bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacogenetics as predictor of sunitinib and mTOR inhibitors toxicity in patients with metastatic renal cell carcinoma (mRCC).
Authors: Urun Yuksel , Gray Kathryn P. , Signoretti Sabina , McDermott David F. , Atkins Michael B. , Lampron Megan E. , Freedman Matthew , Choueiri Toni K. , Pomerantz Mark M 
Published: March 2020

4570 Background: Single nucleotide polymorphisms (SNPs) in major pharmacokinetics (PK) and pharmacodynamics (PD) pathways of targeted agents may affect the incidence of drug toxicities. Methods: Germline DNA was extracted fromwhole blood or normal kidney parenchyma frommRCC pts of European ancestry in two cohorts: those treated with VEGF-targeted therapy (sunitinib) (n=159) or with an mTOR inhibitor (everolimus or temsirolimus) (n=62). Ten SNPs in 6 candidate genes: CYP3A4 (rs2242480, rs4646437, rs2246709), CYP3A5 (rs15524), ABCB1 (rs2032582, rs1045642), VEGFR2 (rs2305948), NR1I3 (rs2307424, rs2307418), FLT3 (rs1933437) were genotyped using Sequenom iPlex Gold platform. Logistic regression model tested the association of genotype variants with adverse events of 1) grade 3/4 (G3/4) toxicity and G3/4 hypertension (for sunitinib cohort) and 2) grade 3/4 toxicity and all grade pneumonitis (for mTOR inhibitors cohort), adjusted for clinical factors associated with toxicity outcomes. Results: In the sunitinib cohort, median treatment duration was 7.7 months (IQR=3-15.5), 83 (52%) pts had grade 3/4 toxicities and 22 (14%) had grade 3/4 hypertension. Rare variant (AG) of CYP3A4 rs464637 was associated with the reduced risk of grade 3/4 toxicities (4 events/17 cases) vs. wild-type (GG, 73 events/134 cases), (Odds Ratio (OR) = 0.27, 95%CI: 0.08-0.88, p=0.03). No association between SNPs and hypertension was observed. In the mTOR inhibitor cohort, median treatment duration was 3.4 months (IQR=1.4-6), 21(34%) pts had G3/4 toxicities and 27 (43%) had all grade pneumonitis. No association between SNPs and G3/4 toxicities was observed. Rare homozygote (GG) of FLT3 SNP rs1933437 was associated with increased risk of all grade pneumonitis (7 events/ 9 cases) vs. wild-type (AA, 4 events/12 cases), however, given the very small variant group size, further investigation is required to verify the association. Conclusions: The minor allele of SNP rs464637 in the gene CYP3A4 may influence sunitinib toxicity. Further validation is needed to determine if the marker could be used for in targeted therapy dosing strategies and direct patient care. (IQR=Interquartile Range).
Treatment response and survival outcome of patients with late relapse (LR) from renal cell carcinoma (RCC) in the era of targeted therapy.
Authors: Kroeger Nils , Lee Jae-Lyun , Bjarnason Georg A. , Knox Jennifer J. , MacKenzie Mary J. , Vaishamayan Ulka N. , Wood Lori , Srinivas Sandy , Rha Sun Young , Pal Sumanta Kumar , Yuasa Takeshi , Donskov Frede , Agarwal Neeraj , Tan Min-Han , Bamias Aristotelis , Kollmannsberger Christian K. , North Scott A. , Rini Brian I. , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: March 2020

4578 Background: A small subset of localized RCC patients will experience disease recurrence ≥5 years after nephrectomy. Clinical outcome of patients with LR has not been well characterized. Methods: Patients with mRCC treated with targeted therapy were retrospectively characterized according to time to relapse. Replase was defined as diagnosis of recurrent metastatic disease >3 months after initial diagnosis. Patients with synchronous metastatic disease at presentation were excluded. Patients were classified as Early Relapsers (ER) if they recurred within 5 years while Late Relapsers (LR) recurred after 5 years. Demographics and outcomes were compared. Results: 1210 mRCC patients were identified; 903 (74.6%) with relapse within the first 5 years, 200 (16.5%) within >5-10 years, and 107 (8.8%) after 10 years (range 10-35 years). Baseline characteristics are presented in the Table. Overall response rates to targeted therapy were better in LR vs. ER (35% vs. 24%; p=0.009). LR patients had significant longer progression free- (10.7 vs. 8.5 months; log rank p=0.004) and overall survival (34.0 vs. 27.3 months; log rank p=0.003). Conclusions: One quarter of patients that eventually developed metastatic disease treated with targeted therapy relapsed over 5 years from initial diagnosis. The proportion of patients that relapse after five years is substantial. mRCC patients presenting with LR have more favorable prognostic features, treatment response, and overall survival. [Table: see text]
Continuation of sunitinib following RECIST progression on first-line sunitinib.
Authors: Burotto Pichun Mauricio Emmanuel , Wilkerson Julia , Stein Wilfred Donald , Motzer Robert John , Bates Susan Elaine , Fojo Tito 
Published: March 2020

4585 Background: In the last seven years the FDA and the EMA have approved seven agents for treatment of RCC. Five of these target the VEGF pathway. Methods: We conducted a detailed analysis of data from the sunitinib registration trial examining the growth and regression rate constants and the stability of the growth rate as measures of effectiveness and to understand development of resistance. Results: Sufficient data was available for the analysis of 350/374 patients enrolled. Statistically valid data was obtained in 321(91.7%). The median regression rate constant was 0.0048 days-1, and in 59 patients no evidence of growth was recorded while on study, only regression. The median growth rate was 0.00082 days-1 and this rate was stable a median of 267 days, remaining stable beyond 300 days in 172 patients, beyond 600 days in 95 patients, and beyond 900 days in 49 pts. A suggestion of a possible increase of the growth rate while sunitinib was administered could be discerned in only 15/321 pts. With a median growth rate 0.00082 days-1 the estimated time to progression were sunitinib discontinued and then re-started would have been a minimum of 7.3 months. Thus a meaningful outcome could be achieved provided continued sunitinib is tolerable. Finally with an estimated 47%, 27% and 13% of tumor still sensitive to sunitinib 100, 200 and 300 days after starting therapy, shrinkage with a new TKI in patients who discontinue sunitinib before day 300 for toxicity may not be a sign of non-cross resistance, but of residual sensitive tumor. Conclusions: Prolonged stability of the growth rate of RCC on sunitinib is consistent with intrinsic and not acquired resistance. Baring toxicity, continued sunitinib beyond RECIST criteria for progression may provide a beneficial outcome and can be considered a treatment alternative in selected patients. Randomized trials to assess the value of VEGF TKI’s in patients whose disease has “progressed” on sunitinib should consider including an arm that continues sunitinib to test this hypothesis.
aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer.
Authors: Gray Richard G. , Rea Daniel , Handley Kelly , Bowden Sarah Jane , Perry Philip , Earl Helena Margaret , Poole Christopher John , Bates Tom , Chetiyawardana Shan , Dewar John A. , Fernando Indrajit Nalinika , Grieve Robert , Nicoll Jonathan , Rayter Zenor , Robinson Anne , Salman Asad , Yarnold John , Bathers Sarah , Marshall Andrea , Lee Martin ,   on behalf of the aTTom Collaborative Group
Published: March 2020

5 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
Impact of neoadjuvant chemotherapy plus HER2-targeting on breast conservation rates: Surgical results from CALGB 40601 (Alliance).
Authors: Ollila David W. , Berry Donald A. , Cirrincione Constance , Carey Lisa A. , Amos Keith D. , Henry Norah Lynn , Winer Eric P. , Hudis Clifford , Golshan Mehra ,   Alliance for Clinical Trials in Oncology
Published: March 2020

501 Background: Neoadjuvant systemic therapy improves breast conserving therapy (BCT) rates, but the magnitude of this benefit is unknown in operable breast cancer. We sought to quantify this benefit in CALGB 40601, a phase III trial of paclitaxel (T) + HER2 blockade with either trastuzumab (TH), lapatinib (TL), or both (THL), by requiring the treating breast surgeon to determine BCT eligibility before and after neoadjuvant therapy and examining surgical results. Methods: Eligible patients (pts) had operable, newly diagnosed, noninflammatory stage II-III HER2+ breast cancer randomized to receive TH, TL or THL. Prior to, and again after neoadjuvant therapy, the treating breast surgeon determined whether the patient was a BCT candidate based on clinical and radiographic criteria, but the subsequent breast cancer operation was at the discretion of the surgeon and patient. Two endpoints examined were: (1) the conversion rate from BCT-ineligible to BCT-eligible and (2) the rate of successful BCT as determined by tumor-free surgical margins. Results: Of 305 pts randomized (118 THL, 120 TH, 67 TL), 294 were evaluable. Prior to neoadjuvant therapy, 136 (46%) patients were candidates and 158 (54%) were non-candidates for BCT. 107/136 (79%) remained BCT candidates following neoadjuvant therapy and 78 chose BCT, of whom 69 (88%) were successful. 29 pts (21%) initially thought to be BCT candidates became non-candidates after neoadjuvant therapy. Conversely, 76/158 (48%) pts considered non-BCT candidates prior to neoadjuvant therapy down-sized sufficiently to be considered BCT candidates; 40 of these opted for BCT with a 75% (30/40) BCT success rate. In total, 183 pts were deemed BCT candidates after neoadjuvant therapy, yet 65 (36%) proceeded directly to mastectomy. Conclusions: This is the first neoadjuvant trial to prospectively quantify a nearly 50% conversion rate from BCT-ineligible to BCT-eligible in HER2+ breast cancer pts treated with modern systemic therapy. Neoadjuvant chemotherapy combined with targeted anti-HER2 treatment permits potential BCT in approximately 80% of properly selected patients. Clinical trial information: NCT00770809.
Survival with newly diagnosed metastatic prostate cancer in the “docetaxel era”: Data from >600 patients in the control arm of the STAMPEDE trial (NCT00268476).
Authors: Clarke Noel W , James Nicholas David , Mason Malcolm David , Aebersold Daniel M. , Dearnaley David Paul , De Bono Johann Sebastian , Parker Chris , Parmar Mahesh , Ritchie Alastair WS , Russell J. Martin , Spears Melissa Ruth , Thalmann George N. , Sydes Matthew Robert ,   STAMPEDE Investigators
Published: March 2020

5012 Background: STAMPEDE (www.stampedetrial.org) recruits men with newly-diagnosed or rapidly relapsing prostate cancer (PCa) that is metastatic (M1) or high-risk locally advanced, all commencing long-term androgen ablation therapy (AAT) for the first time. This is now the largest therapeutic RCT in PCa. We report survival outcomes for newly-diagnosed M1 control arm men in order to inform future trials in this setting. Methods: Newly-diagnosed men with M1 disease in the trial’s control arm (standard of care: AAT alone for at least 2yr), diagnosed up to 6 months prior to randomisation, were identified from trial records in Dec-2012. We report overall survival (OS) and failure-free survival (FFS) from randomisation by primary disease characteristics. Results: 3703 men were recruited to STAMPEDE Oct-2005 to Dec-2012, including a control arm cohort of 630 M1 men with newly-diagnosed disease. This cohort has median age at randomisation 66yr (quartiles 60-71), median PSA 105 (quartiles 34-379) IU/l; metastases to bone only (B) 393 (62%), soft tissue only (ST) 78 (13%) or bone and soft tissue (B+ST) 159 (25%). ST was mainly lymph nodes. Median time from diagnosis to randomisation is 69 days (max 180 days). Median duration of AAT prior to randomisation is 46 days (max 105 days). There were 129 deaths, of which 111 were from PCa. Median OS from randomisation is 42 months, with 2-yr OS 74% (95%CI 68, 78) in this cohort; B 77% (95%CI 71, 83), ST 85% (95%CI 70, 93), B+ST 57% (95%CI 45, 68). Median FFS is 12 months, driven by rising PSA; 2-yr FFS 32% (95%CI 27-37). Median time from FFS event to death was 22 months. Additional data on relapse therapies will be presented. Conclusions: Survival, and particularly FFS, remains relatively poor for men presenting with M1 disease starting long-term AAT, despite potential access when castration-resistant (CRPC) to docetaxel and other newer therapies. Better first-line therapy is required; STAMPEDE will report many comparisons in the future. Different M1 patterns may vary prognostically. Men with M1 disease will now spend most time in a state of CRPC, which has important implications for clinicians and trialists. Clinical trial information: NCT00268476.
Evolving patterns of metastatic disease in castration-resistant prostate cancer (CRPC) reported in clinical trials from 1990 to 2011.
Authors: Doctor Stephanie , Tsao Che-Kai , Godbold James H. , Galsky Matt D. , Oh William K. 
Published: March 2020

5015 Background: Bone remains the most common site of metastasis in CRPC. With new therapies extending survival in metastatic CRPC (mCRPC), we hypothesized that the incidence of non-osseous metastases is increasing over time. In this study, we evaluated the pattern of metastatic disease in mCRPC as reported in baseline characteristics of prospective clinical trials over 2 decades. Methods: We identified all therapeutic studies in patients with mCRPC in Pubmed and ASCO abstracts from 1990-2011. Inclusion criteria included phase 2 or 3 clinical trials in mCRPC with available baseline demographic data and no exclusion of specific site of metastatic disease (except brain). ASCO abstracts were limited to presentations in which data were available online. For each study, demographic data and study-reported sites of non-osseous metastatic disease were recorded (lymph node, visceral, soft tissue, liver). For each type of metastasis, weighted least squares linear regression models were used to evaluate temporal trends. Results: We identified a total of 290 eligible studies (270 phase II and 20 phase III) involving 19,110 patients. Of these, 127 studies reported data on non-osseous metastases and prior chemotherapy. There was a significant trend over time (p=0.001) of increasing proportions of patients with non-osseous metastasis in both chemotherapy- naïve and treated groups (1.4% per year increase). Increased lymph node, visceral, and soft tissue metastases were seen over the study period. However, the proportion of patients with liver metastasis remained relatively stable Conclusions: In this study, we noted an increasing trend of non-osseous metastatic disease in patients with mCRPC over 20 years. This included lymph node, visceral and soft tissue metastatic disease, and this trend was observed in both chemotherapy-naïve and treated patients. Longer survival and new therapies may be changing the clinical presentation of patients with mCRPC.
ACOSOG Z1041 (Alliance): Definitive analysis of randomized neoadjuvant trial comparing FEC followed by paclitaxel plus trastuzumab (FEC → P+T) with paclitaxel plus trastuzumab followed by FEC plus trastuzumab (P+T → FEC+T) in HER2+ operable breast cancer.
Authors: Buzdar Aman , Suman Vera J. , Meric-Bernstam Funda , Leitch A. Marilyn , Ellis Matthew James , Boughey Judy Caroline , Unzeitig Gary Walter , Royce Melanie , Hunt Kelly ,   for the Alliance for Clinical Trials in Oncology
Published: March 2020

502 Background: Neoadjuvant chemotherapy (NAC) and concomitant trastuzumab (T) have produced high pathologic complete response (pCR) rates in HER2+ breast cancers. Z1041 addresses the timing of initiation of T with NAC. Methods: Women with operable HER2+ invasive breast cancer were randomized 1:1 to: FEC → P+T (Arm 1) or P+T → FEC+T (Arm 2) where treatment was administered as 5-FU 500 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 day 1 of a 21-day cycle x 4 (FEC); paclitaxel 80 mg/m2 weekly x 12 and trastuzumab 4 mg/kg once then 2 mg/kg weekly x 11. Eligibility also included: tumor > 2 cm or a positive lymph node and left ventricular ejection fraction > 55%. The primary aim was to compare the pCR rates in the breast (pBCR) between the regimens. Secondary endpoints were pCR rate in the breast and lymph nodes (pBNCR) and safety profile. All pts who began study treatment were included in the analyses. With 128 pts per regimen, a two-sided alpha=0.05 test of proportions would have a 90% chance of detecting a difference of 20% or more in the pBCR rates, when the pBCR rate with the poorer regimen is ≤ 25%. Results: From September 15, 2007 to December 15, 2011, 282 women (Arm 1: 140 pts) were enrolled. Two pts (Arm 1) withdrew without receiving treatment. The two arms were similar in age, stage, and hormone receptor (HR) status (HR neg: 40%). The severe (grade 3+) treatment-related toxicities included: neutropenia (Arm 1: 24.6%; Arm 2: 32.4%), fatigue (Arm 1: 4.3%; Arm 2: 8.5%), and neurosensory problems (Arm 1: 3.6%; Arm 2: 4.9%). The pBCR rate and pBNCR rates (Table) were not found to differ between the two regimens (Fisher’s exact p values: 0.905 and 0.811, respectively). Conclusions: High pCR rates can be achieved with trastuzumab in combination with anthracyclines and taxanes. The pBCR or pBNCR was not different between regimens based on the timing of initiation of trastuzumab. Clinical trial information: NCT00513292. [Table: see text]
Prospective evaluation of testosterone (T) recovery and PSA relapse following 18 months of androgen deprivation (ADT) after prostatectomy (RP): Results from the TAX-3501 trial.
Authors: Schweizer Michael Thomas , Huang Peng , Sternberg Cora N. , De Wit Ronald , Ecstein-Fraisse Evelyne Brana , Kattan Michael W. , Kibel Adam S , Eisenberger Mario A. 
Published: March 2020

5023 Background: Surgical adjuvant trials in men with prostate cancer (PCa) employing progression free (PFS) and overall survival (OS) endpoints require large sample sizes and long-term follow-up, challenging planned study completion. Recent adjuvant trials are designed to evaluate PSA progression as the primary study endpoint. Since PSA is T-responsive, a thorough understanding of T recovery kinetics after ADT is needed. Methods: TAX-3501 was a randomized phase III adjuvant study post-RP in men with high-risk PCa (n=228) comparing 18 months of hormonal therapy with (CHT) or without (HT) docetaxel either immediately (I) or deferred (D). We analyzed the T recovery data in 108 patients treated with HT who had at least one post-treatment T value. Results: After a median post-treatment follow-up of 676 days (d) (interquartile range 478-847 d) 90 (83%) and 64 (59%) of men had T recovery to >150 ng/dL and to baseline respectively. No significant differences in T recovery between groups were observed (Table). The median time to T recovery from the last day of treatment to >150 ng/dL was 306 d (95% CI, 294-345 d) and to baseline was 487 d (95% CI, 457-546 d). The baseline T recovery in the combined docetaxel [i.e. I(CHT)+D(CHT)] and HT arms [i.e. I(HT)+D(HT)] was not significantly different at 458 d (95% CI, 336-529 d) and 535 d (95% CI, 457-749 d) respectively (HR 1.4, P=0.18). After a median total follow-up of 3.4 years(IQR 2.3–3.8 years) 39/228 (17%) patients had PSA progression, metastatic progression occurred in 1 patient. Conclusions: Prospective analyses of T kinetics in TAX-3501 indicate that recovery is prolonged after 18 months of HT and PSA relapses occur late. Given that PSA is androgen responsive, concomitant post-HT T monitoring is critical for understanding PSA relapse rates after HT. Further, since the correlation of PSA relapse with PFS and OS in the adjuvant setting remains poorly defined, metastasis-free survival may be a more reliable and meaningful clinical endpoint. Clinical trial information: NCT00283062. [Table: see text]
Evaluation of clinical phenotype, survival, and circulating tumor cell (CTC) enumeration in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Bitting Rhonda Lynn , Healy Patrick , Halabi Susan , George Daniel J. , Ko Jung Hyun , Armstrong Andrew J. 
Published: March 2020

5031 Background: The presence of ≥ 5 CTCs is prognostic for shorter survival in mCRPC men. However, many men have low CTCs despite widespread metastatic disease, suggesting heterogeneity in CTC phenotype or detection. We evaluated the association of baseline CTC enumeration with clinical characteristics and survival in mCRPC men at our institution. Methods: CTCs were enumerated with the standard CellSearch method in mCRPC men in a prospective correlative clinical study. The association between baseline CTC count and prostate-specific antigen (PSA), alkaline phosphatase (AP), lactate dehydrogenase (LDH) was explored using the Spearman correlation (r), and the relationship with Gleason sum, sites of metastasis (mets), and prior docetaxel exposure was explored using summary statistics. The overall survival probability (OS) was estimated by the Kaplan-Meier method. Results: In our cohort, 59/82 men had prior docetaxel exposure, and the median CTC count was 16.5. There were 25 men with visceral mets, 55 with bone-predominant mets, and 2 with lymph node only mets. We found a weak relationship between CTCs and PSA (r=0.20), but a more moderate and significant association with AP (r=0.48) and LDH (r= 0.50). We found no relationship between CTCs and Gleason sum, site of mets, or prior docetaxel. 66 men died, and the median OS was 11.2 months (95% CI: 9.2, 12.7). OS was improved in patients with <5 CTCs at baseline compared to ≥ 5 (8.9 vs. 16.6 months, HR=0.47 (95% CI: 0.27, 0.80)). CTC enumeration may further stratify outcomes in men with mCRPC and either visceral or bone metastasis as shown in the table below. Conclusions: The prognostic significance of CTCs is distinct from other established biomarkers and may reflect a unique biology of metastasis, dissociated in part from androgen receptor activity (as reflected by PSA values) but related in part to bone microenvironment, hypoxia, and tumor burden (as reflected by AP and LDH values). These associations need to be validated in larger trials. [Table: see text]