bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase II trial of neoadjuvant androgen deprivation therapy plus abiraterone and apalutamide for patients with high-risk localized prostate cancer: Pathologic response and PSMA imaging correlates.
Authors: Bastos Diogo Assed , Coelho Rafael , Cardili Leonardo , Galiza Felipe , Ilario Eder Nisi , Viana Públio , Murta Claudio Bovolenta , Guglielmetti Giuliano , Cordeiro Mauricio , Pontes Jr Jose , Muniz David Queiroz Borges , Silva Jamile Almeida , Mota Jose Mauricio , Fialho de Freitas Guilherme , Leite Katia Ramos Moreira , Buchpiguel Carlos Alberto , Nahas William Carlos 
Published: June 2022

5085 Background: Patients (pts) with high-risk localized prostate cancer (HRLPC) have a significant risk of disease recurrence and metastasis after radical prostatectomy (RP). Neoadjuvant therapy remains investigational but there may be a role for the next-generation androgen signaling inhibitors. We sought to evaluate pathologic and imaging response after the intense neoadjuvant approach. Methods: This is a phase II investigator-initiated randomized trial of 3-month neoadjuvant therapy with goserelin (androgen deprivation therapy, ADT) + abiraterone acetate and prednisone (AAP arm) or AAP + apalutamide (A-APA arm) before RP for pts with HRLPC (Gleason ≥ 8 and/or cT3N0-1 and/or PSA ≥ 20 ng/mL). The primary endpoint was the rate of pathologic complete response (pCR) or minimal residual disease (MRD, tumor ≤ 0.5 cm). The secondary endpoints were safety, rate of residual cancer burden ≤0.25 cm3 (RCB = tumor volume x cellularity), Gallium 68 prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/magnetic resonance correlates and rate of biochemical relapse (BR). Results: Sixty-two pts were randomized to A-APA (N = 31) or AAP (N = 31). Median age was 65 (range 47-77) years. NCCN risk groups included high-risk disease in 19%, very high-risk in 76% and regional (N1) disease in 5% (79% cT3, 65% Gleason 8-10, 57% PSA ≥ 20 ng/mL). Outcomes after intense neoadjuvant ADT are described in the Table. There was no statistically significant difference between study arms regarding pCR/MRD or RCB ≤ 0.25 cm3 rates. Patients with complete PSMA-PET response (psmaCR) demonstrated a RCB ≤ 0.25 cm3 rate of 50% compared to 7.5% in pts without a psmaCR ( P= 0.001). The rate of BR was 14% for pts with RCB ≤ 0.25 cm3 versus 38% in pts with RCB > 0.25 cm3 ( P= 0.118). At current median follow-up of 2.6 years, all patients with both psmaCR and RCB ≤ 0.25cm3 (N = 11, 18%) are free of BR. There were 2 grade (G) 5 adverse events (AEs) in the AAP arm (pulmonary embolism and sudden death, both after surgery). Nine (14.5%) pts (6 in A-APA; 3 in AAP) experienced G3-4 treatment-related AEs. The most common G3-4 AEs were hypertension (11.3%), AST/ALT elevations (3.2%) and skin rash (1.6%). Conclusions: No difference in pCR or MRD was observed between arms. Although pCR or MRD after intense neoadjuvant ADT was infrequent, a significant proportion of pts achieved a favorable pathologic response with RCB ≤ 0.25 cm3. PSMA-PET response is a potential surrogate for pathologic response. Clinical trial information: NCT02789878. [Table: see text]
Methylated DNA markers in urine aid in the selective identification of patients with prostate cancer as well as clinically significant pathology.
Authors: Shah Paras , Taylor William R. , Gysbers Brianna J. , Mahoney Douglas W. , Then Sara S. , Devens Mary E. , Foote Patrick H. , Doering Karen A. , Burger Kelli , Nikolai Brandon , Kaiser Michael W. , Allawi Hatim T. , Kisiel John B. , Gettman Matthew 
Published: June 2022

5091 Background: Controversy surrounding prostate-specific antigen (PSA) based screening for prostate cancer (PCa) highlights the need for non-invasive assays that better discriminate patients with and without clinically significant prostate cancer (csPCa). Such distinction avoids overtreatment in patients with absent or indolent disease while capturing pathology that would derive benefit from intervention. We analyzed the presence of specific methylated DNA markers (MDMs) within urine samples of patients with biopsy proven PCa and assessed the ability to discriminate these patients from healthy controls with no clinical suspicion for PCa. Methods: 24 healthy volunteers with no clinical suspicion for PCa were age-matched to 24 patients with biopsy-confirmed disease across all Gleason scores. Urine collected from subjects was centrifuged with the cell-free supernatant analyzed in a blinded fashion for methylation signal within specific DNA sequences across 14 genes ( HES5, ZNF655, ITPRIPL1, MAX.chr3.193, SLCO3A1, CHST11, SERPINB9, WNT3A, KCNB2, GAS6, AKR1B1, MAX.chr3.727, GRASP, ST6GALNAC2) by target enrichment long-probe quantitative-amplified signal assays. A patient was considered to have a positive MDM panel if any individual marker exceeded the corresponding100% specificity cut-off value (overall MDM panel specificity of 100%). MDM panel positivity was used to evaluate the sensitivity for distinguishing patients with PCa (any Gleason score) from controls as well as discriminate csPCa cancers from PCa Gleason 6. Results: Median age of healthy controls and PCa patients was 70 years (IQR 67-72) and 65 years (IQR 61-71), respectively. Median PSA was 6.4 (IQR 4.9-9.0) among PCa patients, including median PSA of 5 (IQR 4.0-6.1) for Gleason 6, and 7.8 (IQR 5.1-9.2) for Gleason ≥7 disease. Gleason 6, Gleason 7, and Gleason 8+ cancer was noted in 8, 10, and 6 patients, respectively. Utilizing an overall specificity cut-off of 100% for discriminating normal controls from PCa cases across the MDM panel revealed an overall sensitivity of 83% (95% CI: 63-95%) for detection of PCa (6 of 8 Gleason 6, 9 of 10 Gleason 7, 5 of 6 Gleason 8+) and 88% (95% CI: 62-98%) for csPCa (Gleason ≥ 7). When considering a 100% specificity threshold for controls and Gleason 6 patients, the sensitivity the MDM panel was 69% (95% CI: 41-89%) for csPCa (6 of 10 Gleason 7, 5 of 6 Gleason 8+). Conclusions: We describe a panel of 14 MDMs within urine that offer high specificity and sensitivity for detection of prostate cancers as well as selective identification of clinically significant disease states. Prospective comparison between urine MDMs and PSA blood testing is necessary to discern the differential clinical impact of each screening methodology.
Molecular subtype to predict pathologic complete response in HER2-positive breast cancer in the I-SPY2 trial.
Authors: Thomas Alexandra , Clark Amy Sanders , Yau Christina , Wolf Denise M. , van 't Veer Laura , Douglas Emily H. , Chien Amy Jo , Huppert Laura Ann , Rugo Hope S. , Shatsky Rebecca Arielle , Isaacs Claudine , Berry Donald A. , Yee Douglas , DeMichele Angela , Esserman Laura ,   I-SPY2 Consortium
Published: June 2022

510 Background: HER2-positive breast cancer (bc) is a very heterogenous disease. We hypothesized that molecular subtype may predict disease response to investigational agents in HER2+ bc. Here, we report the pathologic complete response (pCR) rate in the first six agents tested in HER2+ bc in the I-SPY 2 trial for the full HER2+ cohort, by molecular subtype, and by disease receptor status. Methods: Women with HER2+ tumors which were > 2.5 cm were eligible. The I-SPY2 platform trial tests novel agents given neoadjuvantly with a backbone of taxol (T) and trastuzumab (H) followed by doxorubicin and cyclophosphamide. Agents investigated in HER2+ bc were TH (control), MK2206, AMG386, pertuzumab (P), neratinib (N (given in place of H), and TDM1+P (given in place of TH). An investigational arm graduated if there was >85% chance of success compared to control in a 300-person phase 3 neoadjuvant trial. Further details of the I-SPY2 methods have been previously published. Molecular subtyping based on gene expression was utilized to categorize tumors into 5 response predictive subtypes (RPS) (HER2-/Immune-/DRD (DNA repair deficiency)-, HER2-/Immune+, HER2-/Immune-/DRD+, HER2+/Her2_or_Basal and HER2+/Luminal). Results: For the full HER2+ cohort (N=245) pCR rate was higher in all investigational arms than control (Table). By tumor receptor status, HER2+/HR- tumors (N=89) had a higher pCR rate than HER2+/HR+ tumors (N=156; 63% vs 37%, p = 0.0001). In HER2+/HR- tumors N, MK2206, P and TDM1/P graduated. In HER2+/HR+ tumors P and TDM1/P graduated. 76% (185/245) of I-SPY 2 HER2+ patients were classified as HER2+/Her2_or_Basal and 24% (60/245) were HER2+Luminal. pCR rate was significantly higher in the HER2+/Her2_or_Basal group than in the HER2+/Luminal group (57% vs 15%, p < 0.0001). All agents, except for MK2206, where numbers were small, showed greater efficacy in the HER2+/Her2_or_Basal group than in the HER2+/Luminal group. HER2+/Luminal appeared to be more sensitive to the AKT inhibitor MK2206 than to targeted HER2 agents, though numbers are small. Conclusions: pCR rates for patients with HER2+ bc treated with investigational agents, particularly dual HER2-blockade, were promising. Molecular response predictive subtype classification provides insight on how to better target therapy. The HER2+/Luminal group had low pCR rates with dual HER2-blockade but may have higher pCR rate with the addition of an AKT inhibitor and identifies a subgroup of HER2+ tumors in need of novel approaches. AKT inhibition for HER2/Luminal is being tested in I-SPY 2.2. Clinical trial information: NCT01042379. [Table: see text]
Estradiol (E2) levels in premenopausal women with hormone receptor-positive (HR+) breast cancer (BC) on ovarian function suppression (OFS) with gonadotropin-releasing hormone agonists (GnRHa).
Authors: Tesch Megan Elizabeth , Zheng Yue , Rosenberg Shoshana M. , Poorvu Philip Daniel , Ruddy Kathryn Jean , Tamimi Rulla , Schapira Lidia , Peppercorn Jeffrey M. , Borges Virginia F. , Come Steven E. , Snow Craig , Partridge Ann H. 
Published: June 2022

524 Background: OFS is an important treatment component for premenopausal women with early and advanced HR+ BC and optimal efficacy may depend on complete E2 suppression with GnRHa, especially when combined with aromatase inhibitors (AI). However, standard assays lack sensitivity and accuracy at very low E2 concentrations, rendering detection of breakthrough ovarian function challenging. More informative data regarding endocrine effects of GnRHa are needed, particularly in young women who derive the most benefit from OFS yet more frequently had breakthrough E2 levels in the SOFT trial substudy, SOFT-EST. Methods: Using a prospective cohort study of women with BC diagnosed at age ≤ 40 years, we identified participants with stage I-IV HR+ BC on OFS treatment with leuprolide, goserelin or triptorelin and blood collected 1 year after diagnosis. Clinical data were obtained through surveys and medical records. Plasma estrogens were measured by liquid chromatography-tandem mass spectrometry, with a limit of detection of 0.2 pg/mL compared to 10 pg/mL with standard assays. We assessed the proportion of women on OFS with E2 > 2.72 pg/mL (10 pmol/L) and > 10 pg/mL. Patient characteristics, estrone (E1) and FSH levels, and disease-free (DFS) and overall survival (OS) were compared between those with and without elevated E2 using Fischer’s exact, Wilcoxon rank sum and log rank tests, respectively. Results: Of 84 patients who met inclusion criteria, 72 (86%) had stage I-III and 12 (14%) had stage IV BC; 25 were on OFS plus AI and 59 were on OFS plus tamoxifen (TAM). Median E2 was 3.1 pg/mL (range 0.2-30.9). 46 patients (55%) had E2 > 2.72 pg/mL, including 8 on AI and 38 on TAM; 4 (5%) had E2 > 10 pg/mL, including 1 on AI and 3 on TAM. Factors associated with E2 > 2.72 pg/mL were no prior chemotherapy, TAM and high E1 ( P ≤.05), but not age, BMI or GnRHa schedule (Table). After a median follow-up of 7 years, DFS events were seen in 6 patients with E2 > 2.72 pg/mL and 5 without ( P =.232); OS events were seen in 7 patients with E2 > 2.72 pg/mL and 5 without ( P =.608). Conclusions: More than half of young women with ER+ BC had E2 > 2.72 pg/mL on OFS, 91% of whom would not have been detected by standard assays. This may be an area amenable to intervention to improve outcomes in young women. However, larger studies are needed to elucidate the optimal E2 target on OFS and clinical implications of incomplete E2 suppression on ultrasensitive assays. [Table: see text]
Adherence to EndoPredict test scores for extended endocrine therapy management in the prospective EndoPredict Extended Endocrine Trial (EXET).
Authors: Brufsky Adam , Lenz Lauren , Pudusseri Anita , Wright David , Patel Kashyap B. , Clifford Brad T. , O'Connor Tracey L. , Strain Sasha , Kayali Fadi , Ratzel Sarah , Cummings Shelly , Kronenwett Ralf , Slavin Thomas Paul 
Published: June 2022

537 Background: Current guidelines advise that individuals with estrogen receptor-positive (ER+) breast cancer (BC) undergo 5 years of endocrine therapy with consideration of up to 10 years of extended endocrine therapy (EET). The relative benefit of EET beyond 5 years is minimal for many patients, yet a significant group of patients at higher risk of late recurrence may benefit. EndoPredict is a gene expression assay to stratify those with high versus low BC recurrence risk and is validated to predict early and late distant metastasis up to 15 years using an EPclin score. In the prospective EXET study we evaluated adherence to EndoPredict test results when making decisions regarding EET. Methods: Patients with prior ER+, human epidermal growth factor 2 negative (HER2-) BC diagnosis and 4-6.5 years of endocrine therapy underwent EndoPredict testing. To evaluate the impact on decision making for EET, chart review was performed at or after test results were clinically disclosed. Univariable analysis was used for EPclin risk classification (high, low), multivariable analysis was used to evaluate the EPclin score with clinical variables and Firth logistic regression was used to assess the association of a given variable with the therapy decision. Results: The cohort consisted of 411 patients with an average age of 62 years (range 27, 90), 107 received adjuvant chemotherapy (26%), and 71 were lymph node positive (17.3%). The rate of EET was significantly different for those with low-risk scores (EPclin Score ≤ 3.3) compared to high-risk scores (EPclin Score > 3.3; OR 8.5×10-4 [95% CI 6.8×10-6, 6.0×10-3], p-value 5.7×10-68). All patients with high-risk scores received EET. Within the low-risk group, those treated with adjuvant chemotherapy and those who were lymph node positive chose to extend endocrine therapy at higher rates. The EPclin score provided significant information in predicting EET status, even when accounting for clinical variables such as node status, tumor grade, age at diagnosis, adjuvant chemotherapy status and tumor stage (EPclin Score OR 20.2 [10.1, 44.0]; p-value=3.1 × 10-25). Conclusions: Even after adjusting for other clinical factors, EndoPredict is a significant predictor of clinical decision on EET. High adherence to EndoPredict test results in EET decision making was noted in our study. Clinical trial information: NCT04016935. [Table: see text]
Type of endocrine therapy and DFS in patients with early HER2+/HR+ BC: Analysis from the phase III randomized ShortHER trial.
Authors: Dieci Maria Vittoria , Bisagni Giancarlo , Brandes Alba Ariela , Frassoldati Antonio , Vicini Roberto , Balduzzi Sara , D'Amico Roberto , Conte Pier Franco , Guarneri Valentina 
Published: June 2022

547 Background: Optimal adjuvant endocrine therapy for HER2+/HR+ patients treated with chemotherapy and trastuzumab is still unclear. We evaluated the impact of the type of endocrine therapy on DFS in patients with HER2+/HR+ breast cancer enrolled in the phase III ShortHER trial. Methods: The Short-HER study randomized 1254 patients with HER2+ early breast cancer to receive 9 weeks vs 1 year of adjuvant trastuzumab combined with anthracycline-taxane chemotherapy. The type of adjuvant endocrine was collected every 6 months during the first 5 years of follow-up and was classified as: aromatase inhibitor (AI), tamoxifen and aromatase inhibitor (TAM-AI, in case of both drugs were administered for at least 1 year each), or tamoxifen (TAM). For premenopausal patients, the use of GnRH analogue was also collected. DFS was calculated from randomization to disease recurrence (locoregional or metastatic), second primary invasive cancer, or death. Results: 853 patients with HR+ BC (ER and/or PgR >10%) were included: 60% postmenopausal, 40% premenopausal. The pattern of endocrine therapy was: 55% AI, 22% TAM, 15% TAM-AI (8% missing data). Among premenopausal patients, 51% received GnRH. At a median follow up of 8.7 years (IQR 7.6-9.0), patients who received AI had a significantly better DFS as compared to patients who received TAM or TAM-AI: 7-yr DFS 87.3% vs 81.7%, log-rank P=0.017 (HR 1.46, 95%CI 1.05-2.03). In multivariate analysis including menopausal status, stage, and treatment arm, the type of endocrine therapy maintained a significant association with DFS (Table). In the subgroup of premenopausal patients, the use of GnRH was associated with numerically improved DFS: 86.6% vs 81.6%, log-rank P=0.168 (HR=0.70, 95%CI 0.43-1.16). Conclusions: In this post-hoc analysis of the ShortHER trial, adjuvant treatment with aromatase inhibitor was independently associated with improved DFS. Subgroup analysis in premenopausal patients suggests potential benefit with ovarian suppression. Clinical trial information: NCT00629278. [Table: see text]
Molecular diagnostics to reduce inequity in breast cancer diagnosis.
Authors: Adebamowo Clement Adebayo , Ezeome Emmanuel , Yawe King-David Terna , Ayandipo Omobolaji , Badejo Olawale , Adebamowo Sally Nneoma , Achusi Izu Ben , Fowotade Abike , Ogun Gabriel Olabiyi ,   AFBRECANE Research group is part of the H3Africa Consortium
Published: June 2022

548 Background: Modern management of breast cancer requires proper subtyping of the breast tumor to guide appropriate treatment and prognostication. However, there are barriers to availability of this resource in low- and middle-income countries (LMIC) which contributes to global inequalities in breast cancer management and outcomes. The non-availability is due to high cost, and lack of personnel and infrastructure required for immunohistochemistry (IHC), the current gold standard for subtyping. IHC results are affected by pre-analytic and analytic handling and are subjective. Alternative methods that are more objective, cost less and require less infrastructure and skilled personnel will improve access and reduce disparities. Methods: In the AFBRECANE Project, we compared the results of ER and PR subtyping of 1,000 breast cancer tumors from patients recruited from 5 clinical sites in Nigeria using IHC and Cepheid GeneXpert RNA STRAT4 biomarker assay at ACCME Lab in Nigeria and University of Maryland. Results: For ER, the sensitivities, specificities, and agreement between IHC and STRAT4 ranged from 50.0%, 71.4% and 59.4% to 77.1%, 80.0% and 78.5% while for PR, they ranged from 58.1%, 66.7% and 62.5% to 84.6%, 84.2% and 84.4%. Conclusions: The wide range of sensitivities, specificities, and agreement between IHC and STRAT4 in this study confirms the challenges of molecular subtyping of breast cancer in LMICs like Nigeria. Sustainable objective methods are sorely needed to improve diagnosis, treatment and prognostication, and reduce global disparities.
Maintenance olaparib in patients (pts) with platinum-sensitive relapsed ovarian cancer (PSROC) by somatic (s) or germline (g) BRCA and other homologous recombination repair (HRR) gene mutation status: Overall survival (OS) results from the ORZORA study.
Authors: Pignata Sandro , Oza Amit M. , Hall Geoff , Pardo Beatriz , Madry Radoslaw , Cibula David , Klat Jaroslav , Montes Ana , Glasspool Rosalind , Colombo Nicoletta , Pete Imre , Herrero Ana , Romeo Marga , Ilieva Rumyana Nedyalkova , Timcheva Constanta , Di Maio Massimo , Barnicle Alan , Taylor Rosemary , Bashir Zahid , Clamp Andrew R. 
Published: June 2022

5519 Background: In the SOLO2 (NCT01874353) trial, maintenance olaparib provided clinically meaningful improvement in OS for PSROC pts with a gBRCA mutation (m) compared with placebo (median 51.7 vs 38.8 months [mo], respectively). The ORZORA trial (NCT02476968) assessed efficacy and safety of maintenance olaparib in PSROC pts with a BRCAm (s or g) or a non-BRCA HRRm. Median progression-free survival (18.0 mo, BRCAm; 16.4, non-BRCA HRRm) was reported at primary data cutoff (DCO). We report final OS analyses. Methods: We conducted an open-label, single-arm, multicenter study of PSROC pts in response to platinum-based chemotherapy (PBC) after ≥2 prior lines of PBC. Pts underwent prospective central screening for tumor BRCAm status (myChoice CDx, Myriad Genetic Laboratories, Inc.), then central gBRCAm testing (BRACAnalysis CDx, Myriad Genetic Laboratories, Inc.) to determine s or g status. An exploratory cohort comprised of pts with predefined non-BRCA HRRm (FoundationOne CDx, Foundation Medicine, Inc.). Pts received maintenance olaparib (400 mg bid; capsules) until progression. OS and time to second progression (PFS2) were secondary endpoints. Results: 181 pts were enrolled (BRCAm n = 145 [s, n = 55; g, n = 87; s/g status unknown, n = 3]; non-BRCA HRRm, n = 33; unassigned, n = 3). At DCO (June 25, 2021), median OS follow-up in censored pts was 42.6 mo in BRCAm and 39.3 mo in non-BRCA HRRm pts. OS and PFS2 are reported in the Table. PBC was received as a subsequent therapy by 33.1% BRCAm, 32.7% sBRCAm, 33.3% gBRCAm, and 45.5% non-BRCA HRRm pts. 177 pts received ≥1 dose of olaparib and were included in safety analyses; 6.2% of pts discontinued because of adverse events (AEs). 37.9% of pts reported grade ≥3 AEs, the most common being anemia (16.4%). Since primary DCO, one new primary malignancy and four myelodysplastic syndrome events occurred. Conclusions: In final OS analyses, maintenance olaparib capsules showed consistent clinical activity in BRCAm and sBRCAm PSROC pts. Exploratory analyses suggest similar activity in non-BRCA HRRm pts. No new safety signals were observed. Findings highlight that PSROC pts, beyond those with a gBRCAm, can benefit from maintenance olaparib. Clinical trial information: NCT02476968. [Table: see text]