions for fellows to update the scaffolds without exceeding 20 slides per scaffold, 5 lines per slide, or 7 words per line. The scaffolds were reintroduced to new fellows at the beginning of each academic year. SB audited to ensure no erroneous information was added. In December 2021 we reviewed updates tracked in Google Slides and conducted one UCSF and one Stanford focus group with four 1st-3rd year fellows each. Results: Between 7/2019 and 12/2021, fellows made 60 updates to the scaffolds, with a mean of 5 updates per scaffold ranging from new trials to changes in management. During the same period, the auditor made 9 updates and found no erroneous fellow updates. Fellow updates occasionally exceeded specified limits, requiring correction. Content analysis revealed that fellows considered the scaffolds to be accessible and succinct learning tools that 1) addressed a dearth of similar resources, 2) served as effective preparation for clinical work and examinations, 3) provided structured information for rapid review, and 4) made subsequent interactions with complex resources such as NCCN guidelines easier. Barriers to fellows updating the scaffolds included lack of ownership and low confidence in judgment regarding appropriate updates. Conclusions: In this two-institution pilot, oncology fellows used and subsequently updated online scaffolds in a constructivist fashion. This model has the potential to fill a crucial gap in available learning resources and can be applied to other specialties. Assigning scaffolds to fellows with faculty mentorship may facilitate ownership and bolster fellow confidence in updating these tools. Individual institutions may update their own versions of the scaffolds to align with institution-specific needs.

Molecular correlates of Delta-like-ligand 3 (DLL3) expression in neuroendocrine neoplasms (NENs).

4127 Background: NENs can occur in many locations but have limited precision therapy options. DLL3 is a cell surface protein that is emerging as a promising therapeutic target in NENs including neuroendocrine prostate cancer (NEPC) and small cell lung cancer (SCLC). Our recent study indicated that ̃77% of NEPCs expressed DLL3, with expression in circulating tumor cells being highly concordant with matched biopsies. While there are ongoing clinical trials of drugs targeting DLL3, the repertoire of clinical and genomic features shared across other DLL3-expressing NEN cancers is ill-defined. Methods: We analyzed WES and WTS data from NENs identified across 29 different sites of origin using the Caris Life Sciences platform, excluding SCLC and including neuroendocrine carcinomas and neuroendocrine tumors. We used values above or below median DLL3 expression of all NEN samples to define DDL3-High/Low (H/L). Significance of molecular alterations in DLL3-H vs L was determined using Fisher’s-Exact/Mann Whitney/X2 test with Benjamini-Hochberg correction. Results: DLL3 expression across all 2672 NEN samples was observed in 27 of 29 NENs after excluding SCLC. NENs of anus, prostate, lung, bladder, and bile duct exhibited the greatest median DLL3 expression, whereas adrenal gland, small bowel, and nervous system displayed the lowest. Certain tissues of origin displayed more robust DLL3 expression, with 71% (50/66) of NEPC, 75% (87/122) of lung, and 77.3% (51/66) of bladder being DLL3-H compared to 14.4% (13/90) of adrenal and 7.9% (12/151) of small bowel NENs. DLL3-H NENs were associated with TMB-high status ( > 10 muts/Mb; 12.1% vs 4.5%, OR 2.7, q < 0.001) and more genomic alterations in several driver genes, including tumor suppressors TP53 (51% vs 23%, OR 2.3, q < 0.001) and RB1 (42% vs 10%, OR 4.2, q < 0.001), and oncogenes KRAS (14% vs 5.4%, OR 2.5, q < 0.001), MYC (5.7% vs 0.9%, OR 6.3, q < 0.001) and CCNE1 (5.3% vs 1.3%, OR 4.0, q = 0.001). Conversely, DLL3-L NENs exhibited more alterations in CTNNB1 (2.2% vs 5.2%, OR 0.42, q = 0.04), MEN1 (3.3% vs 11%, OR 0.30, q < 0.001), and BCOR (1.3% vs 4.1%, OR 0.32, q = 0.02). DLL3-H NENs also had significantly more alterations in PIK3CA (6.4% vs 3.0%, OR 2.1, q = 0.04), chromatin remodeling genes KMT2D (6.7% vs 2.6% OR 2.6, q = 0.005) and CREBBP (3.2% vs 0.9%, OR 3.6, q = 0.03), and WNT signaling gene APC (9.7% vs 5.2%, OR 1.9, q = 0.02). Conclusions: We confirmed DLL3 expression in NENs across different tissues of origin, with highest expression in poorly differentiated NENs. DLL3-H expression was associated with genomic features considered “undruggable” based on current precision therapy approaches. Therefore, DLL3-targeted therapies may serve as a promising strategy for NEN patients with functional loss of tumor suppressors TP53 and RB1, as well as increased activity of KRAS, WNT and MYC signaling.

Outcomes of second-line therapies in patients with metastatic de novo small cell prostate cancer (SCPC) and treatment-emergent neuroendocrine prostate cancer (tNEPC).

e17022 Background: De novo SCPC and tNEPC in metastatic castrate resistant prostate cancer (mCRPC) are rare, aggressive cancers with a poor prognosis. After first-line (1L) platinum chemotherapy (PLT), there is no consensus on 2L treatments. This multi-institutional, retrospective study examines practice patterns among clinicians and evaluates the outcomes of patients (pts) with SCPC or tNEPC in the 2L setting. Methods: After IRB approval, pts with a pathologic diagnosis of SCPC or tNEPC (any % of SC or NE histology defined by institutional review) were identified. Pts diagnosed between 2000-2020 who received 1L PLT and any 2L systemic therapy (tx) for SCPC or tNEPC were included. Standardized data collection templates containing demographic, clinical, and pathologic variables were collected. The primary endpoint was objective response rate (ORR) to 2L tx. Secondary endpoints included PSA response, time on 2L treatment, and overall survival (OS) from time of 2L tx. Data was analyzed using descriptive statistics. Results: Forty-two pts (21 SCPC, 21 tNEPC) from 6 institutions were included. At SCPC/tNEPC diagnosis, the overall cohort had a median age of 65.0 years (IQR 60.5, 68.0) and median PSA of 3.0 ng/dL (IQR 0.5, 21.8). The most common sites of metastasis included lymph node (78.6%), bone (54.8%), and liver (52.4%). For 1L tx, 37 pts (88.1%) received PLT and 5 (11.9%) had PLT + immunotherapy (IMM). For treatment to the prostate, 21 (51.2%) had none, 7 (17.1%) radiation (RT), 9 (22.0%) surgery, 3 (7.3%) RT + surgery, and 1 (2.4%) brachytherapy alone. Concurrent ADT was given to 32 pts (76.2%) in the 1L and 2L. At last follow-up, 34 pts (81.0%) were dead, 4 (9.5%) were alive, and 4 (9.5%) were lost to follow-up/censored. For 2L tx, 10 pts (23.8%) received PLT, 8 (19.0%) taxane monotherapy (TAX), 10 (23.8%) IMM, 8 (19.0%) other chemotherapy (CHX), and 6 (14.3%) other tx. Among 38 pts evaluable for response, the ORR was 15.8% (6 pts with PR: 4 PLT, 1 IMM, 1 CHX). PSA response ≥ 50% to 2L tx was seen in 5 of 29 pts with PSA data (17.2%). Other outcomes data are reported in Table. Conclusions: In this retrospective study, pts with SCPC or tNEPC who reached 2L tx received a wide variety of treatment regimens, reflecting the lack of consensus in this tx setting. ORR was low and overall prognosis was poor in the 2L regardless of tx choice. Pts on 2L immunotherapy seemed to have the shortest mOS. [Table: see text]

Interim results of a phase Ib single-center study of pembrolizumab in combination with chemotherapy in patients with locally advanced or metastatic small cell/neuroendocrine cancers of the prostate and urothelium.

510 Background: Small cell/neuroendocrine cancers irrespective of origin share aggressive phenotypes. Pembrolizumab (MK-3475) is a humanized antibody targeting programmed cell death protein 1 (PD-1) that has shown activity against small cell lung cancers. Preclinical studies showed molecular commonality amongst small cell/neuroendocrine cancers across multiple tissue types. This study evaluated the safety and efficacy signals of pembrolizumab and chemotherapy in patients with small cell/neuroendocrine cancer of the prostate and urothelium. Methods: Patients with locally advanced or metastatic small cell cancer of the bladder or upper urinary tract (cohort 1) and primary small cell or treatment-derived neuroendocrine prostate cancer (NEPC) (cohort 2) received pembrolizumab and standard of care chemotherapy (etoposide and cisplatin/carboplatin for cohorts 1 and 2, with option of docetaxel and carboplatin for cohort 2) with maintenance pembrolizumab for 2 years until unequivocal progressive disease or unacceptable toxicity. The primary endpoint was to estimate ORR and PFS compared to historical controls as well as safety and tolerability. Pretreatment targeted gene mutation sequencing was performed. Results: 14 patients were enrolled (7 cohort 1, 7 cohort 2) with mean age 64.9 (range 53 to 81). ORR across cohorts was 43% (95% CI: (0.17, 0.69)), and 43% (95% CI: (0.06, 0.80)) within each cohort. PFS rate at 12 months (proportion of patients who have not progressed at 12 month) was 61% (95% CI: (0.40,0.95)) across cohorts, 86% (95% CI: (0.63,1.00)) within cohort 1, and 36% (95% CI: (0.12,1.00)) within cohort 2. 3 patients in cohort 1 with locally advanced disease exhibited SD and underwent radical cystectomy, with one patient pT0 and no PD at a mean follow up of 20 months. Grade 3 or higher AEs occurred in 71% of patients, while 29% of patients experienced grade 3 or higher AEs related to pembrolizumab. No patients died or discontinued therapy secondary to adverse treatment effects. In 12 patients where tissue was sufficient, all patients had genomic alterations in either p53 (75%) or Rb (58%). Of the 5 available patients with NEPC, 60% had alternations in DNA damage response genes. Conclusions: In patients with locally advanced or metastatic small cell/neuroendocrine prostate and bladder cancers, combination pembrolizumab with standard of care chemotherapy and maintenance pembrolizumab showed promising efficacy with tolerable adverse events. Clinical trial information: NCT03582475.

Abstract PO-100: Association of B7-H3 expression with racial ancestry, immune cell density and AR activation in prostate cancer

Abstract Background: B7-H3 (CD276, PD-L3) is an immunomodulatory molecule highly expressed in prostate cancer and belonging to the B7 superfamily that also includes PD-L1 (B7-H1). Immunotherapies (antibodies, antibody-drug conjugates, and CAR-T cells) targeting B7-H3 are currently in clinical trials; thus elucidating the clinical, molecular and tumor immune microenvironment correlates of B7-H3 expression may help to guide trial design and interpretation. Methods: We developed an automated, clinical-grade immunohistochemistry assay to digitally quantify B7-H3 protein expression across two racially diverse cohorts of primary prostate cancer (including one with previously reported transcriptomic data), a set of prostatic neuroendocrine small cell carcinoma, and pre- and post-treatment tumor tissues from a trial of intensive neoadjuvant hormonal therapy. Results: B7-H3 protein expression is significantly lower in self-identified Black patients and inversely correlates with percent African ancestry by ancestry-informative markers. This association with race is independent of the significant association of B7-H3 expression with ERG/ETS and PTEN status. CD276 mRNA level, but not B7-H3 protein expression, is significantly correlated with regulatory (FOXP3+) T-cell density. Finally, androgen receptor activity (AR-A) scores are significantly correlated with CD276 mRNA expression, and neoadjuvant intensive hormonal therapy is associated with a significant decrease in B7-H3 protein expression. Conclusion: These data underscore the importance of studying racially and molecularly diverse prostate cancer cohorts in the era of immunotherapy. Our study is among the first to use genetic ancestry markers to add to emerging evidence that prostate tumors from men of African ancestry may have a distinct immune milieu associated with B7-H3 expression. Citation Format: Adrianna A. Mendes, Jiayun Lu, Harsimar B Kaur, Siqun Zheng, Jianfeng Xu, Edward M. Schaeffer, Karen S. Sfanos, Janielle Maynard, Ashley E. Ross, Steven P. Balk, Mary-Ellen Taplin, Emmanuel S. Antonarakis, Corinne E. Joshu, Eugene Shenderov, Tamara L. Lotan. Association of B7-H3 expression with racial ancestry, immune cell density and AR activation in prostate cancer [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-100.

Hepatobiliary and Pancreatic: Liver lesions in cirrhosis: When to biopsy?

A 70-year-old man originally from Poland was referred to the hepatoma service for investigation of two liver lesions found during routine hepatocellular carcinoma (HCC) screening. Active medical history included both castrate sensitive metastatic prostate cancer and Child–Pugh A cirrhosis secondary to type 2 diabetes mellitus and previous heavy alcohol use. For his prostate cancer, he was treated with androgen deprivation therapy (ADT) with goserelin and received upfront docetaxel chemotherapy with prednisolone, before being enrolled on a clinical trial of enzalutamide. Prostate specific antigen (PSA) level remained suppressed at <0.01 μg/L on therapy. The patient was asymptomatic with no features of hepatic decompensation. His Child–Pugh status was A6. Biochemistry revealed preserved synthetic liver function; alpha fetoprotein (AFP) level was 5 μg/L. Computed tomography (CT) chest, abdomen, and pelvis demonstrated two 10-mm arterially enhancing hepatic nodules in segments 7/8 and 4a (Fig. 1a) with no portal venous washout (Fig. 1b). On magnetic resonance imaging (MRI) with Primovist, both lesions retained Primovist and hence both were indeterminate (Liver Imaging Reporting and Data System [LI-RADS]-3). Differentials at discussion at the Hepatoma Multidisciplinary meeting included regenerative or dysplastic nodules, given metastatic prostate cancer typically shows hypodensity on contrast-enhanced imaging. The nodules were followed up in tandem with the patient's prostate cancer at 6 monthly intervals and were stable on contrast-enhanced CT (LI-RADS 3) at 12 and 18 months (Fig. 1c) (LI-RADS 3) and therefore did not meet criteria for biopsy. In addition, there were numerous new pulmonary nodules. At 24 months however, CT revealed new lesions concerning for multifocal HCC (Fig. 1d), increase in the size of the segment 7 and 8 lesions with a new 1.5-cm lesion in segment 2 with washout (LI-RADS 5). The patient remained clinically stable and had a suppressed PSA level. He underwent an ultrasound guided biopsy of the segment 2 lesion. Histopathology was consistent with a diagnosis of metastatic small cell neuroendocrine carcinoma. The patient was commenced on single agent Carboplatin to treat his now de-differentiated small cell prostate cancer, to which he has responded well with interval response demonstrated on serial CT of pulmonary and liver lesions in addition to the bony disease on CT SPECT. The diagnosis of HCC is typically made on cross-sectional radiological findings without the need for confirmatory tissue in cirrhotics. LI-RADS scoring system has high sensitivity and specificity in diagnosing HCC in cirrhotic patients and is applicable to lesions ≥ 1 cm. Thus, biopsy is rarely required to diagnose HCC. Current guidelines support the use of the LI-RADS as a classification system for reporting liver lesions. The decision to biopsy is a contentious clinical question that is not definitively answered by current guidelines. Biopsy carries known risks of bleeding, tumor seeding, and failure to obtain adequate tissue for sampling. There are several mimics of HCC on imaging. Intrahepatic cholangiocarcinomas are known to mimic HCC. Tumors such as neuroendocrine tumors, squamous cell carcinoma metastases, and lung cancer metastases require pathological differentiation from HCC. Prostate cancer metastasis to the liver is heralded by hypoenhancement on contrast-enhanced imaging, whereas small cell prostate cancer itself is ill defined in imaging and there is currently a paucity of literature describing its imaging characteristics. It is aggressive in nature and 40–50% of cases are reported to occur in men with pre-existing prostate adenocarcinoma. The PSA is highly sensitive to progression of metastatic prostate adenocarcinoma but not to de-differentiated carcinoma, and it can therefore be difficult to differentiate de-differentiated prostate cancer from HCC in the cirrhotic patient. This case demonstrates that although current clinical practice guidelines deliver a safe approach to the diagnosis of HCC, alternative diagnoses can be missed if they carry similar characteristics on cross-sectional imaging, especially in cirrhotic patients and particularly in those with a cancer history. The role of biopsy in indeterminate liver lesions is often a discussion point and requires multidisciplinary team discussion, and the LI-RADS criteria should always be interpreted in the clinical context.

Abstract 463: Features consistent with a small-cell neuroendocrine like (SC/NE-L) transformation can be readily detected and quantified in circulating tumor cells (CTCs)

Abstract Background: The increasing availability and earlier use of life prolonging drugs targeting the androgen receptor signaling axis (ARSI) has resulted in an increase in the frequency of late state tumors with “small cell/neuroendocrine like (SC/NE-L) phenotypes” similar to small-cell lung cancer (SCLC). These tumors are typically heterogenous wherein the small-cell component represents only a portion of CTC's present. Definitive pathologic criteria to diagnose small-cell neuroendocrine transformation are lacking, and the eligibility criteria across trials in this space inconsistent, limiting the ability to relate outcomes between studies. We hypothesize that an analytically validated assay for a rigorously defined “small-cell CTC” phenotype would clarify the identification and diagnosis of SC/NE-L tumors. Methods: Using the WHO guidelines for small-cell diagnosis in tissue as reference, we defined an equivalent set of single-cell criteria for defining a CTC with small cell or neuroendocrine like (SC/NE) histology that include: a circulating CD45- cell with a high nuclear to cytoplasm area ratio, small size, high circularity, lack of detectable nucleoli, salt and pepper chromatin, SC/NE or tumor-related protein expression (DLL3, CD56, CK etc.), and other features associated with lineage plasticity (i.e., CK speckling). Clinical feasibility of feature extraction was explored on CTCs detected using the Epic Sciences platform in the blood of patients with small-cell lung and late state prostate cancers. Results: Using the Epic Sciences platform, morphologic features associated with small-cell or neuroendocrine transformation can be readily identified and quantified automatically in CTCs in a liquid biopsy from patients with small-cell lung and prostate cancers. Conclusions: Identifying small-cell to neuroendocrine like (SC/NE-L) CTC subtypes may aid in establishing that lineage transformation to a SC/NE-L phenotype has occurred where invasive single site tissue biopsies may not be informative or feasible. Citation Format: Howard I. Scher, Adam Jendrisak, Cole Gilbertson, Audrey Gill, Ethan Barnett, Anuradha Gopalan, Niamh Keegan, Samir Zaidi, Hannah Benoliel, Carbone Emily, Eva Wang, James Lu, Alisa Tubbs, Amanda Anderson, Joshua Jones, Joseph D. Schonhoft, Rick Wenstrup. Features consistent with a small-cell neuroendocrine like (SC/NE-L) transformation can be readily detected and quantified in circulating tumor cells (CTCs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 463.

Abstract 1458: Targeting fibroblast growth factor receptors in castration-resistant prostate cancer

Abstract Background: Androgen receptor (AR) pathway inhibition remains the cornerstone for prostate cancer therapies. Although AR signaling inhibitors (ARSI), such as enzalutamide (ENZ) and abiraterone (ABI), extend survival in recurrent and castration-resistant prostate cancer (CRPC), durable complete responses are rare. Bypass mechanisms employed by metastatic CRPC include amplification of AR and AR splice variants in AR-high CRPC (ARPC) and conversion to AR-null phenotypes, such as double-negative prostate cancer (DNPC) and small cell or neuroendocrine prostate cancer (SCNPC). We showed previously that DNPC bypasses AR-dependence through fibroblast growth factor (FGF) signaling. However, the utility of targeting the FGF pathway in other molecular subtypes of CRPC remains to be determined. Methods: RNASeq was conducted on 98 patient metastases, 18 LuCaP patient-derived xenograft (PDX) models and CRPC cell lines. Sensitivity to ARSI and FGFR inhibitors (FGFRi) alone or in combination in cell lines (C4-2B, VCaP, 22Rv1, DU145 and NCIH660) or ex vivo PDX tumor cells (10 ARPC models, 2 DNPC models, and 6 SCNPC models) was measured through CellTitre Glo assays. On-target effects of inhibitors were assessed through immunoblot and qPCR. In vivo efficacy of FGFRi in ARPC and SCNPC was conducted using LuCaP PDX models. Results: Interrogation of FGF pathway activity and FGFR expression using RNASeq and FGF signature scores in CRPC metastases, LuCaP PDX models and CRPC cell lines revealed upregulated FGF pathway activation in AR-null DNPC and SCNPC and in subsets of ARPC. In vitro/ex vivo analysis of FGFRi (erdafitinib, CH5183284 and rogaratinib) demonstrated robust growth suppression in DNPC and moderate growth suppression in SCNPC. In vivo CH5183284 administration recapitulated the growth suppression observed in vitro for SCNPC LuCaP 93 and LuCaP 173.1 but not for SCNPC LuCaP 49. Furthermore, in vitro/ex vivo analysis of AR-expressing CRPC models determined that combination ARSI (ENZ, ABI or darolutamide) with FGFRi was superior to ARSI or FGFRi monotherapies in a subset of models. Immunoblot and qPCR analyses verified that FGFRi-mediated growth suppression occurs through inactivation of the MAPK/MEK and ERK signal transduction cascade in AR-expressing CRPC. Finally, ARPC LuCaP PDX models treated with combination ARSI and FGFRi showed significant tumor growth inhibition compared to control and monotherapy groups in vivo. Analysis of resistance mechanisms to FGFRi therapy are ongoing. Conclusions: The emergence of bypass mechanisms that subvert AR-dependence in mCRPC highlights a need for novel therapeutic strategies. Our data nominate the FGF pathway as an actionable target in diverse phenotypes of treatment-refractory mCRPC. Citation Format: Mark P. Labrecque, Lisha G. Brown, Ilsa M. Coleman, Bryce Lakely, Holly M. Nguyen, Eva Corey, Peter S. Nelson, Colm Morrissey. Targeting fibroblast growth factor receptors in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1458.

Phenotyping of clinical trial eligibility text from cancer studies into computable criteria in electronic health records.

6592 Background: Clinical trial phenotyping is the process of extracting clinical features and patient characteristics from eligibility criteria. Phenotyping is a crucial step that precedes automated cohort identification from patient electronic health records (EHRs) against trial criteria. We establish a clinical trial phenotyping pipeline to transform clinical trial eligibility criteria into computable criteria and enable high throughput cohort selection in EHRs. Methods: Formalized clinical trial criteria attributes were acquired from a natural-language processing (NLP)-assisted approach. We implemented a clinical trial phenotyping pipeline that included three components: First, a rule-based knowledge engineering component was introduced to annotate the trial attributes into a computable and customizable granularity from EHRs. The second component involved normalizing annotated attributes using standard terminologies and pre-defined reference tables. Third, a knowledge base of computable criteria attributes was built to match patients to clinical trials. We evaluated the pipeline performance by independent manual review. The inter-rater agreement of the annotation was measured on a random sample of the knowledge base. The accuracy of the pipeline was evaluated on a subset of randomly selected matched patients for a subset of randomly selected attributes. Results: Our pipeline phenotyped 2954 clinical trials from five cancer types including Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Prostate Cancer, Breast Cancer, and Multiple Myeloma. We built a knowledge base of 256 computable attributes that included comorbidities, comorbidity-related treatment, previous lines of therapy, laboratory tests, and performance such as ECOG and Karnofsky score. Among 256 attributes, 132 attributes were encoded using standard terminologies and 124 attributes were normalized to customized concepts. The inter-rater agreement of the annotation measured by Cohen’s Kappa coefficient was 0.83. We applied the knowledge base to our EHRs and efficiently identified 33258 potential subjects for cancer clinical trials. Our evaluation on the patient matching indicated the F1 score was 0.94. Conclusions: We established a clinical trial phenotyping pipeline and built a knowledge base of computable criteria attributes that enabled efficient screening of EHRs for patients meeting clinical trial eligibility criteria, providing an automated way to efficiently and accurately identify clinical trial cohorts. The application of this knowledge base to patient matching from EHR data across different institutes demonstrates its generalization capability. Taken together, this knowledge base will be particularly valuable in computer-assisted clinical trial subject selection and clinical trial protocol design in cancer studies based on real-world evidence.

Neuroendocrine and Aggressive-Variant Prostate Cancer.

Simple SummaryProstate cancer may in some cases exhibit microscopic and molecular characteristics of a distinct subtype of disease which is referred to as neuroendocrine differentiation. This entity is rarely found in patients initially diagnosed with metastatic disease and most commonly occurs after treatment of prostate cancer in advanced stages with hormonal agents. This specific presentation of the disease is not effectively targeted by the hormonal therapies used in prostate cancer and exhibits an aggressive clinical course. Interestingly, some tumors may have molecular and clinical characteristics of a neuroendocrine tumor subtype, without however exhibiting the respective histomorphologic features. This aggressive-variant prostate cancer (AVPC) subtype is sensitive to platinum-based chemotherapy, without, however, an impressive long-term response. In this review article we provide an overview of neuroendocrine prostate cancer focusing on the AVPC subtype and we approach current treatment options as well as ongoing research efforts.In prostate cancer, neuroendocrine (NE) differentiation may rarely present de novo or more frequently arises following hormonal therapy in patients with castration-resistant prostate cancer (CRPC). Its distinct phenotype is characterized by an aggressive clinical course, lack of responsiveness to hormonal therapies and poor prognosis. Importantly, a subset of CRPC patients exhibits an aggressive-variant disease with very similar clinical and molecular characteristics to small-cell prostate cancer (SCPC) even though tumors do not have NE differentiation. This aggressive-variant prostate cancer (AVPC) also shares the sensitivity of SCPC to platinum-based chemotherapy albeit with short-lived clinical benefit. As optimal treatment strategies for AVPC remain elusive, currently ongoing research efforts aim to enhance our understanding of the biology of this disease entity and improve treatment outcomes for our patients. This review is an overview of our current knowledge on prostate cancer with NE differentiation and AVPC, with a focus on their clinical characteristics and management, including available as well as experimental therapeutic strategies.

Small cell carcinoma of the prostate after low-dose-rate brachytherapy: a case report

BackgroundSmall cell carcinoma of the prostate is a rare condition with important differences from prostatic adenocarcinoma in terms of clinical and prognostic characteristics. A low prostate-specific antigen and a symptomatic patient, including paraneoplastic symptoms, characterize small cell carcinoma of the prostate. Diagnosis is made on the basis of prostate biopsy, and fluorodeoxyglucose positron emission tomography/computed tomography is often used for staging because up to 60% of patients present with de novo metastatic disease. Patients with metastatic disease are usually treated with platinum-based cytotoxic chemotherapy regimens similar to those used for small cell carcinoma of the lung. However, prognosis remains poor, with a median overall survival of 9 to 17 months despite therapy.Case presentationThis report describes a case of an 80-year-old Caucasian patient with lymph node and bone metastatic small cell carcinoma of the prostate following low-dose-rate brachytherapy for a low-risk prostate carcinoma and treated with chemotherapy and immunotherapy.ConclusionLow-dose-rate brachytherapy might be an etiology of small cell prostate cancer.

Abstract 3083: Selective inhibition of transcription factor BRN2 as a treatment strategy for Small Cell Prostate Cancer

Abstract Introduction: Resistance to newly developed androgen receptor pathway inhibitors (ARPIs), such as Enzalutamide (ENZ), rapidly emerges. In particular, a subset of patients who relapse following ARPI therapy their dependence on AR signaling and emerge with neuroendocrine features. These tumors, termed treatment induced small-cell prostate cancer (t-SCPC) or neuroendocrine prostate cancer (t-NEPC), carry an extremely poor prognosis and, to date, treatment remains decades old cytotoxic chemotherapies. Previously, our group identified the neural transcription factor BRN2 as a major clinically relevant driver of SCPC and now report that targeting BRN2 is a promising strategy to prevent neuroendocrine differentiation or treat NEPC.Methods/Results: In silico screening of small molecules was conducted on a model of BRN2 which was later validated with the first-in-field crystal structure of BRN2 DNA binding domain. On the basis of the model, several small molecules were identified that showed direct binding to BRN2 and inhibited its activity. Pharmacokinetic studies measured stability and bioavailability of med-chem optimized lead compound (BRN2i) that significantly reduced tumor growth in multiple xenograft models with no measurable side-effects. In silico modeling predicted a 7Å “closing” in the DBD once it was bound to BRN2i, this shift translated to reduced interaction with DNA by chromatin fractionation and ChIP-seq, thus confirming the mode of action for BRN2i is through loss of DNA binding. Loss of BRN2 binding reduced cell proliferation in tSCPC cell line 42DENZR, de novo SCPC cell line NCI-H660 and NEPC organoids as well as downregulated several known targets like EZH2, ASCL1, SOX2 and PEG10. Down-regulation of these target genes was also measured in the xenograft tumors, confirming on target effect in vivo. Moreover, the specificity of BRN2i was validated with CRISPR/Cas9 mediated knockout of BRN2 with downstream mRNA expression and phenotypic changes. Conclusion: The described work aims to lay the pre-clinical foundation for the integration of BRN2 targeted therapies into the treatment landscape to improve survival for patients suffering from small-cell neuroendocrine prostate cancer. Citation Format: Daksh Thaper, Ravi Munuganti, Adeleke Aguda, Soojin Kim, Shungyu Ku, Sahil Kumar, Sepideh Vahid, Shaghayegh Nouruzi, Olena Sivak, Dwaiyapan Ganguli, Colm Morrissey, Eva Corey, Himisha Beltran, Amina Zoubeidi. Selective inhibition of transcription factor BRN2 as a treatment strategy for Small Cell Prostate Cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3083.

Abstract 4849: YPN-005, an oral CDK7 inhibitor, shows a significant antitumor activity in Myc amplified solid tumors and MCL-1 overexpressed blood cancer

Abstract Background: Cyclin dependent kinase 7 (CDK7) has been recognized as one of potential therapeutic targets in Myc-driven cancers. Previously, we synthesized selective irreversible CDK7 inhibitor and we demonstrated a significant inhibition of the proliferation of TNBC and HCC cells by down-regulation of c-Myc and MCL-1. We further report YPN-005 of the preclinical data with biological characterization. Methods: Antiproliferative activity of YPN-005 was measured in solid tumor cell lines with Myc amplification and in hematologic cancer cells with MCL-1overexpression. To investigate the mechanism of action of YPN-005, the expression levels of phospho-RNA polymerase II, phospho-CDK2 and -CDK4, BClXL, cleaved-PARP, c-Myc and MCL-1 were analyzed by Western Blot analyses. CDK7 occupancy was determined by using a biotinylated small molecule probe following incubating of TNBC, HCC, AML cells and hPBMC with YPN-005. The therapeutic efficacy of YPN005 was evaluated in TNBC and HCC xenograft mouse model. Results: YPN-005 treatment induced apoptosis and cell cycle arrest. Selectivity of YPN-005 on CDK7 was confirmed in the 468 kinases panel assay. YPN-005 significantly inhibited the proliferation of TNBC, ER+ breast cancer, HCC, ovarian cancer, small cell lung cancer (SCLC), pancreas, prostate and various types of blood cancer cells and IC50's were determined in 1-20 nM range. Inhibition of cell proliferation was accompanied by down-regulation of RNA PolII phosphorylation, c-Myc and MCL-1 expression. Washout assay by Western Blot demonstrated that YPN-005 irreversibly blocked RNA PolII phosphorylation. In addition, YPN-005 downregulated the adaptive immune checkpoint PD-L1 by the depletion of c-Myc in TNBCs. CDK7 occupancy over 90% was observed in TNBC, HCC, and AML cells with 100nM of YPN-005. In vivo xenograft models of TNBC and HCC showed that daily oral administration of YPN-005 for 21 days (once, and 10~20mg/kg) efficiently inhibited the growth of tumor. All the mice survived and there was no significant changes in their hematologic profiles. Conclusion: Our findings suggest that YPN-005 is an orally available, potent, and selective CDK7 inhibitor which can be used for the treatment of Myc and MCL-1 overexpressing cancer patients. These data support the rationale for advancing YPN-005 towards IND-enabling studies. Citation Format: Jakyung Yoo, Jun Hee Lee, Mi Jung Lee, Kang Woo Lee, Ji Eun Min, Jinhwan Kim, Ki-Nam Min, Da-Hye Jeon, Dae Seong Lim, Kwang-Ok Lee. YPN-005, an oral CDK7 inhibitor, shows a significant antitumor activity in Myc amplified solid tumors and MCL-1 overexpressed blood cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4849.

Abstract 6109: Enzalutamide treatment of patient derived bone metastatic prostate cancer xenograft models implanted in the bone resulted in durable progression to castration resistant prostate cancer (CRPC)

Abstract Background: Upon diagnosis of castration-resistant prostate cancer (CRPC), 84% of patients present with metastases and their survival rate is 28% despite improvements in treatment options. PCSD1, a patient-derived xenograft from a prostate cancer bone metastasis replicated the donor patient's CRPC and was resistant to the anti-androgen drug, bicalutamide, in the bone niche. To further understand the mechanisms of androgen deprivation therapy (ADT) resistance, we treated PCSD1 and PCSD13, a novel patient derived xenograft model from a small cell prostate cancer bone metastasis, with the more potent anti-androgen, Enzalutamide. Methods: PDX cells were implanted into male Rag2−/−γc−/− mice intra-femorally (IF) or subcutaneously (SC). Mice with established tumors were treated o.g. for 4-5 weeks with Enzalutamide (10mg/kg/day) or Vehicle control. Tumor growth was measured bi-weekly with calipers and in vivo bioluminescence (IVIS). Tumors were analyzed using FACS, RNASeq, whole exome sequencing (WES) and Oncoscan. Results: PCSD1 and PCSD13 tumors were resistant to enzalutamide when implanted in the femur bone but not sub-cutaneously. When the enzalutamide-resistant tumor cells from the bone were re-injected sub-cutaneously they retained their enzalutamide resistance in contrast to treatment-naïve PCSD1 SC tumors. Transcriptomic analysis revealed significant modulation of WNT5A, EMT and neuronal programs. Single cell analyses revealed heterogeneous sub-populations that behave as cancer stem cells in 3D organoid cultures. Genome-wide CNV analysis of patient bone metastasis samples from the same patient obtained 10 months apart and his xenografts revealed extensive CNVs which were highly conserved between the patient samples and xenografts. Conclusions: Our PDX models demonstrated that the bone niche promotes tumor growth and malignant progression even when treated with the potent anti-androgen, enzalutamide. These PDX models of bone metastatic prostate cancer were resistant to enzalutamide in the femur bone (IF) but sensitive in the sub-cutaneous environment (SC). Enzalutamide resistance in the bone produced a permanent change in the tumor cells that was retained when re-injected in the sub-cutaneous location. This elucidates the importance of utilizing in vivo patient derived models to gain a better understanding of why the bone niche supports tumor growth. Citation Format: Christina A.M. Jamieson, Michelle T. Muldong, Sanghee Lee, Christina N. Wu, Danielle N. Burner, Theresa R. Mendoza, Catalina Arreola, Abril Zuniga, Nicholas A. Cacalano, Catriona H. Jamieson, Christopher J. Kane, Anna A. Kulidjian. Enzalutamide treatment of patient derived bone metastatic prostate cancer xenograft models implanted in the bone resulted in durable progression to castration resistant prostate cancer (CRPC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6109.

Increased nuclear factor I/B expression in prostate cancer correlates with AR expression.

Most prostate cancers express androgen receptor (AR), and our previous studies have focused on identifying transcription factors that modify AR function. We have shown that nuclear factor I/B (NFIB) regulates AR activity in androgen-dependent prostate cancer cells in vitro. However, the status of NFIB in prostate cancer was unknown. We immunostained a tissue microarray including normal, hyperplastic, prostatic intraepithelial neoplasia, primary prostatic adenocarcinoma, and castration-resistant prostate cancer tissue samples for NFIB, AR, and synaptophysin, a marker of neuroendocrine differentiation. We interrogated publically available data sets in cBioPortal to correlate NFIB expression and AR and neuroendocrine prostate cancer (NEPCa) activity scores. We analyzed prostate cancer cell lines for NFIB expression via Western blot analysis and used nuclear and cytoplasmic fractionation to assess where NFIB is localized. We performed co-immunoprecipitation studies to determine if NFIB and AR interact. NFIB increased in the nucleus and cytoplasm of prostate cancer samples versus matched normal controls, independent of Gleason score. Similarly, cytoplasmic AR and synaptophysin increased in primary prostate cancer. We observed strong NFIB staining in primary small cell prostate cancer. The ratio of cytoplasmic-to-nuclear NFIB staining was predictive of earlier biochemical recurrence in prostate cancer, once adjusted for tumor margin status. Cytoplasmic AR was an independent predictor of biochemical recurrence. There was no statistically significant difference between NFIB and synaptophysin expression in primary and castration-resistant prostate cancer, but cytoplasmic AR expression was increased in castration-resistant samples. In primary prostate cancer, nuclear NFIB expression correlated with cytoplasmic NFIB and nuclear AR, while cytoplasmic NFIB correlated with synaptophysin, and nuclear and cytoplasmic AR. In castration-resistant prostate cancer samples, NFIB expression correlated positively with an AR activity score, and negatively with the NEPCa score. In prostate cancer cell lines, NFIB exists in several isoforms. We observed NFIB predominantly in the nuclear fraction of prostate cancer cells with increased cytoplasmic expression seen in castration-resistant cell lines. We observed an interaction between AR and NFIB through co-immunoprecipitation experiments. We have described the expression pattern of NFIB in primary and castration-resistant prostate cancer and its positive correlation with AR. We have also demonstrated AR interacts with NFIB.