bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tamoxifen-induced hot flashes are associated with estrogen receptor polymorphisms
Authors: Stearns V. , Hayes D. F. , Li L. , Robarge J. , Skaar T. , Nguyen A. , Schott A. , Storniolo A. , Flockhart D. A. , Jin Y. 
Published: March 2020

501 Background: Hot flashes are the most common side effect of tamoxifen. The pharmacogenetic predictors of hot flashes are not known. We hypothesized that estrogen receptor (ER) genotypes that have been associated with clinical phenotypes may predict the frequency and composite score of tamoxifen-associated hot flashes. Methods: We conducted a prospective observational study in 3 academic centers to evaluate the associations between ER and hot flash composite scores in women with breast cancer during the first year of adjuvant tamoxifen treatment. Menopausal status and prior chemotherapy history were collected at baseline. Medication records and validated hot flash diaries were prospectively collected before and following 1, 4, 8 and 12 months of starting tamoxifen. ERa (ESR1) PvuII (rs2234693) and XbaI (rs9340799) genotypes were determined using a Restriction Fragment Length Polymorphism (RFLP) assay; and ERβ (ESR2–02; rs4986938) genotype was determined using a Taqman™ assay. The haplotype of two ESR1 SNPs and their association with the baseline hot flash score were analyzed with haplo.stat function in R. Individual SNPs and their interactions in baseline hot flash score and month 4 hot flash score change were analyzed with SAS PROC GLM. Results: Of the 298 women recruited to the trial, 286 returned their baseline diaries and 251, 239, 214, and 213 women returned their diaries 1, 4, 8, and 12 months after tamoxifen treatment. At baseline, premenopausal women who were homozygous for the ESR1 CG haplotype reported higher hot flash scores (17.2±3.7) than carriers with one or less CG allele (5.2±3.9), p=0.01. After tamoxifen treatment, postmenopausal women with ESR1 PvuII CC and ESR2–02 GG genotype had the greatest increase (p=0.0004) in hot flash score (53.9±16.4) as compared with women with other genotypes (12.5±3.6). Women who were homozygous for the ESR2–02 AA allele were significantly less likely to experience tamoxifen-induced hot flashes than women with at least one G allele (OR=4.0, P=0.0006) regardless of menopausal status and chemotherapy history. CYP2D6 analysis in underway and results will be available for the meeting. Conclusions: Menopausal status, history of prior chemotherapy, and ER genotype may be used to predict who may suffer hot flashes during tamoxifen treatment. [Table: see text]
The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded access trial in North America: Safety and efficacy
Authors: Knox J. J. , Figlin R. A. , Stadler W. M. , McDermott D. F. , Gabrail N. , Miller W. H. , Hainsworth J. , Ryan C. W. , Cupit L. , Bukowski R. M. 
Published: March 2020

5011 Background: A prior phase III trial (TARGETs) demonstrated that sorafenib (SOR) doubled median progression-free survival versus placebo in previously treated clear cell renal cell cancer (RCC) patients (pts). The ARCCS trial made SOR available to a broader range of RCC pts through an expanded access program. Methods: This open-label, nonrandomized trial enrolled pts with advanced RCC not eligible for, or without access to, other SOR clinical trials; ECOG PS 0–2 with waivers granted for pts with ECOG PS 3–4; age =15 yrs; and adequate prior treatment of brain metastases. Major exclusion criteria included treatment <4 wks prior, life expectancy <2 mos, uncontrolled hypertension, and severe renal impairment requiring dialysis. Objectives were to analyze the safety and efficacy (response by RECIST) of 400 mg bid SOR in a community-based setting. Enrollment ceased on 12/20/05 when SOR became commercially available in the US, and those with no prior therapy or non-clear cell RCC continued in an extension protocol. Enrollment completed in Canada in 8/06. Results: A total of 2488 pts were valid for safety: 69% male with median age 63 yrs and most (83%) had prior nephrectomy; histologies included 78% clear-cell, 7% papillary, 1% chromophobe, and <1% collecting duct and oncocytoma. Median time from diagnosis for all pts was 1.4 yrs (range <1–34). Of those pts receiving prior therapy (n=1249), treatments included interferon alfa (54%), interleukin 2 (43%), bevacizumab (23%), thalidomide (12%), and sunitinib (2%). Grade 3 and 4 adverse events occurring in > 2% pts were hand- foot skin reaction 7.2%, fatigue 5.3%, hypertension 4.4%, rash/desquamation 4%, dehydration and dyspnea 2.7%, and diarrhea 2.5%. Efficacy assessment, mainly PFS, was limited by the short median time (14 wks) on study due to many pts enrolling during the last 2 months of the study. Of 1,850 pts evaluable for response, 17.5% had unconfirmed PR. One (0.1%), 67 (3.6%), 1479 (79.9%) and 303 (16.4%) had CR, PR, SD, and PD, respectively. Conclusions: ARCCS pts were representative of the broader range of RCC pts in the community including those excluded from previous SOR trials. Toxicity and response rates were similar to those reported previously, supporting the generalizability of the phase III trial data. [Table: see text]
Kinome in renal cell carcinoma: Mutation analysis of 518 kinases and expression of 400 tumors
Authors: Teh B. T. ,   International Kidney Cancer Study Group
Published: March 2020

5013 Background: Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. In addition, expression levels of these protein kinases have also been associated with drug efficacy allowing prediction of drug response. Renal Cell Carcinoma (RCC) constitutes approximately 3% of all cancer incidence and deaths. Methods: We screened the coding sequences of 518 protein kinases (approximately 1.3 mb of DNA per sample) for somatic mutations in 69 kindey tumors of different subtypes. We also studied the expression of these kinases in 400 kidney tumors of different subtypes and prognosis by gene expression profiling using the Affymetrix HG-U133 Plus 2.0 GeneChip platform. The bioinformatic analysis is focused on the 518 protein kinases. Results: We identified 22 mutations (16 missense, 3 silent, 1 nonsense, 1 frameshift and 1 in-frame) in 16 samples. In expression profiling, we detected differential expression of protein kinases between different subtypes and between good- and poor- prognosis subgroups. Conclusions: This is the most comprehensive kinome profile in RCC known to date. The mutant protein kinases may play a role in the tumorigenesis of a subset of kidney cancer. These, together with over-expressed protein kinases, may serve as potential therapeutic targets and bio-markers for diagnosis, prognosis and drug response prediction. Other gene families may also be involved in RCC. No significant financial relationships to disclose.
Satraplatin (S) demonstrates significant clinical benefits for the treatment of patients with HRPC: Results of a randomized phase III trial
Authors: Sternberg C. N. , Petrylak D. , Witjes F. , Ferrero J. , Eymard J. , Falcon S. , Chatta K. , Vaughn D. , Berry W. , Sartor O. 
Published: March 2020

5019 Background: Chemotherapeutic options for HRPC are limited. S is a novel oral platinum compound. Methods: The SPARC trial is a multinational randomized double blind study comparing S 80 mg/m2/day x 5 q5weeks po + prednisone (P) vs placebo + P in HRPC patients (pts) who failed prior chemotherapy. In this analysis, progression-free survival (PFS) was the primary endpoint, defined as a composite endpoint of radiologic progression, symptomatic progression, skeletal events or death. All cases were blindly adjudicated for progression by an independent review committee (IRC). Results: 950 pts were accrued between Sept 2004 and Jan 2006. Baseline characteristics were well balanced between treatment arms. 51% of the pts had received prior docetaxel. 68% were ≥ 65 yrs old and 27% were ≥ 75 yrs old. Pts received a median of 4 courses in the S arm (range:1–28) vs 2 courses in the placebo arm (range 1–16). 802 pts had an IRC defined progression-free (PFS) event consisting in 80% of the cases of radiologic progression, pain progression or death. All analyses were conducted on an intent-to-treat basis. S was associated with a 31% reduction in the risk of PFS events (HR=0.69; 95% CI: 0.60–0.80; p<0.00001) and a 33% reduction in the risk of pain progression (HR=0.67; 95% CI: 0.54 - 0.83; p=0.00028). Consistent results in favor of S were found for PFS and time to pain progression in all subsets examined, including pts treated with prior docetaxel. Superior PSA response (25% vs.12%, p=0.00007), objective tumor response (7% vs. 1%, p<0.002), pain response (24% vs. 14%, p<0.005), and duration of pain response (HR=0.59; 95%CI: 0.35–1.00; p=0.049) were observed for S. Final analysis of overall survival awaits the occurrence of the pre-specified number of events. S was generally well tolerated - myelosuppression was the most frequent side effect, but grade 4 neutropenia was uncommon (4%) and a single patient had grade 4 thrombocytopenia. Grade 3/4 non-hematologic side effects included infection (4%), vomiting (2%) and diarrhea (2%). Conclusions: S is well tolerated and significantly reduces the risk of disease progression for HRPC pts who have failed prior chemotherapy. Supported by GPC Biotech and Pharmion No significant financial relationships to disclose.
Impact of homozygote variant of bleomycin hydrolase (BLMH) gene on survival after chemotherapy for testicular cancer (TC)
Authors: de Haas E. C. , Zwart N. , Meijer C. , Boezen H. M. , van der Steege G. , Sleijfer D. T. , Gietema J. A. 
Published: March 2020

5022 Background: With bleomycin, etoposide and cisplatin, cure of disseminated TC exceeds 80%. Next to tumor characteristics, response to chemotherapy may be determined by polymorphisms of genes involved in metabolism or target pathways of cytotoxic drugs. We investigated whether the A1450G polymorphic site in the gene for BLMH, an enzyme that inactivates bleomycin, is associated with differences in survival. Methods: Data were collected on survival of non-seminomatous TC patients treated with bleomycin and platinum from 1977–2003. BLMH genotype was determined from genomic DNA by PCR + restriction fragment length polymorphism analysis. The 3 genotypes [AA (wild-type), AG (heterozygote variant) and GG (homozygote variant)] were compared for patient characteristics, prognostic factors and received chemotherapy (Mann-Whitney U or χ2 test) and survival (Kaplan-Meier + log-rank test and Cox regression). Results: Data on BLMH genotype and survival were available for 304/372 patients (82%) with median follow-up of 10 yrs (range 0–27). The 3 genotypes AA (n=140), AG (n=133) and GG (n=31) did not differ significantly with respect to age, IGCCC prognosis, creatinine clearance and received dose of bleomycin and platinum. Overall survival of the GG genotype (61%) was worse than the overall survival of AA and AG combined (83%) (p=0.004), due to worse TC related survival of GG (71%) compared to AA + AG (90%) (p=0.001). Homozygote variants (GG) had a significantly increased risk for TC related death (odds ratio (OR) = 4.97) compared to wildtypes (AA) ( table ). Conclusion: Germline presence of the homozygote variant (GG) of the BLMH gene appears to be an unfavorable prognostic factor for TC related death after chemotherapy, in addition to the commonly used IGCCC prognosis. It is unclear whether this is due to alterations in metabolism or target pathways of bleomycin or other cytotoxic agents, or linkage disequilibrium to a yet unknown involved gene. This needs to be unraveled in future research. [Table: see text] No significant financial relationships to disclose.
Exposure-response of sunitinib in metastatic renal cell carcinoma (mRCC): A population pharmacokinetic/pharmacodynamic (PKPD) approach
Authors: Houk B. E. , Bello C. L. , Michaelson M. D. , Bukowski R. M. , Redman B. G. , Hudes G. R. , Wilding G. , Motzer R. J. 
Published: March 2020

5027 Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs and PDGFRs, and has shown substantial antitumor activity in mRCC (Motzer et al, JAMA 2006 and ASCO 2006). This analysis describes SU, and total drug (TD; SU+SU12662 [active metabolite]) exposure-response relationships in mRCC using a population PKPD approach. Methods: PK and efficacy data from 3 studies (phase II and III) of SU (25–62.5 mg/day; 4 wks dosing followed by 2 wks off) in treatment-naïve (N=44) and cytokine-refractory mRCC pts (N=148) were analyzed. SU and SU12662 concentrations were fitted to a population PK model (a 2- compartment model for both parent and metabolite). Estimates of pt PK were used to calculate steady-state Area Under the Curve (AUCss) for SU, SU12662 and TD, which were used as the exposure measure in a PKPD analysis of partial response (PR) rates, time to tumor progression (TTP), overall survival (OS), and tumor volume changes. Results: The probability of a PR for cytokine-refractory pts increased with increasing AUCss for SU and TD. The odds-ratio suggested a 2.6-fold increase in PR frequency for each unit increase in AUCss. Longer TTP and OS were also noted in pts with high SU and TD AUCss. In treatment-naïve pts on SU, there was very little observed tumor progression or death (only 5 pts progressed and only 1 death) limiting the ability to analyze exposure-response. A tumor growth dynamics model (developed to describe changes in tumor volume [by CT or MRI] in response to treatment, as a function of AUCss) provided a good description of tumor volume changes with SU for both treatment-naïve and cytokine-refractory pts. Efficacy was not related to baseline tumor volume, gender, or race. Based on this model, clinical trial simulations assuming perfect pt compliance predict that 62% of pts would achieve a PR with SU 50 mg/day. Conclusions: SU and TD AUCss correlated significantly with the probability of a PR in cytokine- refractory pts, and longer TTP and OS. Limited data were available for treatment-naïve pts. The tumor growth dynamics model provided a good description of tumor volume changes with SU for both populations. This exposure-response analysis indicates that increased exposure to SU is associated with clinical benefit. [Table: see text]
Treatment outcome for metastatic papillary and chromophobe renal cell carcinoma (RCC) patients treated with tyrosine-kinase inhibitors (TKIs) sunitinib and sorafenib
Authors: Plantade A. , Choueiri T. , Escudier B. , Rini B. , Negrier S. , Ravaud A. , Oudard S. , Elson P. , Bukowski R. 
Published: March 2020

5037 Background: Sunitinib (SUNI) and sorafenib (SORAF) are novel TKIs that have shown significant clinical activity in metastatic clear-cell RCC. Papillary (PAP) and chromophobe (CHRM) histologies represent the majority non-clear-cell RCC. The activity of SUNI and SORAF in non-clear cell histologies has not been evaluated. Methods: Clinical features at study entry and treatment outcomes were evaluated in all patients (pts) with metastatic PAP and CHRM RCC who received either SUNI or SORAF as their initial TKI treatment at one of five different cancer centers in France and USA between 2002 and 2006. Descriptive statistics were used to evaluate the collected data. Overall Response rate (ORR) was investigator-assessed per RECIST criteria. Fisher’s exact test was used for categorical variables and the Kaplan-Meier method was used to estimate survival (Overall Survival (OS) and progression-free survival (PFS)). Results: Median age for the 53 patients was 59 years and 64% were male. The number of patients with PAP and CHRM histologies were 41 (77%) and 12 (23%), respectively. Nephrectomy was performed in 87% of patients and 33/53 (62%) of pts were previously treated (26/33, 79%, with cytokines). ORR, PFS and OS for the entire cohort were 10%, 8.9 months (m) and 12.2 m, respectively. Twenty (38%) and 33 (62%) pts were treated with SUNI and SORAF, respectively. 3/12 (25%) of CHRM pts had an ORR vs. 2/41(4.8%) with PAP histology (P=0.07). PFS for CHRM pts was 9.3 m compared to 6.6 m for PAP pts (p=0.07). OS was not different across histologies and type of TKI received. SUNI treated pts had an ORR of 15% and PFS of 11.9 m compared to 6% (p=0.3) and 5.5 m for SORAF pts (p=0.002), respectively. Other factors found to be associated with shorter PFS include ECOG PS >0 (p=0.03) and hemoglobin< normal (p=0.02). Conclusions: TKI may have activity in metastatic CHRM RCC, similar to what is seen in clear-cell histology. Minimal activity however is noted in PAP RCC, justifying continued investigations of novel agents in this histology. No significant financial relationships to disclose.
Androgen receptor (AR) level in the prostatectomy specimen predicts time to disease progression post androgen suppression therapy
Authors: Cordon-Cardo C. , Donovan M. J. , Khan F. , Teverovskiy M. , Hamann S. , Eggener S. , Vicars A. , Scardino P. 
Published: March 2020

5065 Background: The androgen receptor (AR) plays an important role in the initiation and growth of prostate cancer and its subsequent response to hormone therapy. Previous analyses, including our own, have determined that elevated AR protein in the prostatectomy specimen is associated with progression of disease. We hypothesized that AR levels may also be predictive of response to androgen deprivation therapy (ADT) by evaluating time to castrate rise in PSA in patients treated with ADT at the time of a biochemical recurrence. By utilizing quantitative immunofluorescence (IF) and spectral imaging we evaluated AR content as an independent predictor of therapeutic outcome. Methods: 63 of 881 patients treated by radical prostatectomy had received ADT for a biochemical rise in PSA and or clinical progression of their disease. 32 of 63 patients had progressed post-ADT with a castrate rise in PSA. Tissue microarrays with triplicate patient cores were stained with a multiplex immunofluorescent assay (IF) which contained the nuclear marker DAPI, along with the following antibodies: Androgen Receptor (AR), Racemase (AMACR), CK18, HMWK and p63. IF images were acquired with spectral un-mixing employed to develop antibody-cell-specific gray scale images. Utilizing image analysis algorithms, quantitative features including intensity and area for selected antigens was generated. Results: Eleven IF antigen features were evaluated after feature selection and filtering using the concordance index with respect to outcome. A total of 5 features were statistically significant for predicting time to progression post therapy of which 2 features (AR intensity within AMACR (+) and (-) epithelial cells; p=0.0003 and p=0.0021, respectively) demonstrated that elevated levels of AR were associated with a shortened time to castrate rise in PSA post ADT. Clinical features alone were not found to be statistically significant with respect to predicting outcome. Conclusions: AR levels in the prostatectomy sample appears to be a useful indicator for determining therapeutic ADT response and potentially guiding future treatment decision and patient monitoring. No significant financial relationships to disclose.
Correlation of serum interleukin-6 (IL-6) levels with immunohistochemical p65/nuclear factor-κB (NF-κB) expression and prediction of the clinical outcome of hormone-independent prostate cancer patients (HIPC) treated with docetaxel (D)
Authors: Domingo-Domenech J. , Martinez-Fernandez A. , Garcia-Albeniz X. , Fernandez P. , Filella X. , Gascon P. , Mellado B. 
Published: March 2020

5075 Background: We have recently reported that NF-κB/IL-6 was linked to D response in human prostate cancer cells. In this study we investigated the clinical significance of IL-6 serum levels in HIPC pts treated with D and the correlation between serum IL-6 levels and p65/NF-κB tissue expression. Methods: Pts with HIPC treated with D were prospectively tested for IL-6 levels by ELISA before chemotherapy. In patients with available specimens of hormone-independent tumor p65/NF-κB was determined by immunohistochemistry. PSA response to D, time to progression and survival were analyzed. Results: Sixty pts were included. Median follow-up time was 29.3 (5.3–55.47) months. Median time to D progression was 4.2 (0,6–15.1) months and median survival was 10.1 (1.6- 47.1) months. Median baseline IL-6 were 16 pg/ml (range 0–156). Pts that responded to D had median IL-6 of 15.1±3.9 pg/ml and patients that did not respond had median IL-6 of 34.7±6.5 (p=0.009). IL-6 correlated with the number of bone metastasis (r=0.39, p=0.002), LDH levels (r=0.53, p<0.0001) and inversely with time to PSA progression (r=-0.65, p<0.0001) and survival (r=-0.61, p<0.0001). In the multivariate analysis IL-6 were an independent prognostic factor for time to PSA progression HR 1.026 (CI95% 1.013–1.046) and survival IL-6 levels HR 1.022 (CI 95% 1.006- 1.038, p=0.008). HIPC tissue samples from 12 pts were assessed for p65/NF-κB expression. All tissue samples showed cytoplasmatic and nuclear staining. Median percentage of nuclear p65/NF-κB stained cells was 15% (range 5–45%). P65/NF-κB nuclear staining showed correlation with serum IL-6 levels (r=0.719, p=0.009). Patients with low serum IL-6 levels (= 16 pg/ml) had a median % of nuclear p65/NF-κB staining of 5.4±2.5% and patients with high IL-6 levels had a median % of nuclear p65/NF-κB staining of 30.2±4.9% (p=0.001). Conclusions: High IL-6 serum levels were associated to a worse survival in HIPC pts treated with D. Our data suggest that the determination of serum IL-6 levels may serve as a surrogate marker of NF-κB activity in hormone-independent prostate cancer tumor and may be useful to select patients for NF-κB targeted therapy. No significant financial relationships to disclose.
Phase II study of sunitinib in patients (pts) with relapsed or refractory urothelial carcinoma (UC)
Authors: Gallagher D. J. , Milowsky M. I. , Gerst S. R. , Iasonos A. , Riches J. , Boyle M. G. , Bajorin D. F. 
Published: March 2020

5080 Background: Second-line chemotherapy has limited activity in advanced UC. Pre-clinical evidence demonstrates an important role for angiogenesis in UC biology, thus supporting this study of the novel VEGF targeted agent, sunitinib, in pts with UC. Methods: The primary objectives of this single institution phase II trial of sunitinib in pts with UC who have failed prior chemotherapy are: 1) to determine the response rate (RECIST); and 2) to evaluate toxicity. Prior therapy is restricted to = 4 chemotherapy drugs. Pts receive sunitinib 50 mg orally daily for 4 weeks followed by 2 weeks off (one cycle). Response is assessed after each of the initial 4 cycles and every other cycle thereafter. The Simon 2-stage design requires = 2 responses in the first 21 pts to proceed to maximal accrual of 41 evaluable pts. Results: 21 pts (19 male, 2 female) with median age of 64 yrs (39–76) and median KPS of 80 (70–90) were enrolled between 9/15/06 and 1/4/07. Primary tumor sites include bladder (14 pts), ureter/renal pelvis (6 pts) and urethra (1). Prior therapy included 10 pts with 2 drugs, 9 with 3 and 2 with 4. 14 pts have metastatic visceral disease [lung (11), liver (8) and bone (1)], and 7 pts have only lymph node metastases. To date, 15 pts are evaluable for radiographic response after completing at least one cycle of therapy; 6 pts are too early for response assessment. One pt experienced a treatment-related death. Responses include: 1 PR seen after cycle 1 and confirmed after cycle 2, 8 with SD (range -29% to +16% change compared to baseline) and 6 with POD. Radiographic regression has been observed in liver, lung, soft tissue and lymph node metastases. Clinically significant toxicity (Grade 3/4) includes: hematuria (n= 1 pt, 2 events in a bladder primary), mucositis (2 pts), thrombocytopenia (2 pts), infection (1), stomatitis (1), fatigue (1), rash (1), diarrhea (1), and abdominal pain (1). Conclusions: Sunitinib has clinical activity in pts with advanced UC. Accrual is ongoing to define further the level of activity, the duration of response, and the time to progression. [Table: see text]