tbuckley/cabot-search huggingface dataset:
Phenotypic and proteomic alterations of acquired trastuzumab resistance
Authors: D. Tripathy, S. Hassan, U. Verma, P. Gurnani, A. Nandi, K. Rosenblatt
Journal: Journal of Clinical Oncology (2005)

3121 Background: Trastuzumab, a monoclonal antibody to the HER2 receptor tyrosine kinase leads to clinical responses as a single agent and improves survival when added to chemotherapy for advanced HER2-positive breast cancer. However, some patients do not respond to trastuzumab, and most eventually develop clinical resistance. Mechanisms of intrinsic and acquired trastuzumab resistance are poorly understood, and we therefore undertook a cell line-based approach to delineate genetic and protein alterations associated with resistance. Methods: Two HER2-positive breast cancer cell lines (BT474 and SKBR3) were serially passaged in the presence of trastuzumab until in vitro resistance was documented. DNA histograms and western blotting for signal transduction and cell cycle proteins were performed. Gene expression profiles before and after trastuzumab exposure were assessed using Affymetrix HG-U133A/B human gene arrays. Cell lysate analysis using differential chromatographic fractionation followed by matrix-assisted laser desorption/ionization mass spectroscopy (MALDI-MS) was also done using prOTOF 2000 (Perkin Elmer, Boston, MA). Results: Resistant cell lines emerged after 12 months and exhibited a 3-fold more rapid growth rate in the absence of trastuzumab. Following trastuzumab exposure, G0/G1 arrest was observed in sensitive compared to resistant cells (84 vs. 68%), with fewer cells in S-phase (3 vs. 14%). Resistant cell lines exhibited fewer changes in gene expression with trastuzumab as well as upregulation of the chemokine receptor CXCR4 and mitotic checkpoint regulators, and downregulation of PTEN compared to sensitive cells. Preliminary MALDI-MS data analyzed by an iterative search algorithm identified proteomic patterns that revealed differences in cell lines at baseline and after trastuzumab treatment; these are being further characterized and updated data will be presented. Conclusions: Acquired resistance to trastuzumab develops in HER2-positive human breast cancer cell lines. Intrinsic growth rates in the absence of trastuzumab are higher in resistant cells, with multiple alterations in signal transduction and cell cycle control observed. Causative changes could be targeted to reverse resistance. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Genentech
BASE47 gene set predictor as an identifier of “basal-like” subtype of urothelial carcinoma of the bladder in African Americans.
Authors: David D. Chism, Jeffrey S. Damrauer, Andrew S. Miller, Matthew I. Milowsky, William Y. Kim
Journal: Journal of Clinical Oncology (2014)

300 Background: African-Americans [AAs] have a higher cancer-specific mortality when compared to whites with urothelial carcinoma (UC) of the bladder. Recent gene expression studies identified two intrinsic, molecular subsets of high-grade bladder cancer: “luminal” and “basal-like”, which can be accurately classified using the BASE47 gene set predictor. We applied the BASE47 gene set predictor to AA tumors and assessed enrichment for basal-like bladder tumors. Methods: Gene expression data from 179 high-grade, muscle invasive bladder tumors—9 AAs and 170 non-AAs (whites, Asians, and race not defined) from the TCGA was analyzed. Prediction analysis of microarrays (PAM) was used to derive the Bladder cancer Analysis of Subtypes by Expression (BASE47) gene set predictor and validated with 2 independent datasets. Comparisons of gene expressions patterns between bladder and breast intrinsic subtypes were peformed. Results: The BASE47 subtype classifier was highly concordant with Consensus Cluster subtype calls on 2 independent datasets. Based on the BASE47 gene classifier, a significant fraction of the tumors from AA (7/9) were classified as “basal-like” (P=0.07 Two tail). Basal-like bladder tumors trended strongly towards a worse prognosis (P=0.09 TCGA, 0.0194 MSKCC). Gene expressions patterns for“basal-like” and luminal bladder cancer correlated highly with basal-like breast and luminal A/B subtypes respectively. In addition, a subset of “basal-like” bladder cancer was found to be a claudin-low subtype. Conclusions: We have identified two molecular subtypes of high-grade bladder cancer that highly reflect the intrinsic subtypes of breast cancer. The BASE47 is a robust subtype classifier that can reliably distinguish basal and luminal bladder cancers. African-Americans have enrichment in the “basal-like” subtype of bladder cancer. These results will be validated in an independent set of samples as well as on FFPE tumors.
MD and RN ECOG-PS assessments prior to chemotherapy and concordance rates: A quality initiative at a comprehensive cancer center.
Authors: Arvind Manohar Shinde, Azadeh Dashti, Eve Makoff, Navasard Ovasapians, Andrew Eugene Hendifar, Richard Tuli, Robert A. Figlin
Journal: Journal of Clinical Oncology (2016)

228 Background: ECOG-PS is a widely implemented scale in oncology to assess performance status (PS). Higher scores are associated with poorer tolerance to higher-intensity chemotherapy (Ct). While professional societies recommend limiting Ct in patients with solid tumors and poor PS, the practice remains pervasive. To reduce this practice, in 2014 the Cedars-Sinai (CS) cancer quality committee developed a quality initiative (QI) requiring oncologists to indicate ECOG-PS on IV chemotherapy orders, with a structured hard-stop to evaluate patients with ECOG-PS≥3. Previously ECOG-PS was not required. Ct nurses also scored ECOG-PS, though their evaluation was not reported back to oncologists, and did not affect Ct decisions. Earlier studies have suggested a bias for oncologists to rate the ECOG-PS more positively than nurses when evaluating the same patient. Methods: 1084 of the total 12,259 Ct orders activated from 3/1/14-2/28/15 in a CS infusion center were randomly audited for ECOG-PS scoring by MD and RN for quality assurance. Completion and concordance rates for ECOG-PS were determined. Results: 93% and 83% of charts documented MD and RN ECOG-PS, respectively. 827 charts had both MD and RN ECOG-PS scores. Concordance rates, and discordance directionality are described in the Table. Conclusions: This QI achieved high rates of ECOG-PS documentation by oncologists, and low rates of Ct administration to patients with ECOG-PS≥3. MD/RN concordance rates were similar to those described in the literature. Interestingly, and in stark contrast to previous studies, MDs were more likely to score ECOG-PS as poorer compared to RNs in solid tumor discordant cases. [Table: see text]
Integration of bone scan (BS) and computerized tomography (CT) findings as an endpoint to assess bone metastasis in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Scott J. Parker, Gregory Russell Pond, Guru Sonpavde, Anitha Alex, Marta Elise Heilbrun, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2016)

191 Background: Progression of bone metastasis in mCRPC is assessed solely by BS findings and correlates modestly with overall survival (OS). Given the lack of reliability of BS findings and the ready availability of routinely performed CT scans, which commonly identify bone metastases, we aimed to better assess progression in bone by integrating BS and CT findings and to explore their association with OS. Methods: Data were obtained from patients treated at the University of Utah receiving docetaxel-based chemotherapy (D) or post-docetaxel therapy with orteronel (O). Patients with both baseline and on-therapy CT and BS within 90 days were eligible for analysis. CT and BS underwent central radiology review for bone lesions by a single radiologist. Progressive disease (PD) was defined as ≥ 1 new lesion. Survival was measured from start of therapy. Cox proportional hazards regression was used to explore potential prognosticators of overall survival (OS). Statistical significance was defined as 2-sided p &lt; 0.05. Therapy was a stratification factor. Results: Twenty-eight patients were evaluable including 18 patients receiving D, and 10 receiving O post-docetaxel. The mean age of these patients was 71.4 years and median (95% CI) overall survival was 18.4 (9.7-35.4) months. Four patients had PD on both BS and CT, while 2 (7%) had PD on CT but not BS and 3 had PD on BS but not CT. Patients with PD on BS or CT had worse OS (HR = 2.68, 95% CI = 1.04-6.90, p = 0.041) than those with no PD on either CT or BS. Looking at individual lesions, 4 (14%) patients had new lesions identified on CT which was not observed using BS, and they were associated with worse OS (HR = 3.72, 1.01-13.66, p = 0.048). Conversely, no significant difference in OS was observed for 4 patients with lesions identified on BS which were not observed using CT (HR = 2.67, 0.58-12.32, p = 0.21). Conclusions: This hypothesis-generating study suggests that CT can complement and enhance the ability of BS to capture PD and predict OS. Integration of BS findings using Prostate Cancer Working Group (PCWG)-3 guidelines to define PD and CT bone findings should be investigated in a larger study as an intermediate endpoint.
Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2
Authors: Lian Dee Ler, Sujoy Ghosh, Xiaoran Chai, Aye Aye Thike, Hong Lee Heng, Ee Yan Siew, Sucharita Dey, Liang Kai Koh, Jing Quan Lim, Weng Khong Lim, Swe Swe Myint, Jia Liang Loh, Pauline Ong, Xin Xiu Sam, Dachuan Huang, Tony Lim, Puay Hoon Tan, Sanjanaa Nagarajan, Christopher Wai Sam Cheng, Henry Ho, Lay Guat Ng, John Yuen, Po-Hung Lin, Cheng-Keng Chuang, Ying-Hsu Chang, Wen-Hui Weng, Steven G. Rozen, Patrick Tan, Caretha L. Creasy, See-Tong Pang, Michael T. McCabe, Song Ling Poon, Bin Tean Teh
Journal: Science Translational Medicine (2017)

Bladder cancer with loss of KDM6A expression is vulnerable to inhibition of EZH2.
Allograft versus non-allograft post-transplant lymphoproliferative disorder, characterization of two distinct subtypes as defined by presentation, histology, and outcome: A case series of 165 patients.
Authors: D. E. Tsai, I. S. Hagemann, J. J. Morrissette, R. Daber, D. Xu, S. J. Schuster, R. D. Bloom, V. N. Ahya, M. Jessup, G. A. Makar, S. Chen, R. Reshef
Journal: Journal of Clinical Oncology (2011)

8054
Blind prediction of response to erlotinib in early-stage non-small cell lung cancer (NSCLC) in a neoadjuvant setting based on kinase activity profiles.
Authors: R. Hilhorst, E. Schaake, R. van Pel, P. M. Nederlof, L. Houkes, M. Mommersteeg, R. de Wijn, M. van den Heuvel, P. Baas, R. Ruijtenbeek, H. M. Klomp
Journal: Journal of Clinical Oncology (2011)

10521 Background: Subcategories of NSCLC patients may benefit from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI's). Patients with cancers that harbor mutated EGFR have a higher chance of response. At present, there are no diagnostic tests to identify likely responders more reliably than by mutation testing. Previously, we have shown that a classifier based on kinase activity profiles in the presence and absence of a kinase inhibitor predicted erlotinib response of NSCLC patients in a neoadjuvant setting (Hilhorst et al. J Clin Oncol. 2010;28:7s [suppl; abstr 10566].) The aim of the current study was to evaluate this classifier using a blinded test set of patient tumor samples. Methods: Frozen tumor tissue was obtained from NSCLC patients (stage IA-IIIA) who had received 21 days of neo-adjuvant treatment with erlotinib prior to complete surgical resection. Tissue cryosections were lysed in M-PER buffer supplemented with phosphatase and protease inhibitors. Kinase activity profiles of the lysates were generated in the presence and absence of erlotinib on PamChip peptide microarrays .The classifier profile, as derived from the training set (n=14; Hilhorst et al. J Clin Oncol. 2010;28:7s [suppl; abstr 10566].), was applied to the blinded test set (n=13) of patients. Clinical response evaluation was based on histopathological examination of the tumor tissues. All specimens were analyzed for EGFR and KRAS mutation status. Results: Based on kinase activity profiles in the presence (on chip) and absence of erlotinib, a PLS-DA classifier was obtained that distinguished responders and non-responders in the training set (n=14, with two EGFR and 3 KRAS mutants). Leave-one-out cross validation resulted in misclassification for 3 samples, including both EGFR mutants. Application to the 13 blinded samples resulted in correct prediction of outcome for 11 samples. One of two EGFR mutants and one of three KRAS mutants were misclassified. Conclusions: This blinded study validates the use of a classifier based on kinase activity profiles of patients' own tumor tissue to predict the response to treatment. This test that measures drug effects at the molecular level, may be an important step towards personalized medicine.
Volumetric analysis of anal cancer relapses following radical chemoradiation.
Authors: Rebecca Muirhead, Lisa Durrant, Katherine Hyde, Maria Hawkins
Journal: Journal of Clinical Oncology (2014)

576 Background: Definitive chemoradiotherapy is standard of care in anal squamous cell carcinoma. The ACT II trial set the standard achieving three year overall survival rates of 73%. However patients with locally advanced disease have a ~50% local relapse rate. Studies have failed to demonstrate an improvement in local relapse rate by altering the systemic therapy. Although 2/3 of relapses are local as opposed to regional or distant, there is limited knowledge on the 3D position of these relapses. We aim to retrospectively review the patterns of local failure in three dimensions, relative to the radiotherapy plan. Methods: Between February 2007 and April 2012, 77 patients were treated for squamous cell carcinoma of the anus with radical chemoradiotherapy. Early stage (T0/2) and locally advanced (T3/4) tumours constituted 53% and 44% respectively. 37% of patients had nodal disease. As per ACT II protocol we used a gross tumour volume (GTV) to PTV margin of 3cm and prescribed to a dose of 50.4Gy. In patients with a local recurrence, imaging from the time of recurrence was imported into the radiotherapy planning system. The volume and site of gross recurrence was noted relative to the previous GTV and 95% isodose line. The mean dose delivered to the relapsed area was calculated. Results: Median follow-up was 42 months (range 14 to 78 months). Eight (10%) patients failed to respond. Six (8%) patients developed an isolated local relapse, 2 (3%) distant metastatic disease alone and 1 both local and distant relapse. Of those that relapsed locally, 5 patients were T2N0, one T3N0 and 1 node positive. There were no regional relapses. The entire macroscopic relapse lay within the 95% isodose line of the 50.4Gy in all patients. The median percentage of relapse that lay within GTV was 63% (range 29 to 100%). A GTV to PTV margin of 2cm would have encompassed all macroscopic relapses. The median doses to relapsed area was 52Gy (range 51Gy to 53Gy) with the minimum dose to any relapsed area being 49Gy. Conclusions: The majority of relapses centred on the GTV suggesting the gross tumour was uncontrolled with current doses in these patients. A reduction of GTV to PTV margin may be appropriate, facilitating trials of dose escalation with the aim of improving outcomes.
Oncogenic mutations in <i>MAPK</i> cascade as novel molecular biomarkers for treatment of gastric cancer patients with <i>EGFR</i> inhibitors.
Authors: G. Corso, D. Marrelli, V. Pascale, L. Garosi, S. Velho, R. Seruca, F. Roviello
Journal: Journal of Clinical Oncology (2011)

39 Background: Mitogen-activated protein kinase (MAPK) cascade and phosphatidylinositol 3-kinase (PI3K) survival pathways are frequently activated in the progression of gastrointestinal malignancies. In this study, we aimed to determine the frequency of gene mutations in members of these pathways-EGFR, KRAS, BRAF, PIK3CA and MLK3 in a series of 63 gastric carcinomas with high levels of microsatellite instability. Methods: Gene mutation analysis was performed by PCR amplification followed by direct sequencing. In selected tumor cases, EGFR expression was evaluated by immunohistochemistry. Association studies between molecular data and clinicopathologic characteristics were performed. Results: Mutations in EGFR (3'-UTR polyA repeat), KRAS, PIK3CA and MLK3 genes occurred in 30 (47.6%), 11 (17.5%), 9 (14.3%) and 2 (3.2%) of the MSI gastric cancer (GC) cases, respectively. No BRAF or EGFR hotspot mutations were identified. Overall, mutations in at least one of these genes were found in 55.6% (35/63) of gastric carcinomas. From those mutant cases 40.0% (14/35) of them had concomitant gene mutations, always involving EGFR polyA deletions. Interestingly, we observed significant associations between oncogenic mutations and female gender (p=0.046) old age of diagnosis (p=0.001) and intestinal subtype (p=0.043). Conclusions: Our results show that MSI gastric carcinoma frequently shows activation of EGFR-MAPK and PI3K pathways. Within all alterations found, deletions of the A13 repeats of EGFR were common, suggesting this molecular event as an important biomarker for stratification of GC patients for treatment with EGFR inhibitors. No significant financial relationships to disclose.
Significance of accurate HER2 testing as a new biomarker in advanced gastric cancer.
Authors: Tetsuya Kusumoto, Hajime Ohtsu, Hiroyuki Kawano, Koji Ando, Satoshi Ida, Yasue Kimura, Hiroshi Saeki, Eiji Oki, Masaru Morita, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2013)

106 Background: The Trastuzumab for Gastric Cancer (ToGA) study is the first international trial to include Japanese patients with human epidermal growth factor 2 (HER2)-positive advanced or recurrent gastric or gastroesophageal junction cancer, which demonstrated that trastuzumab plus chemotherapy improved overall survival in the overall population (hazard ratio 0.74). HER2 testing in gastric cancer differs from testing in breast cancer due to inherent differences in tumor biology; gastric cancer more frequently shows HER2 heterogeneity and incomplete membrane staining. The aim of the present study was to evaluate the frequency of HER2-positive cases by application of the standard criteria in Japanese patients with advanced gastric cancer (AGC) and to investigate the relationships between HER2 expression and therapeutic responses. Methods: A total of 199 tumor samples were assessed for HER2 expression both by immunohistochemistry (IHC) and HER2 amplification by fluorescence in situ hybridization (FISH). HER2-positive status was defined as IHC2+ and FISH-positive or IHC3+. Objective responses were evaluated in the patients with AGC who were treated with chemotherapy plus trastuzumab or chemotherapy alone based on the HER2 expression status. Results: HER2-positive tumors were identified in 12 patients (5.5%), less than 28.1% in the Japanese subgroup analyses of ToGA study. The positive rates varied with histological type; 14%, 5.3% and 0.95% in the well, moderately and poorly differentiated adenocarcinoma, respectively. Although high concordance between the results of IHC and FISH in all samples was found, IHC2+ samples retested here showed FISH-negative. Of all 10 patients with AGC, 3 patients with HER2-positive tumor were treated with capecitabine/cisplatin plus trastuzumab, and partial response was found in 2 cases; response rates were 67%. Conclusions: Specific consideration and scoring modification are required before embarking on HER2 testing in gastric cancer. Accurate and reliable HER2 testing and scoring will allow appropriate selection of patients eligible for treatment with trastuzumab.
Validation of 5- and 3-gene expression signatures for predicting outcome in non-small cell lung cancer (NSCLC) patients (p)
Authors: M. Skrzypski, E. Jassem, S. Benlloch, M. Pérez, W. Rzyman, G. Gulida, J. Sánchez, M. Tarón, J. Jassem, R. Rosell
Journal: Journal of Clinical Oncology (2008)

7532 Background: A number of prognostic gene expression signatures have been reported to predict survival in lung cancer, including a 5-gene signature (Chen et al, N Engl J Med 2007) and a 3-gene signature in squamous cell carcinoma (SCC) (Skrzypski et al. ASCO 2007). We have examined these two signatures in tumors from 142 NSCLC p. Methods: From 2000 to 2005, freshly frozen primary tumor specimens were obtained at the time of surgery from 142 NSCLC p (80% stage I and II; 66% SCC, 33% adenocarcinomas). Expression of genes included in the 5-gene signature (MMD, ERBB3, LCK, STAT1, DUSP6) and the 3-gene signature (CSF1, EGFR, CA IX) was assessed by quantitative RT-PCR in low density arrays, using TBP as endogenous control. Risk scores were used to classify p into high- or low-risk according to the expression of the genes in the two signatures. Results: All genes included in the 5-gene signature were more highly expressed in adenocarcinoma than in SCC, leading us to adjust the risk score for histology. According to the original risk score for the 5-gene signature, median survival (MS) for low-risk p was not reached while it was 29.7 months (m) for high-risk p (P=0.22). However, using the adjusted risk score for SCC, MS for low-risk p was 63 m vs 24 m for high-risk p (P=0.003). Using the adjusted risk score for adenocarcinoma, MS for low-risk p was not reached, while it was 46.2 m for high-risk p (P=0.006). According to the risk score for the 3-gene signature, MS for high-risk p was 41 m vs 62.4 m for low-risk p (P=0.009). For stage I-II SCC p, MS in low-risk p was not reached, while it was 34 m for high-risk p (P=0.05). For adenocarcinoma p, MS was not reached for low-risk p, while it was 61.2 m for high-risk p (P=0.04). Conclusions: The 5-gene signature is highly predictive of survival when adjusted for histology. The 3-gene signature is predictive of survival without adjustment for histology. These gene signatures can be useful for selecting high-risk p for adjuvant chemotherapy. No significant financial relationships to disclose.
Advanced Stage Hodgkin Lymphoma: The Predictive Value on Treatment Outcome of Early FDG-PET Scan Is Independent of and Superior to IPS Score.
Authors: A. Gallamini, M. Hutchings, L. Rigacci, L. Specht, F. Merli, F. D’Amore, L. Nassi, M. Hansen, U. Vitolo, P. Kamper, L. Trentin, C. Stelitano, F. Di Raimondo, R. Sancetta, S. Luminari, S. Viviani, E. Iannitto, A. Levis
Journal: Blood (2006)