tbuckley/cabot-search huggingface dataset:
Gene expression changes during acquired resistance to tamoxifen and letrozole; a preclinical model of post-menopausal breast cancer
Authors: N. Macpherson, S. Moore, A. Brodie, A. Thiantanawat, D. Jelovac, C. C. Nelson
Journal: Journal of Clinical Oncology (2005)

9620 Background: Most metastatic breast cancers initially respond to hormonal treatment but all become resistant to these treatments over time. The genetic events that occur during acquired resistance are unknown. To examine the gene expression changes during acquired hormonal resistance, we used a model that mimics ER positive breast cancers in the post-menopausal setting with the tumours responsive to both Tamoxifen (TAM) and aromatase inhibitors. Tumours were analyzed with high density cDNA arrays to identify genes associated with TAM and Letrozole (LET) resistance. Methods: Aromatase-transfected MCF-7Ca human breast cancer cells were grown as tumour xenografts in female ovariectomized athymic nude mice in which an androstenedione supplement was converted to estrogen to stimulate tumour growth. When tumour volume was approximately 300 mm3, the animals were grouped (4 groups, n=20) for continued supplementation with androstenedione (Δ4A) only (control), Letrozole(an aromatase inhibitor) 10 μg/day + Δ4A, TAM 100 μg/day + Δ4A, or vehicle. Animals were sacrificed and tumours retained at various time points during the development of hormone resistance. Tumour RNA samples were compared to reference RNA from Stratagene and incubated with 14K microarrays (Array-Ready Oligo Set, Qiagen). Expression results were analyzed with Genespring 6.1 (Silicon Genetics). Results: We have identified 35 TAM-resistant and 30 LET-resistant associated genes that are over-expressed by at least 2-fold and significant by ANOVA. They include; lysyl oxidase-like 2, Homo sapien partial N-myc, and TNF superfamily member 12. Her 2 neu was not over-expressed in acquired hormone resistance (TAM or LET). ER coactivators and corepressors including nuclear receptor coactivator 1and p300/CBP were altered in TAM resistance. At the meeting we will present data on the observed expression changes. We are collecting biopsies from patients to validate these observations Conclusions: Chromatin remodeling genes are among the genes that are over-expressed in acquired TAM- and LET-resistance. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis
Pancreatic squamous cell carcinoma: Epidemiology, clinicopathologic characteristics, and outcomes.
Authors: Oxana V. Makarova-Rusher, Susanna Varkey Ulahannan, Tim F. Greten, Austin G. Duffy
Journal: Journal of Clinical Oncology (2016)

220 Background: Although squamous metaplasia is commonly detected in pancreatic parenchyma, primary pancreatic squamous cell carcinoma (SCC) is a rare malignancy with unknown incidence and unclear prognosis. Methods: Using SEER-18 database primary code C25 in conjunction with histology codes for SCC (8052-8053, 8070-8078, 8083-8084) and for adenocarcinoma (AC) (8052-8053, 807-8078, 8083-8084), we identified cases diagnosed from 2000 to 2012. Age-adjusted incidence rates and trends over time were calculated. Patients with SCC were compared with AC by clinical features (TNM categories and histological differentiation), and 1-year and 2-year relative survival (RS) outcomes. Chi-square tests for categorical variables and t-tests for continuous variables were conducted. Kaplan-Meier method was used to estimate RS and Z-test was used to compare RS rates. SEERStat and GraphPad were used for analysis. Results: We identified 214 patients with microscopically confirmed SCC and 72,860 patients with AC. SCC constituted less than 1% of all cases of primary pancreatic cancer; however, age-adjusted incidence rates for this subtype tripled between 2000 and 2012. The annual percent increase of SCC incidence rate was 5.5%. Significant differences were observed by age, gender and race: older age groups, blacks and males had higher SCC incidence rates. Compared to AC, a greater proportion of patients with SCC had poorly differentiated histology (15.8% vs. 30.4%, p &lt; 0.01). Similar to AC, the majority of patients with SCC had stage IV disease at diagnosis, 54.3% for AC vs. 56.4% SCC. The 1-year and 2-year relative survival rates were significantly lower in patients with SCC than AC. The 1-year relative survival rate was 15.8% (95%CI = 10.4-22.3) for SCC, compared with 24.7% (95%CI = 24.3-25.1) for AC, p &lt; 0.001. Conclusions: Although primary squamous pancreatic carcinoma is a rare neoplasm, incidence rates for this subtype are markedly rising. Relative to adenocarcinoma, pancreatic squamous cell carcinoma is characterized by poorly differentiated histology and worse survival.
Differential gene expression in normal prostate epithelium of men with and without prostate cancer
Authors: M. Risk, I. Coleman, R. Dumpit, R. Gentleman, A. R. Kristal, B. S. Knudsen, P. S. Nelson, D. W. Lin
Journal: Journal of Clinical Oncology (2008)

5142 Background: Several solid tumors are associated with molecular changes in adjacent, histologically normal cells, the so-called “field effect”. This field effect may predispose the normal cells to the development of frank malignancy. We sought to determine if normal epithelium from prostates harboring prostatic adenocarcinoma harbor changes in gene expression suggestive of pre- malignancy or field effect. Methods: Prostate needle biopsies from 15 men with high grade (Gleason 8–10) prostate cancer and 15 age- and BMI-matched controls were identified from a pool of biopsies collected from >500 men since 2003. Normal epithelia from each patient were isolated via laser capture microdissection (LCM) of fresh frozen biopsy tissue with review by a pathologist. RNA was isolated, amplified, then utilized for microarray analysis using the Agilent Human 4x44K array platform. The data were analyzed by paired two-sample T- test using Significance Analysis of Microarrays (SAM). Quantitative PCR (qPCR) was also used to determine the expression of various genes of interest identified by microarray analysis. Results: One control patient was excluded for prostate cancer on repeat biopsy. The remaining 14 control and 15 cancer samples were included in the final analysis. Microarray analysis revealed that these two groups had very similar patterns of gene expression overall. SAM analysis found significant q values (q <1%) in 2 genes previously associated with prostate cancer, namely PSMA and SSTR1. We examined other prostate cancer-associated genes by qPCR and found significant differential expression changes in ERG, HOXC4, HOXC5 and MME, although other cancer markers (HPN, AMACR, FASN) were not different between the two groups. Interestingly, the elevated ERG expression in the normal epithelia adjacent to prostate cancer did not appear to be associated with the TMPRSS2:ERG fusion with the exception of one patient. Conclusions: Overall gene expression profiles between normal prostatic epithelia of patients with and without prostate cancer are very similar. However, several of the differentially expressed genes found in this study have been implicated in prostate cancer progression and prognosis in prior studies, and thus may represent the earliest events in prostate carcinogenesis. No significant financial relationships to disclose.
Metabolic landscape using 18F-FDG PET and its clinical significances in advanced biliary tract cancer.
Authors: Kyoung - Min Cho, Tae Yong Kim, Do-Youn Oh, Kyung-Hun Lee, Sae-Won Han, Seock-Ah Im, Tae-You Kim, Yung-Jue Bang
Journal: Journal of Clinical Oncology (2014)

252 Background: Metabolic landscape evaluated by 18 F-FDG positron emission tomography (PET) in advanced biliary tract cancer (BTC) has not been studied. Furthermore, the clinical meanings of metabolic features have rarely been reported. We evaluated the metabolic features using 18 F-FDG PET and its clinical significances in advanced BTC. Methods: We consecutively enrolled advanced BTC patientswho underwent PET prior to palliative chemotherapy between 2003 and 2013. We retrospectively evaluated the findings of PET such as SUVmax, lesion numbers, involved organ and pathologic findings and other clinical factors including response to chemotherapy, progression-free survival (PFS) and overall survival (OS). Results: A total of 106 patients were enrolled (intrahepatic cholangiocarcinoma (ICC):53, extrahepatic BTC :7, gallbladder cancer (GB Ca) :30, and ampulla of vater cancer (AoV Ca): 16 patients) ECOG PS 0-1 in 89 and PS 2 in11 patients. 52.8 % of patients received gemcitabine-based chemotherapy and 47.1% of patients received 5-FU-based chemotherapy. The SUVmax was median 7.8 (range 0-44). Fifty-four percent of patients showed higher SUVmax in metastatic lesion than primary site. The SUVmax was different according to primary origin (ICC: 9.10, extrahepatic BTC: 5.90, GB Ca : 9.10, AoV Ca :6.37, p=0.008) and histologic differentiation (well-differentiated: 4.95, moderately-differentiated :6.60, poorly-differentiated :14.50, p=0.004) Patients with a SUVmax of &gt;7.5 had more poorly differentiated histology and more PET uptake-lesions (p &lt; 0.05) than those with a SUVmax of &lt;7.5. The OS and PFS of all patients were 8.3 (95% CI: 5.7 – 10.8 ) and 4.9 months (95% CI: 3.4 – 6.3), respectively. Patients with a SUVmax of &lt;7.5 had a significantly longer OS (11.4 vs. 7.4 months, p = 0.007) and PFS (6.6 vs. 4.3 months, p = 0.024) than those with a SUVmax of &gt;7.5. In multivariate analysis, SUVmax was also a significant prognostic factor for OS (p=0.012) and PFS (p=0.039). Conclusions: Metabolic landscapes of advanced BTC are different according to primary origin and histology. This metabolic feature such as SUVmax could be a potential prognostic factor for OS and PFS in advanced BTC.
Randomized clinical trial of preoperative chemoradiotherapy by S-1 versus UFT to rectal cancer for personalized therapy.
Authors: Tomohiko Miyatani, Toru Utsunomiya, Nobuhiro Kurita, Takashi Iwata, Hirohiko Sato, Masanori Nishioka, Shinya Morimoto, Kozo Yoshikawa, Jun Higashijima, Hideya Kashihara, Chie Mikami, Mitsuo Shimada
Journal: Journal of Clinical Oncology (2012)

432 Background: Preoperative chemoradiotherapy (CRT) in rectal cancer reduces the local recurrence rate after operation and preserves the anus, but it is difficult to predict the effects of CRT. Our purpose of this study was to determine the effects and adverse events of CRT (S-1 or UFT) and to predict the response to CRT in rectal cancer by using both miRNA and DNA expression patterns. Methods: Rectal cancer patients (n=60) who underwent preoperative CRT were randomly divided into two groups (40Gy radiotherapy combined with S-1: 31 patients or UFT: 29 patients). The effects and adverse events of CRT were compared between S-1 group and UFT group. Additionally, RNA and DNA isolated from biopsy specimens of rectal cancer before preoperative CRT were hybridized to miRNA and DNA microarrays. Response to CRT was determined by histopathologic examination of surgically resected specimens. Results: Response to CRT determined by histopathologic examination of surgically resected specimens and RECIST were as follows: responders (grade 2 or 3) were 60%(S-1) and 52%(UFT) (p=0.52). Adverse events of CRT did not differ significantly between the 2 groups, and there was no adverse event of grade 3 or 4. As candidate predictive genes, 184 genes (S-1 group) and 193 genes (UFT group) were identified by DNA microarray, while 6 miRNA (S-1 group) and 16 miRNA (UFT group) were isolated by miRNA microarray as candidate predictive miRNA. Conclusions: Preoperative CRT using S-1 or UFT to rectal cancer is effective and the adverse events were acceptable. Expression profiling of both gene and miRNA may predict the effects of preoperative CRT, implicating the possible personalized therapy for patients with rectal cancer.
Survival benefit of additional surgery after non-curative endoscopic resection in patients with early gastric cancer.
Authors: Keun Won Ryu, Bang Wool Eom, Young-Il Kim, Kwang Hee Kim, Byung-Ho Nam, Hong Man Yoon, Soo-Jeong Cho, Jong Yeul Lee, Chan Gyoo Kim, Myeong-Cherl Kook, Young Woo Kim, Il Ju Choi
Journal: Journal of Clinical Oncology (2016)

106 Background: The aim of this study is to compare the long-term outcomes between patients who underwent endoscopic submucosal dissection (ESD) and those who underwent surgery for early gastric cancers (EGCs) turned out to be out-of-indication of ESD. Methods: We retrospectively reviewed database on gastric cancer patient cohort who underwent ESD or surgery from 2004 to 2014. Patients whose lesions revealed to be out-of-indication for endoscopic resection after ESD or surgery were included in the analysis after 1:1 propensity score matching for baseline clinicopathologic characteristics. Overall survival (OS) and gastric cancer recurrence rates were compared between the matched ESD and surgery groups. Results: After propensity score matching, a total of 193 pairs of patients were included, and 126 pairs were ESD with additional operation group and 67 pairs were ESD without additional operation group. OS (5-year OS rates, 89.5% vs. 89.9%; P=.105) and gastric cancer recurrence rates (5-year recurrence rates, 2.6% vs. 1.6%; P=.080) were not different between the ESD and the matched surgery group. In the matched subgroups, ESD with additional operation group had comparable OS and gastric cancer recurrence rates in comparison with matched surgery group. However, ESD without additional operation group had significantly shorter OS (5-year OS rates, 76.8% vs. 86.3%; P=.032) and higher gastric cancer recurrence rates (5-year recurrence rates, 11.9% vs. 0%; P=.002) than matched surgery group. ESD without additional operation was also significant risk factor for overall mortality and gastric cancer recurrence in multivariate analyses. Conclusions: Patients who did not undergo additional operation after ESD for EGCs turned out be the out-of-indication had worse long-term outcomes. Additional operation should be recommended, when EGC was identified to be the out-of-indication after ESD.
Radical cystectomy versus trimodality bladder-preserving therapy for muscle-invasive bladder cancer among elderly (80-84 years old) patients.
Authors: Shingo Hatakeyama, Hayato Yamamoto, Akiko Okamoto, Atsushi Imai, Takahiro Yoneyama, Yasuhiro Hashimoto, Takuya Koie, Chikara Ohyama
Journal: Journal of Clinical Oncology (2014)

340 Background: Management of muscle-invasive bladder cancer (MIBC) in elderly patients is issue of vital importance. The aim of the present study was to compare the oncological outcome of radical cystectomy to trimodality bladder preservation therapy. Methods: Between 1996 and 2013, we treated consecutive 419 patients with MIBC. Of these, we identified 44 patients with MIBC (cT2-4aN0M0) aged 80-84 years. We retrospectively reviewed the clinical charts of these patients. All patients received maximally safe transurethral resection of the bladder tumor before definitive therapy. The patients were categorized according to the treatment options into 2 cohorts; radical cystectomy cohort (RCx, n = 22), or radiotherapy with chemotherapy cohort (Trimodality, n = 22). All patients in trimodality cohort received at least 2 courses of gemcitabine plus carboplatin chemotherapy. Each patient was evaluated every 3-6 months by blood test, urine cytology, and computed tomography. Overall survival (OS), progression free survival (PFS) was estimated by Kaplan-Meier method. Multivariate analysis was used to identify independent factors to predict OS or PFS. Results: There were no significant differences in patient backgrounds between the groups, except for ECOG performance status (ECOG-PS), Charlson comorbidity index (CCI) and eligibility for cisplatin. The mean ECOG-PS, CCI and the number of cisplatin-unfit patients were significant higher in trimodality cohort (p = 0.001, p = 0.034, and p = 0.003, respectively). There were no significant differences in OS and PFS between the groups. On multivariate analysis, ECOG-PS &gt;1 was the independent prognostic factors for OS and PFS. Conclusions: Trimodality bladder preservation therapy for MIBC in elderly patients is comparable to those who received radical cystectomy. For patients with MIBC who are non-cystectomy candidates, or select patients who are motivated to keep their native bladders, trimodality bladder preservation therapy should recognized as an effective alternative to radical cystectomy, and be considered.
A novel class of mono-alkylating agents with highly potent and selective tumor cell growth inhibitory activity.
Authors: G. A. Piazza, H. N. Tinsley, B. D. Gary, M. R. Knight, N. Li, K. N. Tiwari, W. Zhang, W. R. Waud, L. U. Coward, G. Gorman, A. B. Keeton, R. F. Struck, A. H. Abadi
Journal: Journal of Clinical Oncology (2011)

e13523
Hyper-CVAD and rituximab-hyperCVAD in Burkitt lymphoma (BL): A multi-institutional experience.
Authors: T. M. Wildes, L. Farrington, C. C. S. Yeung, A. Harrington, K. V. Foyil, F. Kreisel, N. Bartlett, T. Fenske
Journal: Journal of Clinical Oncology (2011)

e18541 Background: High intensity regimens have improved outcomes in BL, but the optimal regimen remains to be defined. Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine) has been reported in a single-institution experience to yield a complete response (CR) rate of 81% and 3 year (yr) overall survival (OS) rate of 49% (Thomas et al, JCO 1999). With the addition of rituximab (R), a CR rate of 86% and 3 yr OS rate of 89% were reported by investigators from MD Anderson (Thomas et al, Cancer 2006). Methods: We retrospectively identified 23 HIV-negative patients with BL diagnosed from 1999-2008 who received HyperCVAD or R-HyperCVAD at Washington University School of Medicine, St. Louis, MO or the Medical College of Wisconsin, Milwaukee, WI. All cases were reviewed by hematopathologists and confirmed using the WHO 2008 classification, including immunohistochemistry and c-myc in situ hybridization. Medical records were reviewed for baseline characteristics, treatment, and outcomes. Results: Baseline characteristics include: mean age 40.7 yrs (range 20-70), 52.2% male, 87% white, 43.5% with bone marrow involvement, 26.1% with central nervous system involvement. Mean LDH at diagnosis was 1060 IU/L (range 175-5320), and mean uric acid 8.5 mg/dL (range 3-17). Six patients received HyperCVAD and 17 received R-HyperCVAD. 20/23 patients (87.0%) achieved CR [94.1% with R-HyperCVAD and 66.7% with HyperCVAD]. Median event free survival (EFS) was 71.9 months (95% CI 0-161 months) with R-HyperCVAD vs. 9.2 months (95% CI 0.0-19.7 months) without R [log rank chi-square 1.64, P=0.20]. 1-yr, 2-yr and median OS rates with R-HyperCVAD were 88.2%, 62.4% and 71.9 months (95% CI 0-146 months) respectively, versus 33.3%, 16.7% and 10.1 months (95%CI 0-20.5 months) without R [log rank chi-square 5.15, P=0.023]. Conclusions: In this two-institution experience of BL confirmed by rigorous hematopathology review, R-HyperCVAD resulted in durable remissions in approximately 60% of patients with BL, significantly lower than the previously published report. While the addition of R has improved the outcome for patients with BL, better approaches are still needed.
Impact of early tumor shrinkage on long-term outcome in metastatic colorectal cancer (mCRC) treated with FOLFOX4 with or without cetuximab: Lessons from the OPUS trial.
Authors: H. Piessevaux, C. Bokemeyer, M. Schlichting, S. Heeger, S. Tejpar
Journal: Journal of Clinical Oncology (2011)

398 Background: The measurement of tumor shrinkage at the first evaluation (8 weeks) was reported to predict long-term outcome in mCRC treated with irinotecan-based chemotherapy (CT) + cetuximab (cet) in first-line and chemorefractory patients (pts). The predictive power of early tumor measurements was restricted to pts treated with CT + cet compared with CT alone but isn't known for cet with other CT regimens. This was investigated in pts treated with the FOLFOX4 regimen ± cet in the OPUS trial. Methods: Based on the 8-weekly radiological assessments reported by the investigator and reviewed by an independent review committee, relative changes in tumor size from baseline were computed and dichotomized using a 20% relative decrease cut-off value. Kaplan-Meier curves were constructed for progression-free survival (PFS) and overall survival (OS), stratified by treatment arm and KRAS status. Results: Tumor measurements at week 8 with KRAS status were available in 297 pts. Tumor shrinkage ≥20% was associated with significantly better PFS and OS in KRAS wild-type (wt) pts treated with FOLFOX4 + cet but not in those treated with CT alone (Table). Conclusions: When combining cet with FOLFOX4 in first-line KRAS wt mCRC, early tumor shrinkage is associated with long-term outcome. This finding is specific for the effect of cet, confirming this drug to have distinctive and rapid effects on tumor size leading to long-term outcome measures unrelated to the effect of CT. [Table: see text] [Table: see text]
Molecular markers and outcomes in penile squamous cancer (PSC).
Authors: T. B. Dorff, A. Schuckman, R. Schwartz, K. Danenberg, Y. Ma, J. Cai, S. Rashad, E. C. Skinner, D. I. Quinn, J. K. Pinski
Journal: Journal of Clinical Oncology (2011)

e15016 Background: Penile cancer is uncommon but can be disfiguring and aggressive. We explored specific molecular changes in PSC and their relationship to outcomes. Methods: After IRB approval, 52 patients were identified from 1995 and 2010 with tissue specimens and clinical data available. ERCC1 and EGFR expression were evaluated by RT-PCR plus IHC for a subgroup; TS expression was by RT-PCR only. RNA results represent a ratio of the gene of interest to internal reference gene β-actin. Immunohistochemistry (IHC) was graded 0-2+ by an experienced pathologist. Results: Median age is 52 (36-80) and 72% are Hispanic, 15% white, 6.5% each Asian and African-American. 6 had stage Tis, 10 had T1, 23 had T2, 12 had T3; 19 had pathologic documentation of lymph node involvment. With a median follow-up of 1.8 years the (longest 16.3 yrs) median survival is 4.9 years. 17 men received neoadjuvant chemotherapy for >N2 disease or for distant metastases; 7 had disease progression on chemo, 8 (47%) had objective response including 1 pathologic CR. EGFR over-expression was common both by RNA amplification (median 5.09, range 1.92-104.5) and immunohistochemistry (IHC); 7/22 had 2+ staining. EGFR expression >7 correlated significantly with more advanced T stage and poor differentiation (p=0.01 and 0.034 by Fisher’s exact test, respectively); it did not correlate with survival or lymph node involvement in multivariate analysis. ERCC1 expression was less common, median RNA expression 0.65 and range 0.21-1.87 with only 4/22 2+ by IHC. TS expression was intermediate, median 1.88 (range 0.54-6.47). ERCC1 and TS expression were not associated with grade, stage or survival. There were no KRAS mutations identified. There was a trend for lower expression of EGFR corresponding to a higher likelihood of response (RR) to chemotherapy; 67% RR in EGFR<7 vs. 33% in EGFR>=7, p=0.31) and the trend was similar using IHC scores with no responses seen in thsoe wtih 2+ EGFR expression (p=0.16). Conclusions: We did not find a significant correlation between survival and EGFR, ERCC1, or TS expression in penile SCC. EGFR expression showed a trend for inverse relationship with chemotherapy response. The lack of KRAS mutation may predict a good likelihood of response to EGFR-targeted therapy.
Erratum: PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis
Authors: Gang Huang, Pu Zhang, Hideyo Hirai, Shannon Elf, Xiaomei Yan, Zhao Chen, Steffen Koschmieder, Yutaka Okuno, Tajhal Dayaram, Joseph D Growney, Ramesh A Shivdasani, D Gary Gilliland, Nancy A Speck, Stephen D Nimer, Daniel G Tenen
Journal: Nature Genetics (2008)