tbuckley/cabot-search huggingface dataset:
Complete responses (CR/CRu) on a phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL).
Authors: S. M. Horwitz, B. Coiffier, F. M. Foss, H. M. Prince, L. Sokol, M. Greenwood, D. Caballero, P. Borchmann, F. Morschhauser, M. Wilhelm, L. C. Pinter-Brown, S. Padmanabhan, A. R. Shustov, J. Nichols, J. Balser, S. Carroll, B. Pro
Journal: Journal of Clinical Oncology (2011)

8033 Background: Potent histone deacetylase inhibitor, romidepsin, has shown durable clinical benefit and tolerability in patients (pts) with R/R PTCL with objective response rates of 38% (17/45, NCI1312) and 26% (34/130, GPI-06-0002) reported in phase II, single-arm, open-label trials. This abstract provides a subset analysis of pts who achieved CR/CRu on the GPI-06-0002 trial. Methods: Pts with R/R PTCL received romidepsin 14 mg/m2 as a 4-h IV infusion on days 1, 8, and 15 every 28 days. An Independent Review Committee made blinded efficacy assessments in a 2-step process: initial radiographic review followed by an overall clinical assessment based on radiology and relevant clinical parameters. Results: The CR/CRu rate was 13% (17/130); median time to CR/CRu was 4 mo (range 2-9 mo). At the data cut-off (March 31, 2010), median duration of response (DOR) was not reached with longest DOR of 26+ mo. With a median follow-up of 8.2 mo, 16/17 (94%) pts had not progressed. Pts who achieved CR/CRu were representative of the overall pt population (Table). The majority of pts who achieved CR/CRu were > 60 years of age (10/17, 59%); receiving > 2 prior systemic therapies or being refractory to last prior therapy did not impact CR/CRu rate. Most common grade 3/4 adverse events (AEs) were thrombocytopenia (24%), neutropenia (20%) and anemia (10%). Rates of grade 3/4 AEs were similar for pts who did or did not achieve CR/CRu. At the time of submission, 7 pts who achieved CR/CRu continue on romidepsin; long-term follow-up data will be presented. Conclusions: Durable CR/CRu were observed with single-agent romidepsin in pts with R/R PTCL, including those with advanced and heavily pretreated disease. Baseline characteristics CR/CRu (n = 17) Other (n = 113) Age in years, median (range) 62 (37-78) 61 (20-83) Stage III/IV disease, n (%) 13 (77) 78 (69) PTCL subtype, n (%) PTCL NOS 9 (53) 60 (53) AITL 4 (24) 23 (20) ALK1-negative ALCL 4 (24) 17 (15) Bone marrow disease, n (%) 6 (35) 30 (27) International Prognostic Index, n (%) < 2 2 (12) 29 (26) ≥ 2 15 (88) 84 (74) Number of prior systemic therapies, n (%) ≤ 2 10 (59) 72 (64) > 2 7 (41) 41 (36) Refractory to last prior systemic therapy, n (%) 7 (41) 42 (37) Prior stem cell transplant, n (%) 2 (12) 19 (17)
Evaluation of the anticarcinogenic effect of <i>solanum</i><i>rastratum</i> dunal (Mexican thistle) on breast cancer cells MDA.
Authors: Maria Del Carmen Valadez Vega, Laura Garcia Velasco, Clara Zuniga Perez, Manuel Sanchez Gutierrez, Jose Antonio Morales Gonzales
Journal: Journal of Clinical Oncology (2013)

84 Background: The use of medicinal plants has been very common since ancient times, used for the treatment of several diseases such as cancer. In many towns in Mexico are used extracts from plants such as Solanum rastratum Dunal (buffalo bur, spiny nightshade, Colorado bur, Kansas thistle, Mexican thistle, and Texas thistle), which has shown to be effective in improving symptoms of some diseases conditions, there are reports indicating its use in the treatment of some types of cancer, such as the breast and cervical cancer. For this reason, in this work the aim was to evaluate the anticarcinogenic effect of extracts of Solanum rastratum Dunal on human breast cancer cells MDA. Methods: The plant was collected, cleaned, separate the different sections, were dried in darkness in special panels at room temperature; subsequently the extracts were prepared from the leaf, stem and flower-fruit using solvents of different polarity (methanol, ethyl acetate and hexane). Extracts were analyzed in cultured MDA cells line and the cytotoxic effect was evaluated by MTT technique. Results: The results showed that the stem and leaf extracts were those which showed higher inhibitory effect on cell viability, with those obtained with ethyl acetate which showed better anti-carcinogenic effect, while the hexane extract of the flower and fruit mixture which was showed higher inhibitory effect on this part of the plant; however generally the ethyl acetate extract obtained from the leaf was the one with greater cytotoxic effect in this cell line. Conclusions: The results of this work lead to the conclusion that is greater cytotoxic effect of ethyl acetate extract of the leaf than the other extracts tested. These results are contrasting with the traditional use of the extract of this plant, since traditionally people employ the aqueous extract of this plant, which would be equivalent to methanolic extract used in this study, which was who presented the lower cytotoxic effect of three solvents studied.
Subgroup classification of receptor tyrosine kinase (RTK) pathway activation in<i> KRAS</i>-mutated metastatic carcinoma.
Authors: Y. Wang, J. P. Windham, R. A. Samul, M. A. Sanidad, A. Farooqui, B. M. Gorman, J. C. Kelly, A. M. Meloni-Ehrig, D. Jones
Journal: Journal of Clinical Oncology (2011)

e18019 Background: Molecular stratification of metastatic carcinoma in body fluids has become critical to therapy selection, as these are often the only accessible disease sites. We performed multimodality RTK pathway analysis of metastatic carcinoma in pleural fluid to assess how functional RTK dysregulation correlates with initiating mutation. Methods: Tumor samples from 45 patients with metastatic carcinoma diagnosed in pleural fluid were assessed (22 lung adenocarcinomas, 7 breast, 3 gastric, 4 ovarian, 9 others); with sequential analysis in 9 patients. Site of origin was determined by a combination of clinical history, cytomorphology, and CK7/20, CK5/6, napsin A, and TTF-1 immunostains. Mutation analysis of KRAS (codons 12, 13, and 61), BRAF, and PIK3CA (exons 1, 9, and 20) was performed with PCR-based pyrosequencing, with EGFR mutations in exons 18-21 assessed by Sanger sequencing. FISH analysis to assess copy number of the HER2, MET, ALK, and EGFR loci was performed using commercially available probes. Functional RTK pathway activation was assessed using semi-quantitative analysis using a panel of phospho(p)-antibodies including MET, EGFR, HER2 and AKT activation sites. Results: KRAS mutations were common in all tumors, including lung (11/22, 50%), breast (6/7, 86%), gastric (2/3, 67%), and ovarian (4/4, 100%) carcinomas. Cases without KRAS mutation showed EGFR mutations or BRAF mutations (lung), with PIK3CA mutations in 2 breast, 1 lung, and 1 endometrial tumor. The KRAS-mutated cases showed distinct subgroups characterized by other TK abnormalities, including genomic amplification of HER2 (17.2%), EGFR (3.4%), and MET (13.8%) and strong p-activation of MET (3.4%), EGFR (24.1%), and AKT (32.1%). Conclusions: Metastatic carcinoma in pleural fluid has high rates of KRAS mutation, regardless of site of origin Among KRAS-mutated tumors, there is a stable subgrouping/clustering of RTK activation patterns, indicative of distinct progression events. Given that KRAS mutation predicts lack of response to current RTK-targeted therapies, functional correlates of these observed genetic subgroups will be critical to designing novel treatments for this high-risk subgroup of carcinomas.
Somatostatin receptor subtypes 1-5 gene expression in multiple sites in the same individual.
Authors: Michael Anthony Hall, Tanja Milosavljevic, Peter Casey, Catherine T. Anthony, Eugene Woltering
Journal: Journal of Clinical Oncology (2012)

182 Background: Metastatic tumors may be fundamentally different than the primary tumor. This phenomenon may partially explain resistance of metastatic disease to therapy. We evaluated the gene expression levels of somatostatin receptor subtypes 1-5 (SSTR 1-5) in patients with disseminated neuroendocrine tumors (NETS) undergoing cytoreduction of their primary tumor and its nodal and liver metastasis. Methods: We compared the gene expression levels for SSTR 1-5 in primary tumor and their nodal and liver metastasis. The small bowel primary (SB), a mesenteric lymph node (LN) and a liver metastasis and their normal tissue counterparts were evaluated in four patients. RNA samples from each tissue underwent gene expression analysis using a customized Real Time Quantitative PCR (RT-qPCR) gene array. Normal tissue gene expression was compared to that obtained from the tumor sample at each site. Results: SSTR 2 was overexpressed (four-fold or greater, p≤ 0.01) compared to control levels in 8/12 (67%) specimens; 4/4 (100%) of the liver specimens, 3/4 (75%) of the SB specimens, and 1/4 (25%) of the LN specimens. SSTR 2 gene overexpression was not observed in all three tumor sites in any patient. No tumor had SSTR 2 downregulation. SSTR 5 was overexpressed (four-fold or greater, p≤ 0.01) compared to control levels in 6/12 (50%) specimens; 3/4 (75%) of the liver specimens, 2/4 (50%) of the SB specimens, and 1/4 (25%) of the LN specimens. SSTR 5 gene expression was up-regulated in all three tumor sites in one individual. SSTR 5 was down-regulated (7-fold, p&lt;0.01) in one LN specimen. Changes in gene expression levels of SSTR 3 and SSTR 4 showed inconsistency between tumor sites, whereas that of SSTR1 was observed only at the metastatic sites. Conclusions: These results explain the observed variability in somatostatin receptor expression seen in 111 In pentetreotide scans in multiple tumor sites from the same individual. The observation that gene expression varies from metastasis to metastasis may also help explain the difficulty in designing therapies that cure patients rather than inducing partial remissions.
Assimilation of evidence-based medicine into clinical practice: Adjuvant radiotherapy in the multidisciplinary treatment of rectal cancer.
Authors: Timothy Louis Fitzgerald, Jason Brinkley, Emmanuel E. Zervos, Jan H. Wong
Journal: Journal of Clinical Oncology (2012)

552 Background: Implementation of evidence based standards is recognized to be problematic. Level 1 evidence supports the superiority of neoadjuvant therapy for stage II/III rectal cancer. The purpose of this study was to determine to what extent evidence based medicine has impacted clinical practice. Methods: Stage II/III rectal cancer patients undergoing surgery from 1998-2007 were identified in the SEER tumor registry using SEER*Stat 6.2. Variables were extracted and analyzed in SPSS; trends were evaluated with regression models and survival with log rank test. Results: A total of 25,129 patients were identified, 15,769 (63%) were treated with adjuvant radiotherapy. A majority were &gt; 60 years old (56%), white (82.8%), male (60.9%), had stage III cancers (59.2%) and treated with neoadjuvant radiotherapy (54.5%). Significant changes in timing of adjuvant radiotherapy were noted over the study period. In 1998 28.1% of patients were treated neoadjuvantly, this increased to 74% in 2007, a 263% increase. Scatter plot best fit lines intersect in approximately year 2002, p value of trend &lt;0.001. On univarate analysis race (p=0.018), sex (p&lt;0.001), year of diagnosis (p&lt;0.001), age (p&lt;0.001), and stage (p&lt;0.001) were associated increased likelihood of neoadjuvant radiotherapy. Logistic regression found male sex (OR 1.14, p&lt;0.001), year (OR 1.223, p&lt;0.001) and stage II (OR 1.39, p&lt;0.001) were predictors of neoadjuvant therapy. Significant increases in preoperative radiotherapy were observed for all races and cancer stages (p&lt;0.001). There was a significant survival advantage for those treated with adjuvant radiotherapy, median survival 39 vs. 93 months p&lt;0.0001. There, however, was no survival advantage to neoadjuvant vs. postoperative radiotherapy, median survival 94 vs. 93 months, p=0.749. Conclusions: When adjuvant radiotherapy is utilized, there has been rapid adoption of evidence based standards for Stage II/III rectal cancer. However, substantial numbers of patients are not receiving care recognized to improve outcomes.
A phase II study of multikinase inhibitor sorafenib in patients with relapsed non-small cell lung cancer (NSCLC)
Authors: M. Gutierrez, S. Kummar, D. Allen, B. Turkbey, P. Choyke, J. J. Wright, C. Kurkjian, G. Giaccone, J. H. Doroshow, A. J. Murgo
Journal: Journal of Clinical Oncology (2008)

19084 Background: Sorafenib is a potent inhibitor of c-Raf, b-Raf VEGFR-1/2/3 and PDGFR-β. In NSCLC, proliferative signaling through the Ras/Raf/MEK/ERK pathway is often activated from K-ras mutations. We conducted a phase II study to determine the clinical and biological activity of Sorafenib in patients with relapsed NSCLC. Methods: Pts with recurrent NSCLC with measurable disease who have received no more than one prior chemotherapy regimen for metastatic disease, ECOG 0–2, and adequate organ function were eligible. Sorafenib was administered at a starting dose of 400 mg bid continuously on 28-day cycles. Dynamic contrast enhanced MRI (DCE- MRI) was performed before cycle 1 and at C1 day 15 to study early changes in tumor vascularity. Results: 15 pts enrolled, median age 64.5 yrs (range 35–84), 9 males, 6 females. Fourteen of 15 pts had only 1 prior platinum-doublet regimen; 1 pt had only prior erlotinib. No G4 toxicities have been observed. Hematological toxicity: G3 anemia (1 pt), G1–2 leukopenia (4 pts). G3 non-hematological adverse events: hyponatremia (3 pts), hypokalemia (1 pt), hypocalcemia (1 pt), hypophosphatemia (2 pt), nausea (1 pt), dyspnea/hypoxia (2 pt), syncope (1 pt), retinopathy (1 pt) and hypertension (1 pt). G1–2 non-hematological toxicities: hypertension, diarrhea, fatigue, elevated LFT’s, amylase and lipase. Skin toxicity has been seen in all pts and includes G1- 2: acne like drug-related rash (10 pts), hand-foot syndrome (7 pts), keratoacanthoma (1 pt) and vasculitis (1 pt); G3 hand-foot syndrome (2 pt). All toxicities have responded to temporary withdrawal of sorafenib and supportive care. 15 patients have completed at least 2 cycles of therapy and were evaluable for response (>8 weeks of treatment) and toxicity: 2 PR (13%) and 7 SD (46%), with a median time to progression of 5 months (range 1 -11+ months). DCE-MRI results: the DCE-MRI showed a reduction in the parameters of permeability, with decreased values in ktrans and kep, associated with reductions in the tumor size. Conclusions: Sorafenib monotherapy is well-tolerated with manageable toxicity and is active against relapsed NSCLC with only one prior line of systemic treatment. Accrual to this phase II trial continues in the second stage. No significant financial relationships to disclose.
To assess the effect of ridaforolimus on the QTc interval in patients with advanced cancer.
Authors: D. Sullivan, A. Patnaik, K. P. Papadopoulos, J. B. McCrea, K. Cerchio, X. Li, M. Stroh, K. W. Orford, M. Trucksis, S. Ebbinghaus, N. Agrawal, M. Iwamoto, J. A. Wagner, A. W. Tolcher
Journal: Journal of Clinical Oncology (2011)

e13088 Background: Ridaforolimus (RIDA) (AP23573; MK-8669), a unique rapamycin analog and potent inhibitor of mTOR signaling, is being developed for treatment of solid tumors. We aimed to assess the effect of a single supratherapeutic dose of 100 mg RIDA on the QTc interval in advanced cancer patients. This dose was used to achieve an exposure similar to that following the clinical dose regimen. Methods: This was a partially blind, placebo-controlled, 2-part study of RIDA in advanced cancer patients. In Part 1, 2 days of ECG were performed for QTc assessment in a fixed sequence. On Day 1, patients received a single oral dose of placebo; on Day 2 they received a single oral dose of RIDA 100 mg. Each dose was followed by 24 h of Holter ECG. Blood samples for RIDA were measured at pre- and up to 24 h postdose on Day 2. In Part 2, patients had continued access to RIDA for potential clinical benefit, with only safety data collected. Results: 23 patients (8 males; 15 females) were enrolled. For Day 1 placebo treatment, 22 patients were included in the QTcF data; for Day 2 RIDA treatment, 20 were included in the QTcF data and 21 in the pharmacokinetic data. RIDA 100 mg did not prolong the QTcF interval. Upper bound of the 90% CI of the placebo-adjusted mean QTcF interval change-from-baseline was <10 ms at every time point through 24 h. The largest placebo-corrected RIDA change from baseline QTcF occurred at 10 h postdose, mean difference 3.89 ms, 90% CI (0.60, 7.17). After placebo or 100 mg RIDA administration, only 1 patient had QTcF values >450 ms (on both placebo and RIDA) and none had values >480 ms. Neither placebo nor treatment patients had a QTcF change-from-baseline >30 ms. Exposures after single dose RIDA 100 mg were a geometric mean whole blood AUC0-24 of 1875 h·ng/mL and Cmax of 186 ng/mL, approximating steady state exposure with the clinical dose regimen of 40 mg po QD x 5 consecutive days/week. However, these values do not achieve supratherapeutic exposure. RIDA was generally well tolerated, with no patients discontinued from Part 1 due to drug-related AEs. Conclusions: A single dose of RIDA (100 mg) does not prolong the QTc interval in advanced cancer patients and achieved exposures that approximated steady state exposures at the maximally tolerated clinical dose and regimen.
A phase I/II study of the investigational drug alisertib in combination with abiraterone and prednisone (AP) for patients with metastatic castration-resistant prostate cancer (mCRPC) progressing on abiraterone.
Authors: Jianqing Lin, Ashwin Reddy Sama, Jean H. Hoffman-Censits, Brooke Kennedy, Deborah Kilpatrick, Zhong Ye, Hushan Yang, Zhaomei Mu, Benjamin E Leiby, Nancy Lewis, Massimo Cristofanilli, William Kevin Kelly
Journal: Journal of Clinical Oncology (2016)

311 Background: Aurora A kinase (AK) phosphorylates and interacts with androgen receptor (AR) and enhances AR DNA binding activity. We hypothesized that AK contributes to castration resistance in PCa, and targeting AK can inhibit AR function and re-sensitize PCa cells to AR signaling inhibitors such as abiraterone. Methods: Aphase I/II, open label, single institution trial to determine the safety and efficacy of AK inhibitor alisertib when given in combination with abiraterone plus prednisone (AP) was planned. Eligible subjects had mCRPC with disease progression on abiraterone. Androgen deprivation plus abiraterone and prednisone were maintained through the trial. Subjects were treated with dose escalation per standard 3+3 design. Planned 3 dose cohorts of alisertib were 30, 40, 50 mg PO BID D 1-7 every 21 D. Correlative studies included kinetics of neuroendocrine tumor markers, enumeration and AK gene amplification of CTCs. Results: Nine of 43 planned subjects were enrolled, 3 in cohort 1 without DLT. Two DLTs developed in cohort 2, thus 3 more patients were enrolled into cohort 1, and 2 developed DLT (total 2/6) in this cohort. The grade 3/4 toxicities (4/9) include neutropenic fever (1/9), neutropenia (1/9), fatigue with memory impairment (1/9), and mucositis (diarrhea and mouth sores, 1/9). Pharmacodynamically, adding alisertib did not affect circulating total testosterone and DHEA levels. Only one patient had decreased Chromogranin A level lasted for 4 months when compared to baseline. Four (4/9) patients had ≥ 5 CTCs at baseline but no conversion ( to &lt; 5) was observed. No PSA decrease was observed during the study. Mean duration of study was 2.5 months. The toxicity / efficacy ratio did not warrant further dose expansion and the trial was terminated early after discussion with sponsor. Conclusions: A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone. Clinical trial information: NCT01848067.
Serum insulin-like growth factor-1 levels in response to dasatinib-based regimens in bone-metastatic prostate cancer.
Authors: Farshid Dayyani, Andreas Varkaris, John C. Araujo, Jian H. Song, Geralyn C. Trudel, Christopher Logothetis, Gary E. Gallick
Journal: Journal of Clinical Oncology (2013)

166 Background: Dasatinib, an inhibitor of Src-family kinases, combined with docetaxel in men with castrate-resistant prostate cancer (CRPC), affects bone turnover markers. Only a subset of men benefit from this therapy, and predictive markers are lacking. We hypothesized a role for insulin-like growth factor-1 (IGF-1) as a predictive marker, since IGF-1 is important in both prostate cancer (PCa) progression and bone development. Hence, we determined the association of IGF-1 expression to treatment response, and whether this expression resulted from tumor cells, the microenvironment, or their interactions. Methods: We first measured serum IGF-1 levels in men with CRPC treated with dasatinib plus docetaxel. To investigate the source of IGF-1, we utilized different mouse models harboring human PCa cells, and used species-specific IGF-1 ELISA kits (mouse vs. human). Results: In men with CRPC, an increase in IGF-1 levels after one cycle of treatment is associated with a higher response rate and longer duration of treatment with docetaxel and dasatinib. Xenograft experiments with subcutaneous, and intratibial injection of PCa cells and treatment of mice with dasatinib-based combinations suggest that direct interaction of PCa cells with bone microenvironment is necessary for IGF-1 induction, is entirely host-derived, and occurs only in mice that respond to dasatinib-based therapy. Conclusions: Our results support a role for serum IGF-1 as a potential biomarker for dasatinib-based combination treatments in CRPC. Inoculation of human PCa cells into murine hosts was essential in determining that IGF-1 results from the bone microenvironment. Further studies are warranted to validate these findings in a larger cohort of patients in a prospective manner.