tbuckley/cabot-search huggingface dataset:
Activity of the MEK1/2 inhibitor AZD6244 (ARRY-142886) in combination with standard and approved therapies: impact of in vivo sequencing of drug administration
Authors: Robert Wilkinson, Armelle Logie, Nicola Haupt, Nicola Curtis, Mark Hickinson, Barry Davies, Jennifer McKay, Paul Smith
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

4012 

MAPK/ERK kinase (MEK1/2) is an integral component of the RAF/MEK/ERK signaling pathway implicated in uncontrolled cell proliferation and cell survival. AZD6244 (ARRY-142886), a novel, selective, ATP uncompetitive inhibitor of MEK 1/2 is currently in phase II monotherapy clinical trials in a range of diseases. In order to evaluate the potential of AZD6244 to combine with the agents currently used to treat these cancers we have used in vivo human tumor xenograft models. The agents used included drugs with a cytotoxic mechanism for example, irinotecan, docetaxel, gemcitabine and also those with a targeted mechanism, for example, gefitinib. Since the predominant effect of MEK inhibition is inhibition of cell proliferation by arresting tumor cells in phases G0/G1 of the cell cycle we investigated the impact of altering the sequence of administration with drugs that may require cells to be in a different phase of the cell cycle. The combination of AZD6244 and gefitinib was found to offer a significant improvement in tumor growth inhibition in a colorectal cancer xenograft, LoVo which carries a KRAS gene mutation. Acute dosing studies with pharmacodynamic assessments were utilized to investigate the mechanisms of the beneficial effects of the combination of AZD6244 with docetaxel and gefitinib.
Establishment of primary gastric and gastroesophageal (GE) junction xenografts: A model for characterizing disease heterogeneity.
Authors: Yelena Yuriy Janjigian, Robert Mazgaj, Gregory Carbonetti, Laura H. Tang, Blake Hefter, David Paul Kelsen, Elisa de Stanchina, Vivian E. Strong
Journal: Journal of Clinical Oncology (2012)

51 Background: Gastric cancer is a heterogeneous disease that may be subdivided into distinct subtypes—proximal/gastroesophageal (GE) junction, diffuse/signet ring type, and distal gastric cancers—based on histopathologic and anatomic criteria. Each subtype is associated with unique epidemiology and gene expression. Human epidermal growth factor receptor (HER2) is a validated treatment target in gastric cancer. For patients with metastatic disease, the available cytotoxic agents are applied indiscriminately to all disease subtypes, and with only modest success. The purpose of this study is to establish xenograft models from gastric cancer subtypes to improve our understanding of disease heterogeneity and develop therapies geared for each subtype of gastric cancer. Methods: Fresh specimens obtained from resected primary or metastatic tumors under aseptic conditions. 1 g tumor samples injected SQ into flanks of NOD/SCID mice. Xenografts established after 5 passages and maintained by serial transplantation into new mice. Cell cultures established after 5 in vitro passages; cell lines after 15 passages. Results: To date 26 tumor samples have been implanted from which 8 xenografts have been established. Table below summarizes the results. Cell line established from HER2-positive, trastuzumab refractory tumor resected from brain metastasis. Conclusions: HER2-positive tumors have a favorable xenograft yield. Prior chemo or radiation therapy does not impact engraftment. Standard and experimental therapies are being tested on these xenografts to further validate difference in their biology and guide rational design of clinical trials. [Table: see text]
Ten years free of disease of differentiated thyroid carcinoma (DTC) with interdisciplinary approach in an Andean region of Quito.
Authors: W. DelaTorre, S. Lopez, I. Vega, R. Contreras, F. Vallejo*
Journal: Journal of Clinical Oncology (2011)

e16004 Background: The DTC is a tumor with low impact on mortality (survival >90% at 30years follow up).In this sense the prospective ten years (2000-10) results are presented of 50 patients (78% women) diagnosed and treated with multidisciplinary approach (level A and B evidence). Methods: a) fine-needle aspiration-FNA,with first 66%(33 cases) and second 88%(17 cases) cytological report of malignancy and suspected or follicular lesions; highlighting a 52%(p<0.05) of multinodular goitre(4.8+/-2cm);b)total thyroidectomy (TT: 94%) with central cervical lymph node dissection in 82 %); c) radio-iodine ablative standard dose(100mCi 131I) at 6weeks post-TT, included a 131I diagnosis body scan (DBS) 94% (+) thyroid tissue: TSH 87 mUI/ml and 73% serum thyroglobulin(sTg)<4+/-0.5 ng/ml. Results: Postoperative morbidity was 4% and 30% for laryngeal dysfunction and temporary hypocalcemia (3 to 6 months). Histopathologic features of tumor: malignancy in 97% of the frozen biopsies, tumor size 2.3+/-0.7cm (80%TNM low risk,p<0.05),unilaterality 70%(p<0.05,right 63%); neoplasia good differentiation 72%(p<0.05), papillary variety 82%(p<0.05, follicular differentiation 34%), local tumor invasion 66%(capsular 69%,p<0.05), lymph node involvement 66%(central 57%,p<0.05). Prospective follow-up:suppression phases of TSH (0.35mUI/ml, LT4 130+/-15ug/day and sTg 1.4ng/ml in 77%) cervical ultrasound (+) in thyroid region15%; hypothyroidism phases without LT4(TSH 80mUI/ml,sTg 2.5+/-1ng/ml) 131 I-DBS was(-) in 78% and 90% at the1st and 8th-10th years of the evaluation respectively,DBS(+) received other standard 131I dose or 300-450 mCi cummulative dose in 3 cases with pulmonary metastases(sTg> 100ng/ml). Conclusions: This report with 50 DTC patients staging clinical (60% <45 years) and pathological (76%TNM I-II) low risk,during 5.8+/-2.1 years of follow-up there was no death/severe morbidity cases and healing can fit criteria for “disease free”: clinic (94% thyroid /cervical),biological (93% low sTg) and 131 I- DBS (-) in 89%, demonstrating so that the application of this interdisciplinary management allows high survival rates with minimal morbidity.
INCA-GYN001: Erlotinib added to cisplatin and definitive radiotherapy in untreated patients with locally advanced squamous cell cervical carcinoma—Final report of a phase II trial.
Authors: A. N. Rodrigues, I. A. Small, C. C. Carmo, G. M. Moralez, F. Erlich, R. Grazziotin, M. H. Lewer, C. c. Camisao, F. V. Alves, C. G. M. Ferreira
Journal: Journal of Clinical Oncology (2011)

5033 Background: Concurrent cisplatin (C) based chemoradiotherapy (CRT) is the standard treatment for locally advanced cervical cancer (LACC). New strategies that increase the complete response (CR) rates may lead to longer progression-free(PFS) and overall survival(OS). Pre-clinical data indicates that inhibition of the epidermal growth factor receptor (EGFR) potentiates the effect of RT. We previously reported a phase I trial of the tyrosine kinase EGFR inhibitor erlotinib (E) administered concurrently with standard CRT for LACC that confirmed the safety of E at 150mg/day and preliminary efficacy data on the phase II. Methods: Eligibility - stage IIB to IIIB squamous cell cervical carcinoma; no prior therapy; ECOG PS 0-2; adequate end-organ function. Patients (pts) received E 150mg/day one week before and combined with C (40mg/m2, weekly, X 5) and RT (external beam - 4500cGy in 25 fractions, followed by 4 fractions/600cGy/weekly of brachytherapy). Pre and post treatment tumor tissue was obtained for molecular analysis.Response was assessed after a 3 month-interval with MRI, CT, PET and biopsy. Results: Patient characteristics: median age 44 (27-68), stage IIB 22 (57.9%), IIIA 1 (2.6%) and IIIB 15 (39.5%). 41 pts were enrolled and 3 excluded. 38 patients were available for toxicity. Two pts did not complete planned treatment (one presented Raynaud's Syndrome and had C interrupted and one presented grade 4 hepatotoxicity). Of 36 pts who completed E+CRT, median duration of treatment was 77 (64-129) days and median follow-up was 39.4 months(m) (IC95%35.5-43.3). Overall E+CRT was well tolerated. Most common grade 3 toxicity was skin rash (13%). Of 36 evaluable for response, 34 pts, (94.4%-IC 95% 79.99- 99.03) had CR and two pts had partial response. Cumulative OS and PFS survivals were 91.7% and 80.6% at 24m, and 80% and 73.8%, respectively, at 36m of follow-up, superior to historical control. Conclusions: In this cohort of LACC patients the combination of E+CRT is efficacious and feasible, with a CR rate of 94.4%. This combination is worth exploring in a randomized clinical trial. Molecular correlative studies will be presented at the meeting.
Retrospective analysis of prognostic factors associated with response and overall survival in patients with RAEB-t MDS treated with decitabine.
Authors: A. Malik, G. Garcia-Manero, M. Welch, H. Kantarjian, K. Stein, A. Teng, E. Jabbour
Journal: Journal of Clinical Oncology (2011)

6598 Background: Response to decitabine, a hypomethylating agent for treatment of MDS of all FAB subtypes and Intermediate-1, Intermediate-2 and High-risk IPSS groups, was assessed using IWG 2000 criteria. The revised WHO definition of AML is ≥20% blasts instead of ≥30% blasts, so IWG updated its response criteria in 2006. The current analysis updates response data using IWG 2006 criteria. Methods: A retrospective analysis was conducted of a pooled subset of patients with MDS from two decitabine trials: 3-day dosing (phase III) or 5-day dosing (phase II). Patients with baseline marrow blasts ≥20% receiving decitabine (RAEB-t group) were compared with patients with baseline marrow blasts <20% (MDS group). Comparisons were made of baseline characteristics (Fisher’s exact test and t test); overall response rates (ORR) (Fisher’s exact test); and overall survival (OS) (log-rank test; significance p<.05). Results: The RAEB-t group (n=26) had a significantly shorter time from MDS diagnosis (7.3 vs 18.3mo), higher IPSS risk (76.9% vs 15.9% of patients), and lower median baseline platelet count (62.3 vs 112.7 x103/mL) vs the MDS group (n=157), yet the two groups still had similar OIR, PR, mCR, HI, stable disease, and disease progression. Adverse events were similar between groups. Conclusions: Based on this retrospective analysis, decitabine yielded a similar response rate in RAEB-t patients as in other MDS patients, except for a lower CR rate, consistent with the higher proportion of IPSS high-risk. Moreover, the RAEB-t patients did not progress to AML (≥30% blasts) more rapidly than the MDS population. As such, clinical responses in the RAEB-t group are encouraging. RAEB-t (n=26) n (%) MDS (n=157) n (%) P* ORR (CR+mCR+PR) 4 (15.4) 44 (28.0) 0.2311 OIR (CR+mCR+PR+HI) 9 (34.6) 67 (42.7) 0.5223 CR 0 25 (15.9) 0.0278 mCR 2 (7.7) 14 (8.9) 1.0000 PR 2 (7.7) 5 (3.2) 0.2602 HI 5 (19.2) 23 (14.7) 0.5589 Stable disease 8 (30.8) 43 (27.4) 0.8137 Progressive disease 4 (15.4) 27 (17.2) 1.0000 Abbreviations: CR, complete response; HI, hematologic improvement; mCR, marrow complete response; OIR, overall improvement rate; PR, partial response. *Fisher’s exact test.
Gemcitabine in combination with vinorelbine for heavily pretreated advanced breast cancer
Authors: C. Gennatas, D. Mouratidou, N. Tsavaris, C. Andreadis, V. Michalaki, J. Psychogios, N. Poulakaki, S. Gennatas
Journal: Journal of Clinical Oncology (2005)

741 Background: Gemcitabine and vinorelbine are two newer cytotoxic agents that have demonstrated promising antitumor activity and favorable toxicity profiles as single-agent therapy for metastatic breast cancer. The purpose of this study was to evaluate the efficacy and safety of the combination of these agents in pretreated advanced breast cancer. Methods: A total of 86 heavily pretreated patients with metastatic breast cancer (median age 62 years, range 35–75 years) with ECOG Performance status of 0–2, entered the study. All patients had received prior adjuvant chemotherapy. Thirty-six patients had been pretreated with anthracyclines, and 8 were resistant. The combination of Gemcitabine (1000mg/m2) and vinorelbine (25mg/m2) was administered on days 1 and 8 every 3 weeks, for a total of 6 cycles. Results: A total of 344 cycles of chemotherapy were administered (median 4 cycles per patient, range 1–9). Partial responses were observed in 31 patients (36.0%). The median duration of response was 7 months (range 3–11 months) and the median overall survival was 14 months. In the anthracycline pretreated population (n=36) there were 2 partial responses (5.5%), while among the patients pretreated with both anthracyclines and taxanes (n=8) a total of 2 achieved a response (25.0%). The scheme was well tolerated. Grade 3/4 toxicity was limited to leucopenia in 4 patients (4.7%), thrombocytopenia in 2 patients (2.3%) and anemia in 13 patients (15.1%). No patient was hospitalized due to febrile neutropenia, and there were no treatment related deaths. Conclusions: The combination of vinorelbine and gemcitabine is an active and manageable scheme in patients with metastatic breast cancer pre-treated with anthracycline-based schedules, or with combinations of anthracyclines and taxanes, demonstrating an acceptable toxicity profile. No significant financial relationships to disclose.
S100A2 as a prognostic marker in patients receiving adjuvant therapy for pancreatic cancer (PC): A secondary analysis of RTOG 9704.
Authors: M. A. Tempero, K. A. Winter, G. E. Kim, S. Kakar, T. S. Hyun, W. Regine, R. B. Mowat, K. Charpentier, W. Small, C. Guha, D. K. Chang, A. V. Biankin
Journal: Journal of Clinical Oncology (2011)

4118 Background: S100A2, a calcium-binding protein, has been validated as a prognostic marker in a retrospective cohort of patients with PC who did not receive adjuvant therapy. Methods: A secondary analysis of S100A2 expression on archival tissue from a subset of patients with head of pancreas lesions from a prospective adjuvant trial, RTOG 9704, was performed. Immunohistochemistry was performed on a tissue microarray (TMA) including triplicate samples from each specimen. Tissue was scored for % labeled cells and intensity to establish 4 levels of expression. Disease-specific survival (DSS) was estimated univariately with the Kaplan-Meier method and multivariate Cox proportional hazards models were used to determine if there is a correlation between S100A2 expression and DSS. Results: The analysis was based on 150 specimens. For DSS, the hazard ratio (HR) for no, low, mod, or high expression for each subgroup is as follows: 1.0, 1.22 (95% C.I. = [0.70, 2.12]), 1.36 (95% C.I. = [0.77, 2.41]), and 1.37 (95% C.I. = [0.95, 1.99]), respectively. For high vs. low/no expression, the curves separated at 1 year but were not significantly different (p=0.09) (Table). Interestingly, the 2-year DSS in the retrospective S100A2 cohort was only 17% compared to 29% in the prospective RTOG cohort, while the 2-year DSS of the S100A2 negative cohorts were similar in both studies. In this clinical setting, S100A2 expression was not an independent prognostic factor based on multivariate analysis. Conclusions: Failure to validate S100A2 as a prognostic marker in RTOG 9704 may be a function of small number of archival samples available for analysis. In addition, comparison to the historical retrospective untreated cohort suggests that S100A2 may also be a predictive biomarker for response to treatment. S100A2 deserves further study as a prognostic and predictive biomarker. This project was supported by the RTOG U10 CA21661, U24 CA114734, and CCOP U10 CA37422 grants from the National Cancer Institute (NCI). DSS 1 Year 2 Years S100A2 Expression # Pts % % High intensity 72 73 29 Low/no expression 78 76 46
Integrative oncology from the patient advocate perspective.
Authors: Ann Fonfa
Journal: Journal of Clinical Oncology (2014)

133 Background: As a 20+ year breast cancer survivor I sought to find and offer information on natural cancer strategies. At first I needed them for my own cancer protocol, then to help others Integrative Oncology refers to the simple, natural and non-toxic approaches that can reduce toxicity, possibly enhance the efficacy of conventional treatment, and create feelings of well-being and control in people dealing with cancer. Many studies, some from long ago, have pointed to the strong patient interest in Integrative Oncology (formerly known as CAM). Yet the professional oncology community’s knowledge has failed to keep up. Trained to seek level 1 studies, they have failed to note the preponderance of all the other evidence available supporting natural approaches. Due to cost, most natural products/substances are not reviewed at level 1 and probably will never be. Methods: We’ve created a simple program we call 3 Steps 4 Health, which offers anyone in cancer treatment a guide to improved health. We will present the research that backs up these simple ideas that can be incorporated into anyone’s protocol. We also have a handout to reduce toxicities that is evidence-based to help with those adverse effects that plague modern cancer patients. So many suffer from neuropathy – there are quite a few methods to protect or treat this with complementary therapies that can be integrated into conventional treatment. Results: ASCO has pointed to the value of Yoga, of ginger, and other natural approaches but oncology professionals have been slow to adopt or recommend. Conclusions: We will provide evidence-based information on integrative oncology and the 3 Steps 4 Health program.
Does the underlying etiology of HCC effect outcome? A single-institution analysis.
Authors: J. Ma, M. Capanu, E. M. O'Reilly, N. E. Kemeny, C. Ang, B. Gansukh, D. P. Kelsen, L. Saltz, G. K. Abou-Alfa
Journal: Journal of Clinical Oncology (2011)

e14636 Background: Several biologic and clinical factors indicate that the underlying etiology of HCC may impact outcome. Methods: We undertook an Institutional Review Board-approved medical record examination for all HCC patients seen by medical oncologists for consideration of systemic therapy between 2001 and 2006. Demographic and clinicopathologic data were analyzed for correlation with overall survival (OS). Independent prognostic factors for OS were identified using a multivariate Cox regression model which included variables significant at the 0.05 level in univariate Cox models. Treatment factors were not assessed in this analysis. Results: Records were examined for 190 patients with advanced HCC. The median age was 63 years (range 24-88): Males 74%, females 26%. Baseline variables with significance in at least univariate analysis are shown in the table. Conclusions: In this multivariate analysis, etiology was unrelated to OS. Both HCV and alcohol showed significance in the univariate analysis for OS. This may be due to the association of these etiologies with more advanced cirrhosis compared to HBV-related HCC. Advanced stages of cancer (T stage, bilobar disease) and cirrhosis (Child-Pugh C) correlated with worse OS in the multivariate analysis. The observation that the African-American race is an independent variable for OS deserves further exploration. Variable at baseline Distribution n, (%) Univariate hazard ratio P Multivariate hazard ratio P Race White 120 (63) 1.00 African American 23 (12) 2.06 0.0019 1.88 0.0176 Asian 37 (20) 0.67 0.0478 0.76 0.22 Hispanic 8 (4) 1.25 0.54 1.48 0.33 Etiology HCV 56 (29) 1.53 0.0093 1.06 0.7614 HBV 66 (35) 0.94 0.71 Alcohol 57 (30) 1.56 0.0058 1.22 0.25 ECOG 1 143 (75) 1.00 2-3 39 (21) 1.73 0.0029 1.31 0.18 AJCC 6 stage T 0-2 70 (37) 1.00 T 3-4 120 (63) 2.40 <0.0001 1.72 0.0083 N + 70 (37) 1.17 0.31 M + 116 (61) 0.72 0.0292 0.96 0.79 Portal vein thrombosis (PVT) 58 (31) 1.79 0.0003 1.24 0.53 Liver disease extent >50% 56 (29) 1.88 <0.0001 Bilobar disease 131 (69) 1.68 0.0012 1.56 0.0124 Vascular Invasion 70 (37) 1.56 0.0039 0.97 0.91 Child-Pugh A 127 (67) 1.00 B 55 (29) 1.49 0.0155 1.27 0.18 C 8 (4) 2.56 0.0112 2.38 0.0272
Long-term evaluation of patients (Pts) with malignant melanoma (MM) treated with autologous cancer vaccine HSPPC-96 at three different dose levels
Authors: L. H. Camacho, K. A. Hawkins, M. I. Ross, C. Savary, A. Y. Bedikian, J. E. Lee, N. E. Papadopoulos, R. Gupta, P. K. Srivastava
Journal: Journal of Clinical Oncology (2005)

7550 Background: HSPPC-96 is a polyvalent vaccine produced from resected cancer tissue. Limited understanding exists regarding the implications of cellular mediated immunity on the overall outcome of pts with cancer. Herein we evaluated the long-term outcome of a group of pts with MM treated with HSPPC-96. Methods: We analyzed the records of 36 Stage (St) III [N=11;(31%)] or limited St IV [N=25;(69%)] pts with resected MM (>5 grams of resected tissue) treated in a Phase I-II Trial. Following surgery, 16 (44%) pts (2 St III; 14 St IV) had residual disease & 20 (56%) (9 St III; 11 St IV) no evidence of disease (NED). All pts received 4 weekly I.D. injections of HSPPC-96 at 1 of 3 dose levels: 2.5μg (N=11), 25μg (N=16), 100μg (N=9). Two pts received an additional course of 4 vaccines. Peripheral blood mononuclear cells (PBMC) from 25 pts were tested at time 0, 2 wks, 3 wks, and 8 wks after initial vaccination. ELISPOT assay was performed by stimulating cryopreserved, uncultured PBMC with CD45-depleted autologous tumor cells. Results: No objective anti-tumor responses were observed. Median overall survival (OS) was 2.1 yr. Twelve of the 20 NED pts (60%) were alive after 4.5 yr, while only 1 pt (6%) with residual disease was alive > 3.5 yr. The median overall time to progression (TTP) was 0.6 yr. The median TTP for NED pts was 2.7 yr and only 0.3 yr for pts with residual disease. Thirteen of 20 (65%) NED pts remained disease free after a median of 1.7 yr of follow-up, with 8 pts remaining NED after 2 yr (range 2.0 - 2.8 yr). No significant increases in IFNγ ELISPOT numbers were seen after immunization. Conclusions: Cytoreductive surgery in combination with HSPPC-96 vaccination may increase TTP in pts with MM rendered NED. However, ELISPOT assay does not seem to correlate with clinical outcome. More sensitive assays against specific candidate peptide antigens are in progress. A larger, randomized study of HSPPC-96 in pts with metastatic MM is underway. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Antigenics Antigenics Antigenics Antigenics Antigenics Antigenics