tbuckley/cabot-search huggingface dataset:
Long term outcome of patients with mantle cell lymphoma following autologous stem cell transplantation
Authors: E. D. Jacobsen, D. Neuberg, D. C. Fisher, L. M. Nadler, R. J. Soiffer, A. S. Freedman
Journal: Journal of Clinical Oncology (2005)

6660 Background: Mantle cell lymphoma (MCL) is considered incurable with conventional chemotherapy. The role of autologous hematopoietic stem cell transplantation (ASCT) in treating patients with MCL remains controversial. Methods: We reviewed the outcome of patients undergoing ASCT as part of treatment protocols at Dana-Farber Cancer Institute and Brigham and Women’s Hospital from September 1984 through December 2002. For the purposes of this analysis, progression free survival (PFS) is defined as time from transplant (date of cell infusion) to progression or death in remission. Patients alive in remission were censored. Overall survival (OS) was defined as time from transplant to death. Patients last known to be alive were censored. Results: Thirty patients underwent ASCT after cyclophosphamide and total body irradiation (Cy/TBI) while 7 patients received BCNU, etoposide, cyclophosphamide (CBV) conditioning. One patient was in first complete remission (CR1), 3 were in CR2, 1 was in CR3 and 7 were in first partial remission (PR). The remaining 25 patients were in second or greater PR. No patient underwent ASCT with refractory disease. Thirty patients received stem cell grafts that were purged with anti-B cell antibodies in combination with rabbit complement (28) or immunomagnetic beads (2). Following ASCT, the median PFS and OS were 28 months and 46.3 months, respectively. The median PFS and OS following ASCT for patients with relapsed disease were 20.6 and 45.4 months respectively. Of the 8 patients transplanted in first remission (PR or CR), all have relapsed and 6 have died with a median PFS of 40.8 months and a median OS of 89.5 months. 4 patients developed therapy related myelodysplastic syndrome or acute myelogenous leukemia and all had received previous TBI. Conclusions: ASCT can achieve prolonged remissions in MCL but there is no evidence of a plateau in the PFS curve. The subset of patients transplanted in first remission appear to have superior PFS and OS as compared to conventional therapy, however all eventually relapsed. Newer approaches to ASCT and the use of allogeneic transplantation may improve the outcome for patients with MCL. No significant financial relationships to disclose.
Population pharmacokinetics of doxorubicin and doxorubicinol in Asian breast cancer patients
Authors: E. Sandanaraj, R. Savic, S. Lal, Z. W. Wong, C. S. Ang Peter, N. S. Wong, N. Holford, M. O. Karlsson, B. Chowbay
Journal: Journal of Clinical Oncology (2008)

13501 Background: Doxorubicin, a topoisomerase II inhibitor, is widely used in the management of breast cancer. The aim of the present study was to characterize the population pharmacokinetics of doxorubicin among Asian breast cancer patients and explore the influence of patient covariates on its disposition characteristics. Methods: Asian patients(N=51) receiving adjuvant chemotherapy with Adriamycin(A) and Cyclophosphamide(C) were recruited for the study. Patients received doxorubicin (range:56–61 mg/m2) as a 20 minutes intravenous infusion and blood samples were collected at 0, 0.5, 1, 4, 8 and 24hrs. Plasma concentrations were measured by HPLC. Non-linear mixed effect modeling was applied for the analysis of concentration-time profile of doxorubicin and doxorubicinol using NONMEM(6). Patient covariates such as age, weight, height, ethnicity, ER status, PR status and HER-2/neu status were included in the analysis to explain the pharmacokinetic variability of doxorubicin. Model robustness was assessed by nonparametric bootstrapping and predictive check procedures (N=1000). Results: A 5-compartment model including 3 compartments for doxorubicin and 2 compartments for doxorubicinol was found to adequately explain their pharmacokinetics. Model estimates for doxorubicin clearance(CL) was 34.7L/h. The intercompartmental clearance(Q2) between the central compartment (V1:8.24L) and peripheral compartment I (V2:444L) was 25.5L/h, and the intercompartmental clearance(Q3) between the central compartment and peripheral compartment II (V3:11.1L) was 7.26L/h. The apparent clearance of doxorubicinol(CLm) was 68.1L/h and the intercompartmental clearance(Q4) of metabolite central compartment(Vcm:483L) and its peripheral compartment(Vpm:984L) was 1970L/h. The patient covariates had no significant impact on the doxorubicin pharmacokinetic variability. Conclusions: The final allometrically scaled model showed 22.2% variability of doxorubicin clearance and 32.4% variability in the volume of distribution between the subjects. Further studies are ongoing to investigate the influence of polymorphisms in genes encoding various proteins across the doxorubicin biochemical pathway and their impact on the pharmacokinetic variability of doxorubicin. No significant financial relationships to disclose.
Improvement in multidisciplinary cancer care: The National Cancer Institute Community Cancer Centers Program (NCCCP) Multidisciplinary Lung Cancer Conference and Clinics.
Authors: M. Krasna, R. K. Freeman, N. J. Petrelli, A. L. Salner, J. A. Young, H. A. Zaren, J. Bearden, J. K. Harness, T. Purcell, T. Asfeldt
Journal: Journal of Clinical Oncology (2010)

e16539 Background: One of the goals of the NCCCP pilot is to disseminate the use of multidisciplinary case conferences/clinics (MDC) across community cancer centers. There are studies to show that MDC's translate into better patient care. We describe the use of MDC clinics and prospective tumor conferences since the inception of the NCCCP. Methods: Each NCCCP site recorded the level of lung cancer MDC integration in their program at baseline, 2007, and in December 2009. A multidisciplinary matrix tool (MDX) developed by the NCCCP site investigators was utilized (http://ncccp.cancer.gov/about/progress.htm). The tool has 7 variables including case planning, coordination of care, physician engagement, infrastructure support, financial integration, accrual to clinical trials, and medical record integration with a score of 1-5 on each variable (maximum score -35). Results: From 2007-2009, ten of 16 NCCCP sites had initiated disease specific MDC clinics and/or conferences for lung cancer. Seven have utilized MDC clinics as well as prospective tumor conferences. Three sites instituted MDC prospective tumor conferences alone. The ten sites with existing lung cancer MDC's prior to initiation of the NCCCP saw their mean score increase from 16 at baseline to 24.7. Conclusions: The NCCCP has utilized an MDX tool to describe the level of MDC care with improvement since the inception of the program. Further prospective data collection is ongoing to determine the impact on patient outcomes including time to treatment, patient satisfaction and survival. No significant financial relationships to disclose.
Constitutional WT1 mutations in Wilms' tumor patients.
Authors: L Diller, M Ghahremani, J Morgan, P Grundy, C Reeves, N Breslow, D Green, D Neuberg, J Pelletier, F P Li
Journal: Journal of Clinical Oncology (1998)

PURPOSE Patients with Wilms' tumors (WT) who carry constitutional mutations in the WT1 gene have been described in case reports and small case series. We sought to determine the frequency of constitutional WT1 mutations in a larger cohort, and to identify clinical manifestations associated with the risk for carrying a WT1 mutation. METHODS We collected clinical data and blood samples from 201 patients with a history of WT. Southern blot analysis, single-strand conformation polymorphism (SSCP) analysis, and direct DNA sequencing were performed on DNA isolated from peripheral-blood lymphocytes from each patient. Odds ratios (ORs) for the carriage of a germline mutation of the WT1 gene were calculated for patients who had specific clinical risk factors compared with those who did not. RESULTS Of 201 patients with WT in the cohort, eight patients were carriers of mutations in the WT1 gene. Six of the eight mutations were protein-truncating nonsense mutations. None of 56 patients with isolated unilateral WT was a carrier. The OR of carrying a WT1 mutation was elevated for patients with genitourinary anomalies (OR19.3; P &lt; .002). Seven of 28 boys with WT with cryptorchidism carried WT1 mutations. No increased risk was observed for patients with nephrogenic rests, bilateral tumors, history of secondary cancers, or family history of WT. CONCLUSION Germline WT1 mutations in patients with WT are associated with genitourinary anomalies, especially cryptorchidism and/or hypospadias. Patients with WT and no genitourinary anomalies are at low risk for carrying a WT1 mutation. Constitutional WT1 mutations that encode truncated WT1 proteins may predispose to the development of cryptorchidism, hypospadias, and WTs.
Gene expression signatures in pre- and post-therapy (Rx) specimens from CALGB 40601 (Alliance), a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer (BrCa).
Authors: Lisa A. Carey, William Thomas Barry, Brandy Pitcher, Katherine A. Hoadley, Maggie Chon U. Cheang, Carey K. Anders, N. Lynn Henry, Sara M. Tolaney, Chau T. Dang, Ian E. Krop, Lyndsay Harris, Donald A. Berry, Charles M. Perou, Eric P. Winer, Clifford A. Hudis
Journal: Journal of Clinical Oncology (2014)

506 Background: Response to chemotherapy and HER2-targeting varies by molecular subtype. In C40601, 305 patients (pts) with stage II-III HER2+ BrCa were randomized to receive 16 weeks of preoperative paclitaxel and trastuzumab (TH), T and lapatinib (TL), or THL, and were followed for pCR. Primary data were reported previously. Methods: Gene expression by mRNA sequencing (RNAseq) was performed on 271 pre-Rx and 136 matched post-Rx samples. RNAseq was normalized to HER2+ tumors in The Cancer Genome Atlas Project, and genomic signatures applied including intrinsic subtype and immune cell features. Results: 60% of pre-Rx specimens were hormone receptor+. Overall, 30% were Luminal A, 31% Luminal B, 31% HER2-Enriched, 5% Basal-like, 2% Normal-like, and 1% Claudin-Low. In-breast pCR was 46%, which varied significantly by subtype: Luminal A 35%, Luminal B 36%, Basal-Like 36%, HER2-Enriched 69% (p<0.0001). Within HER2-Enriched, pCR rates by arm were: 50% TL, 71% TH, 80% THL. pCR also varied by risk of relapse score including proliferation genes (ROR-P): high 56%, medium 44%, low 33% (p=0.01). RNAseq on pre/post-Rx pairs revealed a change in subtype prevalence to: 43% Luminal A, 3% Luminal B, 2% Basal-like, 9% Claudin-Low, 5% HER2-Enriched, and 38% Normal-like. Excluding 49 normal-like tumors, which likely represent little tumor remaining after Rx, the most frequent subtype change among 84 paired non normal-like samples was to the Luminal A subtype, which occurred in 70% of baseline Luminal B, 20% of Basal-like, and 67% of HER2-Enriched tumors. Most (87%) had decreased ROR-P scores (p<0.0001). High expression of immune signatures, especially B-cell related, were significantly associated with pCR (IgG signature high 59%, low 32%, p=0.0002). Conclusions: HER2-Enriched had substantially higher pCR rates to chemotherapy + HER2-targeting than other subtypes. Residual disease was enriched for Luminal A and Normal Breast-like profiles. Among HER2-Enriched, taxane plus trastuzumab alone produced pCR rates in excess of 70%, which suggests that dual HER2-targeting or more aggressive chemotherapy may not be needed in this biologic subtype. Clinical trial information: NCT00770809.
Randomized phase II neoadjuvant study of temozolomide (TMZ) alone or with pegylated interferon-alfa 2b (PGI) in patients with resectable AJCC stage IIIC or stage IV (M1a) metastatic melanoma
Authors: W. Hwu, D. Ivan, V. G. Prieto, J. Simon, D. Jones, S. Ekmekcioglu, M. Davies, A. E. Ayala, M. Garcia, M. I. Ross
Journal: Journal of Clinical Oncology (2008)

20024 Background: With current therapies, the estimated 10-year survival rate for stage IIIC melanoma is < 30%. Our previous neoadjuvant studies of combination chemotherapy either alone or in combination with IFN-α or IL-2 demonstrated improved 10-year survival in responders, but approximately one third of these pts developed recurrence in the brain as the initial site of relapse. Therefore, chemotherapy with activity in the brain may improve clinical outcomes. Methods: This ongoing randomized phase II study is being conducted to evaluate the safety and efficacy of TMZ with or without PGI as neoadjuvant therapy in 124 pts with resectable stage IIIC or stage IV (M1a) melanoma. The primary endpoints are pathologic response and tolerability. Secondary endpoints are disease-free and overall survival, the effect of response to chemotherapy on clinical outcome, and cellular/molecular studies of pre- and post-treatment tumors and PBMCs. Patients are randomized to TMZ 150 mg/m2/day x 7 days, alternating weekly (Arm A) or TMZ plus PGI 0.5 μg/kg/week (Arm B) for 8 weeks (1 cycle) before definitive surgery. Patients with a pathologic complete or partial response (pCR or pPR) or stable disease (pSD) can receive up to 3 additional cycles of the assigned regimen as adjuvant therapy after surgery. Results: Since November 2006, 16 pts (50% male, median age 60 years, range 33–72 years) with stage IIIC melanoma have completed neoadjuvant therapy (9 in Arm A and 7 in Arm B). Treatment-related toxicity included 1 G3 fatigue in arm B and 1 G4 thrombocytopenia and neutropenia in each arm. Among evaluable patients, 4 (25%) had a near pCR, 3 (19%) had a pPR, 2 had pSD, and 7 had progressive disease. Post-treatment surgery showed extensive tumor necrosis and fibrosis. Tumor and PBMC samples are being analyzed to differentiate in vivo treatment effects of TMZ alone versus TMZ + PGI and to correlate response to treatment with clinical outcome, molecular markers, and genomic expression profiles. Conclusions: Neoadjuvant therapy with TMZ alone or in combination with PGI is well tolerated. Clinical activity was observed in both arms. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Schering-Plough Schering-Plough Schering-Plough Schering-Plough Schering-Plough
Genetic evolution of EGFR and the clonal origin of adenocarcinomas exhibiting various degrees of bronchioloalveolar carcinoma
Authors: W. Zhong, X. Yang, A. Guo, J. Su, X. Zhang, H. Chen, G. Qiao, R. Liao, J. Yang, Y. Wu
Journal: Journal of Clinical Oncology (2009)

e22050 Background: EGFR mutations may accumulate during multistage progression of bronchioloalveolar carcinoma (BAC), leading to heterogeneity within the tumor. Moreover, intrapulmonary emersions are the predominant sites of BAC progression in the absence of other distant metastases. In cases of emerging bilateral lung lesions during the follow-up to complete resection, the issue of how to differentiate between lesions originating from multifocal BACs or distant metastases/local recurrence is an important and unresolved issue. This study was performed to determine whether sequential adenocarcinoma with BAC features emerges in the lung field arises from a single clone or multiple clones in the same individual. Methods: Samples of adenocarcinomas exhibiting various degrees of BAC were obtained by thoracotomy. Sequential specimens were obtained on detection of novel lesions in the lung field. Genomic DNA was extracted from the specimens, and the presence of activating mutations in EGFR was analyzed by direct sequencing. Our pathological findings, sequential imaging, and EGFR sequence data were compared to monitor evidence of cancer evolution. Results: Based on an analysis of EGFR in tumor specimens from 428 lung cancer patients, fifteen cases of sequential BAC-related adenocarcinoma obtained by thoracotomy were identified. Together with alterations in BAC/adenocarcinoma components, the EGFR-TKI untreated series with at least one episode of EGFR-activating mutations represented three typical models: no significant EGFR evolution for a single clone, genetic alterations from mutant to wild-type EGFR for multifocal lesions, and a switch from wild-type to mutant EGFR, which might exhibit uncertain circumstances of cancer progression. Conclusions: Genetic analysis in conjunction with pathological and radiological diagnoses can be used to explore the origin of multifocal BAC. The single clone model indicates subsequent disease progression, whereas genetic alterations from mutations to wild-type EGFR are suggestive of secondary primary carcinoma. When additional lesions emerge after radical resection of BAC-related lung cancer, sequential tumor samples should be obtained for further evaluation. No significant financial relationships to disclose.
Phase II trial of lapatinib in patients in stage D0 prostate cancer (E5803): Effect of Kras and EGFR status on clinical outcome.
Authors: Y. Chen, J. Kolesar, W. Huang, R. S. DiPaola, M. Pins, M. A. Carducci, M. N. Stein, G. Bubley, G. Wilding, G. Liu
Journal: Journal of Clinical Oncology (2010)

4668 Background: Activation of epidermal growth factor is important in prostate cancer (PC) development and the transcription of androgen receptor regulated genes. Lapatinib is a selective dual tyrosine kinase inhibitor of EGFR and ErbB2. Here we report the effects of Kras 38 mutation, EGFR expression/mutation, and drug metabolizing enzyme polymorphisms on clinical outcome. Methods: Patients (pts) with rising PSA after primary therapy for PC were enrolled. A PSA doubling time (PSADT) of ≤ 12 months was required (calculated from a minimum of 3 PSA obtained at least 6 weeks apart, within 6 months of enrollment). No radiographic evidence of metastasis was allowed. Lapatinib was administered orally at 1,500 mg once daily. Primary tumor blocks were obtained and assessed for EGFR expression, EGFR Q787Q polymorphism, and Kras 38 mutational status. Drug metabolizing enzyme single-nucleotide polymorphism was assessed in PBMCs. Results: 49 pts were enrolled (14 ineligible), resulting in 35 pts for analysis. Of these, 14 tumor blocks and 29 whole blood samples were available. High EGFR expression (using AQUA) was seen in 4 pts (low EGFR expression in 10) and Kras 38 mutation present in 3 of 13 evaluable samples. No PSA response was observed; however, 28 (80.0%) maintained stable disease. Pre-treatment average slope was 0.19 log PSA/month (PSADT=3.70 months), in contrast to on-treatment average slope of 0.13 log PSA/month (PSADT=5.44 months) using linear mixed effects models (p = 0.006). Median progression-free survival was 17.4 months for the high EGFR group and 6.0 months for the low EGFR group (p = 0.50). Pts with Kras 38 mutation had shorter PFS than those without Kras 38 mutation, but the difference was not statistically significant (p = 0.09). No association between SNPs and drug toxicity was found. Conclusions: Although no PSA responses were observed, lapatinib may have biologic activity in men with androgen-dependent PC as evidenced by a decrease in PSA slope in this nonrandomized study. Trends towards improved PFS in pts with EGFR overexpression and Kras wild type status support that a biologic effect is present in this patient population and that further trials using lapatinib in pre-castrate PC warranted. No significant financial relationships to disclose.
Effect of tibolone on tumor angiogenesis parameters in short-term treated women
Authors: F. E. Frankenne, C. Munaut, F. Wijzen, J. Planellas Gomez, L. Kloosterboer, J. Foidart
Journal: Journal of Clinical Oncology (2006)

10519 Background: Large recent studies have shown increased mammographic density, breast pain and a marginally increased risk of breast cancer in women treated with continuous combined estrogen/progestogen (ccEPT), while tibolone has a minimal effect. A placebo-controled clinical trial (STEM), approved by several ethical comities, has been initiated to assess effect and potential mechanism of action of tibolone on breast tumor. We present the results on 12 angiogenesis-related parameters. Methods: 102 women with breast cancer who had to undergo a mastectomy were treated for 2 weeks with tibolone 2.5 mg/day or placebo. RNA was extracted from tumor snap-frozen biopsies (paired before and after treatments) and reverse-transcripted into 2 cDNA batches on which 6 distinct PCRs were performed in duplicate per parameter/sample. A vascular density (VD) index was determined on CD31 specifically stained tumor sections by counting 10 fields per section on 5 distinct sections per biopsy. Results: The validity of the VD evaluation is highlighted by the high correlation coefficient (r = 0.81) between the data within the placebo group at a 2 week interval. In the tumor samples, no change of the VD index was seen. Since it could be argued that VD index could not correctly reflect a modulation of angiogenesis after only 14 days of treatment, we looked at a potential change of the expression of a large array of angiogenesis-related factors (VEGFs, VEGFRs, PAI-1). No modification of the expression in any of these factors was observed. Conclusions: Our data lead to conclude that, in this study, tibolone displays a neutral effect on angiogenesis in breast tumor. [Table: see text]
A phase II study of pegfilgrastim to support ACE 14 chemotherapy for the treatment of subjects with small cell lung cancer (SCLC; extensive disease)
Authors: R. Pirker, E. Ulsperger, K. Aigner, J. Messner
Journal: Journal of Clinical Oncology (2004)

7216 Background: Thatcher (JCO 2000; 18:395–404) showed that dose dense ACE with GCSF allows delivery of “chemotherapy planned dose on time” (CPDOT) leading to improved survival in subjects with extensive SCLC. The aim of this study was to show that pegfilgrastim can also support ACE 14 CPDOT in this setting. Methods: All 30 subjects received ACE (doxorubicin 40 mg/m2 and cyclophosphamide 1000 mg/m2 iv d1, etoposide 120 mg/m2 iv d1 and 240 mg/m2PO d2–3) every 14 days for up to 6 cycles, with a single dose per cycle of pegfilgrastim 6 mg SC on d4. A cycle was considered “on time” if it started no more than 17 days after the start of the previous cycle, and “at planned dose” if ≥75% of drug was administered for each agent. For any given cycle, subjects were defined as having CPDOT if both criteria were satisfied. Results: 27 subjects received pegfilgrastim and at least 1 cycle of ACE and 17 received all 6 cycles of ACE. Twenty subjects (74%) had no bone marrow involvement at baseline. The mean baseline ANC was 7.4x109/L (range 3.0–23.3); over the study, mean ANC levels at the start of each cycle were ≥1.5x109/L and were comparable to baseline levels. All 22 subjects who started cycle 2 received full CPDOT. Of the 121 cycles delivered over the study, 107 (88%) were full CPDOT. In addition, 18 subjects (67%) received all their cycles according to full CPDOT. Of the 22 subjects who were assessed for disease response, 2 (9%) had CR, 15 (68%) PR (with ORR 77%) and 2 (9%) SD. Safety data were consistent with the underlying patient group. Nine (33%) and 6 (22%) subjects experienced hematological and non-hematological events of toxicity grade 3–4: anemia 15%, leukopenia 7%, thrombocytopenia 11%, and febrile neutropenia 15%. All other adverse events were single episodes. Conclusions: These results indicate that pegfilgrastim enables delivery of dose intensified ACE chemotherapy every 14 days in SCLC patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Ltd. Amgen Amgen Ltd. Amgen Ltd.