tbuckley/cabot-search huggingface dataset:
Outcome of operable male breast carcinoma: One hundred eighteen patients.
Authors: Ü. Yalçintas Arslan, O. B. Oksuzoglu, N. Ozdemir, S. Aksoy, N. Alkis, A. Gok Durnali, M. A. Kaplan, M. Gumus, V. Berk, D. Uncu, M. Baykara, D. Colak, U. Uyeturk, I. Turker, A. Isikdogan
Journal: Journal of Clinical Oncology (2011)

e11034 Background: Male breast cancer (MBC) is a rare malignant neoplasm which represents 1% of all breast cancer cases. The best treatment strategy is still undefined. The aim of this retrospective study was to determine characteristics, treatment approaches and survival outcomes in operable MBC patients. Methods: The medical records of 148 MBC patients followed between the years 1986 and 2009 at 7 cancer center were evaluated retrospectively. 118 operable patients had sufficient data were included the study. Demographic, treatment charecteristics and survival were analysed. Results: One hundred-eighteen operable MBC was found to be eligible. Median age was 60 (range 29-83) years. Thirty-two percent of the patients had T3-4 tumors. Approximately half of the patients had node positive disease. Infiltrating ductal carcinoma was the most frequent histopathological type (89.8%). The proportion of positivity among patients of whom estrogen receptor, progesterone receptor and cerbB2 status were 82.9%, 75.8% and 23.4%, respectively. Surgical management consisted of modified radical mastectomy (82.2%), simple mastectomy or tumorectomy (17.8%). Adjuvant radiotherapy was performed 61.1% of the patients. Adjuvant hormonotherapy was advised for 86 (72.8%) patients. Adjuvant chemotherapy was given for 73.7% of the patients. Anthracycline-based chemotherapy regimens were used in 48 cases. Twenty-one patients treated with taxane-based chemotherapy protocols. Median follow-up was 40.9 months (range 3.8-186 months). Locoregional and/or distant recurrence developed in thirty-eight patients. Twenty-three patients died during the follow-up period. Three-year and 5-year disease-free survival (DFS) was found to be 72% and 60%, whereas overall survival (OS 91% and 82%, respectively. Larger tumor size and lymph node positivity has poor prognostic factors for OS and larger tumor size were significantly affected DFS also. Conclusions: Considerable amount of MBC has still been diagnosed in locally advanced stages. Although, the frequency of the use of adjuvant systemic therapy in MBC has been gradually increasing in the recent years, lymph node status and tumor size are the most important determining factors for prognosis.
Effect of TGF-β1 expressed on tumor-derived exosomes on survival and function of regulatory T cells.
Authors: H. Onishi, J. Wada, H. Suzuki, A. Yamasaki, S. Nagai, T. Morisaki, M. Katano
Journal: Journal of Clinical Oncology (2010)

2567 Background: We have already indicated that regulatory T cells (Treg) negatively control the antitumor immune response in colon cancer (Suzuki H et al: Cancer Immunol Immunother, in press). We have also shown that exosomes (Ex) secreted by monocyte-derived dendritic cells support naïve CD4+ T-cell survival via NF-κB activation (Matsumoto K et al: Cell Immunol, 2004). Interestingly, our recent preliminary data suggest a possible contribution of malignant effusion-derived Ex (Eff-Ex) to the increased number of Treg in malignant effusions. To develop more effective immunotherapy against cancer, we analyze a contribution of Eff-Ex to number and function of Treg in malignant effusions. Methods: Eff-Ex were collected from the malignant effusion of 23 cancer patients and purified by a combination of a series of centrifugations and sucrose-density ultracentrifugation. Peripheral blood mononuclear cells (PBMCs) were co-cultured with various concentrations of Eff-Ex. FOXP3+CD4+ T cells were defined as Treg. Expression of molecules on Eff-Ex was determined by flow cytometry analysis (FACS). Results: 1) The ratio of Treg in malignant effusion was significantly higher than that in PBMCs from healthy volunteers. 2) Eff-Ex may be tumor origin because Eff-Ex is CEA- positive. 3) Eff-Ex prevented the decrease in both Treg number and FOXP3 expression level in a dose-dependent manner. 4) TGF-β1 was expressed on the surface of Eff-Ex. 5) Anti-TGF-β1 antibody-treatment in Eff-Ex abrogated the effects of Eff-Ex on both survival and FOXP3 expression of Treg. 6) Anti-TGF-β1 antibody-treatment in Eff-Ex also reduced the suppressive function of Eff-Ex. Conclusions: Surface-bound TGF-β1 on Eff-Ex may contribute to the maintenance of Treg numbers and suppressive function in malignant effusions. If so, elimination of Eff-Ex or control of Eff-Ex-expressing TGF-β1 could be new therapeutic strategies for tumor immunotherapy. No significant financial relationships to disclose.
Associations between chromosome 7 aneusomy and EGFR copy number with survival and response to gefitinib in NSCLC
Authors: L. E. Morrison, S. S. Jewell, K. K. Jacobson, K. Kaiser, M. Gale, T. Muzzafar, A. M. Mauer, V. M. Villaflor, P. Bonomi, J. S. Coon
Journal: Journal of Clinical Oncology (2006)

7171 Background: EGFR, the presumed target of gefitinib and erlotinib, has been studied (expression, gene copy number, &amp; mutations) for predicting response to these tyrosine kinase inhibitors (TKI), in non-small cell lung cancer (NSCLC). ’High polysomy’ and ’amplification’ of the EGFR gene, as defined by Cappuzzo et al. JNCI 97:643, using fluorescence in situ hybridization (FISH), showed significant association with objective response (Resp) and survival. We also measured EGFR and chromosome 7 (C7) copy numbers by FISH in 81 gefitinib-treated NSCLC patients (12 Resp). Using Cappuzzo’s FISH± parameter alone we saw similar trends but no statistical significance in the 81 patient group. Therefore we sought to optimize FISH parameters for these patients. Methods: FISH was performed (paraffin sections) using a 2-color probe set (Vysis LSI EGFR/CEP 7), median 80 cells per specimen. &gt;50 parameters were derived from the data (e.g. mean EGFR/cell, C7/cell etc) and compared, using different threshold values, to Resp and survival. Results: The best single parameter associated with survival was the average C7/cell. Applying upper and lower thresholds of 3.6 and 2.0 C7/cell to delineate moderate from extreme ratios yielded median survival of 177 and 465 d, respectively (Kaplan-Meier, p &lt; .002). A single threshold of 3.6, separating low from high, yielded survival of 201 and 522 d, respectively (p &lt; .01). For these thresholds C7/cell was not associated with Resp, however, thresholds could be found for which both survival and Resp were significant. The best single parameter associated with Resp was average EGFR/cell. Of the 70 patients with EGFR/cell≤6.0, 63 (90%) did not respond while 5 of 11 patients (45%) with EGFR/cell &gt;6.0 responded (p &lt; .01). No EGFR/cell threshold could be found for which both survival and Resp were significant. Many 2-parameter combinations provided significant associations with both survival and Resp. Conclusions: Several FISH-derived parameters were significantly associated with either survival or Resp to gefitinib and a subset were associated with both. These parameters must be tested on independent data sets to determine their value in directing TKI therapy. [Table: see text]
Inhibition of histone deacetylase (HDAC) 6 sensitizes human leukemia and breast cancer cells to antagonists of heat shock protein (hsp) 90 and/or bortezomib (BZ)
Authors: K. N. Bhalla, P. Bali, M. Balasis, W. Fiskus, M. Pranpat, K. Rocha, R. M. Rao, S. Kumaraswamy, P. Atadja
Journal: Journal of Clinical Oncology (2006)

13039 Background: HDAC6 is a cytosolic α-tubulin deacetylase, which shuttles misfolded polyubiquitylated proteins into aggresomes. Our studies demonstrated that the hydroxamic acid (HA) analogue pan-HDAC inhibitors (HDIs), e.g., LAQ824 and LBH589, induce α-tubulin and hsp90 acetylation, thereby inhibiting ATP-binding and chaperone function of hsp90. This promotes the polyubiquitylation and degradation of the pro-growth and pro-survival hsp90 client proteins, e.g., Bcr-Abl, mutant FLT-3, c-Raf and AKT in leukemia and Her-2 in breast cancer cells. Methods: Human CML K562 and breast cancer SKBR-3 and BT-474 cells were exposed to LAQ824 (100 nM) or LBH589 (20 to 50 nM) and/or 17-AAG (1 to 5 μM) and/or BZ (5 to 100 nM). K562 and BT-574 cells were also transfected with siRNA to HDAC6. Immunoprecipitation and/or immunoblot analysis were performed to determine the expression or binding of HDAC6 with hsp90, and of hsp90 acetylation and binding with its co-chaperones and client proteins. Immunofluorescent microscopy was utilized to estimate aggresome formation. Cellular cytotoxicity was determined by % inhibition of colony growth. Results: HDAC6 knockdown by its siRNA induced the acetylation of hsp90 and α-tubulin but not of the co-chaperones p23 and hsp40. HDAC6 binds to hsp90. Hsp90 acetylation increased its binding to biotinylated-geldanamycin (GM) and its analogue 17-AAG. Depletion of HDAC6 levels (∼70%) or its activity by treatment with HA-HDI also inhibited the binding of hsp90 to ATP, p23 and hsp90 client proteins, which was augmented by co-treatment with 17-AAG. Knockdown of HDAC6 sensitized the cells to loss of clonogenic survival induced by HA-HDI and/or BZ and/or 17-AAG. Depletion of HDAC6 led to attenuation of Her-2 levels and loss of survival of Her-2 amplified SKBR-3 and BT-474 cells. Co-localization of HDAC6 and polyubiquitylated proteins into aggresomes was enhanced by co-treatment with BZ and/or 17-AAG. This was inhibited by depletion of HDAC6 activity. Conclusions: These findings support the in vivo testing of HDAC6 inhibitors, which through inhibition of hsp90 and aggresome formation sensitizes cancer cells to 17-AAG and/or BZ induced cellular stress due to misfolded and polyubiquitylated proteins. [Table: see text]
Fc gamma receptor polymorphisms and KRAS status as predictive biomarkers in patients with metastatic colorectal cancer treated with biweekly cetuximab-based salvage therapy.
Authors: R. Zarate, E. Bandres, J. Rodriguez, N. Bitarte, B. Honorato, V. Boni, I. Sola, M. Ponz-Sarvisé, C. Garzon, J. Garcia-Foncillas
Journal: Journal of Clinical Oncology (2010)

e13523 Background: Cetuximab has shown a clinically significant antitumor activity against metastatic colorectal cancer (mCRC) both in first and subsequent lines of therapy. Biweekly schedules have shown similar PK/PD behaviour and inhibition of EGFR downstream pathway compared to the weekly schedule. Several molecular factors have been found to predict response to Cetuximab. Among them a role of ADCC has been suggested. We aimed to investigate the association of Fc gamma Receptor (Fcg R) polymorphisms and KRAS mutation with the outcome of mCRC patients (pts) treated with salvage biweekly Cetuximab-based therapy. Methods: Tumor from 66 mCRC pts was screened for KRAS mutations using a sensitive multiplex assay. Fcg RIIa and Fcg RIIIa polymorphisms were detected using the TaqMan genotyping assays (Applied Biosystems, CA). The results were correlated with objective response (OR), disease control rate (CR+PR+SD>6 months) and progression-free survival (PFS). Results: KRAS mutations were associated with a lower OR (52,9% vs 29%, p=0.04), a lower DCR (68,6% VS 29%, p=0.001) and a shorter PFS (6.6 vs 4.0 months, p=0.0007). Whereas no correlation was found for FCg RII and clinical outcome, pts with V-containing FCg RIII polymorphism had a longer PFS (5.5 vs 3.2 p=0.001) and a significantly higher OR and DCR. The difference in PFS remained significant in both KRAS wild type (wt)(6.7 vs 3.2 months, p=0,036) and mutated pts (4.8 vs 2.6 months, p=0.024), all favouring the V-containing FCg RIII genotype. KRAS mutated pts carrying any V-containing Fcg RIII genotype had a longer PFS than KRAS wt pts with the PP-Fcg RIII allele. Considering KRAS wt and any V-containing FCg RIII genotype as favourable factors, median PFS was 6.7, 4.6 and 2.6 (p=0.002) in pts harbouring 2, 1 or none of them. In the multivariate model, considering clinically relevant parameters, KRAS, Fcg RIII and Köhne index were all significantly associated with PFS. Conclusions: Fcg RIII polymorphisms have a clinically relevant role in cetuximab efficacy, even in KRAS mutated pts. Strategies aimed at enhancing activation of NK cell effector functions in this subset of pts seem warranted. No significant financial relationships to disclose.
Effects of different chemotherapy regimens and tamoxifen for HER2 over-expressed breast cancer adjuvant therapy
Authors: J. Zhang, Y. Liu, X. Hao, Z. Fang, L. Ning
Journal: Journal of Clinical Oncology (2007)

11048 Background: To evaluate effects of different adjuvant chemotherapy regimens and TAM in HER-2-overexpressed breast cancer patients. Methods: To study 1625 primary breast cancer cases after operation from 2002.7 to 2005.11 given adjuvant chemotherapy ,600 cases given CMF, 600 cases given CEF, and 425 cases given T-regimen (anthracyclines follow taxanes),1090 HR+ cases given tamoxifen. HER-2 expression were measured by immunohistochemistry (IHC). Median follow-up time is 42 months. Results: (1)3yr DFS of HER-2 over-expression is inferior to HER-2 negative ones in CMF group(p&lt;0.05), no difference between HER-2- overexpressed and HER-2-negative group treated with either CEF or taxanes-based regimen (p&gt;0.05). Subgroup analysis suggested: patients treated with CMF, 3yr DFS of HER-2 over-expression is inferior to HER-2-negative ones in node-positive subgroup, but no difference in node-negative ones; HER-2 expression has no influence on effects of CEF or T-regimen in node-positive or node-negative subgroup. (2) 425 HER-2 over-expressed patients(183 cases given CMF , 121 cases given CEF , and 121 cases given T-regimen): compared to CMF, anthracyclines and taxanes are more effective, but no difference between anthracyclines and T-regimen. (3) 235 patients with HER-2 over- expression and node-postive (72 cases given CMF , 68 cases given CEF, and 95 cases given T-regimen):, anthracyclines and taxanes are more effective than CMF, but no difference between anthracyclines and T-regimen. (4)3yr DFS is 91.23% in HER-2 over-expressed group and 93.42% in HER-2-negative group (p=0.04) with TAM. HER-2 over-expressed patients are resistant to TAM. (5) Subgroup analysis suggested that: 3yr DFS is 88.67% with HER-2 over-expression and 92.20% with HER-2-negative in postmenopausal node-positive subgroup(p=0.0069), postmenopausal patients with HER-2 over-expression and node-positve are resistant to TAM; no difference in either premenopausal or postmenopausal node-negative subgroup (p&gt;0.05). Conclusions: No difference between Anthracyclines based and T-regimens for HER2 over-expressed patients with node-positive for 3yr DFS.Postmenopausal ER+/PR+ patients with HER2 over- expression are resistant to Tamoxifen endocrine therapy. No significant financial relationships to disclose.
A prospective PGx and PK/PD dose-finding study of irinotecan based on <i>UGT1A1*6</i> and <i>*28</i> genotyping (UGT0601)
Authors: T. Esaki, T. Satoh, T. Ura, T. Tsujinaka, Y. Sasaki, K. Yamazaki, Y. Yamada, N. Ishizuka, I. Hyodo, Y. Sakata
Journal: Journal of Clinical Oncology (2009)

e14560 Background: UGT1A1*6 as well as UGT1A1*28 polymorphisms is associated with decreased glucuronidation of SN-38, the active metabolite of irinotecan (CPT-11). Although the maximum tolerated dose (MTD) and the recommended dose (RD) in Hetero was determined 150 mg/m 2 (approval dose in Japan), those of Homo were unknown. Methods: Pts received prior chemotherapies except for CPT-11 for metastatic gastrointestinal cancer were enrolled. UGT1A1 polymorphisms were categorized into Wild(*1/*1), Hetero(*1/*28, *1/*6), and Homo(*28/*28, *6/*6, *28/*6). CPT-11 was administered biweekly. Starting doses were 150 mg/m 2 in Wild, 100 mg/m 2 in Hetero, and 75 mg/m 2 in Homo. DLT was defined as grade 4 hematological, or grade 3 non-hematological toxicity. MTD closest to dose-limiting toxicity (DLT) appearance of 30% was guided by the continual reassessment method in the cohort of Hetero and Homo. DLT and pharmacokinetic (PK) sampling was evaluated during the 1st cycle. Results: Eighty-two pts were enrolled from November 2006 to November 2008 (Wild, Hetero, Homo: 41, 20, and 21, respectively). The dose level reached at 150 mg/m 2 in Homo. At 150 mg/m 2 , DLT was observed in six pts of Homo (grade 4 neutropenia, grade 3 diarrhea: 6 and 1, respectively). The probability of DLTs were 22.2% at 125 mg/m 2 , and 37.4% at 150 mg/m 2 . The MTD was determined 150 mg/m 2 in pts with Homo group. However, the incidences of grade 3/4 neutropenia at 150 mg/m 2 during the 1 st cycle were 9.8% (4/41), 18.8% (3/16), and 62.5% (10/16) in Wild, Hetero, and Homo, respectively. And the second administration was delayed 7 days or more in most pts in Homo (63% at 150 mg/m 2 ). In one pt of Homo for *28/*28 died of septic shock during the 2 nd cycle. SN-38 AUC (0–24h, ng*hr/mL, median) was 239 in Wild, 237 in Hetero, and 410 in Homo. Pts with Homo showed the different trend of PK/PD compared to those with Wild and Hetero. Conclusions: The MTD was 150 mg/m 2 in pts with Homo group and the most frequent DLT was grade 4 neutropenia. However, our findings suggest that 150 mg/m 2 q2w is difficult to recommend and the initial dosage and administration should be considered carefully for pts with Homo. [Table: see text]
Treatment of unresectable or metastatic pancreatic cancer in the VA population: Does it improve survival?
Authors: S. F. Mekan, R. S. Komrokji, M. S. Beg, Z. A. Nahleh, M. M. Safa
Journal: Journal of Clinical Oncology (2007)

15121 Background: Locally advanced and metastatic pancreatic adenocarcinoma present as a treatment challenge because of poor outcomes with current treatment modalities. Therapy of unresectable or metastatic disease has not been studied in the VA population. Methods: We reviewed all cases of pancreatic cancer presenting to the system from 1995–2005. Cases were extracted from the VA Cancer Registry (VACCR). Results: There were 5522 cases identified; 5218 were adenocarcinomas. Out of these, there were 263 (5.1%) patients with unresectable locally advanced disease and 2778 (53.2%) patients with metastatic disease. Median survival for patients with unresectable disease was 5.6 months. Chemotherapy was administered to 94 patients and chemoradiation to 31 patients. No difference in survival was noted between the two groups (8.4 vs. 7.9 months, P = 0.434). In patients with metastatic disease, median survival was 2.2 months. Chemotherapy was administered to 760 (27%) patients in this group and showed improved survival as compared to patients who did not receive chemotherapy (5.3 vs. 1.5 months, p = 0.000). Conclusions: In VA patients with locally advanced unresectable disease, there is no difference in survival in patients treated with chemoradiation versus chemotherapy alone. In patients with metastatic disease, chemotherapy conferred a survival advantage. No significant financial relationships to disclose.
Phase II study of pazopanib (GW786034) in patients (pts) with relapsed or refractory soft tissue sarcoma (STS): EORTC 62043
Authors: S. Sleijfer, Z. Papai, A. Le Cesne, M. Scurr, I. Ray-Coquard, F. Collin, L. Pandite, S. Marreaud, A. De Brauwer, J. Blay
Journal: Journal of Clinical Oncology (2007)

10031 Background: Currently, there is no standard treatment for pts with advanced STS who relapse after or during standard chemotherapy. Since VEGF is involved in the pathogenesis of STS subtypes, pazopanib, a multi-targeted tyrosine kinase inhibitor of VEGF- receptors 1–3, PDGFR-a and β, and c-kit was explored. Methods: Pts had intermediate or high grade advanced or metastatic STS, were ineligible for chemotherapy or had received no more than one combination or 2 single cytotoxic agents for advanced disease. Pts had WHO performance 0–1 and adequate organ function. Progressive disease had to be documented within the last 6 months. Treatment was oral pazopanib at 800 mg daily. Primary end point was progression-free survival at 12 weeks. Secondary end points included response, safety, and overall survival. 4 different strata were studied: leiomyosarcomas, adipocytic STS, synovial sarcomas, and other types of STS. Simon 2-stage design was applied (P1: 40%; P0: 20%; a=β=0.1). Results: As of 11 October, 2006, 111 pts were enrolled. 98.2% had received prior chemotherapy. In 44 pts with validated data no grade 3–4 hematological toxicities were seen, grade 3–4 bilirubin and creatinine elevations in 2 and 1 pts, respectively. Other toxicities (all grades; grade 3–4) were fatigue (53.6%; 9.7%), hypertension (31.7%; 9.7%), and diarrhea (29.3%; 4.8%). Of 80 pts included in the 1 st stages of all 4 strata together, 27 were alive and progression-free at 12 weeks. The 2 nd stage was opened for further accrual in 3 strata. Complete accrual is anticipated in February 2007. Conclusions: In relapsed or refractory advanced STS, pazopanib has acceptable toxicity. These preliminary results justify further investigation of pazopanib in STS. No significant financial relationships to disclose.
Synergistic inhibition of EGFR tyrosine kinase and tumor cell growth in non-small cell lung cancer (NSCLC) by combination treatment with FUS1-nanoparticles and gefitinib
Authors: L. Ji, H. Kawashima, C. Lu, J. Kurie, S. Chada, J. D. Minna, J. A. Roth
Journal: Journal of Clinical Oncology (2005)

7081 Background: FUS1 is a novel tumor suppressor gene (TSG) identified in the human chromosome 3p21.3 region that functions in the Apaf1-associated apoptotic pathway, and is a potent tumor suppressor. We explored the use of FUS1 for enhancing chemotherapeutic potency of Gefitnib and overcoming Gefitnib-resistance in both Gefitnib-sensitive and resistant NSCLC cells. Methods and Results: We found that expression of wt-FUS1 by FUS1-nanoparticle-mediated gene transfer in FUS1-deficient and Gefitinib-resistant NSCLC H1299, H358, and H460 cells significantly sensitized the response to Gefitinib treatment, as demonstrated by a more than additive inhibitory effect on tumor cell growth and a synergistic induction of apoptosis. Enhanced growth inhibition was also observed in the Gefitnib-sensitive HCC827 (EGFR mutant) and H1819 (EGFR amplification) cells co-treated with FUS1-nanoparticles and a low dose of Gefitnib (IC10). A marked inhibition of phosphorylated EGFR protein was also detected in cells treated with FUS1-nanoparticles alone or in combination with Gefitnib, as shown by Western-blot analysis with phospho-EGFR-specific antibodies. A significant inhibition (P<0.001) of tumor growth was detected in animals treated by FUS1-nanoparticles in less than 2 weeks of treatment compared to those untreated or treated by GFP-nanoparticles, as shown by MR imaging and volume analysis. Induction of apoptosis was also detected in tumor cells in mice treated by FUS1-nanoparticles by an in situ apoptosis assay with TUNEL staining in frozen tissue samples. We have an ongoing phase I study of single agent FUS1-nanoparticles given intravenously in stage IV NSCLC patients who have progressed on chemotherapy. The treatment is well-tolerated in seven patients entered to date with a median survival of 17+ months. Conclusions: Our results suggest that wt-FUS1 may play a critical role in modulating the sensitivity of tumor cells to protein tyrosine kinase inhibitors. Supported by grants from NIH NCI (SPORE P50CA70907), DOD (TARGET, DAMD17002-1-0706) and Introgen Therapeutics, Inc. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Introgen Therapeutics