tbuckley/cabot-search huggingface dataset:
Abstract 14138: Changes in Sympathetic Tone With Her2+ Antagonists: An Early Marker of Cardiotoxicity in a Breast Cancer Cohort?
Authors: Carrie G Lenneman, Wissam Abdallah, Sachin Y Paranjape, Vandana Abramson, Ingrid Mayer, Julie M Powell, Daniel Lenihan, Douglas B Sawyer, Satish R Raj
Journal: Circulation (2013)

Background:  HER2 antagonists (anti-HER2) are effective in treating an aggressive form of breast cancer (BC) but causes cardiotoxicity in select patients. Cardiotoxicity observed with anti-HER2 therapy is linked to the disruption in neuregulin (NRG) / HER2 receptor signaling. Recent data shows that NRG-HER2 receptors are also located in the medulla and are important regulators of vasomotor tone. Disrupting the NRG-HER2 signaling in the medulla resulted in increased hypertension and a shift toward increased sympathetic nerve output. Therefore we hypothesized that women treated with an anti-HER2 agent would exhibit increased sympathetic tone with changes in plasma catecholamines, heart rate (HR) variability (HRV), and circulating NRG, which may be an early sign of cardiotoxicity.   Methods:  In a pilot study, 17 newly diagnosed female HER2+ BC patients receiving an anti-HER2 agent were enrolled. Supine plasma epinephrine (EPI), norepinephrine (NE), NRG levels were drawn (n=17), and 10-minute continuous ECG recordings were obtained at baseline, and 3 months into anti-HER2 therapy (n=13). HRV was measured using a Fourier transform and low frequency (LF; 0.04-0.15Hz) and high frequency (HF; 0.15-0.4Hz) power were normalized to total power (no units). Parasympathetic cardiac modulation was estimated by HF, and LF/HF ratio was a marker of relative sympathoneural cardiac modulation. Paired analyses were performed with Wilcoxon-Rank Sum tests and P   Results:  Compared to baseline, 3-months of anti-HER2 treatment significantly increased plasma NE (382 ±210 pg/ml vs. 528±340 pg/ml; p=0.004), significantly decreased plasma NRG (12.7±15.7 ng/ml vs. 10.9±13.3 ng/ml; p=0.04), but did not change plasma EPI (31.5±27.0 pg/ml vs. 28.6±30.6 pg/ml; p=0.47). Anti-HER2 treatment resulted in a trend to lower LF/HF.   Conclusions:  Anti-HER2 treatment results in increased circulating NE levels and decreased circulating NRG, suggesting that inhibition of NRG-HER2+ signaling leads to increased sympathoneural tone. Larger studies are needed to determine if plasma NE and NRG are prognostic markers of early cardiotoxicity and if beta-blockers offer cardioprotection by suppressing the shift in sympathetic tone.
Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma
Authors: Robert J. Motzer, Bernard Escudier, David F. McDermott, Saby George, Hans J. Hammers, Sandhya Srinivas, Scott S. Tykodi, Jeffrey A. Sosman, Giuseppe Procopio, Elizabeth R. Plimack, Daniel Castellano, Toni K. Choueiri, Howard Gurney, Frede Donskov, Petri Bono, John Wagstaff, Thomas C. Gauler, Takeshi Ueda, Yoshihiko Tomita, Fabio A. Schutz, Christian Kollmannsberger, James Larkin, Alain Ravaud, Jason S. Simon, Li-An Xu, Ian M. Waxman, Padmanee Sharma
Journal: New England Journal of Medicine (2015)

Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.
Phase I study of gemcitabine and S-1 combination therapy in patients with advanced pancreatic cancer
Authors: H. Ueno, T. Okusaka, M. Ikeda, Y. Takezako, C. Morizane, J. Furuse, H. Ishii, M. Nagase
Journal: Journal of Clinical Oncology (2004)

4160 Background: Gemcitabine (GEM)-based chemotherapy has been actively investigated in the treatment of pancreatic cancer. S-1, an oral fluoropyrimidine derivative, demonstrated a response rate of 21% in 19 patients with advanced pancreatic cancer (Okada et al. ASCO 2002). The aim of this phase I study is to determine the maximum-tolerated doses (MTD), dose-limiting toxicities (DLT), and antitumor activity of GEM and S-1 combination therapy in patients with advanced pancreatic cancer. Methods: Histologically or cytologically proven chemotherapy-naïve patients with unresectable or metastatic pancreatic cancer were enrolled in this study. Patients received a combination of GEM intravenously over 30 minutes on day 1 and day 8, and S-1 orally twice daily from day 1 to day 14. Cycles were repeated every 21 days. Patients at 4 dose levels were scheduled to receive escalating doses of GEM and S-1: 800/60, 1,000/60, 1,000/70, 1,000/80 [GEM (mg/m2/week)/ S-1 (mg/m2/day)]. DLT was defined as grade 4 hematologic toxicity or grade 3 non-hematologic toxicity excluding nausea, vomiting and anorexia during the first 2 cycles. MTD was defined as one dose level below the dose at which 3/3 or at least 3/6 patients experienced DLT. Results: To date, 6 patients have been registered (3 patients in level 1 and 3 patients in level 2). All patients had metastatic disease and had a performance status of 0 to 1. No grade 3 or 4 toxicities were observed at dose level 1. At dose level 2, although 2 patients developed grade 3 neutropenia and 1 patient developed grade 3 nausea and anorexia, all toxicities were reversible and DLT has not been observed. Of 3 evaluable patients receiving more than 2 cycles (6 weeks) of treatment, 1 patient with liver metastasis achieved partial response (CA19–9 level was reduced from 120,000 to 21,660 U/ml), and in 1 patient, malignant pleural effusion vanished after 2 cycles of chemotherapy (CA19–9 level was reduced from 9,060 to 2,085 U/ml). Conclusions: This combination chemotherapy regimen was well tolerated and showed promising antitumor activity in the treatment of pancreatic cancer. Accrual is ongoing, and updated results will be presented at the meeting. No significant financial relationships to disclose.
Docetaxel (D) versus docetaxel/gemcitabine (D&amp;G) in the treatment of older patients with advanced non-small cell lung cancer (NSCLC): An Alpe Adria Thoracic Oncology Multidisciplinary Group randomized phase II trial (ATOM 017).
Authors: E. Rijavec, O. Belvedere, M. Aita, C. Rossetto, A. Follador, C. Sacco, T. Ceschia, P. Pronzato, G. Fasola, F. Grossi
Journal: Journal of Clinical Oncology (2010)

e18028 Background: Optimal chemotherapy for older patients with advanced NSCLC is still undetermined. Both single agent D and the combination of D&G are active and well-tolerated. The aim of this study was to compare the efficacy of single-agent weekly D with weekly D&G in elderly patients with advanced NSCLC. Methods: This multicenter, one-stage, randomized phase II trial aimed to identify the most promising of the two regimens; 49 patients per arm were planned, with ≥ 8 objective responses required for the “winner” to warrant further study. Chemotherapy-naive patients with stage wet-IIIB/IV NSCLC aged ≥ 70 years, with ECOG performance status ≤ 2 were randomized to receive D (35 mg/m2) on days 1, 8, and 15 (arm A) or D (35 mg/m2) plus G (800 mg/m2) on days 1, 8, and 15 (arm B). In both arms, treatment was repeated every 4 weeks for a maximum of 4 cycles. The primary end point was response rate (RECIST); secondary endpoints were: toxicity, time-to-progression (TTP), survival. Results: between July 2002 and November 2009, 75 patients were randomized; 69 were evaluable (intention to treat). Enrollment was closed early due to slow accrual. Median age was 75 years (range 70-82). There was 1 (3%) CR in arm B, with 5 (14%) and 10 (28%) PRs in arms A and B, respectively. Disease control (CR+PR+SD) was achieved in 56% and 73% of patients in arms A and B, respectively. Median survival was 7.2 months in arm A and 7.9 months in arm B (p = 0.58; HR = 1.15, 95% CI 0.69-1.9). Median TTP was longer in arm B (7.4 months and 3.9 months; p = 0.099, HR = 1.57, 95% CI 0.91-2.7). Grade 3-4 neutropenia was more common with D&G than D (3% and 25%, respectively; p = 0.013), as was anemia (3% and 9%, respectively). No case of neutropenic fever was observed. Nonhematological toxicity was mild with all grades fatigue occurring in 58% and 78% of patients receiving D and D&G, respectively. Conclusions: treatment with D&G resulted in higher response rate and modest improvement in TTP but not survival when compared with single-agent D. The combination of D&G has met the statistical endpoint of ≥ 8 responses and is worthy of further investigation. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly, sanofi-aventis Lilly
Association of <i>PIK3CA</i> mutation with response (ExRx) to cetuximab (C) in metastatic (met) triple-negative breast cancer (TNBC).
Authors: Joyce O'Shaughnessy, Corinne Ramos, Phil Stephens, Nicholas N Hoke, Norma Alonzo Palma, Maren K. Levin, Marina Horiates, Christine E. Horak, Kai Wang
Journal: Journal of Clinical Oncology (2015)

151 Background: 10 to 17% of TNBCs harbor PIK3CA mutations (TCGA Nature 490:61, 2012; Khambata-Ford S. ASCO 2010, abst 1056). Here we report clinical history and molecular findings for a TNBC patient with loss of mutant PIK3CA in a C-refractory metastasis that was present in her primary BC, who has had an ExRx to C. Methods: Following IRB-approved informed consent, targeted NGS was performed on the pt’s FFPE primary TNBC and on a C-refractory recurrent lung metastasis at a CLIA-certified laboratory (Foundation Medicine) to characterize all classes of genomic alterations across 287 cancer-related genes. RPPA was performed at a CLIA-certified laboratory (Theranostics Health) where immunostaining with 24 antibodies was directed against HER1/2/3 pathway proteins and AR. Results: 37 yo woman presented in 2006 with grade 3 primary TNBC, infraclavicular LNs and lung metastases at 33 weeks gestation. There was no response to preop doxorubicin/cyclophosphamide and following delivery of a healthy baby, she was treated with irinotecan, carboplatin, and C (#NCT00248287) and had near complete response (CR) in her lungs and pathologic CR in breast. In 2008, after 20 mos on C, chest CT showed a new lung met which was resected and she remains disease-free on C alone. NGS: Primary BC: PIK3CA C420R, TP53 mutations, MCL1 amplification (amp), and RAD51D germline mutation; C-refractory lung met: TP53, MLL2 mutations, MCL1, MYC, KDM5A, CCNE1 amp and RAD51D germline mutation (loss of PIK3CAmutation confirmed). RPPA: Primary BC: p-AR S650 (3+); p-ERK (2+), and HER1, p-HER1, p-HER3, p-AKT, p-S6, p-4EBP1 (1+); C-refractory lung met: loss of p-ERK; p-HER1, p-4EBP1 (2+), and p-AR, p-AKT, p-mTOR (1+). PTEN: Primary BC: 60% cells positive by IHC MAb 6H2.1 (Cascade Biosciences). Conclusions: The pt’s ExRx to C was dependent on presence of PIK3CA mutation which was lost in the C-refractory lung met. Loss of RAD51D function may also have contributed (Liping L. Ca Res 68:9141, 2008). High p-AR expression did not preclude response to C. Activating PIK3CA mutations induce an EGFR/ERK paracrine signaling axis in TNBCs (Young CD. Mol Cell Proteomics 2015). A prospective trial of EGFR inhibition in PIK3CA-mutant TNBC is warranted.
Clinical correlates of circulating immune complexes and antibody reactivity in squamous cell carcinoma of the head and neck. The Department of Veterans Affairs Laryngeal Cancer Study Group.
Authors: D R Vlock, S P Schantz, S G Fisher, H E Savage, T E Carey, G T Wolf
Journal: Journal of Clinical Oncology (1993)

PURPOSE To evaluate the correlation between the presence and titer of host-derived antibody reactivity, circulating immune complexes, and clinical course and prognosis in patients with squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS Serum samples, obtained from untreated patients with squamous cell carcinoma of the larynx entered onto a multiinstitutional trial, were evaluated for the presence of elevated circulating immune complexes (221 patients) and host-derived antibody directed against two SCCHN cell lines (107 patients). RESULTS Patients had significantly elevated levels of circulating immune complexes as measured by C1q binding compared with normal controls. Patients with higher levels of circulating immune complexes were less likely to respond to chemotherapy. No correlations were noted between immune complex levels and stage of disease, nodal status, site of disease, recurrence, or survival. Evaluation of native antibody titers for their relationship to clinical correlates showed no statistically significant associations. In sera subjected to immune complex dissociation, patients with moderately or poorly differentiated tumors had significantly higher antibody titers when compared with patients with well-differentiated tumors. Because marked variation in the increase of antibody titers following immune complex dissociation was noted, the ratio of immune complex-dissociated to native antibody titer was examined. Patients with a high ratio had a lower proportion of complete and partial responses to chemotherapy. CONCLUSION Our results support the conclusion that the formation of tumor-associated immune complexes in patients with SCCHN is associated with a decreased response to chemotherapy.
Quantification of HER2 from gastroesophageal cancer (GEC) FFPE tissue by mass spectrometry (MS).
Authors: Todd A. Hembrough, Les Henderson, Brittany Rambo, Wei-Li Liao, Sheeno Thyparambil, Kathleen Bangali, Jamar Uzzell, Marlene Darfler, David Krizman, Peng Xu, Shu-Yuan Xiao, Lei Zhao, Jon Burrows, Daniel Virgil Thomas Catenacci
Journal: Journal of Clinical Oncology (2014)

17 Background: Trastuzumab had a survival benefit in ‘HER2 positive’ GEC, determined by IHC/FISH. These companion diagnostics have limitations. IHC is semi-quantitative, subjective, and sensitive to antigen instability in FFPE; FISH is laborious, expensive, and subjective. Gene amplification may not correlate to protein expression. Moreover these are low throughput assays. There is increased recognition of profound interpatient molecular heterogeneity with several putative biomarkers, and only scarce tissue to assess for each one. We sought to evaluate our MS platform on GEC FFPE tissues for HER2 status compared to IHC/FISH. We also applied the “GEC-plex” of 11 other potentially predictive/prognostic markers for GEC. Methods: We utilized trypsin digestion mapping of rHER2 to identify unique peptides for SRM development. Stable isotope-labeled peptides were synthesized as internal standards, and standard curves were generated in a complex eukaryotic matrix (PC3 cells) to determine LOD, LLOQ, accuracy, precision and linearity of the assays. The assay was run on 17 GEC cell lines, in parallel with FISH/IHC, and expression thresholds were established for HER2+/HER2-; the sensitivity/specificity of the established cutoffs were then tested prospectively in FFPE GEC tissues on 10uM FFPE LCM slides (n=121). HER2 stability from FFPE sections was assessed by assaying 33 freshly cut FFPE samples; the adjacent sections were processed one year later. Results: The HER2 peptide chosen (ELVSEFSR) had a LOD of 100 amol and CV&lt;20%. HER2 MS on GEC cell lines revealed concordance with FISH (HER2:CEP17) ratio (R 2 =0.96). The analysis suggested HER2 expression &gt; 750 amol/ug was indicative of HER2 amplification. The assay was stable in archival FFPE sections (R 2 =0.76). For GEC FFPE cases, ‘any’ HER2 expression was seen in 69.4% of cases; 8.2% showed HER2 &gt; 750 amol (10/121) - all were HER2 amplified. No cases &lt;550 amol/ug were HER2 amplified. IHC/FISH results for cases with 550-750 amol/ug demonstrated a heterogeneous ‘equivocal’ zone, not unlike ‘IHC 2+’, which may require FISH confirmatory testing. Conclusions: ‘GEC-plex’ has a quantitative, sensitive, and specific HER2 assay that can be multiplexed along with other GEC biomarkers.
Targeted plasma cell FISH analysis detects residual disease in multiple myeloma missed by standard FISH
Authors: M. L. Slovak, V. Bedell, K. Pagel, K. L. Chang, G. Somlo
Journal: Journal of Clinical Oncology (2004)

6553 Background: Fluorescence in situ hybridization (FISH) enables the rapid detection of nonrandom karyotypic abnormalities in the low proliferating lymphoid disorders by evaluating the non-proliferating (interphase) neoplastic cells. In multiple myeloma (MM), untargeted FISH usually provides meaningful results at disease presentation. However, untargeted FISH for minimal residual disease (MRD) testing correlates poorly with pathology, underscoring the need for a more sensitive MRD FISH assay. Methods: Using FISH to detect IgH rearrangements and abnormalities of 13q or 17p, we investigated unselected white blood cell nuclei or targeted plasma cell nuclei from bone marrow aspirates or stem cell aliquots from 30 MM pts at various stages in their treatment. 200 nuclei were scored for each probe in the untargeted analysis; only plasma cells (1–167 cells) were scored in the targeted analysis using an image analyzer. Results were correlated with cytogenetics (CG) and pathology. Results: Untargeted and targeted FISH were concordant in 16 cases (53.3%) but discrepant in 14 cases (46.6%). The discrepant cases showed chromosome 14/IgH rearrangements (11 cases), del(13q)/-13 (7 cases), and 17p-/TP53/+17 (3 cases). Targeted FISH results were in agreement with residual disease observed by pathology. The clinical impact of these findings is underscored by: 1) A smoldering MM case with loss of the Y chromosome as the sole karyotypic aberration by CG showed both IgH rearrangement and –13 in 8 and 22 plasma cells, respectively, whereas the untargeted scan of 240 cells was within normal limits; 2) 7 of 10 plasma cells detected among 7295 white cells in a stem cell aliquot collected for possible autologous transplant showed an IgH rearrangement; 3) One del(13q) case was found to have normal pathology and disomy 13 in the plasma cells, with a del(13q) in myeloid precursor cells, indicating evolving myelodysplasia not residual MM. Conclusions: Targeted FISH adds valuable diagnostic, prognostic and MRD testing in MM. We suggest the use of targeted FISH analysis in clinical trials if risk stratifications and MRD testing take into consideration IgH, 13q and 17p status. No significant financial relationships to disclose.
Measurement of the width and the depth of internal mammary lymph nodes according to internal mammary artery and vein on CT simulition in breast cancer post-surgery
Authors: M. Xu, J. B. Li, J. M. Yu, J. Xing, Y. J. Zhang, S. Y. Tian, C. Q. Liang, Q. Shao, T. Y. Fan, L. Jie
Journal: Journal of Clinical Oncology (2008)

11586 Background: To measure the depth and width of the internal mammary lymph nodes according to internal mammary artery and vein on CT simulation in breast cancer after surgery. Methods: Between July 2001 and June 2007, 73 breast cancer patients who received IMRT after surgery in our hospital were randomly selected. The internal mammary lymph nodes were contoured according to the internal mammary artery and vein showing on CT graphs as the center in the ADAC Pinnacle3 TPS. The horizontal distance against the midsternal line and vertical distance against skin surface in 1∼5 intercostal spaces were measured and the difference between the injured side and the uninjured side were tested. Results: On the injured side of the first three intercostal spaces, the mean width of the internal mammary lymph nodes was 2.676±0.334 cm, with the maximum 3.880 cm and the minimum 1.970 cm, and the mean depth was 2.355±0.700 cm, with the maximum 4.584 cm and the minimum 0.705 cm. On the uninjured side of the first three intercostal spaces, the mean width of the internal mammary lymph nodes was 2.670±0.347 cm, with the maximum 3.780 cm and the minimum 1.925 cm, and the mean depth was 2.317±0.602 cm, with the maximum 4.198 cm and the minimum 0.906 cm. There is no significant difference between two sides on the width and the depth. Conclusions: Internal mammary artery and vein can clearly shown on CT images. The depth of most internal mammary lymph nodes contoured according to internal mammary artery and vein were less than 3 cm (83.6%).The position of the arm has no significant influence on the width and depth of the internal mammary lymph nodes. No significant financial relationships to disclose.
Identification of candidate genetic markers predicting sensitivity to sorafenib and sunitinib.
Authors: J. Li, J. Wu, G. Jiang, S. Yashinsky, L. Li
Journal: Journal of Clinical Oncology (2010)

e13610 Background: Sorafenib and sunitinib are multitargeted tyrosine kinase inhibitors with effects on tumor cell proliferation and angiogenesis. They are approved for the treatment of advanced renal cell carcinoma and other solid tumors. Identification of genetic markers predicting response could assist in selecting patients most likely derive clinical benefit. Given the polygenic determinants of drug disposition and action, a genome-wide search for molecular markers predicting response is needed. In this study, we employed a genome-wide approach to identify genetic markers that were associated with in vitro sensitivity to sorafenib and sunitinib in a panel of 60 cancer cell lines (the NCI-60). Methods: The antiproliferative activities of both drugs were assessed in the NCI 60 cell lines by using MTS proliferation assay. IC50 was determined for each cell lines by curve fitting of percent cell survival against drug concentrations. Using the publicly available Affymetrix 100K SNP array data and Affymetrix HG-U133A gene expression data generated on the untreated NCI-60 cell lines, we evaluated associations between genotype and IC50, gene expression and IC50, and genotype and gene expression. Pearson correlation analyses were performed and top candidate SNP and gene expression markers were selected based on both p-values and false discovery rates (FDR). Results: The expressions of 173 gene probe sets (p < 0.001, FDR = 0.15) were identified to be significantly associated with sorafenib IC50; while only 16 gene probe sets (p < 0.001, FDR = 1.00) were associated with sunitinib IC50; and only one overlap between two list. Similarly, 434 SNPs (p < 0.001, FDR = 0.25) and 187 (p < 0.001, FDR = 0.55) SNPs were associated with the IC50 of sorafenib and sunitinib, respectively; and only 5 overlaps. The significant genes associated with sorafenib sensitivity were enriched in cell cycle and immune cell trafficking. Conclusions: Sorafenib and sunitinib exhibited distinct genomic signatures that were associated with their in vitro sensitivity. The ability of these signatures predicting response to sorafenib and sunitinib are being further determined and validated in independent cell lines and patient tumor samples. No significant financial relationships to disclose.