bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating tumor DNA fraction (ctDNA%) to independently predict for clinical outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Maurice-Dror Corinne , Fonseca Nicolette , Herberts Cameron , Fan William , Wyatt Alexander W. , Chi Kim N. 
Published: June 2021

5049 Background: CtDNA% (the tumour-derived proportion of cell-free DNA (cfDNA)) is abundant in >60% of mCRPC pts and associates with adverse clinical prognostic factors. However, prognostic associations have not been comprehensively tested across clinical contexts. We evaluated the utility of ctDNA% as an independent prognostic biomarker in patients with mCRPC prior to first-line (1L) therapy. Methods: 410 treatment-naïve mCRPC pts had blood samples drawn prior to 1L therapy and followed prospectively for outcomes. Plasma cfDNA was subjected to deep targeted sequencing and ctDNA% was calculated using validated methods ( Annala, Cancer Discov, 2018 ). Overall survival (OS), PSA progression free survival (PSA PFS) and PSA declines ≥50% from baseline (PSA50 response rate (RR)) were stratified by ctDNA% and compared using Kaplan-Meier and Cox proportional hazards analysis. Results: Median age was 73 yrs. (range 45-98), the majority of pts had ECOG PS 0-1 (78%) and 9.5% had liver metastases at baseline. The most common 1L therapy employed was androgen receptor pathway inhibitors (90%). Median follow-up was 21 mo. (range 1-75) and median ctDNA% was 4.9% (range: 0-89%). Stratifying patients into high ctDNA (>30%) and Low ctDNA (≤2%) groups showed stronger association with OS and PSA PFS than grouping by median (Table). In a univariate comparison to pts with low ctDNA (≤2%), pts with high ctDNA% (>30%) had significantly shorter median PSA PFS, median OS and a lower PSA50 RR (Table). In a multivariable adjustment for clinical prognostic factors and cfDNA concentration, high ctDNA% remained strongly associated with OS (HR= 3.3, 95%CI: 2.1-5.3, p<0.001) and PSA PFS (HR: 3.7, 95%CI: 2.4-5.9, p<0.001). Although ctDNA% and total cfDNA concentration were correlated (R2=0.55), association with OS was stronger for ctDNA% than cfDNA concentration (stratified at median; HR: 2.9 (2.3-3.7), p<0.001 vs HR: 2.1 (1.7-2.6), p<0.001). Conclusions: In a large cohort of treatment-naïve mCRPC pts, ctDNA% prior to 1L treatment provided strong prognostic information independent of known clinical factors. These data further demonstrate the multipronged clinical utility of ctDNA-based profiling for actionable genomic alterations.[Table: see text]
Proliferation index and survival in men with prostate cancer starting long-term androgen deprivation therapy in the STAMPEDE clinical trial.
Authors: Mendes Larissa , Brawley Christopher D. , Grist Emily , Ali Adnan , Santos Vidal Sara , Parry Marina , Lall Sharanpreet , Atako Nafisah B. , Ishaq Sofeya , Richmond Malissa , Haran Aine , Hoyle Alex , Zakka Leila , Sweeney Christopher , Clarke Noel W. , Parmar Mahesh K. B. , James Nicholas D. , Brown Louise C. , Berney Daniel , Attard Gerhardt 
Published: June 2021

5076 Background: Treatment intensification with docetaxel or abiraterone improved survival for advanced prostate cancer starting androgen deprivation therapy (ADT) in the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE, NCT00268476) trial. However, survival and time-to-progression is highly variable on ADT, introducing the risk of unnecessary toxicity from additional treatments for some patients. Here we test the prognostic association of proliferation index using Ki67 scores in the control arm of the STAMPEDE population of high-risk localised (M0) and metastatic (M1) prostate cancer. Methods: Pre-ADT diagnostic needle biopsies were obtained from 517 men randomized in STAMPEDE arm A between 2006 and 2015. These were assessed for proliferation using an analytically optimised Ki67 immunohistochemistry assay. Ki67 was tested for associations with baseline clinico-pathological variables (Grade group, pre-ADT serum PSA and imaging metastatic burden) in univariable linear-regression models, and for associations with survival outcomes in multivariable Cox-regression models adjusted for these and additional confounding variables. Primary outcome measure was overall survival, secondary outcomes were prostate cancer-specific, failure-free, progression-free and metastatic progression-free survival. Results: Ki67 was available for 475 patients who received ADT only for at least 2 years ± radiotherapy. Of 202 M0, 74 were node positive. Of 273 M1, 116, 127 and 30 were respectively low, high and unknown radiological M1 volume. Ki67 score associated with higher Gleason (p=7.15x10-11) and presence of extra-pelvic metastases (p=1.41x10-8). Increasing Ki67 scores showed a strong linear association with poorer overall survival, with an estimated 2% increase in the hazard of death per percentage increase in the score (adjusted HR=1.02, 95% CI 1.01-1.02; p=1.04x10-5). There was also strong evidence that Ki67 associated positively with all secondary outcomes, including prostate cancer-specific survival (adjusted p=5.50x10-6) and metastatic progression-free survival (adjusted p=3.50x10-9). Conclusions: Ki67 immuno-score is strongly prognostic in clinically advanced prostate cancer independent of Gleason score and the other clinicopathological variables tested in this study. Ki67 is a clinically scalable assay that could improve selection for treatment intensification and provide a tool for screening patients most likely to benefit from further molecular investigation.
A phase II randomized controlled trial of exercise on biochemical progression in men with prostate cancer on active surveillance.
Authors: Kang Dong-Woo , Fairey Adrian S. , Boulé Normand G. , Field Catherine J. , Wharton Stephanie A. , Courneya Kerry S. 
Published: June 2021

5080 Background: Men with prostate cancer (PCa) undergoing active surveillance (AS) are at increased risks of cardiovascular death and disease progression. Any intervention that can address these issues during AS would be highly beneficial. Clinical and preclinical studies have demonstrated the benefits of exercise to improve cardiovascular health in cancer patients and suggested the potential role of exercise in suppressing PCa progression in men with PCa undergoing AS. Therefore, the purpose of this study was to investigate the effects of exercise on cardiorespiratory fitness and biochemical progress of PCa in men with PCa on AS. Methods: The Exercise During Active Surveillance for Prostate Cancer (ERASE) Trial was a single-centre, two-armed, randomized controlled trial in Edmonton, Canada. 52 men with localized PCa who were undergoing AS were randomized to high-intensity interval training (HIIT; n = 26) or usual care (UC; n = 26). The HIIT group performed thrice-weekly, supervised, aerobic HIIT on a treadmill at 85-95% of peak cardiorespiratory fitness (VO2peak) for 12 weeks. The primary outcome was VO2peak, and the secondary and exploratory outcomes included biochemical progression of PCa (prostate-specific antigen [PSA]), PSA kinetics, and growth of prostate cancer cell line LNCaP. Results: 46/52 participants (88%) completed the postintervention VO2peak assessment and adherence to HIIT was 96%. Compared to UC, HIIT significantly improved VO2peak (adjusted between-group mean difference, 1.6 ml·kg-1·min-1; 95% confidence interval [CI], 0.3 to 2.9; p= 0.014). HIIT also significantly reduced PSA level (adjusted between-group mean difference, -1.1 ug/L; 95% CI, -2.1 to 0.0; p= 0.043) and PSA velocity ( p= 0.040), and suppressed LNCaP cell growth ( p =0.024). No significant differences were found in PSA doubling time ( p= 0.10) and testosterone ( p= 0.24). Conclusions: The ERASE Trial is the first randomized controlled trial to demonstrate the impact of HIIT exercise for improving physical fitness and inhibiting biochemical progression of PCa in men with localized PCa on AS. Our findings suggest that supervised aerobic HIIT may be a promising intervention in this clinical setting. Larger-scale randomized controlled trials are warranted to determine if improvements in physical fitness and PCa-related markers translate into improved long-term clinical outcomes in these men such as disease progression, receipt of radical treatments, posttreatment complications, and survival. Clinical trial information: NCT03203460.
Active surveillance of postradical prostatectomy biochemical recurrence: Long-term assessment of outcomes.
Authors: Ahlering Tom Edward , Huang Erica , Huynh Linda My , Su Huang Wei 
Published: June 2021

5081 Background: Biochemical recurrence (BCR) following radical prostatectomy (RP) is an unreliable predictor of distant metastatic progression/prostate cancer death, resulting in potential complications & expenses of overtreatment. Little has been published on management decisions & outcomes of active surveillance (AS). We characterize our long term experience with AS following post-RP BCR without radiation/androgen deprivation therapy. Methods: From June 2002 - September 2019, 1865 men underwent RP. 406 experienced BCR; of these, 138 (34%) were observed without treatment intervention. BCR defined as PSA>0.2 ng/dl, x2. PSAs checked every 1-3 months and entered into a PSADT graph. Men were considered to be formally AS after 3+ years of increasing DT following RP. Men with decreasing DT were treated and censored. Results: The table depicts demographics of the AS patients; median follow-up was 7.3 years (IQR: 4.6-10.6) post-RP. Of patients on AS, average age was 63.7 +/- 7.2 years and 86%, 48%, 40%, 51% and 14% were GG 1 through 5, respectively. Current DT of AS patients averages 20 months, with 0% PCSM. Only 10% of patients with decreasing DT began treatment after average 4 years following BCR. Conclusions: Of 406 patients experiencing post-RP BCR, 34% of patients are effectively managed with AS, with 0% PCSM across all GG. Presently 69 (50%) AS men have been under observation for 7.3 to 18 years. This suggests that significant portion of patients display benign recurrence, characterized by increasing DT following BCR and can be managed safely with observation alone.[Table: see text]
Dose escalation for mitigating diarrhea: Ranked tolerability assessment of anti-diarrheal regimens in patients receiving neratinib for early-stage breast cancer.
Authors: Marx Gavin M. , Chien Amy Jo , García-Sáenz José A. , Chan Arlene , Ruiz-Borrego Manuel , Barcenas Carlos Hernando , Thirlwell Michael P. , Trudeau Maureen E. , Bose Ron , Egle Daniel , Pistilli Barbara , Wassermann Johanna , Cheong Kerry A. , Semsek Dieter , Singer Christian F. , Hunt Daniel , Khambholja Utpal , Xu Feng , Shah Naisargee , Brufsky Adam 
Published: June 2021

536 Background: The primary tolerability concern with neratinib (NERLYNX®; N), an irreversible pan-HER tyrosine kinase inhibitor, is diarrhea. Data from the multi-cohort, open-label, phase 2 CONTROL trial [Barcenas et al. Ann Oncol 2020] demonstrated significant improvement in grade 3 diarrhea and diarrhea-related discontinuations vs the ExteNET trial, which did not mandate anti-diarrheal prophylaxis. We report a systematic analysis of tolerability in CONTROL and ExteNET. Methods: Patients (pts) ≥18y with stage I–IIIc HER2+ breast cancer received N (240 mg/d po for 1y) after trastuzumab-based adjuvant therapy and were enrolled sequentially into cohorts assessing different modalities to mitigate diarrhea. Cohorts with complete data were included: loperamide (L); L+budesonide (BL); L+colestipol (CL); CL as needed (CL-PRN); and N dose escalation (DE; 120 mg/d on d1–7, 160 mg/d on d8–14, and 240 mg/d thereafter). Integrated ranking (IR) analysis was performed on 13 endpoints in 4 domains (exposure, diarrhea, adverse events [AEs], quality of life [QoL]) identified with input from clinicians; cohorts were ranked from 1 (best) to 5 (worst). Index scores (IS) based on individual pt data from CONTROL were calculated as supportive analysis to confirm selection of the regimen with best overall tolerability, which was then compared with ExteNET. Results: Of the 5 CONTROL cohorts evaluated, DE ranked best for most endpoints. Average ranks per IR method: L 3.4; BL 3.2; CL 3.0; CL-PRN 3.3; DE 2.0. The IS analysis supported DE as the cohort with best overall tolerability. Comparison of CONTROL DE vs ExteNET showed improvement in tolerability in all domains (table). Conclusions: These analyses suggest superiority of weekly DE vs other anti-diarrheal strategies. A lower rate of grade 3 diarrhea was observed with CONTROL DE vs ExteNET (13.3 vs 39.9%, respectively), as well as a comparable or improved AE profile. The data also reveal greater compliance with N (fewer early discontinuations, longer treatment duration, higher cumulative dose) and reduced impact on QoL with DE, suggesting improved tolerability. Clinical trial information: NCT02400476. [Table: see text]
Postoperative adjuvant dose-dense chemotherapy with bevacizumab and maintenance bevacizumab after neoadjuvant chemotherapy for advanced ovarian cancer: A phase II AGOG/TGOG trial.
Authors: Chen Wei-Chun , Chou Hung-Hseuh , Yang Lan-Yan , Huang Huei-Jean , Chang Wei-Yang , Lin Hao , Wu Ren-Chin , Chen Min-Yu , Qiu J. Timothy , Huang Kuan-Gen , Chao Angel , Chang Ting-Chang , Lai Chyong-Huey 
Published: June 2021

5540 Background: The objective of this study is to evaluate the safety and efficacy of adding bevacizumab to dose-dense adjuvant chemotherapy with bevacizumab maintenance after neoadjuvant chemotherapy (NAC) and interval debulking surgery (IDS) for stage III/IV ovarian, tubal, and primary peritoneal cancer. Methods: This phase II clinical trial using Simon's minimax two-stage design was conducted. At the first stage, 13 subjects were enrolled, and the trial would proceed to second stage if ≤3 subjects discontinued treatment for study-defined significant adverse events (AEs). Patients with stage III/IV ovarian, tubal, and primary peritoneal cancer deemed not feasible for primary cytoreductive surgery were enrolled after 3 to 4 cycles of NAC and IDS without disease progression. NAC could be either weekly paclitaxel (80mg/m2) (dose-dense) plus 3-weekly carboplatin (AUC5-6) or 3-weekly conventional schedule. After IDS, postoperative dose-dense adjuvant chemotherapy for 3 cycles at least (best to 6 cycles), and 3-weekly bevacizumab 15mg/kg was given since postoperative cycle 2. Further 3-weekly maintenance bevacizumab 15mg/kg was given intravenously for 17 cycles. Results: Of the 22 enrolled subjects, 13 (59.1%) had no gross lesion after IDS. Of the 13 subjects enrolled on the 1st stage, one study-defined significant AE occurred, therefore the trial proceeded to the 2nd stage (n = 9). The median progression-free survival (PFS) was 22.1 months (95% confidence interval [CI], 13.7 – 30.5), and the median overall survival (OS) was 49.2 months (95% CI, 33.8 – 64.6). Peritoneal Cancer Index score at entering abdomen during IDS was significant for PFS (>12 vs ≤ 12: p = 0.003). One of the 22 subjects did not receive any study treatment. In the safety analysis (n = 21), grade 3/4 AEs included thrombocytopenia of 38.1%, neutropenia 71.4%, and anemia 28.6%. Study-defined significant AEs of bowel perforation, poor-healing wound, and hypertension were found in 1 case each, respectively. Conclusions: This phase II trial demonstrated adding bevacizumab to dose-dense adjuvant chemotherapy with bevacizumab maintenance after NAC was feasible with tolerable toxicity and comparable PFS/OS as compared to other studies using bevacizumab in the NAC phase or dose-dense scheduling throughout. Clinical trial information: NCT02022917.
Open-label, multicenter, phase 1b/2 study of rebastinib in combination with paclitaxel to assess safety and efficacy in patients with advanced or metastatic endometrial cancer.
Authors: Janku Filip , Hamilton Erika P. , Mathews Cara Amanda , Chu Christina , Diamond Jennifer Robinson , Hays John L. , Arend Rebecca Christian , Cristofanilli Massimo , Jewell Andrea , Reichmann William , Kuida Keisuke , Achour Haroun , Ruiz-Soto Rodrigo , Richardson Debra L. 
Published: June 2021

5576 Background: Rebastinib is a first-in-class investigational, orally administered, potent and selective switch-control kinase inhibitor of tunica interna endothelial cell kinase (TIE2). This is a 2-part open-label, multicenter Phase 1b/2 study of rebastinib in combination with paclitaxel. Here we provide updated results (ASCO 2020) from the fully enrolled endometrial cancer (EC) cohort of the study. Methods: Part 2 of the study has five disease-specific cohorts (EC, platinum-resistant ovarian cancer, gynecological carcinosarcoma, TNBC and inflammatory breast cancer). Patients were treated at the RP2D and evaluated for efficacy (RECIST v1.1) and safety (CTCAE v5.0). Results: As of Jan 8, 2021, 38 EC patients were enrolled (median age of 66 years); 42% were of grade 2/3 endometroid histological subtype. All patients received at least 1 prior line of paclitaxel in combination with carboplatin and 79% of patients received ≥3 prior anti-cancer regimens. Sixteen of 38 patients were initially treated with a starting dose of rebastinib 100 mg BID, 11 of which dose reduced to 50 mg BID, and 22 patients were treated with a starting dose of rebastinib 50 mg BID, in combination with paclitaxel 80 mg/m2 IV weekly (days 1, 8, 15 of 28-day cycle). In 33 evaluable patients with median follow-up of 5.9 months, the ORR was 33% and clinical benefit rate at 8 and 16 weeks was 70% and 55%, respectively, including 11 PRs (8 confirmed) and 12 SDs. Treatment-emergent adverse events ( > 20% of patients; mostly ≤ grade 2) included fatigue (n = 18), constipation, peripheral edema (each at n = 16), peripheral sensory neuropathy, nausea (each at n = 15), dyspnea (n = 13), alopecia, hypokalemia (each at n = 11), diarrhea, hypomagnesemia (each at n = 10), dry mouth, dysgeusia (each at n = 9), arthralgia, hypertension, dehydration, GERD and muscular weakness (each at n = 8). Serious adverse events (SAE) at least possibly related to rebastinib included muscular weakness (n = 2 at 100 mg BID, n = 1 at 50 mg BID), nausea (n = 2), acute myocardial infarction, atrial flutter, dehydration, non-infective encephalitis, peritonsillitis, and stress cardiomyopathy (each at n = 1) and were resolved after dose interruption. Conclusions: The updated results of rebastinib at 50 mg BID in combination with paclitaxel showed encouraging preliminary anti-tumor activity and an acceptable safety profile in heavily pretreated EC patients, and supports further development in patients with EC (NCT03601897). Clinical trial information: NCT03601897.
Trends in breast cancer mortality according to molecular subtypes: A population-based study.
Authors: Han Yunan , Xu Shuai , Colditz Graham A. , Toriola Adetunji T. 
Published: June 2021

572 Background: Breast cancer is the second leading cause of cancer death in U.S. women. On the molecular level, breast cancer is a heterogeneous disease. Heterogeneous expressions of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) are etiologically and clinically meaningful, as they map to distinct risk factors and different treatment strategies. Although breast cancer mortality has been declining since 1990, little is known about mortality trends according to molecular subtypes at the population level. Methods: We examined the incidence-based mortality rates and trends among women who were diagnosed with invasive breast cancer from 2010 through 2017 using the Surveillance, Epidemiology, and End Results (SEER) database. We defined incidence-based mortality using a moving 5-year calendar period starting in 2014. We further assessed mortality according to breast cancer molecular subtypes: luminal A (ER and/or PR positive, HER2 negative), luminal B (ER and/or PR positive, HER2 positive), HER2-enriched (HER2 over-expressed or amplified, ER and PR negative) and triple-negative (ER and PR negative, HER2 negative) tumors. We calculated annual percent changes (APC) in incidence-based mortality using joinpoint regression models. Results: Overall, incidence-based mortality for breast cancer significantly decreased by 1.5% annually from 2014 through 2017 (APC, -1.5%; 95% coefficient interval [CI], -2.3% to -0.7%; p<0.001). Incidence-based mortality decreased annually by 2.0% for luminal A breast cancer (APC, -2.0%; 95% CI, -3.7% to -0.3%; p<0.001), 2.1% for luminal B breast cancer (APC, -2.1%; 95% CI, -5.4% to 1.4%; p=0.1), 1.1% for triple-negative breast cancer (TNBC) (APC, -1.1%; 95% CI, -2.1% to -0.0%; p<0.001). However, incidence-based mortality for HER2-enriched breast cancer increased 2.3% annually during the study period (APC, 2.3%; 95% CI, -2.4% to 7.2%; p=0.2). Conclusions: Between 2014 and 2017, incidence-based mortality for luminal A, luminal B, and TNBC decreased among U.S. women, with a larger decrease observed for luminal tumors. However, incidence-based mortality for HER2-enriched breast cancer increased. The favorable incidence-based mortality trends for luminal tumors and TNBC are likely due to the continuing improvement in treatments and early detection. The increasing trend of incidence-based mortality for HER2-enriched breast cancer constitutes a priority for cancer control activities and further research.
Evaluation of sensitivity to endocrine therapy index (SET2,3) for response to neoadjuvant endocrine therapy (NET) and subsequent prognosis.
Authors: Symmans William Fraser , Du Lili , Hoskin Tanya L. , Anurag Meenakshi , Ma Cynthia X. , Bedrosian Isabelle , Hunt Kelly , Ellis Matthew James , Suman Vera Jean 
Published: June 2021

580 Background: Patients (pts) in Cohort A of the American College of Surgeons Oncology Group Z1031 (Alliance) trial of NET for cStage II-III breast cancer were randomized to anastrozole [ANA], letrozole [LET] or exemestane [EXE] for 16-18 weeks (wks). In Cohort B, pts chose between ANA and LET and switched to chemotherapy or surgery if a tumor biopsy after 2-4 wks of NET had Ki67 >10%. Treatments after surgery were not defined by the trial protocol. SET2,3 measures nonproliferation gene expression related to estrogen and progesterone receptors adjusting for a baseline prognostic index that combines clinical tumor and nodal stage and a 4-gene molecular subtype (RNA4) defined by ESR1, PGR, ERBB2 and AURKA. High SET2,3 in a pre-treatment biopsy using cStage information is defined as SET2,3 >1.77. Methods: 379 pts had gene expression data from a research tumor biopsy prior to NET (Agilent 44K microarrays). A bioinformatician blinded to pt treatment and clinical outcomes determined SET2,3. The trial statistician then examined the association between SET2,3 and pharmacodynamic response at 2-4 wks (N=141, Cohort B): Ki67 ≤10% and complete cell cycle arrest (CCCA Ki67 ≤2.7%); pathologic outcomes in pts who completed NET: ypStage 0/1 (N=329, Cohorts A&B), PEPI-0 rate (N=155, Cohort B); and event-free survival (EFS) post-registration (N=244, Cohorts A&B). We used Fisher’s exact tests to assess whether responses, and Cox modeling to evaluate whether EFS, differed with respect to SET2,3 status. Results: High SET2,3 in 48% of pts (183/379) was associated with older age (median: 66 vs 63 years; p=0.012); cStage II (95% vs 75%; p <0.001); and pre-NET Ki67 ≤10% (37% vs 20%; p< 0.001) in pts with low SET2,3. In Cohort B, pts with high SET2,3 had a higher rate of pharmacodynamic response in their tumor at wk 2-4 than pts with low SET2,3 (Table). In the subset of Cohort B pts with wk 2-4 Ki67 ≤10%, pre-treatment SET2,3 trended numerically higher in pts who achieved PEPI-0 score (p=0.049) but the proportion achieving PEPI-0 did not differ by SET2,3 high/low status (Table). EFS was significantly longer for pts with high SET2,3 than pts with low SET2,3 (HR[H/L]: 0.52; 95% CI: 0.34-0.80; p=0.003). Conclusions: An exploratory analysis of Z1031 data demonstrated that the rate of pharmacodynamic suppression of proliferation by NET at 2-4 wks was greater and EFS was longer for pts with breast cancer expressing high SET2,3 disease than pts with low SET2,3. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ; Clinical trial information: NCT00265759. [Table: see text]