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Long-read sequencing of 945 Han individuals identifies structural variants associated with phenotypic diversity and disease susceptibility
Prostate cancer liver metastases: Genomic profiling and clinical outcomes.
189 Background: Patients (pts) with metastatic prostate cancer and liver metastases have poor prognosis, but clinicogenomic analyses are limited. We examined the clinical and genomic features of a cohort with prostate cancer liver metastases (PCLM). Methods: Pts were identified from a prospective population-based biobank in British Columbia, Canada. Eligible pts had PCLM identified on imaging prior to any line of treatment. We collated clinical outcomes with cell-free DNA (cfDNA) sequencing results including circulating tumor DNA fraction (ctDNA%) and genomic alterations. Results: 2048 metastatic prostate cancer pts were enrolled from October 2016 to July 2024, of whom 1258 had sufficient clinical annotation to evaluate PCLM status. Of these, 167 (13%) were diagnosed with PCLM: 36 (22%) with castration-sensitive prostate cancer (mCSPC), 48 (29%) prior to first-line castration-resistant prostate cancer treatment (1L mCRPC), 30 (18%) prior to 2L mCRPC, and 53 (32%) prior to ≥3L mCRPC. Median follow-up was 60.3 months. Median age at metastatic diagnosis was 68.7 (IQR 61.8-74.7) years, 93 (56%) had de novo metastatic disease, 20 (12%) had histologically proven small cell carcinoma, 27 (16%) had low PSA (<5ng/mL) at baseline, and 111 (66%) had ≥3 liver metastases. For mCSPC pts, 27 (75%) received treatment intensification beyond ADT alone, including 5 (14%) with platinum chemotherapy. Median overall survival (mOS) for mCSPC pts was 15.5 months (95% CI 11.7-28.1), and median time to castration resistance was 8.1 months (95% CI 5.7-10.7). For mCRPC pts, 94 (72%) had prior exposure to ARPI, 56 (43%) to taxane, and 8 (6%) to platinum. mOS for 1L mCRPC pts was 9.4 months (95% CI 6.7-12.6), for 2L mCRPC 4.9 months (95% CI 3.5-9.7) and for ≥3L mCRPC 5.6 months (95% CI 4.1-8.4). For 134 pts with cfDNA results the median ctDNA% was 24.7 (IQR 4.6-53.9). Alterations were found in TP53 (47%), PTEN (26%), RB1 (19%), with 82 pts (61%) having alterations in at least one tumor suppressor gene (TSG) and 34 (25%) in more than one TSG. 14 pts (10%) had a BRCA2 alteration. ctDNA% and detectable TSG alterations were associated with survival of pts with PCLM (Table). Of 17 long survivors (pts who lived >24 months from start of next line treatment), 12 had cfDNA results available, median ctDNA% was 13.6%, and only 1 had TSG loss detected ( PTEN ). Conclusions: Pts with PCLM exhibit poor clinical outcomes; both elevated ctDNA% and TSG loss correlate with reduced overall survival. mCSPCmOS (months)N = 24 pts with cfDNA 1L mCRPCmOS (months) N = 35 pts with cfDNA 2L mCRPCmOS (months)N = 25 pts with cfDNA TSG status No alteration detected 57 23.6 8 Alteration detected 11.7 6.8 4.3 Univariable HR (95% CI) 9.3 (2.0-42.7)p<0.01 5.6 (2.1-15.5)p<0.01 1.4 (0.6-3.2)p=0.4 ctDNA% ≤ median ctDNA% (24.7%) 57 18.1 9 > median ctDNA% (24.7%) 14.7 5.8 12 Univariable HR (95% CI) 2.4 (1.0-5.4)p<0.05 2.7 (1.5-5.0)p<0.01 1.1 (0.6-2.0)p=0.8
The prognostic value of LDH in patients with good risk metastatic seminoma treated with single agent carboplatin AUC10.
644 Background: Raised lactate dehydrogenase (LDH) is a surrogate marker for disease burden and an independent adverse prognostic factor for IGCCCG good risk metastatic seminoma patients treated with cisplatin and etoposide-based chemotherapy (Beyer et al, 2021). Patients with a pre-treatment LDH greater than 2.5x the upper limit of normal (ULN), despite still categorized as good risk disease, have a poorer 3-year progression free survival (PFS) of 80% with this combination treatment. Carboplatin Area Under the Curve (AUC) 10 monotherapy is an alternative to cisplatin and etoposide-based chemotherapy, with comparable effectiveness and a better side effect profile. However, the prognostic value of LDH and specific outcomes of patients with raised LDH in patients treated with carboplatin AUC10 has not been evaluated. Methods: A retrospective analysis of outcomes of good risk metastatic seminoma patients treated with carboplatin AUC10 from January 2000 to January 2021 at two supra-regional cancer centres was conducted. Data were extracted using electronic health records. The variables collected included primary tumor location, stage, tumor markers, relapse date, post-relapse treatment and cause of death. Results: 245 patients were identified with a median follow up period of 5.9 years. The primary site of the tumor was most commonly the testes (n=229, 93.5%). 76 (31%) presented with stage 2a, 81 (33%) with stage 2b and 43 (16%) with stage 2c. 14 patients (6%) experienced a relapse, with 11 patients received bleomycin, etoposide and cisplatin as salvage treatment. 24 patients (10%) had LDH levels >2.5 ULN. The 3-year PFS rate for patients with LDH >2.5 ULN was 79.2% versus 95% in LDH <2.5 ULN (p=0.0004). This was comparable to the 80% reported in the high LDH group by Beyer et al. Conclusions: Our results confirm the validity of raised LDH as an adverse prognostic factor in good risk metastatic seminoma patients treated with carboplatin AUC10, with similar PFS outcomes compared to etoposide-cisplatin based chemotherapy described in Beyer et al. Elevated LDH does not appear to be a contraindication to the use of carboplatin AUC10 monotherapy in this patient population and represents a less toxic alternative to etoposide-cisplatin based chemotherapy.
Efficacy and safety of lenvatinib plus everolimus in metastatic renal cell carcinoma after immune checkpoint and VEGFR tyrosine kinase inhibitors.
489 Background: Limited studies have investigated the real-world effectiveness and safety of Lenvatinib (LEN) combined with everolimus (EVE) in metastatic renal cell carcinoma (mRCC), particularly after failure of immune checkpoint inhibitors (ICIs) and VEGFR tyrosine kinase inhibitors (TKIs). This study aimed to evaluate the efficacy and safety of LEN plus EVE in patients who had progressed after these prior therapies. Methods: This single-center retrospective study included mRCC patients at Asan Medical Center, Korea, who initiated LEN plus EVE as second-line or later therapy between September 2017 and June 2024. We reviewed electronic medical records for dosage, dose reductions, discontinuation, response, progression, and survival outcomes. The primary objectives were objective response rate (ORR) and progression-free survival (PFS), with secondary objectives including overall survival (OS), adverse events, and prognostic factors. Results: Eighty-two eligible patients were included, predominantly with clear cell type (n=74, 90.2%). ECOG performance status was 1 in 54 patients, and 2 in 26. At treatment initiation, the IMDC risk distribution was favorable (n=6, 7.3%), intermediate (n=48, 58.5%), and poor (n=28, 34.1%). The median number of prior therapies was four (range, 1-7), with 80.5% receiving LEN plus EVE as fourth-line or later therapy. All patients had prior anti-angiogenic TKI exposure, 86.6% had been treated with ICIs, and 37.8% had prior mTOR inhibitor therapy. The ORR was 39.0% (n=32/82), with a disease control rate (DCR) of 81.7% (n=67/82). The median follow-up duration was 21.8 months. The median time to progression (TTP) was 6.4 months (95% Confidence Interval [CI], 5.4-9.7), while the median PFS was 5.4 months (95% CI, 4.3-6.4), and the median OS was 7.7 months (95% CI, 6.2-12.1). Subgroup analyses indicated comparable ORR and PFS for patients treated beyond the fourth line (ORR 36.4%, PFS 5.3 months), those previously exposed to mTOR inhibitors (ORR 29.0%, PFS 5.5 months), and those who had progressed after both ICI and TKIs (ORR 38.0%, PFS 5.3 months). The median treatment duration was 6.8 months. Adverse events were significant: 54.9% required dose reductions of LEN, and 25.6% experienced treatment interruptions. For EVE, 17.1% required dose reductions, and 25.6% had interruptions due to toxicities. Notably, 31 patients (37.8%) developed proteinuria, with 18 experiencing grade 3 or higher. Conclusions: LEN plus EVE shows promising efficacy and disease control in heavily pretreated mRCC patients after failure of ICIs and VEGFR TKIs, even beyond the fourth line and in those previously treated with mTOR inhibitors. The safety profile aligns with known adverse effects, but the high incidence of proteinuria is notable. Further studies are warranted to optimize treatment protocols in this patient population.
Stepwise amplification of circularly polarized luminescence in indium-based metal halides by regulating their structural dimension
How unfavorable is AUA unfavorable intermediate-risk prostate cancer? Results from a large, institutional cohort.
342 Background: Major clinical guidelines including the American Urology Association (AUA) defines unfavorable intermediate-risk prostate cancer (UIR-PCa) according to diagnostic PSA, clinical stage, biopsy positive cores, and Gleason grade group (GG). The current AUA guidelines separate patients into 3 primary groups: 1) GG1 with PSA 10-20 and stage T2b-c, 2) GG2 with PSA 10-20 and/or stage T2b-c and/or ≥50% biopsy cores positive, and 3) GG3 with PSA <20. We sought to utilize a large institutional radical prostatectomy (RP) cohort with long-term outcomes data to determine how UIR-PCa has evolved over time, and whether the current groupings are equally unfavorable as defined by the current guidelines. Methods: Participants were diagnosed with UIR-PCa at University of California, San Francisco in 2000-2024 and underwent RP. Disease risk was defined by clinical Cancer of the Prostate Risk Assessment (CAPRA) at diagnosis and post-surgical CAPRA (CAPRA-S) at RP. Lifetable estimates, Kaplan-Meier curves, and Cox proportional hazards regression were performed to evaluate outcomes of recurrence, defined as either biochemical failure (two PSA ≥0.2 ng/ml) or second treatment and metastasis after RP. The model was adjusted for age, PSA density, and high genomic score (OncotypeDx GPS>40, Decipher >0.6 or Prolaris>0.8). Results: 1,394 patients were included in the study. Median (IQR) follow-up was 44 (15-91) months. Clinical CAPRA at diagnosis was 6% low, 73% intermediate, and 21% high risk. From 2000 to 2023, the proportion of UIR-PCa patients defined by biopsy GG3 increased 34% to 63%. During the same period, the number of high-risk patients by CAPRA (≥6) increased from 10% to 31%. At RP, the proportion of patients with pathologic GG3 and GG4-5 increased from 22% to 41% and from 7 to 16%, respectively. Seven years following radical prostatectomy (RP), recurrence-free survival was 57% and metastasis-free survival was 92%. Kaplan-Meier analysis demonstrated that 7-year recurrence-free survival after radical prostatectomy was significantly lower for GG3 patients (48%) compared to GG1/GG2 patients (67%), log-rank p<0.01. Meanwhile, 7-year metastasis-free survival after radical prostatectomy was 90% for GG3 patients relative to 94% for GG1/GG2 patients, log-rank p<0.01. Multivariable Cox regression analysis showed a significant increase in the risk of recurrence after RP for GG3 patients compared to GG1/GG2 (HR 1.64, 95% CI 1.32 – 2.05, p<0.01, Table 1), but not for risk of metastasis. Conclusions: The study shows a significant increase in GG3 among UIR-PCa patients over time, and that UIR-PCa defined by GG3 was associated with adverse outcomes after RP. These findings suggest that the current UIR-PCa groupings as defined by the AUA are not created equal and may warrant revision to address an evolving risk profile of UIR-PCa over time. Cox proportional hazards regression for the outcome of recurrence after RP. Effect Parameter Global p Param p HR 95%CI Lower 95%CI Upper Year of diagnosis Per 10 years 0.28 1.01 0.99 1.04 Age at diagnosis Per 10 years 0.44 1.06 0.91 1.24 PSA density Logarithm <.01 1.53 1.29 1.82 Preop genomic Low vs High <.01 <.01 0.64 0.45 0.90 No test vs High <.01 0.49 0.37 0.66 Unfav subgroup GG3 vs GG1/GG2 <.01 1.64 1.32 2.05
CTC and AR-V7 analysis in the ECOG-ACRIN 8153 (CHAARTED2) randomized trial: Abiraterone (Abi) with or without cabazitaxel (Abi-Cabazi) in extensive mCRPC following docetaxel.
181 Background: The CHAARTED2 trial showed improved PFS with Abi-Cabazi over Abi-alone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who previously received docetaxel for metastatic castration-sensitive disease. Here, we evaluated the prognostic and predictive impact of CTC and AR-V7 circulating biomarkers. Methods: The modified AdnaTest (Qiagen) was used to define CTC detection (+ vs –) and AR-V7 detection (+ vs –) at baseline, C5D1, as well as at the time of progression. We first assessed the prognostic value of baseline and C5D1 CTC and AR-V7 status in the two arms. We also assessed the predictive potential of baseline and C5D1 CTC and AR-V7 status to explore if these biomarkers may aid in treatment selection. Logrank test and Cox proportional hazards models were used to assess for associations between clinical outcomes and baseline biomarker status. Landmark analysis was performed to evaluate associations at C5D1. Results: A total of 223 pts were randomized between the two arms. CTC data were evaluable for 94/112 and 94/111 pts in the Abi-alone and Abi-Cabazi arms, respectively. Baseline CTC detection was prognostic for worse PFS in both the Abi-alone (7.1 vs 31.7 months, HR 3.64, P <0.001) and the Abi-Cabazi (9.6 vs 36.9 months, HR 4.13, P <0.001) arms. Likewise, baseline AR-V7 detection portended worse PFS in the Abi-alone (4.1 vs 12.8 months, HR 3.34, P <0.001) and the Abi-Cabazi (6.9 vs 15.1 months, HR 3.17, P <0.001) arms. At C5D1, there was a higher rate of CTC(-) conversion (60 vs 46%) and AR-V7(-) conversion (69 vs 58%) in the Abi-Cabazi arm. CTC(-) and AR-V7(-) status at C5D1 was prognostic of improved PFS in both arms (all P ≤0.02). In terms of predictive impact, PFS was numerically but not statistically longer in the Abi-Cabazi arm in all biomarker groups; the greatest relative PFS benefit to Abi-Cabazi was in the baseline AR-V7(+) group (HR 0.68, 95%CI 0.36–1.3, P =0.2). Similarly, at C5D1, the greatest relative PFS benefit to Abi-Cabazi was in pts remaining AR-V7(+) (HR 0.57, 95%CI 0.15–2.16, P =0.4). Conclusions: Baseline CTC and AR-V7 detection were both prognostic for inferior PFS in both study arms. PFS outcomes were broadly longer in the Abi-Cabazi vs Abi-alone arm in all biomarker groups. The presence of AR-V7 at baseline and at C5D1 was the strongest relative predictor of Abi-Cabazi benefit, but did not meet statistical significance. Clinical trial information: NCT03419234 .
In-field progression following radiation therapy as a prognostic biomarker for lutetium-177-PSMA-617 response in metastatic castration-resistant prostate cancer.
86 Background: Prostate cancer often expresses prostate-specific membrane antigen (PSMA), which serves as a diagnostic and therapeutic target. Lutetium-177 ( 177 Lu)-PSMA-617 is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing sites. The prognostic implications of in-field progression (IFP) following prior radiation treatment (RT) on 177 Lu-PSMA-617 response in metastatic castration-resistant prostate cancer (mCRPC) are unknown. Methods: We retrospectively reviewed our experience with 177 Lu-PSMA-617 in mCRPC delivered at multiple community-based practices in the Mountain West. Exclusion criteria included death unrelated to prostate cancer before cycle 3 of 177 Lu-PSMA-617 and completing < 4 cycles by June 1 st , 2024. Baseline characteristics and treatment history were collected. Baseline PSMA PET/CTs were evaluated for maximum SUV, visceral metastases, and lesional heterogeneity (LH) and correlated with radiation records to determine IFP. Progression-free survival (PFS) and overall survival (OS) were determined using Kaplan-Meier and Logrank analysis, and Cox proportional hazard model was used for univariate (UV) and multivariate (MV) analysis of suspected risk factors. Results: In total, 72 patients were evaluated with a median follow-up of 10.9 months. Median PFS was 6.5 months (95%CI [4.4 – 9.3]), and median OS was 15.0 months (95%CI [10.9 – undefined]). Fifty-nine patients received either palliative or definitive RT courses for prostate cancer prior to receiving 177 Lu-PSMA-617. Of the 59 patients, 25 patients demonstrated IFP, 34 did not. In-field progression (UV: HR 2.5, p=.003; MV: HR 2.7, p=.003) and LH (UV: HR 1.9, p=.025; MV: 2.1, p=.036) were found to be risk factors for progression during 177 Lu-PSMA-617 therapy. Median PFS among patients with IFP was 3.9 mo (95%CI [2.6 – 6.3]) versus 10.3 mo (95%CI [4.4 – 13.0]) among those without (p=.002). Median PFS among patients with LH was 4.6 mo (95%CI [2.9 – 6.5]) versus 11.6 mo (95%CI [6.9 – 13.0]) for those without (p=.023). IFP (UV: HR 2.5, p=.016; MV: 2.7, p=.021; median OS = 10.2 mo, 95%CI [6.2 – 12.8]) and LH (UV: HR 2.45, p=.027; MV: HR 4.17, p=.018; median OS = 11.7 mo, 95%CI [9.3 – 15.0]) were similarly prognostic for OS. At the current follow-up, median OS has not been reached for patients without IFP or LH, but Logrank testing shows statistically significant improvements in OS for these groups (p=.013 and p=.022, respectively) over those with them. Conclusions: In our real-world experience, PFS and OS for 177 Lu-PSMA-617 in mCRPC were similar to the VISION study results. IFP following RT and LH on baseline PSMA PET/CT were negative prognostic biomarkers. Validation in a larger, prospective cohort is warranted.
Breakage fusion bridge cycles drive high oncogene number with moderate intratumoural heterogeneity
Abstract Oncogene amplification is a key driver of cancer pathogenesis. Both breakage fusion bridge (BFB) cycles and extrachromosomal DNA (ecDNA) can lead to high oncogene copy numbers, but the impact of BFB amplifications on intratumoral heterogeneity, treatment response, and patient survival remains poorly understood due to detection challenges with DNA sequencing. We introduce an algorithm, OM2BFB, designed to detect and reconstruct BFB amplifications using optical genome mapping (OGM). OM2BFB demonstrates high precision (>93%) and recall (92%) in identifying BFB amplifications across cancer cell lines, patient-derived xenograft models, and primary tumors. Comparisons using OGM reveal that BFB detection with our AmpliconSuite toolkit for short-read sequencing also achieves high precision, though with reduced sensitivity. We identify 371 BFB events through whole genome sequencing of 2557 primary tumors and cancer cell lines. BFB amplifications are prevalent in cervical, head and neck, lung, and esophageal cancers, but rare in brain cancers. Genes amplified through BFB exhibit lower expression variance, with limited potential for regulatory adaptation compared to ecDNA-amplified genes. Tumors with BFB amplifications (BFB(+)) show reduced structural heterogeneity in amplicons and delayed resistance onset relative to ecDNA(+) tumors. These findings highlight ecDNA and BFB amplifications as distinct oncogene amplification mechanisms with differing biological characteristics, suggesting distinct avenues for therapeutic intervention.
Olanzapine for managing side effects from tyrosine-kinase inhibitors.
524 Background: Antiangiogenic tyrosine kinase inhibitors (TKIs) play a key role in treating renal cell carcinoma and other solid organ malignancies, but TKIs cause bothersome side effects that frequently necessitate dose reductions or treatment holds. Olanzapine has been useful for palliating symptoms from classical chemotherapies and advanced cancer, but its effect on TKI-related symptoms is largely unknown. This retrospective study aimed to estimate the efficacy of olanzapine for TKI-induced nausea, vomiting, anorexia, weight loss, and insomnia. Methods: All patients prescribed olanzapine with lenvatinib, cabozantinib, axitinib, or tivozanib at Mayo Clinic between January 1, 2018, and June 30, 2024 were assessed for inclusion. For baseline symptom assessment, clinical care team notes documenting the presence or absence of symptoms and indication(s) for starting olanzapine were reviewed. For response assessment, clinical notes and patient portal messages from the first three months after starting olanzapine were evaluated for qualitative descriptions of change in symptom burden. Relevant data were extracted as direct quotations, which were reviewed by the research team and categorized as “improved,” “worsened,” “stable,” or “missing data.” Each symptom domain was analyzed independently when olanzapine was prescribed for multiple interrelated symptoms. Results: A total of 60 patients who received olanzapine for the treatment of TKI-related adverse effects were included. The most common documented indication for olanzapine was nausea without vomiting (n=35), followed by anorexia (n=25), nausea with vomiting (n=16), weight loss (n=16), and insomnia (n=11). In 32 cases (53%), olanzapine was prescribed for multiple, simultaneous symptoms. Response rates for each symptom domain are shown in the table. In addition, prior to olanzapine, 34 patients (57%) had documented weight loss. Following olanzapine, 50% (n=17) gained weight (median increase: 6.1 kg; range: 2.0 - 10.7 kg), 26% (n=9) stabilized their weight (±1 kg), and 24% (n=8) continued to lose weight. Clinicians utilized a TKI dose reduction within one week of olanzapine initiation in 5 cases (8.3%), and 3 of these patients could resume the higher dose of TKI after starting olanzapine. Only 4 patients (7%) discontinued olanzapine within 3 months due to perceived side effects. Conclusions: Olanzapine appears to be effective in treating TKI-induced nausea, vomiting, anorexia, insomnia, and weight loss. Prospective randomized placebo-controlled studies are needed to confirm these findings. Improvedn (%) Worsened n (%) Stablen (%) Missing Datan (%) Nausea without emesis 32 (84) 3 (8) 1 (3) 2 (5) Nausea with emesis 13 (93) 0 (0) 0 (0) 1 (7) Anorexia 26 (74) 2 (6) 4 (11) 3 (9) Insomnia 11 (85) 0 (0) 2 (15) 0 (0)
Impact of variant allele frequency (VAF) of <i>TP53</i> alterations and Signatera circulating tumor DNA (ctDNA) monitoring for patients (pts) with advanced urothelial carcinoma (aUC) treated with enfortumab vedotin (EV).
830 Background: EV is now a standard of care for pts with aUC, both as monotherapy and with pembrolizumab (EVP). Factors predictive of primary refractory disease (PRD) remain poorly understood. Prior investigation correlated low VAF pathogenic TP53 alterations on next-generation sequencing (NGS) with rapid progression on frontline (1L) platinum chemotherapy. Thus, we hypothesized that low TP53 alteration VAF would associate with inferior outcomes on EV. Methods: We generated an IRB-approved, HIPAA-compliant single institution retrospective database of pts with aUC who received EV monotherapy or in combination, starting 1/2019. Data cutoff was 9/2024. Baseline demographics, clinicopathologic features, and somatic NGS data were extracted from the electronic health record. PRD was defined as progressive disease (PD) on the first restaging scan after starting EV or earlier clinical progression resulting in death from disease. Signatera ctDNA was collected every 1-3 months. Statistical analysis included Fisher’s exact test. Results: We identified 82 pts with aUC who received EV, of whom 35 had available NGS data on tumor tissue. 22 pts (63%) had a TP53 alteration with reported VAF, with a median of 48.7% (range 12.1%-81.9%). Amongst the 35 pt cohort, at EV start, median age was 69 yrs, 65% male, 83% white, 40% never smokers, 23% with variant predominant histology, 17% upper tract disease, and metastatic sites included lymph node (77%), lung (26%), liver (20%), and bone (9%). 21 pts received EV as 1L therapy, and 14 pts received EV in the refractory setting (2L+). 21 pts received EVP, 1 pt received EVP with carboplatin, and 13 pts received EV monotherapy. Median follow-up time from EV start was 6.5 months, and 54% of pts were alive at data cutoff. For 1L EV, 29% (6/21) had PRD. Observed response rate (ORR) was 81% (13/16) at first restaging scan. For 2L+ EV, PRD rate was 43% (6/14), and ORR at first restaging scan was 55% (6/11). 8 of 22 pts (36%) with TP53 alteration had PRD. Pts with TP53 VAF below the median had 64% with PRD versus 9% with TP53 VAF above the median ( p =0.024). Among 22 pts with TP53 alterations, 4 pts had serial Signatera testing, of which 1 exhibited PRD. The pt with PRD had low TP53 VAF and persistently rising ctDNA values. 1 pt with low TP53 VAF had a decline in ctDNA that correlated with partial response on initial restaging scan before ctDNA rise corresponded with PD on the following scan, 1 pt with low TP53 VAF had persistent undetectable values, and 1 pt with high TP53 VAF had an initial detectable value become undetectable. Conclusions: Low TP53 alteration VAF was significantly associated with PRD to EV treatment, highlighting its potential as a predictive biomarker. ctDNA monitoring may be useful to monitor treatment response on EV. These findings are exploratory and must be validated in larger cohorts.
Bipolar androgen therapy (BAT) for nonmetastatic castration-resistant prostate (nmCRPC) cancer progressing on darolutamide: Working Out M0 BAT (WOMBAT; ANZUP 2201).
TPS298 Background: The backbone of prostate cancer systemic treatment is androgen deprivation therapy (ADT) increasingly with the use of androgen receptor pathway inhibitors (ARPIs). Mechanisms for ARPI resistance include amplification of the androgen receptor (AR), overexpression of AR variants, aberrant AR activity, and autocrine/paracrine androgen synthesis in tumour cells. Preclinical and clinical studies have identified that bipolar androgen therapy (BAT) may restore the sensitivity of prostate cancer to ARPIs. We plan to test this hypothesis in patients with PSA progression on darolutamide for non-metastatic castrate resistant prostate cancer. Methods: WOMBAT (ANZUP 2201, NCT06594926, ACTRN12624000582550) is a single-arm phase 2 trial. The primary endpoint is to determine metastasis-free survival (MFS; time from commencing BAT to evidence of metastases or death, by conventional imaging as per PCWG3 criteria). Secondary endpoints include toxicity of BAT and darolutamide; effects on health-related quality of life; efficacy measures (PSA response rate; PSA progression-free survival); effects of BAT and darolutamide on bone turnover. Inclusion criteria include: PSA progression on darolutamide for nmCRPC; M0 on conventional imaging. Treatment consists of BAT (IM testosterone enanthate 500mg) day 1 and darolutamide 600mg bd days 29-56 (of a 56-day cycle) with ongoing ADT. The total sample size of 69 (with a first stage of enrolment of 44) is calculated to demonstrate an increase in the proportion of participants without detectable metastases at 6 months from 56.1% to 66.7% (corresponding to a median MFS improvement from 7.2 to 10.27 months, HR 0.6) with a one-sided type I error of α = 10% and power of 80%, based on benchmarks from the ARAMIS trial of darolutamide in nmCRPC. Enrolment has commenced at 8 sites around Australia. Clinical trial information: ACTRN12624000582550 .
Transferrable, wet-chemistry-derived high-k amorphous metal oxide dielectrics for two-dimensional electronic devices
Impact of homologous recombination repair alterations ( <i>HRRalt</i> ) on survival outcomes of patients (Pts) with metastatic hormone-sensitive prostate cancer (mHSPC).
205 Background: Up to 30% of pts with advanced prostate cancer have HRRalt [PMID: 32343890]. The presence of tumor HRRalt has been associated with poor prognosis in the metastatic castration-resistant setting [PMID: 38417742]. However, the impact of HRRalt in patients with mHSPC is unknown. Herein, we sought to interrogate the effect of HRRalt on the survival outcomes of pts with mHSPC. Methods: This IRB-approved retrospective study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine prostate cancer clinico-genomic database (FH-FMI CGDB). The de-identified data originated from approximately 280 US cancer clinics (~800 sites of care). Inclusion criteria: de novo mHSPC, tissue biopsy within 90 days of diagnosis, and initiation of androgen deprivation therapy intensification (ADTi) with androgen receptor pathway inhibitor (ARPI) or taxane within 120 days of diagnosis. Survival outcomes were compared between pts with wild-type HRR ( wtHRR ) and those with HRRalt in 14 pre-specified genes per the olaparib FDA label. Time to castration-resistance (TTCR) was defined from the start of therapy for mHSPC to clinical, biochemical, or radiographic progression or death. Overall survival (OS) was defined from treatment initiation for mHSPC to death, or censored at the last follow-up. TTCR and OS indexed from metastatic diagnosis, were evaluated with Cox proportional hazards models adjusted for baseline prognostic factors. OS risk intervals were left truncated to date of comprehensive genomic profiling report to adjust for immortal time. Exploratory analyses were conducted to evaluate the association of individual HRR genes on survival outcomes in subgroups with sufficient events. Results: 637 pts were eligible and included (181 HRRalt , 28.4%), of whom 378 received an ARPI, and 259 received a taxane. The median age of the overall cohort was 68 (IQR 61 – 75). Results are summarized (Table). Conclusions: This is the largest real-world study to show significantly shorter TTCR in pts with mHSPC harboring HRRalt. No differences were observed in OS. However, CDK12m was enriched for less favorable TTCR and OS for both ARPI and taxane, highlighting an unmet need. These hypothesis-generating data may inform future clinical trial design and counseling of pts with mHSPC and HRRalt . Adjusted hazard ratio (aHR) for TTCR and OS. Genetic alteration Subgroup TTCR (aHR; 95% CI, p) OS (aHR; 95% CI, p) HRRalt vs. wtHRR ADT + ARPI 1.5; 1.1 – 2.0 1.1; 0.80 – 1.6 HRRalt vs. wtHRR ADT + Taxane 1.7; 1.2 – 2.3 1.2; 0.88 – 1.7 BRCA1/2 alt. vs. wtBRCA ADT + ARPI 1.7; 1.1 – 2.5 1.1; 0.67 – 1.8 BRCA1/2 alt. vs. wtBRCA ADT + Taxane 1.5; 0.92 – 2.3 1.1; 0.67 – 1.8 ATMm vs. wtATM ADT + ARPI 0.95; 0.50 – 1.8 0.82; 0.38 – 1.8 ATMm vs. wtATM ADT + Taxane 1.4; 0.65 – 2.9 1.3; 0.53 – 3.2 CDK12m vs. wtCDK12 ADT + ARPI 1.7; 1.1 – 2.8 1.7; 1.0 – 3.0 CDK12m vs. wtCDK12 ADT + Taxane 3.2; 2.0 – 5.3 1.7; 0.98 – 2.9
Temporal trends and socioeconomic determinants of cytoreductive nephrectomy (CN) utilization for metastatic renal cell carcinoma (mRCC) in the United States (US).
447 Background: The evolving treatment landscape in mRCC since the advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has rendered the role of CN unclear. We sought to quantify CN utilization in the US over the past two decades and assess factors that affect equitable access to CN. Methods: We performed an analysis of the National Inpatient Sample database, using ICD-9 and ICD-10 diagnostic and procedure codes to identify mRCC patients undergoing CN from 2006 to 2021. We calculated annual CN utilization rates, stratified by demographic and socioeconomic factors. We then performed univariable and directed acyclic graph-guided multivariable logistic regression analyses to determine the effect of demographic, socioeconomic, and clinical factors on CN utilization rates. Results: There has been a significant decrease in CN utilization in 2021 compared to 2006 (8.7% vs. 15.8%; OR 0.51, 95% CI 0.42-0.61), consistent across all demographic and socioeconomic groups. Factors associated with decreased CN utilization include Black race (OR 0.70, 95% CI 0.64-0.76), Hispanic race (OR 0.87, 95% CI 0.80-0.95), female gender (OR 0.94, 95% CI 0.90-0.98), being a Medicare (aOR 0.69, 95% CI 0.64-0.73) or Medicaid beneficiary (aOR 0.59, 95% CI 0.54-0.64), lowest income quartile (aOR 0.84, 95% CI 0.78-0.90), Southern US location (aOR 0.83, 95% CI, 0.74-0.93), and treatment in small-sized (aOR 0.57, 95% CI 0.51-0.63) or rural hospitals (aOR 0.33, 95% CI 0.27-0.40). CN utilization has significantly decreased during the ICI era compared to the TKI era (OR 0.69, 95% CI 0.64-0.75). Conclusions: CN utilization has steadily declined across the US over the past two decades, reflecting the uncertainty surrounding its role in mRCC management as new systemic therapies emerge. Access to CN is marked by significant demographic and socioeconomic disparities. Defining the evolving role of CN in the current mRCC treatment era and addressing these disparities is crucial to optimize patient outcomes. Characteristic Univariable analysis(OR [95% CI]) p -value Multivariable analysis(aOR [95% CI]) p -value Black race (ref. White) 0.70 (0.64-0.76) <0.001 - - Hispanic race (ref. White) 0.87 (0.80-0.95) 0.001 - - Female gender (ref. male) 0.94 (0.90-0.98) 0.008 - - 1 st quartile income (ref. 4 th quartile) 0.79 (0.73-0.85) <0.001 0.84 (0.78-0.90) <0.001 Medicare (ref. private insurance) 0.55 (0.53-0.58) <0.001 0.69 (0.64-0.73) <0.001 Medicaid (ref. private insurance) 0.58 (0.54-0.63) <0.001 0.59 (0.54-0.64) <0.001 Southern US (ref. Northeastern US) 0.82 (0.73-0.92) 0.001 0.83 (0.74-0.93) 0.002 Small hospital (ref. large hospital) 0.56 (0.50-0.62) <0.001 0.57 (0.51-0.63) <0.001 Rural hospital (ref. urban teaching hospital) 0.32 (0.27-0.38) <0.001 0.33 (0.27-0.40) <0.001
Image-based artificial intelligence algorithms for molecular diagnostics in prostate pathology: How far are we? A systematic review.
193 Background: Guidelines recommend molecular diagnostics for homologous and mismatch repair (MMR) defects in men with metastatic castration-resistant prostate cancer. However, in clinical practice, routine testing is hindered because it is costly, time-consuming and not available in all laboratories. Moreover, many patients need to be tested to identify the few with these genetic aberrations. To address these challenges, image-based artificial intelligence (AI) algorithms have been developed to predict molecular alterations from hematoxylin and eosin (HE) slides that are beyond the pathologist's visual detection. This review aims to assess the advancements of image-based AI algorithms in molecular diagnostics in prostate pathology and their potential in daily clinical practice. Methods: Through a search query, 3213 articles were identified and screened by two reviewers. In total, 12 articles were selected for this review and were assessed using the QUADAS-2 criteria. Results: Out of 12 articles, 5 focused exclusively on a specific set of preselected genes in prostate cancer, while the other articles examined broader ranges of genomic or transcriptomic changes, with some covering various cancer types. Training datasets consisted of up to 451 prostate cancer slides and most studies included only slides from radical prostatectomies. The majority made use of the cancer genome atlas program (TCGA). The best performance reported was 0.91 area under the curve (AUC) on internal and AUC of 0.89 on external validation. However, only 5 of the 12 studies performed external validation and none looked into the application of their algorithm in a clinical setting. Conclusions: Our review shows that in concept, AI is reasonably capable of detecting molecular changes based on HE slides of prostate pathology with reasonable predictive power. This has been shown in different specific genetic alterations, as well as in genome- or transcriptome-wide alterations. The predictive power of AI may however not be good enough to forgo molecular testing in patients predicted negative. Furthermore, these systems have only reached the developmental stage, leaving their potential performance in a clinical setting yet to be determined.
Time to metastasis after prostatectomy (TTM) and survival outcomes in patients (pts) with metachronous metastatic hormone-sensitive prostate cancer (mHSPC): A secondary analysis of the SWOG 1216 phase 3 trial.
173 Background: It is well-established that pts with de-novo mHSPC have poorer survival compared to those with metachronous disease. However, the impact of timing of metastatic recurrence after definitive therapy on survival has not been extensively evaluated in pts with mHSPC. Therefore, we assessed the prognostic value of TTM using the SWOG 1216 trial data which randomized pts with mHSPC to androgen deprivation therapy (ADT) with orteronel (ORT) or bicalutamide (bic) (NCT01809691). Methods: Eligibility: Only pts with metachronous mHSPC who underwent prostatectomy were included in the analysis. Metachronous disease was defined as no evidence of metastasis within 90 days of initial prostate cancer diagnosis. TTM was defined from the time of prostatectomy to the time of initial metastatic diagnosis and was analyzed as a continuous variable, then categorized. Multivariable analyses for progression-free survival (PFS) and overall survival (OS) were performed using a Cox proportional hazards model, adjusting for treatment arm, disease burden, Gleason score, performance status, log-transformed PSA, and age. Results: Of the 1279 study participants, 301 underwent prostatectomy and had metachronous mHSPC, of whom 161 were in the experimental arm and 140 in the control arm. In the overall cohort, a longer TTM was not associated with improved PFS (HR 1.0, P=0.3) and OS (HR 1.0, P=0.14). Similarly, after stratification of TTM using 1, 2, 3, and 4 year-thresholds, there was no association with PFS and OS. Results remained comparable in the subgroups of pts receiving ADT + bic and ADT + ORT separately (Table). Conclusions: The timing of metastatic disease after prostatectomy in pts with metachronous mHSPC did not appear to be related to survival and should not be used as a prognostic factor nor to predict treatment outcomes. ADT + ORT ADT Overall HR (P-value) PFS OS PFS OS PFS OS TTM Continuous 1.0 (0.8) 1.0 (0.8) 1.0 (0.3) 1.0 (0.1) 1.0 (0.3) 1.0 ( 0.1) TTM <1 vs ≥1 1.1 (0.8) 1.4 (0.5) 0.9 (0.9) 1.7 (0.2) 1.1 (0.8) 1.6 (0.1) TTM <2 vs ≥2 1.1 (0.7) 1.6 (0.3) 1.1 (0.6) 1.9 (0.1) 1.2 (0.3) 1.8 (0.04) TTM <3 vs ≥3 1.1 (0.7) 1.4 (0.4) 1.5 (0.1) 1.7 (0.1) 1.4 (0.08) 1.6 (0.09) TTM <4 vs ≥4 0.9 (0.8) 0.9 (0.9) 1.7 (0.03) 1.4 (0.4) 1.5 (0.05) 1.3 (0.4)
Circulating tumor DNA (ctDNA) monitoring in the assessment and prediction of the efficacy of PARP inhibitors (PARPi).
TPS307 Background: PARP inhibitors (PARPi) emerged as an promising treatment for metastatic castration-resistant prostate cancer (mCRPC) patients with BRCA1/2 mutation. However, prediction of treatment response remains a challenge. Still, some patients with mutations other than BRCA1/2 responded to PARPi. Circulating tumor DNA (ctDNA) is a promising biomarker that can offer real-time insights into tumor dynamics, allowing for non-invasive monitoring of therapeutic efficacy. This study aims to assess ctDNA monitoring as a predictor of response and relapse for mCRPC patients receiving PARPi. Methods: This trial is an open-label, single-center, observational, prospective cohort study. This study intends to enroll 30 male mCRPC participants aged 18 to 75 years, who have progressed from second-line treatment at mCRPC stage and exhibit homologous recombination deficiency (HRD) or carrying DNA damage repair (DDR) gene mutations. The study involves whole blood and tumor tissue sampling for ctDNA detection, homologous recombination repair (HRR) gene testing, and whole exome sequencing. The primary outcomes include radiological progression-free survival (rPFS), objective response rate (ORR), and PSA response rate, with overall survival (OS) as a secondary outcome. The Institutional Review Board of Sun Yat-sen University Cancer Center approved this study. Recruitment is ongoing, with a target follow-up duration of 12 months and 26.7% (8/30) of the target sample size achieved. Data analysis is expected to commence in 2025 upon completion of recruitment. Clinical trial information: NCT05116579 .
<i>MTAP</i> loss in primary kidney tumors: A comprehensive genomic profiling study.
564 Background: Kidney tumors (KT) comprises approximately 4% of all new cancer cases in US per year, with about a third being de-novo metastatic. 5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway & has emerged as a putative biomarker for synthetic lethality-based trials testing Protein Arginine Methyltransferase 5 (PTMT5) & Metastasis-associated protein 2 (MTA2) inhibitors. We compared the genomic landscape in KT with vs without MTAP loss (del). Methods: From 541,919 consecutive cases of clinically advanced cancers, 5,467 consecutive cases of recurrent & metastatic KT underwent hybrid-capture based Comprehensive Genomic Profiling (CGP) to identify all classes of genomic alterations (GA), Microsatellite Instability (MSI) status, & tumor mutation burden (TMB). Programmed Cell Death Ligand 1 (PD-L1) expression was determined by IHC (Dako 22C3). Results were evaluated using the Fisher Exact method. Results: The overall MTAP del frequency in all KT was 10.9%. At 26.3% MTAP del frequency was highest in urothelial carcinoma (uCA) followed by not otherwise specified renal cell carcinoma (nosRCC) (13.3%), collecting duct (cdRCC) (12.5%), sarcomatoid (srcRCC) (11.7%), papillary (papRCC) (7.3%) & clear cell (ccRCC) (4.0%). Chromophobe & medullary RCC were devoid of MTAP del cases. Tendencies for patients with MTAP del KT to be slightly older & more often of male gender were noted. Across uCA & the RCC subtypes, the frequencies of driver GA were higher in MTAP del vs MTAP intact cases (Table). CDKN2A was co-deleted in 99.6% & CDKN2B in 92.8% cases of KT. For ccRCC the Von Hippel-Lindau ( VHL) GA was higher in MTAP intact than MTAP del (76.4% vs 67.0%; p=.029). Biomarkers that may correlate with immune-checkpoint inhibitor efficacy, including MSI-high status (0-4%) & median TMB level (2.5-5 mutations/Mb), as well as PD-L1 low-high expression (29-69%), did not differ significantly by MTAP del status in all KT types. Conclusions: At 11% overall, MTAP del is a relatively common GA in advanced KT including uCA & RCC cases. MTAPdel was more frequent in non-clear cell RCC, collecting duct carcinomas, & sarcomatoid histology, generating hypotheses for targeted therapy clinical trials. Limitations include retrospective nature, lack of clinical data annotation, selection & confounding biases. Further evaluation of KT, including uCA & RCC, for MTAP del-enabled PTMT5 & MTA2 inhibitor trials seem warranted. MTAPdel Top GA in MTAP del Top GA in MTAPi ntact uCA 26.3% FGFR3 34.7%, PIK3CA 20.4%, ERBB2 7.4% FGFR3 25.4%, PIK3CA 19.8%, ERBB2 13.0% nosRCC 13.3% NF2 25.6%, VHL 17.9%, PTEN 12.8% NF2 13.0%, VHL 27.6%, PTEN 5.1% ccRCC 4.0% VHL 67.0%, PBRM1 33.0%, BAP1 23.9% VHL 76.4%, PBRM1 45.9%, BAP1 14.6% papRCC 7.3% ERBB2 8.3%, MET 16.7%, NF2 5.6% ERBB2 1.7%, MET 11.5%, NF2 11.1% srcRCC 11.7% VHL 50.0%, NF2 30.8%, TP53 19.2% VHL 39.8%, NF2 18.9%, TP53 37.8% cdRCC 12.5% NF2 33.3%, SMARCB1 0%, TERT 44.4% NF2 25.4%, SMARCB1 17.5%, TERT 1.8%
Development of an miRNA signature for individual prognostic assessment in seminoma patients.
645 Background: Due to the risk of long-term toxicities in young non-metastatic seminoma patients, surveillance regimens nowadays are the standard of care. However, up to 20% of patients will relapse and undergo further treatment, requiring even greater efforts in terms of adjuvant therapy. miRNAs are known to be very stable and robust biomarkers. This study aims to establish a prognostic miRNA profile utilizing bioinformatics tools to differentiate between metastatic (met) and non-metastatic (nmet) seminomas. Methods: MiRNA was extracted from formalin-fixed paraffin-embedded sections. Using microarray analysis (Agilent Technology), two cohorts of patients with seminoma (24 patients each, 12 nmet and 12 met) were examined. The following criteria were used to preselect relevant miRNAs: absolute median log2 fold change >0.5, distance correlation >0.5, accuracy in single-miRNA classifier trained with leave-one-out cross-validation (met vs. nmet) >0.7. Validation was performed in 88 patients (47 nmet and 41 met) through qPCR using the TaqMan assay, with RNU48, miR-191-5p, and miR-361-5p serving as references. Statistical and bioinformatics analyses were performed using the Mann-Whitney U test and machine learning algorithms. Results: The bioinformatics analysis of microarrays identified 16 miRNAs exhibiting an accuracy >70% in differentiating met tumors from nmet ones. The validation of 6 miRNAs by qPCR revealed significant expression differences between met and nmet tumors for miRNAs miR-371a-5p, miR-512-3p, miR−509−3−5p, miR-517a-3p (p<0.05), dependent on the reference used. All 4 miRNAs are higher expressed in met tumors. Synchronous met tumors exhibit stronger differences in the expression of the above-mentioned miRNAs compared to metachronous met tumors, except for miR-509-3-5p. miR-371a-5p was found to be the most robust miRNA to distinguish both synchronous and metachronous met from nmet seminomas. Classifiers trained on the PCR data for different combinations of the 6 investigated miRNAs using leave-one-out cross-validation show a medium performance (average accuracy of 0.59) including one model based on 4 miRNAs with high accuracy of 0.99. Conclusions: By using machine-learning algorithms on microarray data, we have established a miRNA signature that can differentiate metastatic from non-metastatic seminomas with high reliability. Validation of 4 miRNAs by qPCR confirms the high prognostic value of miRNAs in seminoma patients. Currently, we examine the suitability of this miRNA panel in liquid biopsy.