bluuebunny/crossref_metadata_2025 huggingface dataset:
The relationship of K-ras mutations and EGFR gene copy number to outcome in patients treated with Erlotinib on National Cancer Institute of Canada Clinical Trials Group trial study PA.3
Authors: Moore M. J. , da Cunha Santos G. , Kamel-Reid S. , Chin K. , Tu D. , Parulekar W. , Ludkovski O. , Squire J. , Richardson F. , Tsao M.
Published: March 2020

4521

Background: The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) PA.3 study compared treatment with the EGFR tyrosine kinase inhibitor erlotinib to placebo in patients with advanced stage pancreatic carcinoma who were receiving gemcitabine. This study demonstrated a significant advantage in survival [HR=0.82; P<0.04] and in progression free survival [HR=0.77; P<0.004] for patients who received erlotinib [Moore MJ et al, J Clin Oncol 2007]. While high-level expression of EGFR is common in pancreatic cancer, EGFR protein expression level as evaluated by immunohistochemistry did not predict which patients might benefit from erlotinib. In non- small cell lung cancer (NSCLC) where erlotinib has shown a survival benefit; the use of EGFR copy number measured by FISH is a better predictive factor for benefit, and patients whose tumor had a K-ras mutation do not respond nor benefit. Methods: The NCIC-CTG PA.3 trial had a sample size of 569 and NCIC.CTG has collected 280 archival formalin-fixed and paraffin embedded tumor biopsy or primary resection specimens from patients randomized on study. Many were fine needle aspirates and a total of 181 had sufficient tissue to allow molecular analysis. We performed a K-ras mutation analysis by PCR of exon 2 followed by sequencing, with negative results being validated by DHPLC. EGFR gene copy number was analysed by fluorescent in situ hybridization. Both methods were performed on all tumor samples adequate for analysis. Results: Overall 146 cases were suitable for K-ras mutation analysis and preliminary results have identified K-ras mutation in 90 patients [76%] and wild type KRAS in 29 patients; the remainder are pending. A total of 118 cases are suitable for EGFR FISH analysis, results have been obtained in 73 patients, and the remaining cases are pending. The correlations between K-ras mutational status and EGFR copy number, and outcomes [survival and disease control] in patients randomized to both erlotinib and placebo will be presented.

[Table: see text]
p53 adapted neoadjuvant therapy for esophageal cancer: Pilot study
Authors: Kandioler D. , Hejna M. , Zwrtek R. , Kappel S. , Bichler C. , Wrba F. , Ba-Ssalamah A. , Zielinski C. , Jakesz R. , Zacherl J. ,   p53 Research Group Study
Published: March 2020

4535

Background: Randomized trials could not yet prove clinical efficacy of neoadjuvant chemotherapy for esophageal cancer. A survival benefit could be shown for treatment responders only. Using platinum based regimen, yet about 20 % of patients can achieve pathological complete remission which translates in reported 3-year survival rates of 64% in this group. Factors identifying this subgroup of responders and selecting optimal drugs for non responders could dramatically enhance treatment efficacy. Several studies suggest that mutations in the p53 gene may induce drug resistance especially for agents whose effect is based on apoptosis induction, like Cisplatin. Methods: In order to test the hypothesis that the p53 genotype is predictive for chemotherapy response, a prospective study was conducted. Thirty-eight patients with potentially respectable esophageal cancer were evaluated for the relation between p53 genotype and response to two different neoadjuvant treatments. P53 gene mutations were assessed by complete direct sequencing of DNA extracted from diagnostic biopsies. Response to neoadjuvant chemotherapy was assessed pathohistologically in the surgical specimen. Results: 20 squamous cell carcinoma and 18 adenocarcinoma were included. Overall the p53 mutation rate was 58% (22/38), with 66 % for squamous cell and 53% for adenocarcinomas, respectively. 30 patients received CIS/5FU (cisplatin 80mg/m2 d1 5-FU 1,000mg/m2 d 1–5, q21,2 cycles), 8 received docetaxel (75mg/m2, q21,2 cycles). The overall response rate was 48% (18/38). Patients with p53 mutation did not respond to CIS/5-FU (0/16), while all mutant patients responded to docetaxel (6/6). The overall response to p53 adapted neoadjuvant therapy was 94%. P53 adapted treatment was associated with a significant survival advantage (p=0,042) after a median follow up of 15,4 months. Conclusions: A prospective randomized trial was initiated to test the interaction between the predictive marker p53 and response to CIS/5-FU and Docetaxel, respectively.

[Table: see text]

No significant financial relationships to disclose.
Survivin expression in esophageal cancer: Association with histomorphological response to neoadjuvant therapy and prognosis
Authors: Vallboehmer D. , Kuhn E. , Brabender J. , Metzger R. , Warnecke-Eberz U. , Baldus S. E. , Drebber U. , Hölscher A. H. , Schneider P. M.
Published: March 2020

4536

Background: The poor prognosis associated with locally advanced esophageal cancer prompted an evaluation of combined modality treatments including neoadjuvant radiochemotherapy in combination with surgery. However, it has been well established that only patients with a complete pathological response to neoadjuvant therapy will have a significant survival benefit. Therefore, predictive markers to allow a tailored radiochemotherapy are needed. The aim of this study was to examine the association of the protein expression of survivin, an inhibitor of apoptosis, with histopathologic response to neoadjuvant radiochemotherapy and prognosis of patients with locally-advanced esophageal cancer. Methods: 59 patients with esophageal cancer (cT2–4, Nx, M0) received neoadjuvant radiochemotherapy (cisplatin, 5-FU, 36 Gy) followed by esophagectomy. Histomorphologic regression was defined as major response when resected specimens contained less than 10 % and as minor response when resected specimens contained more than 10 % of residual vital tumor cells. Pre- and post-therapeutic intratumoral protein expression of survivin was determined and correlated with clinicopathologic parameters. Results: The pre-therapeutic intratumoral survivin protein expression was not associated with any clinicopathologic factor, including histopathologic response and prognosis. Survivin protein expression was significantly reduced during neoadjuvant therapy, showing lower levels in post-therapeutic tumor samples (p<0.01). Higher postoperative survivin levels were significantly associated with a higher ypT-stage (p<0.009), a poorer histopathologic response (p<0.01) and a shorter overall survival (p<0.028). Conclusions: The intratumoral protein expression of survivin was significantly down-regulated during neoadjuvant therapy, whereas a higher survivin level after pre-operative therapy was significantly associated with a worse histopathologic response and prognosis. Therapeutic strategies which are able to reduce survivin expression or to block survivin mediated pathways might increase the histopathologic response rate and prognosis in the multimodal therapy of patients with locally-advanced esophageal cancer.

No significant financial relationships to disclose.
Utility of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) in the staging, radiotherapy planning and prognostication of anal cancer
Authors: de Winton E. , Heriot A. , Ng M. , Hicks R. , Hogg A. , Milner A. , Leong T. , Fay M. , MacKay J. , Ngan S.
Published: March 2020

4559

Background: Accurate inguinal and pelvic nodal staging in anal cancer is important for prognosis and planning of (chemo)radiation fields. There is strong evidence for the impact of FDG-PET in staging and management of cancer, with early reports of an increasing role in outcome prognostication for a number of tumours. We aimed to determine the impact of FDG-PET on the nodal staging, radiotherapy planning and prognostication of patients with primary anal cancer. Methods: Sixty-two consecutive patients with anal cancer referred to a single tertiary oncology centre between August 1997 and November 2005 were staged with conventional imaging (CIm), computed tomography, magnetic resonance imaging and chest x-ray and by FDG-PET. The stage determined by CIm and the proposed management plan was prospectively recorded and changes in stage and management as a result of FDG-PET assessed. Patients were treated using uniform radiotherapy technique and dose. The accuracy of changes and prognostication of FDG-PET was validated by subsequent clinical follow-up. Kaplan-Meier survival analysis was used to assess survival for the cohort and by FDG-PET and CIm stage. Results: The TNM stage group was changed in 23% (14/62) as a result of FDG-PET (15% up-staged, 8% down-staged). Fourteen percent of T1 patients (3/22), 42% of T2 patients (10/24) and 38% of T3–4 patients (6/16), assessed using CIm, had a change in their N or M stage following FDG-PET. Sensitivity for nodal disease by FDG-PET and CIm was 92% and 72% respectively. The staging FDG-PET scan altered management intent in 3% (2/62), and altered radiotherapy fields in 13% (8/62). Estimated 5 year overall survival and progression free survival (PFS) for the cohort was 77.3% (95% CI 55.3%-90.4%) and 72.2% (95% CI 51.5%-86.4%) respectively. Estimated 5 year PFS for FDG-PET and CIm staged N2–3 disease was 70% (95% CI 42.8%-87.9%) and 55.3% (95% CI 23.3%-83.4%) respectively. Conclusions: FDG-PET shows increased sensitivity over CIm for staging nodal disease in anal cancer and changes treatment intent or radiotherapy fields in a significant proportion of patients. Improved 5 year PFS for FDG-PET staged N2–3 disease could be consistent with more accurate nodal staging and radiotherapy targeting.

No significant financial relationships to disclose.
Tumor progression and chemoradiosensitivity in relation to the expression of apoptosis related proteins in esophageal squamous cell carcinoma
Authors: Tsujitani S. , Saito H. , Tatebe S. , Ikeguchi M.
Published: March 2020

4588

To study apoptosis related protein expression and their impact on patient’s survival time and sensitivity to postoperative chemoradiotherapy (CRT), we examined the expression of RB, mutant p53, MDM2 and Bax proteins using immunohistochemistry in 115 (CRT; 42) surgically resected esophageal squamous cell carcinoma (ESCC). We also investigated the survivin mRNA expression with quantitative analysis by real-time RT-PCR in 57 (CRT; 30) patients with ESCC. CRT contained 40–60 Gy radiation and continuous infusion of 5-FU (300mg/sqm, day1–5qw). Expression of RB, mutant p53, MDM2, Bax proteins and survivin mRNA were detected in 65%, 46%, 33%, 37% and 32% of patients, respectively. Patients with RB(+), MDM2(-), Bax(+) or survivin(-) tumor had significantly better survival rates than those with RB(-), MDM2(+), Bax(-) or survivin(+) tumor, respectively. However, there was no significant difference in survival between patients with and without mutant p53 expression. In patients not treated with CRT, those with RB(+) or survivin(-) tumor survived significantly longer than those with RB(-) or survivin(+) tumor, respectively. In patients treated with CRT, the expression of Bax protein and survivin mRNA was prognostic indicator. The 5-year survival rates of patients with Bax(+) and survivin(-) tumors were 65% and 39%, significantly superior to 21% and 0% of those with Bax(-) and survivin(+) tumors (P<0.05 and P<0.01, respectively). These results indicate that the expression levels of apoptosis related proteins are important for predicting the prognosis of ESCC patients. Furthermore, CRT may be effective in patients with Bax(+) or survivin(-) tumors. Further investigations are required for clarifying the relationship between the efficacy of postoperative CRT and apoptosis promoting status of ESCC.

No significant financial relationships to disclose.
Preoperative level of VEGF and IL-6 are associated with lymph node invasion and stage in gastric cancer
Authors: OH S. , Kwon H. , Yoo H. , Lee S. , Kim S. , Kim S. , Jang J. , Kim M. , Jeong J. , Kim K. , Kim H.
Published: March 2020

4626

Introduction: Angiogenesis plays an important role in growth, progression, and metastasis of tumors, and various cytokines are associated with the spread of cancer cell. In this study, we evaluate the role of VEGF and IL-6 in predicting the spread of gastric cancer. Methods: Preoperative one hundred twenty seven gastric cancer patients and 88 healthy subjects’ specimens were examined. The association of VEGF and IL-6 level with clinical and pathological findings was evaluated Results: Serum VEGF and IL-6 level in gastric cancer patients were higher than those in control (P<0.001, P=0.006, respectively). VEGF and IL-6 level were associated with presence of LN metastasis (P=0.003, P=0.041, respectively). IL-6 level was correlated with stage (P=0.012) and depth of invasion (P=0.018). VEGF level was correlated with invasion of lympho-vascular structure (P=0.021). VEGF and IL-6 level was not related to differentiation, size or CEA level. Conclusions: Serum VEGF and IL-6 levels in gastric cancer patients are higher than those in control. Preoperative VEGF and IL-6 levels could be a predictive marker of tumor invasion and LN metastasis.

No significant financial relationships to disclose.
Intraperitoneal(IP) 5’-fluoro-2’deoxyuridine(FUDR): Safety and outcome when administered prior to adjuvant chemoradiotherapy(chemoRT) following R0 resection for gastric adenocarcinoma
Authors: Cohen D. J. , Ryan T. , Newman E. , Iqbal S. , Liu M. , Utate M. , Moore S. , Potmesil M. , Hochster H. , Muggia F. M.
Published: March 2020

4627

Background: ChemoRT after surgery for locally advanced gastric cancer improves overall and relapse-free survival (OS and RFS) compared to observation (NEJM 2000,345:725–30). However, loco-regional recurrences (>50%) remain high and we hypothesized that adding IP FUDR would further improve outcome. Methods: Patients (pts) ECOG performance status (PS) 0–2, gastric/gastroesphogeal(GEJ) adenocarcinoma stage Ib-IV (M0) undergoing R0 resection were eligible, and had insertion of IP catheters at surgery. IP FUDR(3gm/dose/day) was given on protocol days 1, 2, 3 and 15, 16, 17 prior to 5-FU/LV and external beam RT (45Gy) as in cited study. Simon 2-stage optimum design was used to demonstrate safety. Endpoints also included were loco-regional recurrence and survival. Results: 28 pts with gastric/GEJ adenocarcinoma (25/3) were enrolled from 2002 to 2006 at 2 institutions: median age 59.5 years (range 39–81), M /F (21/7). R0 gastric resection was performed with dissection of median 22 (range 8–102) lymph nodes(LN’s). 22/28 pts were lymph node positive. Full dose IP FUDR was completed in 20/28 pts. 4 pts required dose reduction (1 for grade(gr) 2 hepatic enzyme elevation, 2 gr 2 neutropenia, 1 gr 4 neutropenia), 3 discontinued therapy (1 gr 3 abdominal pain, 1 GI abscess, and 1 bleeding arterial pseudoaneurysm). One pt received no IP treatment due to catheter failure. 24/28 pts completed chemoRT and had toxicity comparable to that previously reported in the Intergroup 0116 trial. At 26 month median follow up (range 2.8–43.4), of the 26 pts evaluable for response, 16 pts are NED, 6 alive with disease, 3 dead of disease, and 1 dead from other cause. 5 recurrences were intra-abdominal, 1 local, 2 distant, and 1 at multiple sites. At present analysis, the median RFS is 32.5 months. Conclusions: IP FUDR prior to chemoRT after R0 gastric cancer resection is well tolerated. A randomized study to test its role in reducing regional recurrence and improving outcome is warranted. (FDA Orphan Products grant# FD-R-2150–04)

No significant financial relationships to disclose.
Mobilized circulating endothelial progenitor cells after the first cycle of chemotherapy with prophylactic G-CSF can be used as a predictive biomarker and patient selection marker for anti-angiogenesis combination treatment
Authors: Shin S. , Jeung H. , Ahn J. , Choi H. , Cho B. , Rha S. , Yoo N. , Roh J. , Chung H. , Chung H.
Published: March 2020

4638

Background: We investigated whether the level of circulating endothelial progenitor cells (CEPs) and endothelial cells (CECs) could be used as surrogate predictors of clinical outcome in patients receiving taxotere-based chemotherapy for advanced gastric cancer. Methods: Peripheral blood mononuclear cells were obtained in 49 gastric cancer patients who received taxotere combined with 5-FU and leucovorine (FLT regimen) after chemotherapy and prophylactic G-CSF treatment. To categorize the endothelial cells, immunofluorescent staining for specific endothelial cell markers (CD34, vWF, P1H12, CD31) was used. The changes of CEPs and CECs and their clinical significance on the response prediction and prognosis were analyzed. Results: After the first cycle of chemotherapy, the numbers of CD34+/vWF+, CD34+, vWF+, P1H12+ and CD31+ cells of 49 patients were 19.5 (2.7% of PBMCs), 20.1 (2.7%), 30.0 (4.8%), 12.9 (2.7%) and 214.3 (26.5%) cells/ml, respectively. The number of CD34+/vWF+ and CD34+ cells after the first and second cycle of chemotherapy were found to be higher in non-responders than responders (the first cycle: P=.012 and P=.008, the second cycle: P=.027 and P=.013, respectively). Moreover, the level of CD31+ cells after the second cycle of chemotherapy were significantly decreased compared with the first cycle in the patients who showed response (P=.026). In non-responders, however, the level of CD34+ cells was significantly increased after the second cycle of chemotherapy (P=.034). The level of CD34+ cells significantly related to the median time to progression (TTP) (6.1 and 4.0 months in CD34low and CD34high, respectively, cutoff level: 5.8, P=.046). Conclusion: CD34+/vWF+ and CD34+ cells can be used as a biomarker for prediction and prognosis in taxotere-based chemotherapy. CEP after the first cycle of chemotherapy can be a selection marker for addition of anti-angiogenic treatment after chemotherapy.

No significant financial relationships to disclose.
Risk factors for low-grade neuroendocrine carcinoma (LGNET): Hospital-based case-control study in US
Authors: Hassan M. , Dagohoy C. , Leary C. , Li D. , Yao J. C.
Published: March 2020

4641

Background: There has been an increase in the diagnosed incidence of LGNET in US over the last 2 decades. Little is known about the etiology of LGNET. In this hospital-based, case-control study we evaluated the association of cigarette smoking, alcohol consumption, diabetes mellitus (DM) and family history of cancers with LGNET of different sites. Method: Cases were patients with LGNET referred to The University of Texas M.D. Anderson Cancer Center between 12/1999 and 9/2005. Controls were selected from healthy individuals who accompanied patients with other cancers. Logistic regression was applied to estimate the adjusted odds ratio (AOR) and 95% confidence interval (CI) for potential risk factors and demographic characteristics. Result: We identified 951 LGNET patients with primary sites including appendix (n=102, 10.7%), small bowel (n=234, 24.6%), lung (n=149, 15.7%), pancreas (n=166, 17.5%), stomach (n=55, 5.8%), rectum (n=56, 5.9%), and others (n=189, 19.2%). Cases were compared to 924 controls. Majority of subjects were white-race (cases, 79.7%; controls, 89.5%). Gender distribution was similar in LGNET patients with 1:1 ratio. DM was associated with pancreatic and gastric primary sites; AOR and 95% CI were 2.5 (1.6–3.9) and 4.5 (2.2–9.3) respectively. Ever cigarette smoking was associated with lung carcinoid (OR=1.3; 95%CI, 1.01–1.9) especially among heavy smokers (20 cigarettes per day), (OR=1.7; 95%CI, 1.01–2.9). Ever or heavy alcohol consumption (= 60 ml ethanol/day) was not significantly related to LGNET of any site. The significantly elevated risk for carcinoid tumors extended to participants with a family history of breast, colon, esophageal, pancreas, prostate, and renal cancers after adjustment for demographic and environmental risk factors (P<.05). Conclusion: Smoking, DM, and family history may increase the risk of LGNET of various sites. Determining environmental and genetic factors related to LGNET may lead to development of surveillance and prevention strategies for high-risk individuals.

No significant financial relationships to disclose.
Value of PSA measured in middle age in predicting diagnosis of advanced prostate cancer in an unscreened population
Authors: Ulmert D. , Serio A. , Vickers A. , Eastham J. , Scardino P. , Berglund G. , Björk T. , Lilja H.
Published: March 2020

5006

Background: The association between PSA-levels in blood and prostate cancer (PCa) is currently under intense debate as many benign conditions also affect blood levels. We recently reported that PSA-levels in blood predicted very strongly later PC-diagnosis at any stage in a large representative population-based cohort in Malmö, Sweden (MPM) where the rate of PSA-testing is very low. Now, we studied predictors of stages =T3 or metastatic (M+) PCa at the time of cancer diagnosis. Material: Among archived bloods from 22,439 men (aged =50 or 60) during 1974–86, 192/549 men diagnosed with PCa until Dec 31, 1999, were eligible cases with =T3 or M+ at time of diagnosis. Median delay from baseline to diagnosis was 17 years among cases aged =50 (n=161) and 10 years among men aged 60 (n=31). Conditional logistic regression between cases and controls nested within our study cohort determined association and interaction between analyte levels, time to diagnosis, and age. Results: There was strong evidence that plasma levels of all PSA-forms and kallikrein 2 (hK2) associate with case status (p<0.01), and even a small elevation in total PSA (tPSA) markedly increased the risk of subsequent event. A tPSA of 2.1 - 3.0 ng/ml raised the odds of subsequent event 22-fold compared to a tPSA =0.5 ng/ml and men with tPSA =2 ng/ml had a predicted probability of advanced prostate cancer of 12% - three times the population mean. AUC for a model with tPSA alone, compared to tPSA+cPSA+%fPSA+hK2 were higher in men aged 60 (AUC increase of 0.054) compared to men aged =50 (AUC increase of 0.030). This is consistent with the results of interaction analysis showing that the association between hK2-level and cases status grows stronger as the interval between date of venipuncture and diagnosis decreases. Similarly, the effect of %fPSA on case status was dependent on age suggesting that the association between %fPSA and case status is stronger in older compared to younger men. Conclusion: Very strong associations exist between levels of all PSA-forms and hK2 measured at middle age and decade(s) before diagnosis of advanced stages of prostate cancer. There is an urgent need to validate these data in independent study cohorts as they could contribute important arguments in the revision of current PC- screening guidelines.

No significant financial relationships to disclose.
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]