tbuckley/cabot-search huggingface dataset:
Identification of a panel of microRNA biomarkers for the management of patients with refractory germ cell tumor of the testis.
Authors: Jim Zhongning Chen, Ahmet Aydin, Neriman Gokden, Timothy Langford, Shi-Ming Tu
Journal: Journal of Clinical Oncology (2024)

521 Background: In 1946, nearly 90% of patients diagnosed with metastatic Testicular Germ Cell Tumor (TGCT) succumbed to the disease within a year. In the present day, over 90% of such patients are successfully cured. However, there is a remaining 10% of patients have tumors that consist of chemotherapy-resistant forms of TGCT, such as yolk sac tumors and teratomas. This underlines the need for developing biomarkers that can guide the choice between additional chemotherapy and surgical intervention. MicroRNAs (miRNAs), non-coding RNA molecules that control post-transcriptional modifications, have shown promise in identifying TGCTs. Research has particularly highlighted the overexpression of miR-371a-3p and miR-375-3p in TGCTs. Nevertheless, these miRNAs are not effective in distinguishing between teratomas and other TGCT types. The Cancer Genome Atlas (TCGA), a publicly accessible database, offers clinical and miRNA data on various tumors, including TGCTs. Our objective is to leverage TCGA to identify miRNAs that can be used to classify TGCTs containing teratomas from those that do not. Methods: Between 2001 and 2013, TCGA gathered a total of 135 primary TGCT samples. We group these tumors into those without teratomas and those with any teratomatous components. We used EdgeR, a Bioconductor package designed for differential expression analysis of RNA that accounts for both biological and technical variation. A false discovery rate of less than 1e-8 was applied. A heatmap was generated to display the hierarchical clustering of differentially expressed miRNAs. Results: Based on the above cut-off, a panel of 50 miRNAs of differentially expressed miRNA were used to generate a hierarchical clustering that showed clear clustering between the two groups. Notably, tumor suppressor miRNAs such as hsa-mir-203a, hsa-mir-199, and hsa-mir-152, which are usually downregulated in non-teratoma TCGT, are overexpressed in teratomas. Other miRNA including hsa-mir-146a and hsa-mir-3607, which are downregulated tumor suppressors for non-TCGT are also downregulated in teratomas but not in teratoma-free TGCT. Conclusions: Despite the high cure rate for TGCTs, tumors containing chemotherapy-resistant teratomas still contribute to elevated mortality rates. Utilizing TCGA data, we identified a set of miRNAs that are effective in distinguishing between teratoma-containing and teratoma-free TGCTs. This miRNA panel has the potential to inform decisions related to surgical treatment plans and provide further insight into the biology of the disease.
<i>FGFR3</i> mutated (<i>FGFR3</i>mut+) urothelial carcinoma of bladder (UCB) or upper tract (UTUC): A comparative genomic landscape study.
Authors: Michael Basin, Rebecca A Sager, Dean C. Pavlick, Andrea Necchi, Philippe E. Spiess, Roger Li, Ashish M. Kamat, Petros Grivas, Liang Cheng, Douglas I. Lin, Jeffrey S. Ross, Alina Basnet, Gennady Bratslavsky, Joseph M Jacob
Journal: Journal of Clinical Oncology (2024)

540 Background: Activating DNA sequence genomic alterations (GA) in the FGFR3 gene including short variant (SV) mutations and kinase domain activating gene rearrangements/fusions (RE-FUS) are known drivers and relevant precision treatment targets for pts with UC. THOR trial showed a significant overall survival benefit with erdafitinib (FGFR inhibitor) vs (taxane or vinflunine) in patients (pts) with advanced UCB or UTUC. PROOF-302 trial showed higher frequency of FGFR3 GA in UTUC (30%) vs UCB (13%). We sought to explore differences in frequency of FGFR3 alterations and the genomic landscapes of FGFR3-altered UCB and UTUC. Methods: 10,402 UCB and 2,325 UTUC (combined ureter and renal pelvis) underwent hybrid capture-based comprehensive genomic profiling (CGP) using a hybrid capture-based to assess all classes of GA and measure MSI status, TMB level, genomic ancestry, genomic signature, germline mutations and HRD score. PD-L1 was determined by IHC (Dako 22C3 using the TPS system. Results were compared using the Fisher Exact method with the Benjamini-Hochberg adjustment. Results: FGFR3mut+ status was significantly more frequent in UTUC than in UBC (24.9% vs 17.7%; p&lt;.0001) (Table). UCB pts were more often male than UTUC (P=.0003). Age (71-72 yrs), EUR ancestry (85%) and GA/tumor (8.9-9.0) were similar. The number of GA/case and the frequency of EUR ancestry were similar. Targetable GA in ERBB2 and PIK3CA were more frequent in FGFR3mut+ UBC vs FGFR3mut+ UTUC. GA in PTEN, TSC1 and MTAP currently associated with clinical trials were similar in UBC and UTUC. The KEGG ERBB and VEGF signaling pathways were more frequently identified in UCB (p=0.036) and the MMR pathway more frequently identified in UTUC (p=0.014). The HRD signature was similar in both groups (2.3-3.1%). Anti-PD(L)1 putative biomarkers included a significantly higher frequency of MSI-high status in UTUC vs UCB but no significant difference in TMB or PD-L1 expression levels. Conclusions: Although histologically similar, the genomic landscape of FGFR3mut+ UTUC has notable differences with FGFR3mut+ UCB. Limitations include lack of clinical data annotation. The findings may impact of clinical trial designs for UCB and UTUC, including evaluating combinations of anti-FGFR3 with other agents. [Table: see text]
Pembrolizumab with favezelimab or vibostolimab for patients with bacillus Calmette-Guérin (BCG)–unresponsive high-risk (HR) non–muscle-invasive bladder cancer (NMIBC): Phase 2 KEYNOTE-057 cohort C.
Authors: Girish S. Kulkarni, Shilpa Gupta, Andrea Necchi, Neal D. Shore, Hema Kishore Dave, Ekta Kapadia, Qing Zhao, Ashish M. Kamat
Journal: Journal of Clinical Oncology (2024)

TPS719 Background: In cohort A of the phase 2 KEYNOTE-057 study (NCT02625961), the PD-1 inhibitor pembrolizumab demonstrated antitumor activity (3-month complete response rate, 41%) in patients with BCG-unresponsive HR NMIBC with carcinoma in situ (CIS) ± papillary tumors who are ineligible for or declined radical cystectomy (RC). However, treatment combinations that improve outcomes and durability of response with pembrolizumab monotherapy are needed. Coinhibitory receptors LAG-3 and TIGIT contribute to immune tolerance in the tumor microenvironment, and co-blockade of PD-1 with LAG-3 or TIGIT has demonstrated antitumor activity in clinical studies. In cohort C of KEYNOTE-057, efficacy and safety of coformulations of pembrolizumab and the LAG-3 inhibitor favezelimab or the TIGIT inhibitor vibostolimab are being evaluated in patients with BCG-unresponsive HR NMIBC with CIS ± papillary tumors. Methods: Key eligibility criteria include adults with histologically confirmed HR NMIBC (CIS ± high-grade Ta or T1 at baseline) that is BCG-unresponsive (persistent or recurrent CIS ± Ta/T1 ≤12 month of completing adequate BCG therapy) who are ineligible for or declined RC and have an ECOG PS of 0-2. Enrollment is planned for 60 patients. Patients will be randomly assigned 1:1 to receive the coformulation of pembrolizumab 200 mg and vibostolimab 200 mg or the coformulation of pembrolizumab 200 mg and favezelimab 800 mg intravenously every 3 weeks for ≤35 cycles or until central pathology–confirmed ≥T1 at any time point, persistent or recurrent CIS or high-grade Ta at 24-week efficacy review or thereafter, unacceptable toxicity, patient or physician decision to withdraw, or administrative reasons to discontinue. Tumor assessment will be performed every 12 weeks for 2 years and every 24 weeks thereafter for up to 5 years. Primary end point is 12-month complete response rate of HR NMIBC by cystoscopy, cytology, biopsy, and radiologic imaging by central pathology and radiology review. Secondary end points include duration of response of HR NMIBC; overall complete response rate and complete response rates at 3 and 6 months; progression-free survival (PFS) to worsening of grade, stage, or death; PFS to muscle-invasive or metastatic disease or death; and overall survival. Efficacy will be evaluated in patients who receive ≥1 dose of treatment and have a baseline evaluation consisting of pre-enrollment cystoscopy, TURBT/biopsy, urine cytology, and baseline CTU imaging. Safety and tolerability will be evaluated in patients who receive ≥1 dose of treatment. Enrollment is ongoing in Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT02625961 .
Molecular profiling and clinical relevance of low <i>PTEN</i> expression in patients with metastatic hormone-sensitive prostate cancer.
Authors: Marta Garcia de Herreros, Natalia Jiménez, Oscar Reig Torras, Vicente Ruiz de Porras, Juan Carlos Pardo, Albert Font Pous, Caterina Aversa, Laura Ferrer-Mileo, Manuel Mazariegos, Leonardo Rodriguez-Carunchio, Isabel Trias, Mireia Jordà, Samuel García-Esteve, Sara Cros Costa, Laia Fernandez-Mañas, Mariona Figols, Enrique Gonzalez-Billalabeitia, Isabel Chirivella, Alejo Rodriguez-Vida, Begoña Mellado-Gonzalez
Journal: Journal of Clinical Oncology (2024)

198 Background: Genomic alterations in PTEN are associated with an aggressive disease and treatment resistance in patients (pts) with castration-resistant prostate cancer (PC). The aim of the present study is to characterize the molecular alterations associated to tumor PTEN-low mRNA expression in different cohorts of metastatic hormone-sensitive PC (mHSPC) pts and its prognostic value. Methods: This is an ongoing multicenter ambispective study enrolling mHSPC pts receiving different treatment strategies. PTEN status was assessed in FFPE tumor samples by mRNA expression by nCounter and RNA-seq. PTEN expression was correlated with castration resistance-free survival (CRPC-FS) and overall survival (OS) by Kaplan Meier and multivariate Cox analysis. Results: 297 pts were included: 125 treated with ADT + docetaxel (ADT+D), 79 with androgen deprivation therapy (ADT) + abiraterone or enzalutamide (A/E) and 93 with ADT alone. Median follow-up of 46.3 months (m) (6.7-223). Median age was 66.4 years, 75.7% of pts presented de novo stage IV and 67.9% had high-volume disease. RNA-seq analysis was performed to assess differences in gene expression between low vs. high/medium PTEN expression tumors in 66 pts. There was a significant correlation between PTEN expression detected by nCounter and by RNASeq (p=8.7e -11 ). Differential expression analysis found 13 genes differentially expressed (padj&lt;0.05 &amp;abs(LFC)&gt;0.26) in PTEN-low (25.8%) vs the rest, including PTEN and 2 novel transcripts (Table). In the functional analysis PTEN-low tumors had overexpression of several pathways including cell cycle, DNA repair, metabolism and immune regulatory response, and infraexpression of the androgen-response hallmark. In the whole cohort (n=297 pts), PTEN-low (30.5%) was independently associated with low CRPC-FS (HR 1.8 (95% CI, 1.3 – 2.4), p=8.7e -5 ) and OS (HR 1.7 (95% CI, 1.2 – 2.2), p=0.0038). Conclusions: Lower expression of PTEN correlates with a distinct molecular profile and a more aggressive disease in pts with mHSPC, supporting the development of new therapeutic strategies in pts. [Table: see text]
Analysis of inactivating <i>TSC1</i> and <i>TSC2</i> alterations in advanced genitourinary (GU) cancers from a real-world patient population in the Foundation Medicine genomic database.
Authors: Gopa Iyer, Norma Alonzo Palma, Willis H. Navarro, David J. Kwiatkowski
Journal: Journal of Clinical Oncology (2024)

704 Background: Identification of genetic alterations in cancer via genomic profiling may contribute to better outcomes for patients with advanced GU cancers. Patients with perivascular epithelioid cell tumors in AMPECT (NCT02494570), who had inactivating alterations in the tumor suppressor genes TSC1 or TSC2, critical negative regulators of mTOR activity, had confirmed responses (8/9 patients with inactivating TSC2 alterations and 1/5 patients with inactivating TSC1 alterations) to the mTOR inhibitor nab-sirolimus. PRECISION 1 (NCT05103358), an enrolling tumor-agnostic study, is assessing nab-sirolimus in patients with advanced cancers bearing inactivating TSC1 and/or TSC2 alterations. We used data from a real-world genomic database to enumerate frequencies of TSC1 and TSC2 inactivating alterations in patients with GU cancers. Methods: Next-generation sequencing data from Foundation Medicine’s database of 463,546 patients with advanced cancer (as of March 29, 2022) were analyzed using the FoundationInsights web-based platform to identify inactivating TSC1 or TSC2 alterations in patients with GU cancers. TSC1 or TSC2 alterations were categorized as short variants [base substitutions, insertions and deletions], rearrangements, and copy number deletions. Tumors with these alterations were also evaluated for mutations in other genes, tumor mutational burden (TMB), and microsatellite instability status. Results: Of patients in the database, 9.6% of those with bladder cancer, 5.2% of those with kidney cancer, and 0.7% of those with prostate cancer had inactivating TSC1 or TSC2 alterations. Overall, inactivating TSC1 or TSC2 alterations were present in 1518 of the 36,920 patients with GU cancers. A majority of these 1518 patients (74%) were male and most (78%) were 51–80 years of age at the time the sample was obtained. Of samples with inactivating TSC1 and TSC2 alterations (n=1518), 84.9% were in TSC1 and 15.7% were in TSC2; alterations included short variants (76.7% and 12.2 %), rearrangements (2.4% and 2%), and copy number deletions (5.6% and 1.3%), respectively. TMB was low (&lt;6 mutations/megabase) in 52% of tumors and most (89%) were microsatellite stable. Other commonly mutated genes in this cohort with TSC1 or TSC2 inactivating alterations were TERT (64.4%), TP53 (44.1%), and CDKN2A (40%). Conclusions: Inactivating TSC1 and/or TSC2 alterations commonly occurred in GU cancers. A proportion of GU tumors have a low TMB and/or are microsatellite stable, suggesting that TSC1 and TSC2 inactivating alterations may be driver mutations rather than passenger mutations in those tumors. Therefore, patients with inactivating alterations in TSC1 or TSC2 may benefit from mTOR inhibition via nab-sirolimus. This hypothesis is being tested in the PRECISION 1 study which is open for enrollment of patients with TSC1 or TSC2 alterations.
Disparities in the incidence of next-generation sequencing (NGS) among patients (pts) with advanced or metastatic prostate cancer (mPC) and urothelial carcinoma (mUC).
Authors: Yeonjung Jo, Nishita Tripathi, Soumyajit Roy, Vinay Mathew Thomas, Gliceida Galarza Fortuna, Chadi Hage Chehade, Georges Gebrael, Arshit Narang, Patrick Campbell, Sumati Gupta, Benjamin L. Maughan, Neeraj Agarwal, Umang Swami
Journal: Journal of Clinical Oncology (2024)

542 Background: Based on availability of approved agents targeting tumor somatic mutations, current guidelines recommend NGS for Pts with mPC and mUC. However, large cohort studies in mPC and mUC evaluating disparities in NGS testing have not been reported. Herein, we investigated the effect of social determinant of health (SDOH) on disparities in NGS testing in a large real-world dataset of pts with mPC and mUC. Methods: Pts data were extracted from the nationwide Flatiron Electronic Health Record (EHR)-derived de-identified database. Inclusion: new diagnosis of advanced or metastatic (adv/met) PCa and UCa between March 2015 to December 2022 and receipt of cancer therapy (to include only treatment eligible pts). Disparities in incidence of NGS testing after adv/met diagnosis by SES, R/E, region, and insurance were assessed using Fine and Grey’s (FG) modified stratified Cox proportional hazard (PH) model. FG model considered death as a competing risk. Stratification was done by year of adv/met diagnosis (accounting heterogeneity) and R/E (an effect modifier for SES, region, and insurance), assuming different baseline hazards in each stratum. All analysis done using R v.4.2.3. Results: Analytic cohorts comprised 11,936 pts with mPC and 6,490 pts with mUC. Hazard ratios (HR) and 95% confidence intervals (CI) from FG Cox PH models are reported in the table. For both cancer types, pts were more likely to get NGS testing when they were White, non-Hispanic (compared to Black, non-Hispanic), had higher SES, and had commercial insurance. Conclusions: Our data suggest an association between incidence of NGS testing and several SDOH in mPC and mUC. Further studies are needed to elucidate the reasons for these disparities and ways to mitigate them. [Table: see text]
Patient characteristics, treatment patterns, and outcomes among early adopters of lutetium Lu 177 vipivotide tetraxetan (<sup>177</sup>Lu-PSMA-617): A real-world United States (US) study.
Authors: Xiao X. Wei, Daniel J. George, Jeetvan Patel, Jennifer Nguyen, Barinder Kang, Amrita Sawhney, Magdaliz Gorritz, Chi-Chang Chen, Queenie Paltanwale, Kainan Sun, Neal D. Shore
Journal: Journal of Clinical Oncology (2024)

81 Background: In March 2022, the US Food and Drug Administration approved 177 Lu-PSMA-617 for the treatment of patients with prostate-specific membrane antigen (PSMA) positive metastatic castration resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition (ARPI) and taxane-based chemotherapy. This real-world study aims to describe clinical characteristics, treatment use, clinical outcomes in patients treated with 177 Lu-PSMA-617 in a growing US dataset. Methods: Adults (≥18 years) with ≥1 claim for 177 Lu-PSMA-617 between 3/01/22 and 6/30/2023 in the IQVIA open-source pharmacy and medical claims databases were retrospectively identified and included in this analysis. Clinical characteristics and treatment use, including prior treatment exposures, were derived from this cohort. A subset of these patients with available PSA results were assessed for PSA response after initiation of 177 Lu-PSMA-617. Baseline PSA was defined as the closest PSA value within 90 days prior to or on the first 177 Lu-PSMA-617 claim (index date). Post-treatment PSA response was defined as the lowest PSA value ≥28 days after the index date. The proportion of patients with ≥ 50%, ≥80% and ≥90% PSA reductions were reported. Results: A total of 1,710 patients treated with 177 Lu-PSMA-617, with mean (standard deviation) age was 72.2 (8.5) years, met eligibility and were included in the study. Common comorbidities included hypertension (34.7%), osteoarthritis (27.3%) and dyslipidemia (23.9%). Based on ICD-10 codes, 1,447 (84.6%) patients had bone metastases, and 575 (33.6%) had visceral metastases, of whom 128 (7.5%) had liver metastases. Only 59 (3.5%) patients had lymph node only metastasis. In the pre-index period, 83.4% patients had used prior ARPI and/or taxane chemotherapy, and 98% patients had used other systemic therapies. In a sub-analysis of 159 (9.3%) patients with pre- and post-index PSA values available (whose clinical characteristics are comparable to the overall cohort of 1,710 patients), median PSA at baseline before initiation of 177 Lu-PSMA-617 was 61 ng/ml. Among these patients, 53.5%, 29.6% and 22.6% had PSA reductions of ≥50%, ≥80% and ≥90%, respectively, while on treatment. Rate of PSA response was similar regardless of history of ARPI or taxane use. Conclusions: To our knowledge, this is the first large-scale report of real-world US patients treated with 177 Lu-PSMA-617. Clinical characteristics and PSA responses observed are consistent with results from the VISION clinical trial demonstrating benefit with 177 Lu-PSMA-617 treatment. Subsequent analysis with longer follow up are needed to understand the long-term outcomes associated with 177 Lu-PSMA-617 in real-world US patients.
Risk factors for neoadjuvant chemotherapy-induced acute kidney injury in patients with muscle-invasive bladder cancer: A multicenter retrospective study.
Authors: Naoki Fujita, Masaki Momota, Toshikazu Tanaka, Shogo Hosogoe, Shingo Hatakeyama, Takahiro Yoneyama, Yasuhiro Hashimoto, Chikara Ohyama
Journal: Journal of Clinical Oncology (2024)

700 Background: Neoadjuvant chemotherapy (NAC)-induced acute kidney injury (AKI) is one of the frequent complications in patients with muscle-invasive bladder cancer (MIBC) and we previously have reported the negative impact of NAC-induced AKI on oncological outcomes. However, its risk factors remain unclear. Methods: This multi-institutional retrospective study included 517 patients with MIBC who received 2–4 cycles of NAC followed by radical cystectomy. AKI was defined according to the KDIGO criteria. Patients were divided into two groups: patients who developed any stage AKI during NAC (AKI group) and patients who did not (non-AKI group). Multivariable logistic regression analysis was performed to identify the risk factors for NAC-induced AKI. The predictive abilities for AKI were evaluated using the area under the receiver operating characteristic curve. Results: The median age was 69 years. Of the 517 patients, 188 (36%) received cisplatin-based regimens and 92 (18%) developed any stage AKI. Approximately 86% AKI were stage 1 AKI. In the univariable analyses, hypertension, impaired renal function, and cisplatin-based regimen were significantly associated with increased risk of AKI. In the multivariable analysis, hypertension, impaired renal function, and cisplatin-based regimen were independently and significantly associated with increased risk of AKI (Table). The optimal cutoff value of estimated glomerular filtration rate for AKI was 65.0 mL/min/1.73m 2 . ROC analysis showed that the AUC of hypertension plus eGFR &lt;65.0 mL/min/1.73m 2 plus cisplatin-based regimen was 0.748 (95% confidence interval [CI]: 0.697–0.799]. Conclusions: Hypertension, impaired renal function, and cisplatin-based regimens were risk factors for NAC-induced AKI in patients with MIBC. [Table: see text]