bluuebunny/crossref_metadata_2025_split huggingface dataset:
Baseline circulating tumor cell (CTC) count as a prognostic marker of overall survival (OS) in metastatic hormone sensitive prostate cancer (mHSPC): Results from SWOG S1216, a phase III randomized trial of androgen deprivation plus orteronel (cyp17 inhibitor) or bicalutamide.
Authors: Goldkorn Amir , Tangen Catherine , Plets Melissa , Bsteh Daniel , Xu Tong , Pinski Jacek K. , Ingles Sue , Triche Timothy Junius , MacVicar Gary R. , Vaena Daniel A. , Crispino Anthony W. , McConkey David James , Lara Primo N , Hussain Maha H. A. , Quinn David I. , Dorff Tanya B. , Thompson Ian , Agarwal Neeraj ,   SWOG GU Committee
Published: June 2023

5080 Background: Biomarkers are needed to predict clinical outcomes in mHSPC. We previously reported that baseline CTC counts in S1216 were prognostic of PSA response and disease progression ( ASCO 2020; CCR 2021). However, the trial’s primary overall survival (OS) endpoint was not yet mature at that time. Here we present the final results of S1216 using all available samples to assess the prognostic value of CTC counts for response, progression, OS, and treatment arm interactions. Methods: In S1216, peripheral blood was drawn with informed consent at registration (baseline) and at progression to metastatic castrate resistant prostate cancer (mCRPC). CTCs were enumerated on the FDA-cleared CellSearch platform (Menarini). CTC counts were evaluated for associations with 3 pre-specified trial endpoints: 7-month PSA (7mPSA) ≤ 0.2 ng/ml vs. 0.2–4.0 vs. > 4.0 using a generalized logit model; and progression-free survival (PFS) and OS using Cox regression. Results: From 2014 to 2021, 503 evaluable samples were collected at baseline and 93 at progression. Baseline CTC count was ≥5 in 11.9% of samples, 1-4 in 19.3%, and 0 in 66.8%. Comparing men with 0 vs. ≥5 CTCs at baseline, those with 0 CTCs were significantly more likely to attain a complete PSA response and had significantly lower risk of a PFS event and death after adjusting for clinical covariates (disease burden, bone metastases, age, race, alkaline phosphatase, hemoglobin, PSA, treatment arm). These associations were not modified by treatment arm. Progression CTCs <5 vs. ≥5 also were prognostic of OS (logrank p=0.001), consistent with prior findings in mCRPC. Same-patient CTC counts in matched baseline-progression pairs (n=61) were highly correlated (Spearman p<0.001). Conclusions: CTC count at the start of treatment for mHSPC was highly prognostic of PSA response, PFS, and OS; associations that held in both treatment arms. Moreover, baseline CTC count strongly correlated with progression count, suggesting that mild vs. aggressive disease phenotypes may persist from mHSPC to mCRPC. This evidence from a large prospective phase 3 trial suggests that baseline CTC count is a valuable prognostic marker in men initiating therapy for mHSPC, discriminating those likely to experience favorable vs. unfavorable response and OS. [Table: see text]
Cost-effectiveness analysis (CEA) of seven treatment regimens in metastatic hormone-sensitive prostate cancer (mHSPC): A public payer perspective using network meta-analysis.
Authors: Kohli Manish , Dougherty Maura , Cutshall Zachary , Beckstead Rylee , Kohli Rhea , Haaland Benjamin , Nelson Richard , Yoo Minkyoung 
Published: June 2023

5081 Background: Recently several new drug treatment regimens have been approved in mHSPC state, building on using androgen deprivation therapy (ADT) alone. These include docetaxel + ADT (DA), Abiraterone Acetate + Prednisone + ADT (AAP), Apalutamide + ADT (AAT), Enzalutamide + ADT (ET), Darolutamide + Docetaxel + ADT (DAD) and AAP + ADT + Docetaxel (AAD). At present, there are no predictive biomarkers for choosing a specific drug regimen over the other. The goal of this study was to conduct an economic evaluation of FDA-approved standard of care drug regimens in the current management of mHSPC state to determine a cost-effective optimal treatment from the US public sector (Veterans Affairs-VA) perspective with a 10-year time horizon. Methods: We developed a partitioned survival model in which mHSPC patients (pts) transitioned between three health states (progression free, progressive disease to castrate resistance state, and death) at monthly intervals based on Weibull survival model estimated from published Kaplan-Meier curves using a network meta-analysis. A Bayesian network meta-analysis of seven randomized clinical trials included 7,208 mHSPC pts. The effectiveness outcome in our model was quality-adjusted life-years (QALYs) with utility values obtained from published literature. Costs in our model included those associated with treatment regimens, subsequent therapies, terminal care, and for managing grade 3-4 drug related adverse events. Costs were obtained from the Federal Supply Schedule and published literature. Incremental cost-effectiveness ratios (ICERs) were calculated for nondominated treatments. Results: Average 10-year costs ranged from $32,697 (ADT) to $649,622 (DAD). Mean QALYs ranged from 3.25 (ADT) to 4.57 (ET). Treatment with DAT, EAD, and DAD were eliminated due to dominance (i.e. they were more costly and less effective than other treatments). AAT was the most cost-effective strategy at a willingness-to-pay threshold of $100,000/QALY (ICER = $70,150/QALY). Results from our analysis for all regimens are shown. Conclusions: Our CEA simulation model found AAT is an optimal cost-effective first-line treatment strategy in mHSPC state from a public (VA) payer perspective. [Table: see text]
Landscape and impact of germline pathogenic variants (PVs) in metastatic hormone sensitive prostate cancer (mHSPC): Ancillary study of E3805 CHAARTED.
Authors: Hamid Anis , Chinsky Tyler M , Vergara Matias , Grist Emily , Attard Gerhardt , Van Allen Eliezer Mendel , Aldubayan Saud , Sweeney Christopher 
Published: June 2023

5082 Background: Enrichment of germline PVs in metastatic castration resistant prostate cancer (mCRPC), compared to localized disease, has directly informed genetic testing guidelines. The prevalence and prognostic/predictive associations of such variants are not well characterized in the mHSPC state, in particular the effect of susceptibility mutations related to DNA damage and repair (DDR) pathways. Methods: We performed whole exome sequencing of germline DNA derived from whole blood available from patients (pts) in the phase III CHAARTED trial (NCT00309985) of androgen deprivation therapy (ADT) versus ADT plus docetaxel (ADT+D). After filtering for low coverage, variant annotation and effect prediction, PVs from a curated list of 588 prostate cancer-associated genes were reviewed. The prognostic effect of PVs was evaluated within each treatment arm. Endpoints of time to CRPC (ttCRPC), time to clinical progression (ttClinPD), and overall survival (OS) were estimated by Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated by Cox models evaluating association of endpoints with biomarkers/arm. Multivariable analysis adjusted for metastatic timing and volume. Results: Of 137 pts, 135 had unique germline exomes that passed downstream analysis. Most pts had synchronous (66.7%) and high-volume (62.2%) disease. This biomarker cohort showed benefit of adding docetaxel to ADT (ttCRPC: HR 0.55, 95% CI 0.37-0.82; OS: HR 0.68, 95% CI 0.44-1.07). In total, 61 PVs were detected; 49 pts (36.3%) harbored at least 1 PV in 41 different genes. The most frequently-mutated gene was BRCA2 (6.67%). In addition, PVs were found in DDR-associated genes including PALB2 (1.48%), CHEK2 (1.48%), BRCA1 (0.74%) and PMS2 (0.74%) for an overall prevalence of 11.1% (15/135). Pts with BRCA2 PV on ADT alone had shorter ttCRPC compared with men without the PV (UVA: HR 2.67, 95% CI 0.93-7.63, log rank p=0.057; MVA: HR 2.59, 95% CI 0.91-7.39, p=0.074). There was no evidence of a difference in the ADT+D arm (UVA: HR 1.00, 95% CI 0.31-3.25, log rank p=0.1). Supportive data was observed for ttClinPD in ADT arm (HR 2.85, 95% CI 1.01-8.08, log rank p=0.04). Metastatic volume and timing were not significantly associated with germline BRCA1/2 or DDR PVs. Conclusions: The prevalence of germline BRCA1/2 and DDR PVs in mHSPC is similar to mCRPC and BRCA2 PV may confer worse outcomes on ADT alone. This supports the need for genetic testing at diagnosis of mHSPC. [Table: see text]
The role of volume of disease for treatment selection in patients with metastatic castration sensitive prostate cancer (mCSPC): A living meta-analysis.
Authors: Naqvi Syed Arsalan Ahmed , Riaz Irbaz Bin , He Huan , Imran Manal , Orme Jacob , Childs Daniel S , Ravi Praful , Hussain Syed A. , Singh Parminder , Bryce Alan Haruo 
Published: June 2023

5088 Background: Previous evidence suggests that there may be no additional benefit of triplet therapy in low volume disease based on limited data. Therefore, we investigated the efficacy of triplet therapy as compared to docetaxel (D) and androgen pathway inhibitor (API) doublets by volume of disease using the most up to date results from the ARASENS trial. Methods: Phase III randomized controlled trials (RCTs) assessing treatment intensification with API, and/or D in patients with mCSPC were included. Precomputed hazard ratios (HR) with 95% confidence intervals (CI) for OS were pooled using an inverse-variance approach. A DerSimonian-Laird random-effects meta-analysis was conducted to assess the efficacy of triplet therapy compared to D doublet therapy. P-value of interaction was computed to assess difference between high (HV) and low volume (LV) disease subgroups (Pint <0.1 - statistical significance). Additionally mixed treatment comparisons were computed using network meta-analysis (NMA) to assess the comparative effectiveness of triplet therapy compared to API doublets by volume of disease. Results: Pairwise meta-analysis included a total of 3 RCTs (ARASENS, PEACE-1, ENZAMET) with 2518 patients (HV: 1820; LV: 698) as shown. In patients with HV disease, 385 (43%) and 484 (53%) deaths were observed with triplet therapy, and D doublet, respectively. Triplet therapy significantly improved OS as compared to D doublet in HV (HR: 0.73; 95% CI: 0.64-0.84). In patients with LV disease, 73 (20%) and 94 (28%) deaths were observed with triplet therapy, and D doublet, respectively. Triplet therapy significantly improved OS as compared to D doublet in LV (HR: 0.71; 95% CI: 0.52-0.97). There was no statistically significant interaction by volume of disease for triplet therapy vs. D doublet (Pint: 0.86). NMA including 10 clinical trials and over 11500 patients updated as of 13th Feb 2023 showed that in HV mCSPC, triplet therapy was ranked as potentially the most efficacious treatment option and may improve OS compared to API doublet therapy (HR: 0.83; 95% CI: 0.66-1.03). In LV mCSPC, API doublet therapy was ranked as potentially the most efficacious treatment followed by triplet therapy. There was no significant difference between triplet therapy and API doublet therapy (HR: 1.12; 95% CI: 0.74-1.12). Conclusions: These results underscore that triplet therapy may be preferred in mCSPC patients with HV disease whereas API doublet therapy may be preferred in LV disease. [Table: see text]
Socio-demographic, clinical, and genetic predictors of low versus high Gleason score among men with prostate cancer in the Detroit Research on Cancer Survivorship (ROCS) cohort.
Authors: Goodenow Samantha , Cackowski Frank Cameron , Heath Elisabeth I. , Ruterbusch Julie J. , Dyson Greg , Beebe-Dimmer Jennifer Lynn , Simon Michael S. 
Published: June 2023

5092 Background: Black men with prostate cancer typically present with a higher Gleason Score (GS) and more aggressive disease than White men. The purpose of this project is to describe the relationship between socio-demographic, clinical and genomic variability with GS categories among 599 men with prostate cancer in the Detroit Research on Cancer Survivorship (ROCS) cohort. Methods: Detroit ROCS is a cohort of Black cancer survivors based in the Detroit Metropolitan area. Patient data was obtained from a self-administered questionnaire, cancer registry and biologic samples were collected through at home phlebotomy or mailed saliva kits. The primary analysis focused on clinical and genetic differences between men with GS ≤ 6 vs. ≥ 7. Germline data was compiled into the multi-ethnic genotyping array (MEGA) data panel and 21 genes were chosen for analysis (2,393 SNPS) based on their clinical applicability. Eight tools were used in ANNOtate VARiation (ANNOVAR) to determine whether a genetic variant was pathogenic. The determination of pathogenicity was defined by at least seven of the tools indicating variant pathogenicity. We assessed the rate of pathogenic variants for each GS category. Multivariable models of predictors of GS categories were conducted using logistic regression. Results: The categories across GS in the ROCS cohort included: ≤ 6 (21.2%), 3+4 (40.4%), 4+3 (20.2%) and ≥ 8 (18.2%). Variables associated with increased GS (≥ 7 vs. ≤ 6) included age (for each 10-year increase the OR was 1.71, 95% CI 1.26-2.34) and body mass index (for each 5 unit increase the OR was 1.27, 95% 1.06-1.54). Higher vs. lower education (some college education or higher vs less than or equal to a high school education) was associated with lower GS, OR 0.58, 95% CI 0.37-0.96. Out of a total of 2,393 SNPs analyzed, 880 (36.8%) were polymorphic, of which 684 had a minor allele frequency (MAF) >0.001, and 282 had a MAF >0.05. Overall, 16.2% of the men were carriers of a pathogenic variant, the most common of which were ATR (9.3%), FANCL (3.5%), and ATM (1.7). Men with GS 6 had a lower rate of pathogenic variants (8.7%), than those with GS 3+4 (18.2%), GS 4+3 (16.5%), and GS 8 (20.2%). Men with a pathogenic variant in ATR were 2.87 (95% CI 1.08- 7.65) times more likely to have GS ≥ 7 vs. ≤ 6. Higher GS was specifically associated with SNP rs33972295 in the ATR gene. Conclusions: The relationship between older age, higher BMI, and less educational background suggests that sociodemographic risk factors should be accounted for when assessing risk for higher grade prostate cancer. Identification of genomic differences associated with aggressive prostate cancer may provide insight into new targeted therapy options.
Prognosis and trends in chemotherapy use for patients with stage IA triple-negative breast cancer (TNBC): A population-based study.
Authors: Tarantino Paolo , Leone Julieta , Vallejo Carlos Teodoro , Freedman Rachel A. , Waks Adrienne Gropper , Martínez-Sáez Olga , Garrido-Castro Ana Christina , Lynce Filipa , Tayob Nabihah , Lin Nancy U. , Tolaney Sara M. , Leone Jose Pablo 
Published: June 2023

510 Background: Outcomes for patients with stage IA TNBC in the modern era remain poorly characterized, and the benefit and utilization of adjuvant chemotherapy (chemo) in this setting remains controversial. Methods: We analyzed data from women diagnosed with pathological stage IA TNBC in the Surveillance, Epidemiology, and End Results (SEER) database during 2010 to 2019. We evaluated the associations of adjuvant chemo with breast-cancer specific survival (BCSS) stratified by tumor size, using multivariate cox models adjusted for tumor size (overall cohort only), age at diagnosis, race, tumor grade, histology, radiation, marital status, income, and rurality. Frequency of chemo use over time was examined by tumor size. Multivariate logistic regression assessed variables associated with chemo administration. Results: In total, we examined data from 8,601 women with stage IA TNBC. Median age at diagnosis was 62 years. Most patients had high-grade tumors (70.1%), ductal histology (92.8%), and received adjuvant chemo (61.6%). Median follow up was 48 months (IQR: 20 – 83). The use of chemo significantly increased during 2010-2019 for both T1b tumors (p for trend = 0.001) and T1c tumors (p for trend < 0.001), with 52.5% and 63% of the patients with T1b and T1c TNBCs receiving chemo in 2010, respectively, compared with 60.5% and 71.1% in 2019. No significant differences were observed in the use of chemo for T1mic (p for trend = 0.567) and T1a (p for trend = 0.637) tumors, with low utilization seen in both cohorts (9.5% overall in T1mic, 22.5% overall in T1a). Variables associated with chemo use included younger age, white race, married status, higher income, more recent diagnosis, higher tumor grade, ductal histology, and larger tumor size (all p < 0.02). Overall, 5-year BCSS was high across T groups ( > 90%; Table). Receiving chemo (vs. none/unknown) was associated with an improved 5-year BCSS (adjusted HR for BCSS = 0.70, p = 0.006). For T1c tumors specifically, adjuvant chemo (vs. none/unknown) was also associated with BCSS (adjusted HR 0.64, p = 0.002). The small number of BCSS events precluded comparisons for other tumor size subgroups. Table shows sample sizes and 5-year BCSS rate by chemo receipt for each T group. Conclusions: In a large population-based cohort of patients with stage IA TNBC, we observed excellent 5-year BCSS outcomes, supporting the good prognosis of this patient population. The use of adjuvant chemo increased over time for T1b and T1c TNBCs, and was associated with improved BCSS for T1c tumors, although evaluation of benefit is limited by the inherent treatment bias in registry data. [Table: see text]
Correlation of HER2 low status in I-SPY2 with molecular subtype, response, and survival.
Authors: Rugo Hope S. , Wolf Denise M. , Yau Christina , Petricoin Emanuel , Pohlmann Paula R , Pusztai Lajos , Symmans W. Fraser Fraser , Borowsky Alexander , Finestone Sandra , Yee Douglas , Hylton Nola , van 't Veer Laura , Esserman Laura , DeMichele Angela ,   I-SPY Investigators
Published: June 2023

514 Background: HER2low, defined as immunohistochemical (IHC) 1+ or 2+ without HER2 gene amplification, predicted improved progression free and overall survival with trastuzumab deruxtecan (TDXd) compared to chemotherapy in patients (pts) with metastatic breast cancer in Destiny Breast04. Controversy exists regarding the correlation of HER2low with molecular subtypes and outcome. We evaluated these associations in the neoadjuvant ISPY2 trial. Methods: We investigated HER2 IHC class in pts with clinically HER2-negative breast cancer (BC) enrolled in the first 10 arms of ISPY2. To explore the biology of HER2low, we used Fisher’s exact test to assess association of IHC class (0 vs 1+ or 2+) with Response Predictive Subtypes-5 (RPS-5; based on immune, DNA repair damage (DRD), HER2, and luminal markers; PMID: 35623341), SET index [endocrine responsiveness], and Mammaprint high1 (MP1) vs high2 (MP2). Association with pathologic complete response (pCR) was assessed using Fisher’s exact test, and association with distant recurrence free survival (DRFS) was assessed using Cox Proportional Hazards modeling. Results: Of 742 HER2negative pts enrolled in the first 10 arms of ISPY2, local HER2 IHC is available for 585; 299 hormone receptor + (HR+) and 286 triple negative (TN). 63% of pts are HER2low, with HER2low status more frequent in HR+ (71%) compared to TN BC (55%; OR = 1.97; p = 0.00011). There was no clear relationship between HER2low IHC and RPS-5 subtypes or endocrine sensitivity measured by the SET index. There was no significant association of HER2low with pCR overall or within treatment arms (p > 0.05); this was true for TN and HR+ subsets. 562 pts with HER2negative disease have distant recurrence free survival (DRFS) data with a median follow-up of 4.23 yrs. Pts with pCR had excellent outcome (5yr DRFS > 94%), with no impact from HER2low vs 0 status. For pts with nonpCR, after adjusting for HR+ status, the DRFS hazard ratio for HER2low vs 0 status is not significant [0.68(0.46-1.02)]. Within HR+, HER2low is found in > 70% for both SET low and high. HR+/MP1 pts (with generally low pCR rates) are significantly more likely to be HER2low (75%; (172/219)) compared to HR+/MP2 (61%; (49/80)) (OR: 1.79; Fisher p = 0.044). Importantly, 70% of HER2-Immune-/DRD- (78% HR+ and 56% TN), a subtype with low response to all ISPY2-tested agents, are HER2Low. Conclusions: In ISPY2 which enrolls patients with MP high risk BC, HER2low by IHC was frequent and higher in HR+ than TN disease. There was no clear association with molecular markers, pCR or DRFS. The frequency of HER2low in the immune-/DRD- subtype raises the potential for exploring T-DXd in this high risk, low-response setting. Clinical trial information: NCT01042379 .
Outcomes according to treatment received for small node-negative HER2+ breast tumors in the Surveillance, Epidemiology, and End Results (SEER) database, 2010-2019.
Authors: Waks Adrienne Gropper , Tarantino Paolo , Freedman Rachel A. , Lin Nancy U. , Tayob Nabihah , Vallejo Carlos Teodoro , Leone Julieta , Tolaney Sara M. , Leone Jose Pablo 
Published: June 2023

517 Background: The magnitude of systemic therapy (tx) benefit for small, node-negative HER2+ breast tumors is unknown, with uncertainty about how benefit varies across stage I tumor sizes. We analyzed treatment patterns and outcomes for patients (pts) with stage IA (pT1N0) HER2+ breast cancer in the national SEER database. Methods: Pts with one lifetime diagnosis of pT1N0 HER2+ breast cancer between 2010-2019 were included. Receipt of chemotherapy (chemo) was categorized as yes vs no/unknown; receipt of endocrine tx is not available in SEER. All systemic tx was administered in the adjuvant setting. The primary outcome variable was breast cancer-specific survival (BCSS; recurrence events are not available in SEER), which was compared between treatment groups using a multivariate Cox model adjusted for age at diagnosis (dx), race, tumor grade/histology/size, hormone receptor (HR) status, radiation, marital status, income, rurality. Chemo use predictors were evaluated by multivariable logistic regression. Results: We identified 12,861 pts with pT1N0 HER2+ breast cancer; 9,513 (74%) HR-positive and 3,348 (26%) HR-. Median age at dx was 59 yrs. Median follow-up was 46 months. In the overall cohort, BCSS at 3, 5, and 7 yrs was: 99.3% (with chemo) vs 99.1% (without chemo); 98.6% (with chemo) vs 97.4% (without chemo); and 97.5% (with chemo) vs 96.4% (without chemo), respectively. Adjusted hazard ratio (HzR) for BCSS events in the chemo vs no chemo group of the overall cohort was 0.63 (p=0.004;). BCSS events by tumor size and HR status are shown; p values are not shown where event rates were too low to run an adjusted model. Chemo use increased significantly between 2010-2019 within each tumor size category (all p for trend < 0.04), except for T1a HR+/HER2+ and T1mi HR-/HER2+. Pts were less likely to receive chemo if they were older, Hispanic (vs non-Hispanic White), separated/divorced/widowed (vs single), or had lower median household income (vs >$75K). Pts were more likely to receive chemo if they had larger tumor size, HR- tumor, higher tumor grade, were married (vs single), or had later yr of dx. Conclusions: Receipt of chemo was associated with higher BCSS in the overall stage IA cohort and among pts with HR+/HER2+ stage IA tumors. Tumors ≤ 1cm had excellent outcomes with or without chemo. Sociodemographic factors including income, race, and marital status impacted chemo receipt. [Table: see text]