bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene expression levels of HER2 and IL-8 and polymorphism in IL-8 associated with clinical outcome in advanced or metastatic gastric cancer treated with lapatinib in SWOG 0413 trial
Authors: Chang H. , Azuma M. , Goldman B. , Nagashima F. , Iqbal S. , Danenberg K. , Benedetti J. , Zhang W. , Blanke C. , Lenz H. 
Published: March 2020

4647 Background: Lapatinib (GW572016) is a dual tyrosine kinase inhibitor of EGFR and HER2. In SWOG0413 trial, advanced or metastatic gastric cancer patients were treated with lapatinib. In this study, we investigated whether gene expressions and polymorphisms of EGF and angiogenesis pathway genes were associated with clinical outcome in the patients enrolled in SWOG0413 trial. Methods: A total of 46 patients were enrolled in SWOG0413 trial and treated with lapatinib. Blood and tissue samples were available from 42 and 37 patients, respectively. RT-PCR was performed for intratumoral gene expression levels of EGFR, HER2, VEGF, IL-8, COX2 and cyclin D1 genes. We also analyzed 8 polymorphisms in the EGF, EGFR, HER2, VEGF, IL-8, COX2 and cyclin D1 genes by PCR-RFLP. Results: Patients who have lower IL-8 [median overall survival (OS), 6 vs 3 months, p=0.03] and higher HER2 (6 vs 3 months, p=0.005) gene expression levels showed better OS. According to gene polymorphisms, patients who have A allele of IL-8 T251A polymorphism showed improved OS (A/A, 10 months vs T/A, 5 months vs T/T 3 months, p=0.04). And patients with A allele of IL-8 T251A and T allele of VEGF C936T polymorphisms showed better response rates (p<0.01, p<0.01, respectively). All other polymorphisms and gene expressions did not show significant association with clinical outcome. Conclusions: Our results suggest that intratumoral gene expression levels of HER2 and IL-8 and polymorphism in IL-8 are potential molecular predictors for survival in patients with advanced or metastatic gastric cancer treated with lapatinib. And polymorphisms in IL-8 and VEGF genes may be potential markers in predicting response in this population. A larger prospective study is needed to validate and confirm these preliminary findings. [Table: see text]
Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC)
Authors: Duffy A. , Capanu M. , Abou-Alfa G. K. , Huitzel D. , Williams P. , Jarnagin W. , Fong Y. , Kelsen D. P. , O’Reilly E. M. 
Published: March 2020

4648 Background: The incidence of GBC in the US is 1.2/ 100,000. Given the dearth of phase III data on the use of adjuvant therapy, institutional review can provide a justification for future studies. This report examines the patterns of presentation, treatment and survival of a large cohort of patients with GBC evaluated at MSKCC over a 10-year period. Methods: A retrospective analysis of patients referred to MSKCC with a diagnosis of GBC between 1/1995 and 12/ 2005 was performed. Patients were identified from the MSKCC cancer registry. Information extracted included, demographics, stage, surgical management, pathology, adjuvant and palliative therapy, date of relapse, death or last follow-up. Date of diagnosis was defined as date of surgery or biopsy. Univariate analysis of survival times and log rank test were employed. Results: 435 GBC cases were identified. 285 (65.5%) females,150 (34.5%) males. Median age 67 years (range 28–100). Pathology: 88% adeno, 4% squamous, 3% neuroendocrine, 2% sarcoma. 36.6% presented as AJCC Stage IV. 47% were discovered incidentally at laparoscopic cholecystectomy (LC). 136 of these were re-explored, of whom 100 (73.5%) had residual disease. Of those who underwent curative resections, 8 received adjuvant chemotherapy, 2 adjuvant radiotherapy and 17 combined chemoradiation. Median OS for the cohort was 9.11 months(m). The median survival(MS) for those presenting with stage IV disease was 4.5 m (95% CI 3.8–6.1) compared to 12.9 m (95% CI 11.7–15.8 m) for those with stage IA-III disease. MS was better for those discovered incidentally at LC (15.7 m,p<.001). For those who underwent re-exploration, MS was 13.9 m if residual disease was present, and 68 m if no residual disease. The MS for those who received adjuvant therapy was 23.4 m. Conclusions: GBC is commonly diagnosed incidentally (47%) at LC. Re- exploration reveals a high incidence of residual disesase (74%). MS is better for patients diagnosed incidentally and those without evidence of disease on re-exploration. Overall prognosis is poor. Although the number of patients was small, adjuvant therapy appeared to confer a survival benefit. Prospective randomized trials of adjuvant therapy are needed in this disease. No significant financial relationships to disclose.
Concurrent and adjuvant docetaxel with three dimensional conformal radiation therapy (3-D CRT) for poor-risk localized prostate cancer: A phase II trial
Authors: FERRERO J. , Bolla M. , Maingon P. , Buffet-Miny J. , Bougnoux A. , Bauer J. , Descotes J. , Conil M. , Colonna M. 
Published: March 2020

5003 Background: Docetaxel increases survival in hormone refractory prostate cancer. The objective of this trial is to evaluate the feasibility of concomitant weekly docetaxel with 3-D CRT and adjuvant docetaxel in unfavorable localized or locally advanced prostate carcinoma. Methods: Sixteen patients with poor risk localized carcinoma (T1c-2b N0M0) and 34 with locally advanced tumors (T3N0- 1M0) according to the 1997 UICC classification, underwent 3-D CRT (72Gy/36 fractions); docetaxel 20mg/m2 iv was delivered concurrently on weeks 1–2-3–5-6–7; adjuvant docetaxel 60mg/m2 q3w started 4 weeks after the completion of radiotherapy for 3 cycles. The patients had to receive LHRH agonist, 6 months to 3 years, according to the number of poor prognostic factors. Acute toxicity was assessed with the NCI CTC v:2.0. Results: From November 2003 to November 2005, 50 patients were included (438 cycles) from six institutions. Median age was 50 years (48–76), median PSA 17.7 ng/ml (3.4–260) and median follow-up 17 months (9–38). Forty six patients completed the chemoradiation regimen (423 cycles), with full dose of docetaxel, 4 patients did not, due to: 1 grade 4 GI toxicity during the cycle 3, 1 grade 3 dysuria after cycle 6, 1 grade 4 myocardial infarction after cycle 6, 1 grade 4 anal fistula between two cycles of adjuvant docetaxel; these patients were excluded. The percentage of grade 3 acute toxicity was 10.8% (5/46): 1 grade 3 neutropenia, 1 grade 3 rectal bleeding, 2 grades 3 diarrhea, 1 grade 3 dysuria. Grade 2 toxicity (nausea, diarrhea and rectitis) were observed, in a percentage of 26%; no grade 2–3 toxicity occurred as regard hypotension, venous thrombosis, peripheral neuropathy, respiratory morbidity, oedemas. Twelve months after the end of the treatment, 44 patients were in complete remission (clinical and biological) and two patients suffer from distant metastases. Conclusion: The feasibility of this combined chemo-radiation regimen deserves to be followed by a phase III trial. No significant financial relationships to disclose.
A phase II trial of rapid androgen cycling and docetaxel (Doc) in prostate cancer patients with a rising prostate-specific antigen (PSA) in the noncastrate state
Authors: Rathkopf D. E. , Carducci M. A. , Slovin S. , Morris M. J. , Kelsen M. , Pili R. , Denmeade S. R. , Eisenberger M. , Scher H. I. 
Published: March 2020

5004 Introduction: Prostate cancer patients in the noncastrate state with a rapidly rising PSA are at high-risk for cancer-specific mortality. Since hormonal therapy alone is not curative, we have explored the use of rapid androgen cycling with Doc to recruit proliferating cells into successive waves of apoptosis, thereby shifting the treatment outcome for these patients from palliation to cure. Methods: Patients with noncastrate levels of testosterone (T), a rising PSA ± metastases, and = 6 months of prior hormones were eligible. Cohort 1: Six 4- week cycles of monthly leuprolide and Doc (75 mg/m2), with 7 days of topical T repletion (AndroGel 1% 5G) prior to each treatment. Cohort 2: Nine 3-week cycles of Doc (70 mg/m2), with 3 days of T repletion per cycle and 3-month depot leuprolide on day 1 of cycles 1, 5, and 9. The primary endpoint was the proportion of patients with a treatment-specific undetectable PSA at 6 and 18 months defined as: = 0.05 after surgery, = 0.5 after radiation, or = 2.0ng/ml with untreated disease. This is based on the premise that an undetectable PSA is a prerequisite to, but no guarantee of cure. Results: There were no increases in sequential PSA peaks or troughs and 100 out of 102 patients completed the planned 6 months of chemohormonal treatment. Twenty three of 62 (37%) patients in cohort 1, and 25 of 38 (66%) patients in cohort 2 achieved the primary endpoint of a treatment-specific undetectable PSA at 6 months. At 12 months, no patient in cohort 1 had maintained an undetectable PSA in the setting of a noncastrate T level; whereas, 8 of 15 (53%) patients in cohort 2 have achieved the endpoint at 12 months. Toxicities were similar to those observed with Doc and hormonal therapy administered separately. Conclusions: Rapid androgen cycling with docetaxel is feasible, and can induce successive declines in PSA peaks and troughs. The more dose-dense cohort 2 schedule of 21-day Doc administration for 9 cycles, along with reduced exposure to androgen repletion from 7 to 3 days, has resulted in a higher proportion of undetectable PSA outcomes at both 6 (66% vs. 37%) and 12 (53% vs. 0%) months. Complete PSA outcomes for cohort 2 at 12 and 18 months are still pending. Supported by Sanofi-Aventis, CA-05816, and PepsiCo. No significant financial relationships to disclose.
The prognostic value of PSA derivatives in favourable risk localised prostate cancer
Authors: van As N. J. , Ng M. K. , Norman A. R. , Huddart R. , Dearnaley D. , Horwich A. , Thompson A. , Woode-Amissah R. , Khoo V. , Parker C. 
Published: March 2020

5008 Introduction: Risk stratification in localized prostate cancer is based on PSA level, Gleason score and T stage. PSA derivatives may be of additional prognostic value. We have assessed the use of PSA derivatives in the prediction of histologic disease progression on repeat biopsy in patients on active surveillance. Methods: In a prospective cohort study of active surveillance, men with untreated, low- and intermediate-risk, clinically localized prostate cancer (T1/2a, PSA < 15 ng/ml, Gleason score ≤ 3 + 4, and % positive cores ≤ 50%) had repeat octant prostate biopsies 18–24 months after diagnosis. Histologic progression was defined as primary Gleason pattern ≥ 4, or % positive cores > 50 %, or an increase in Gleason score from ≤ 6 to ≥ 7. Standard clinical variables and PSA derivatives were analysed with respect to histologic progression. Multivariate analysis was performed including all standard variables both with each PSA derivative individually, and with all PSA derivatives. Results: 175 men had repeat biopsy. Median age was 67 yrs and median initial PSA, 6.5 ng/ml. Histologic disease progression was seen in 50 (29%) cases. Factors associated with histologic progression on univariate analysis were PSA velocity (p=0.0001), PSA density (p=0.0002), free-total PSA ratio (p=0.002), maximal % core involvement (p=0.009), age (p=0.003), and initial PSA level (p=0.02). On multivariate analysis, each PSA derivative was significant, independent of standard clinical variables. On combined multivariate analysis, free-total PSA ratio (p=0.0027), PSA velocity (p=0.009), age (p=0.0057) and maximal % core involvement (p=0.011) were significant determinants of histologic progression. Conclusions: Free-total PSA ratio and PSA velocity may be useful in the subclassification of favourable-risk localized disease. Larger validation studies in active surveillance patients are warranted. No significant financial relationships to disclose.
Multi-center study evaluating circulating tumor cells (CTCs) as a surrogate for survival in men treated for castration refractory prostate cancer (CRPC)
Authors: Moreno J. , DeBono J. S. , Shaffer D. , Montgomery B. , Miller M. C. , Tissing H. , Doyle G. , Terstappen L. W. , Pienta K. J. , Raghavan D. 
Published: March 2020

5016 Background: Monitoring CTCs in patients undergoing therapy for metastatic breast cancer is an effective means to predict outcome and monitor treatment. The primary endpoint of this prospective multi-center study was to demonstrate a significant relation between the presence of CTCs and survival in men treated for CRPC. Methods: 276 patients with diagnosed CRPC, PSA progression, and an ECOG score of 0–2 about to begin initial or salvage chemo and/or combination therapy were enrolled. CTCs were enumerated with the CellSearch System in blood drawn pre-treatment and monthly thereafter for up to 18 months. Patient data were collected and maintained by an independent CRO. Median overall survival (OS) was determined for patients with =5 CTC /7.5mL at baseline and specified intervals. Results: Of 240 evaluable patients, 142 (59%) are alive - mean follow-up 11.4 ± 4.4 months. Median OS (in months) and significance between the two groups (logrank p-value) at different time points after the initiation of therapy are indicated in the table . Median OS for 40 (19%) patients with a reduction of CTCs below 5 CTCs 2–5 weeks after initiation of therapy was significantly longer as compared to those 78 (38%) patients that remained above 5 CTCs (>20 vs. 9.3mth, p=0.0000) and was not significantly different from the 83 (40%) patients with 20 vs. >20mth, p=0.2725). In multivariate analyses, which included stage at diagnosis, age, ECOG, Gleason score, LDH, Alkaline Phosphotase, and PSA, CTCs remained the most significant independent predictor of outcome. Conclusions: CTC levels in CRPC patients are a strong predictor of OS. The persistence of CTCs after initiation of therapy suggests that the patients are deriving less than optimal benefit from their current therapy. CTC levels may be a valid surrogate end-point in monitoring response to chemotherapy. [Table: see text] No significant financial relationships to disclose.
Use of a tissue biomarker panel to predict which men with a rising PSA post-definitive prostate cancer therapy will have systemic progression
Authors: Jenkins R. B. , Nakagawa T. , Kollmeyer T. , Morlan B. , Bergstrahl E. , Davis B. , Klee G. , Ballman K. V. 
Published: March 2020

5017 Background: The majority of men with prostate cancer are diagnosed with cancers with low mortality. Such men are treated with radical prostatectomy, external beam radiotherapy, or brachytherapy and followed by serum PSA evaluations. Some men with a rising PSA therapy will have local recurrence or metastasis, but many will have no other evidence of recurrent disease other than a rising PSA. The PSA doubling time has been used to determine which of these men deserve adjuvant hormonal ablation, radiation therapy, or observation. We hypothesize that additional biomarkers will predict which men with a rising PSA post-definitive therapy would benefit from additional therapy. Methods: We designed a custom array containing 526 RNA targets whose expression has been reported to be altered in association with prostate cancer progression. We included targets from Mayo Clinic prostate cancer research. Together with a second commercial array, 530 genes implicated in prostate cancer progression and 420 other cancer-related genes were evaluated. A case-control design was used to test the association of the expression results with outcome. Cases were men post-radical prostatectomy who developed systemic progression within 5 years after PSA recurrence (N=213). Controls were matched men post-radical prostatectomy with PSA recurrence but no evidence of clinical progression within 5 years (N=213). Results: Of 426 eligible patients, paraffin blocks were available on 418 (98.1%). RNA was prepared from all 418 blocks, and both arrays were both successful on 405 (96.9%) RNAs. Upon univariate analysis, 40 genes were highly significantly over- or under-expressed in the cases versus controls (1x10-22 < p < 1x10-7). Recursive partitioning (RP) selected 4 genes (TPX2, FAM13C1, TOPO2A and TSP2) that distinguished cases from controls. Random Forest analysis selected 24 genes (including 3 of the RP 4). A multivariable ROC analysis using these 24 genes generated an AUC of 0.80 (95% CI: 0.75–0.84). Conclusions: A specific gene expression pattern was significantly associated with systemic progression after PSA recurrence. The measurement of gene expression pattern may be useful for determining which men may benefit from additional therapy after PSA recurrence. No significant financial relationships to disclose.
Initial versus recent outcomes with a non–risk adapted surveillance policy in stage I non-seminomatous germ cell tumors (NSGCT)
Authors: Duran I. , Sturgeon J. F. , Jewett M. A. , Anson-Cartwright L. , Berthold D. R. , Kakiashvili D. , Warde P. R. , Alison R. E. , Pond G. R. , Moore M. J. 
Published: March 2020

5021 Background: Since 1981 the Princess Margaret Hospital testicular cancer group has used surveillance as the preferred management option for all patients (pts) with clinical stage I NSGCT. In a report of the first 105 pts [Sturgeon et al. J Clin Oncol, 1992] the relapse rate was 35% and the disease specific 5-year survival 99%. Improvements in imaging technique over time could cause stage migration with an overall lower relapse rate in this patient population. We compare our experience with surveillance over different time points. Methods: Three-hundred and five pts with stage I NS-GCT were placed on an active surveillance protocol between 1981–2004. They were not stratified by risk and only received treatment on the event of a relapse. Recurrence rates, time to relapse, risk factors predictive for recurrence, disease specific and overall survival were determined. For the analysis by time period, pts were divided in two groups based on diagnosis date. (Initial=1981–1992 [N=141] and Recent=1993–2004 [N=164]). Results: With a median follow-up of 6.3 years, 77/305 pts (25%) relapsed; 46/141 pts (32.6%) in the initial group and 31/164 (18.9%) in the recent. All but 3 (4%) relapses occurred within 2 years after orchiectomy with a median time to relapse of 7 months. A multivariate analysis established lympho-vascular invasion (p<0.01) and pure embryonal carcinoma (p= 0.03) as independent predictors of recurrence. Overall 104/305 (34.1%) pts were designated as ‘high- risk’ based on the presence of at least one of these factors. In the initial group 60/141 (42.6%) pts were high risk and 32/60 (53%) relapsed versus 14/81 (17.3%) low-risk (p=0.047). In the recent group 44/164 (26.8%) pts were high-risk and 17/44 (38.6%) recurred, versus 14/120 (11.7%) low-risk (p<0.001). There were 2 (0.7%) deaths due to testis cancer. The estimated 5-year disease specific survival was 98.9% in the initial group and 100% in the recent one. Conclusions: Surveillance is an effective strategy for the management of all stage I NSGCT. A risk-adapted policy would result in more than 50% of the patients being unnecessarily treated. The relapse rate has reduced over time, likely due to improvements in imaging causing stage migration. No significant financial relationships to disclose.
Sequential use of sorafenib and sunitinib in renal cancer: Retrospective analysis in 90 patients
Authors: Sablin M. P. , Bouaita L. , Balleyguier C. , Gautier J. , Celier C. , Balcaceres J. L. , Oudard S. , Ravaud A. , Négrier S. , Escudier B. 
Published: March 2020

5038 Background: Sorafenib (So) and sunitinib (Su) have been recently approved for the treatment of advanced renal cell carcinoma (RCC). Following this approval, sequential use of both drugs is often proposed, although very few data are available to support it. Material and Methods: We reviewed all patients (pts) who received sequentially So-Su or Su-So in the last 3 years from 4 sites in France. All pts had been enrolled in clinical studies or in the extended access programs. In all patients demography, prognostic factors (MSKCC score), number of metastatic sites, best response (BR) and PFS with each treatment were recorded. Some patients are still too early for response and PFS assessment under the second treatment. Results: 68 pts first received So while 22 pts received Su first (continuous dosing in 12, intermittent in 10). Results under the first treatments were as follows: median PFS 26.1 wks, mean duration of treatment 33.2 wks; and median PFS was 22 wks, mean duration of treatment 26.9 wks for So and Su respectively. BR in terms of partial response (PR), stable disease (SD), progressive disease (PD) is given in the table . 2 pts stopped So because of toxicity and response is not available (NA), and 22 pts (NE) are too early in the course of the second treatment. Overall, PR rate was 17.6% for So and 22.7% for Su. PR or SD was observed as best response in the second treatment in both sequences. Only 6 pts had PD with both drugs: all of them had 3 or more metastatic sites and were in intermediate or poor MSKCC risk groups. Conversely, 4 pts had PR with both drugs, and were in good (n=2) or intermediate (n=2) risk groups. 11 pts only have died so far. Conclusions: these results suggest the lack of cross resistance between So and Su, and support the sequential use of So and Su in RCC. Updated data will be presented at ASCO. [Table: see text] No significant financial relationships to disclose.
Phase I study of PTK787/ZK222584 (PTK/ZK) and RAD001 for patients with advanced solid tumors and dose expansion in renal cell carcinoma patients
Authors: Speca J. C. , Mears A. L. , Creel P. A. , Yenser S. E. , Bendell J. C. , Morse M. A. , Hurwitz H. I. , Armstrong A. J. , George D. J. 
Published: March 2020

5039 Background: PTK/ZK is an orally active tyrosine kinase inhibitor that blocks all known VEGF receptors. RAD001 is an orally active macrolide which selectively inhibits mTOR. Combination therapy with VEGFR and mTOR inhibition may have additive efficacy in several tumor types, particularly renal cell carcinoma (RCC). Materials and Methods: A phase I/II study of PTK/ZK and RAD001 was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), safety and tolerability. Patients were given escalating daily doses of PTK/ZK in combination with RAD001 (see table ) in 28-day cycles. Patients were assessed for adverse events every 2 weeks and tumor response every 2 cycles. A dose expansion cohort of 20 patients with metastatic RCC is ongoing to further evaluate safety and preliminary efficacy. Results: To date, 27 patients have received a total of 136 cycles. The dose escalation phase included 14 patients and 3 dose levels; dose-limiting toxicities included grade 3 diarrhea and hypertriglyceridemia (14%); asthenia, fatigue and mucositis (7%). Pharmacokinetic studies are pending. A MTD of PTK/ZK 1,000 mg and RAD001 5 mg daily was determined and studied in an expanded cohort of RCC patients. Prior therapy with a VEGF inhibitor was allowed. To date, 13 evaluable RCC patients demonstrate 2 (15%) partial responses and 8 (62%) with stable disease > 3 months; median TTP is 6 months. Conclusions: PTK/ZK and RAD001 combination is well-tolerated and demonstrates clinical activity in patients with RCC despite prior exposure to VEGF inhibition. An MTD of 1,000 mg daily of PTK/ZK and 5 mg daily of RAD001 is the recommended dose for Phase II/III testing. [Table: see text] No significant financial relationships to disclose.