tbuckley/cabot-search huggingface dataset:
Impact of neratinib on patient-reported outcomes.
Authors: S. Iyer, K. W. Turnbull, C. Powell
Journal: Journal of Clinical Oncology (2011)

e11078 Background: Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor was evaluated in an open label multi-center phase 2 study, with a daily oral dose in advanced breast cancer patients split into 2 cohorts, based on prior trastuzumab (n=66) and no prior trastuzumab treatment (n=70) with the primary endpoint being 16- week progression free survival rate (59% vs 78% with and without prior trastuzumab respectively) as reported by Burstein et al. Here we assess the impact of Neratinib on patient reported outcomes (PROs). Methods: PROs were measured as secondary endpoints at screening, months 3, 5 and final visit using EORTC-QLQ breast cancer module (BR-23) that includes 5 multi-item scales assessing breast symptoms, arm symptoms, side effects, body image, sexual functioning and 3 items assessing sexual enjoyment, hair loss and future perspective. Items are measured on a 4-point Likert scale ranging from 1 (not at all) to 4 (very much). Raw scores were transformed using a standard algorithm into scores ranging from 0 - 100. Change from baseline was analyzed using within subjects t-test and repeated-measures analysis of variance across visits using baseline as covariate. Results: In patients treated with prior trastuzumab, there was significant decrease (–12.1± 16.8; p<0.05: n=11) from baseline in the sexual enjoyment scores at month 3 and significant improvement from baseline in the body image (13.4 ± 30.63; p<0.05: n=28) and future perspective (24.7± 31.48; p<0.001:n=27) scores at month 5. There were no significant changes in side effects, breast and arm symptoms. In trastuzumab naïve patients, significant improvement was observed in breast symptoms (–10 ± 22.27, p<0.01: n=50) at month 3. A significant improvement was observed at month 5 in breast symptoms (–11.5± 21.04; p<0.001: n=45) and body image (7.1± 21.97, p<0.05: n= 46). Repeated-measures analysis showed significant changes in side effects (p<0.05), body image (p<0.05), and future perspective (p<0.001) scores in cohort with prior trastuzumab and in side effects (p<0.05) and breast cancer symptoms (p<0.01) scores in the trastuzumab naïve cohort. Conclusions: The impact of neratinib on PROs as assessed by the BR-23 was found to differ based on status of the patient’s prior exposure to trastuzumab.
Small tumor size and limited smoking history predicts activated EGFR-Stat3 in early stage non-small cell lung cancer
Authors: E. B. Haura, Z. Zheng, A. Cantor, G. Bepler
Journal: Journal of Clinical Oncology (2005)

7075 Background: A key pathway downstream of the epidermal growth factor receptor (EGFR) is the Signal Transducers and Activators of Transcription (STAT) pathway. Stat3 can control multiple oncogenic pathways including pathways regulating tumor cell survival. We evaluated Stat3 activation in early stage non-small cell lung cancers (NSCLC) and how this relates to EGFR signaling. Methods: High density tissue microarrays using tissues from 176 surgically resected stage NSCLC were immunostained with a phospho-tyrosine Stat3 antibody (pStat3) and phospho-tyrosine EGFR antibody (pEGFR). The score system for pStat3 included estimating the intensity of pStat3 nuclear stained tumor cells in a semi-quantitative manner. For each tumor, the sum of the triplicate nuclear pStat3 intensity was recorded and correlated with clinical and pathological variables. The score system for pEGFR included counting the percentage of positively stained tumor cells and estimating the intensity staining in a semi-quantitative manner. For triplicate samples, median values of the percentage of staining, the intensity, and a composite score (percentage multiplied by intensity) were derived. Results: We identified nuclear pStat3 expression in 54% of tumors. We found higher expression of pStat3 in smaller tumors (p=0.0002) and in patients with limited smoking history (p=0.03). We found a trend towards higher pStat3 expression in adenocarcinomas compared with other histologies (p=0.13). pStat3 had no influence on either overall or disease-free survival following surgical resection. Most importantly, we found a very strong correlation between pEGFR expression and pStat3 expression in this patient cohort (Spearman correlation coefficient = 0.52, p<0.0001). Conclusions: These results suggest that small NSCLC tumors have activated EGFR-Stat3 signaling and may be dependent on continuous signaling from this pathway for survival. Our finding that pEGFR and pStat3 is expressed in nearly 50% of patients suggests that agents targeting this pathway may have better efficacy in earlier stage NSCLC compared with more advanced stage patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca
Pharmacokinetics of recombinant immunotoxin BL22 during phase II testing in chemo-resistant hairy cell leukemia
Authors: R. J. Kreitman, W. H. Wilson, M. Stetler-Stevenson, P. Noel, D. J. FitzGerald, I. Pastan
Journal: Journal of Clinical Oncology (2008)

3001 Background: BL22 is a 63 kDa anti-CD22 recombinant immunotoxin containing truncated Pseudomonas exotoxin. In phase I testing, BL22 induced 61% CRs and 19% PRs in 31 with cladribine (CdA)-pretreated hairy cell leukemia (HCL). Four (13%) had a completely reversible hemolytic uremic syndrome (HUS). In a phase II trial 36 patients received 40 ug/Kg every other day for 3 doses (QOD x3) for cycle 1 and those retreated received 30 ug/Kg QOD x3 at 4 week intervals. Best response was 69% including 47% CRs. Compared to phase I, phase II response was similar (p=0.4) but need for plasmapheresis for HUS (0% vs 13%, p=0.041) and immunogenicity (11% vs 35% p=0.021) were lower. Methods: Neutralizing antibodies in the serum and active BL22 in the plasma were quantified by cytotoxicity assays using CD22+ Raji cells. Area under the curve (AUC) was calculated on the first dose of the cycle for each patient from either a mono- or biexponential model based on Aikake’s rule. Results: Median half-lives of BL22 were 157 min during cycle 1 (n=36), 153 min during cycle 2 (n=20), and 131 min during cycle 3 (n=15). Plasma levels were higher with lower tumor burden, due to less BL22 binding to tumor cells and soluble CD22. For 27 patients with spleens, AUC was inversely proportional to the log of the HCL count by flow cytometry before cycle 1 (r=0.67, p=0.0001) or before retreatment cycles (r=0.4, p=0.045) and to spleen height before cycle 1 (r=0.51, p = 0.007), or retreatment (r=0.6, p<0.0001). AUCs in 8 asplenic patients were also inversely proportional to log of HCL count before cycle 1 (r=0.4, p=0.045) or retreatment (r=0.66, p=0.015). Response was 95% in 22 with spleens < 200 mm vs 20% in 5 with spleens > 200 mm (p=0.001), vs 33% in 9 with prior splenectomy (p=0.0007). Conclusions: BL22 is highly active in HCL despite CdA resistance. Patients with limited tumor burden may have higher response rate because of better tumor penetration and less reduction in plasma levels due to CD22-binding sink. While plasma levels were higher in asplenic patients, response was lower probably due to more advanced disease and denser bone marrow infiltration. Patients should consider BL22 before splenectomy and before waiting for massive splenomegaly to develop. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Medimmune
Novel strategy to restore the activity of taxanes: A multicenter phase II study of combination therapy with taxanes and toremifene at 120 mg for advanced/recurrent breast cancer—Kinki Multidisciplinary Breast Oncology Group (KMBOG0612).
Authors: T. Nakayama, T. Arai, J. Yamamura, T. Morimoto, Y. Komoike, K. Yoshidome, S. Kamigaki, N. Matsunami, N. Masuda
Journal: Journal of Clinical Oncology (2011)

e13611 Background: A preclinical study reported that toremifene (TOR) increased the level of an anticancer agent such as doxorubicin and paclitaxel in the breast cancer cell which has acquired resistance to them by the expression of P-glycoprotein. Methods: The subjects were postmenopausal females with advanced/recurrent breast cancer who showed PD after PR or SD to mono therapy with taxanes (paclitaxel or docetaxel) was confirmed. In a phase II prospective study, 120 mg of TOR was administered orally every day after the treatment failure of taxane mono therapy, while continuing the respective taxane regimen. As a primary end point, we assessed the response rate (RR) including clinical benefits. Secondary end points were the time to progression (TTP) and adverse reactions. Results: Twenty-seven patients were registered between November 1, 2006 and October 31, 2010, and 25 patients were analyzed at this time. The median age was 57 years (range: 36-79) and the median ECOG PS was zero (range: 0-1). The RR, clinical benefit (CB) rate, and median TTP were 8.7%, 21.7%, and 12.1 weeks (range: 3.1-69.6), respectively. Moreover, with adding TOR to taxanes, treatment duration could be extended more than 100% in 5 patients (i.e., paclitaxel+TOR 323 days / paclitaxel 288 days = 112%). Adverse reactions to this combination regimen were observed in 8 patients. In 2 cases, grade 2 numbness was noted. However, the other patients showed grade 1 adverse reactions; this therapy was tolerable. Conclusions: Combination therapy with taxanes and TOR at 120 mg was tolerable and useful. The results suggest that TOR may restore the activity of taxanes in taxane refractory advanced/recurrent breast cancer patients.
<sup>18</sup>FDG PET/CT after intensified chemo-immunotherapy in diffuse large B-cell lymphoma (DLBCL), aged 18-65 with aaIPI 2-3 positive or indeterminate lesions are often false-positive: A Nordic phase II substudy.
Authors: H. Holte, T. Bogsrud, S. Leppa, M. Laukka, M. Bjorkholm, H. Jacobsson, S. Jyrkkio, M. Seppanen, M. Jerkeman, E. Brun, O. Fluge, L. M. Pedersen, M. Eriksson
Journal: Journal of Clinical Oncology (2011)

e18519 Background: In a phase II study for patients with DLBCL aged 18-65 and high-risk disease (aaIPI 2-3), we evaluated end-therapy FDG PET analysis performed at five of the centres and a score using internal standards Methods: Patients were given 6 courses of R-CHOEP14 with G-CSF-support, 1 high dose cytarabine and 1high dose methotrexate. 18FDG PET / CT were scored as negative, indeterminate or positive. Retrospectively, PET intensity was scored as follows (Barrington protocol): 1: no uptake, 2: uptake ≤ mediastinum, 3: uptake > mediastinum, but ≤ liver, 4: moderately- and 5: markedly increased uptake compared to liver. Results: PET scan was performed in 53 patients who all received the planned therapy out of a total of 156 eligible patients from all centres. Median observation time for live patients: 30 months. OS and FFS at 30 months: 91.3% (95% CI 82.7-99.9%) and 88.4% (95% CI 78.0-98.8%), respectively. Nine patients were given consolidating radiotherapy. 18FDG PET / CT were originally considered negative in 39 cases (1 relapse), indeterminate in 6 cases (1 relapse) and positive in 8 cases (2 relapses, 1 secondary cancer). Only 1 of 17 cases had a positive biopsy, 3 were undetermined with fully necrotic cells. Forty-eight of the cases were scored according to the Barrington protocol: 1: 14 cases, 2: 17 cases, 3: 8 cases, 4: 3 cases, 5: 6 cases. For 1-3 scored as negative and 4-5 as positive, there were 2 out of 39 and 2 out of 9 relapses, respectively. Four of the 17 cases with PET score 3 or higher were given radiotherapy, all these patients are in CR1. The original and the Barrington score dichotomising for neg. and pos. cases between 3 and 4 were equally effective in predicting FFS (p < 0.03). Conclusions: Patients with a negative FDG PET / CT have an excellent prognosis while PET positive ones have a low positive predictive value. For a few patients, a relapse may have been avoided by the use of radiotherapy. The Barrington score seems useful for multicenter analysis. Positive lesions should be documented with a biopsy or with a follow-up PET before further chemotherapy is initiated.
The synergistic clinical effect of autologous tumor-stimulated T lymphocyte and herceptin on the immunotherapy of breast cancer
Authors: K. Tayama, T. Fujii, U. Toh, G. Yokoyama, K. Miwa, S. Takamori, K. Shirouzu, E. Ogo, H. Yamana
Journal: Journal of Clinical Oncology (2005)

775 Background: To investigate a synergistic anti-cancer effect in the killing activity on human breast cancer cells and the clinical responses between the autologous tumor-stimulated T lymphocytes (AuTL) in combination with anti-HER2 Mab (Herceptin). Methods: AuTL were generated in vitro against primary-cultured autologous tumor cells incubated with peripheral blood lymphocytes (PBL). Six patients with recurrent breast cancer (3 HER2/neu +; 3 HER2/neu -)were enrolled in a pilot clinical trial and they all failed the conventional chemoradiotherapy. The cultured AuTLs and the cytokine productions were analyzed by Flow Cytometry and ELISA. The killing activity of the AuTLs was evaluated before each treatment. AuTLs were administrated into recurrent tumor directly by intra-peritumoral injection biweekly and Herceptin was infused systemically every week. The treatments were repeated for 6 to 11 injections in the patients. The mean total administered T cells were reached to 3.2 - 4.6 x 10 9, respectively. The dosage of Herceptin was 2mg/kg in each patient. Results: The cultured AuTLs containing a preponderance of CD3+ CD8+ T cells and CD56+ NK cells, expressed significant degrees of cytotoxicity in 4 of 6 cases. CD4+CD25+ T cells proliferated markedly after day 14. ADCC was enhanced in 4 of 6 cases. The cytokine production of TGF-b1 in the supernatant revealed a significant increase after day 14. The clinical response showed the carcinomatous pleural effusion was disappeared and well controlled in one pt and one pt with marked regression in injected field was observed. The tumor marker proteins (CEA, etc.) were also decreased significantly in 2 of 6 pts. The adverse effects of the immunotherapy were tolerable with grade 1∼2 infusion reaction in each patient and no cardiac dysfunction was observed. Conclusions: These results suggested the synergistic enhancement of antitumor effect could be induced between AuTLs and anti-HRE2 Mab (Herceptin). Clinical responses were observed in two pts with refractory recurrent breast cancer after receiving the intra-peritumoral AuTL injection plus Herceptin immunotherapy. Thus this immunotherapy will be applicable for the patients with breast cancer. No significant financial relationships to disclose.
Updated results of neoadjuvant chemotherapy with carboplatin AUC 6 and docetaxel 75 mg/m<sup>2</sup> in triple-negative breast cancer (TNBC).
Authors: Peter Kern, Hans C. Kolberg, Anne Kalisch, Rainer Kimmig, Dirk Pott, Friedrich Otterbach, Christian M. Kurbacher
Journal: Journal of Clinical Oncology (2013)

149 Background: Triple-negative breast cancer (TNBC) is associated with a poor prognosis unless a pathological complete response (pCR) is achieved or almost achieved (near-pCR). Treatment of TNBC remains a challenge as some patients fail to respond to the use of standard anthracyclin-based chemotherapy regimens. Phenotypic and molecular similarities between TNBC and BRCA1-associated breast cancer suggest that TNBC may share the same sensitivity to platinum analogues as tumors associated with BRCA1. Methods: 30 patients with primary, unilateral, non-metastasized TNBC (majority of them cT1 or cT2, two cT4) had to be unsuitable for standard anthracycline-based chemotherapy. They received 6 cycles, respectively in two case sonly 5 cycles, of carboplatin AUC 6 and docetaxel 75 mg/m² q3w. Adverse effects were recorded according to CTCAE V4.07. Primary endpoint was pathological complete response (pCR) and near-pCR, secondary endpoint toxicity. Results: 70% (21/30) of patients had either a pathological complete response (55%; 15/27) or a near-complete response (20%; 6/30) - defined as pT1mic and ypT1a - both being associated with a good prognosis. Eight remaining patients had still good partial response, leaving only low residual cancer burden, which was specified as ypT1, in contrast only one ypT4 tumor. Treatment was well tolerated - grade IV toxicities were predominantly hematological side effects (especially concerning neutropenia) and in 2 cases grade IV edema and joint pain. Carboplatin dose reduction (to an AUC of 5) was required in 5 cases (because of limited renal function, hematological side effects or patient’s age). Conclusions: Our results demonstrate a high-anti-tumour activity of docetaxel 75mg/m² in combination with carboplatin AUC 6, promising high rates of tumour regression and pathological complete remission. The omission of exposure to anthracyclines in patients with considerable heart disease risks seems to be feasible with a good pCR-rate, the latter being a surrogate-marker for long-term survival. Survival data of this trial are currently being updated and will be presented on the Breast Cancer Symposium.
CD44-overexpressed gastric cancer imaging by near IR using HA-based supramolecular hydrogels.
Authors: Jungmin Park
Journal: Journal of Clinical Oncology (2014)

34 Background: To establish NIR optical probe based on the HA-based supramolecular hydrogels (HASHs) conjugated with Cy5.5 for CD44-overexpressed gastric cancer imaging. Methods: To establish HASHs, Cy5.5 NHS ester was conjugated with polyethyleneimine (PEI, 25k Da) and mixed with hyaluronic acid (HA, 1M Da) by an electric interaction. The optimazed ideal molar ratio of PEI to HA was confirmed by DLS and gel electrophoresis. The CD44-expression level for various gastric cancer cell lInes (MKN1, MKN28, MKN45, MKN72, AGS, and N87 cells) was evaluated by FACS analysis. For establishment of the gastric cancer xenograft model, CD44-overexpressed gastric cancer cells were implanted into the BALB/c nude mouse's proximal thigh region. For in vitro targeting study, the cellular affinity of HASHs for CD44-low expressed gastric cancer cell line and CD44-overexpressed gastric cancer cell line was verified by confocal microscopy and IHC staing. For in vivo NIR imaging, HASHs were injected into established xenograft mouse via tail vein and NIR optical imaging was conducted time-dependently. Results: The colloidal size of HASHs was 1.4 micrometer and their morphology was confirmed by electron microscopy. CD44-expression level of MKN45 cells was 92.53% that was higher than MKN28 cells (2.66%). After the treatment of HASHs, the endocytosis into the cytosol was examined for MKN45 cells, but not observed in MKN28 cells due to the deficiency of CD44. 30 days after the transplantion of MKN45 cells, for in vivo imaging study, the prepared HASHs were intraveneously injected into tumor-bearing mouse model. By NIR optical imaging, the optical intensity at tumor site was enhanced upto 3 hours and the maximum intensity was 350 times larger than normal tissue. Conclusions: HASHs was established using supramolecular HA and Cy5.5-conjugated PEI for the targeted imaging of CD44-overexpressed gastric cancer cells. In vitro and in vivo studies demonstrated that SHAHs can visualize the individualized CD44-overexpressed gastric cancer cells by non-invasive optical imaging.
Pancreaticoduodenectomy versus radiosurgery for octogenarians with pancreatic head adenocarcinoma.
Authors: Melissa Ellen Hogg, Carolyn H Kim, Brian A. Boone, Kenneth K Lee, Arthur J. Moser, David L Bartlett, Dwight Earl Heron, Steven A. Burton, Herbert J. Zeh, Amer H. Zureikat
Journal: Journal of Clinical Oncology (2013)

220 Background: Recent reports have justified pancreaticoduodenectomy (PD) in octogenarians. Given the morbidity of PD and the increasing availability of stereotactic body radiosurgery (SBRT) we compared survival and morbidity of PD vs SBRT in octogenarians. Methods: A retrospective chart review was performed on all octogenarians with pancreatic head adenocarcinoma (PDA) who underwent open PD or SBRT from 2002-2011. Results: Twenty-six patients underwent PD, 17 (65%) resectable and 9 (35%) borderline, and 14 patients underwent SBRT, 10 (71%) resectable and 4 (29%) borderline (p=NS). All PD pts underwent R0/R1 resection. The groups differed in mean age (PD=83 vs SBRT=86 years, p=.01) and sex [males: PD=16 (62%) vs. SBRT=4 (29%)], but had the same BMI, Charlson Comorbidity Index, Karnofsky Performance Status, tumor size, and nodal status (p=NS). Of the SBRT group, 8 (57%) refused surgery; females were more likely to refuse surgery than males (8 (80%) vs 0, p=.0063). Compared to PD, SBRT patients took longer to intervention (26 vs 68 days, p=.0001). Twelve (46%) PD and 5 (36%) SBRT patients received chemotherapy (p=NS).Compared to the PD group, SBRT patients had no treatment related 90 day mortalities (0 vs 2 (8%), p=0.29), no complications (0 vs 14 (54%), p=.0007), and reduced length of hospital stay (0 vs 18.5 days, p=.0001). PD complications included pancreatic fistula and delayed gastric emptying in 3 (12%) and 4 (15%) patients respectively, and disposition was home=8 (31%), rehab=12 (46%), Skilled Nursing Facility =5 (19%), and Long Term Acute Care 1=(4%). Median time to metastasis was similar (PD=8.7 vs SBRT=7.3 months, p=NS). Median overall survival (PD=10.4 vs SBRT=10.2, p=NS) was the same in both groups. Four (15%) PD patients, stage II, are still alive (42-58 months); however, no SBRT patients are alive or have survived greater than 17 months. Conclusions: Octogenarians tolerated SBRT without morbidity, mortality, admission, or loss of independence compared to PD. Within this small series, disease specific survival and disease progression were not different between SBRT and PD raising a provocative question when counseling octogenarians about treatment strategy for head PDA.