bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pilot study on the clinical value of 18F-sodium fluoride PET/CT in advanced prostate cancer.
Authors: Kim Joseph W. , Lindenberg Maria Liza , Dahut William L. , Gulley James L. , Madan Ravi A. , Wood Lauren V. , McKinney Yolanda , Choyke Peter L. , Kurdziel Karen A , Apolo Andrea Borghese 
Published: March 2020

10589 Background: We evaluated the clinical utility of 18F-sodium fluoride PET/CT bone scan (18F-NaF) in the detection of bone metastases in patients (pts) with prostate cancer in comparison with Technetium-99m MDP bone scan (TcBS). Methods: In a prospective study, from October 2010-December 2011, 30 prostate cancer pts (ages 51-79), 21 with known bone metastases and 9 without known bone metastases, had18F-NaF and a TcBS performed. Abnormal foci of uptake on both TcBS and 18F-NaFwere classified as benign, malignant or indeterminate. Benign lesions included uptake in the joints and linear uptake at the endplates of the vertebral bodies consistent with degenerative changes. Malignant uptake on 18F-NaF scans was confirmed by characteristic osteoblastic features on CT. All TcBS and 18F-NaF were reviewed by an experienced nuclear medicine physician. For the patient-based analysis, scan results were categorized as positive (POS) = any malignant lesion; indeterminate (IND) = not distinctly malignant or benign; negative (NEG) = benign lesions only. Results: In the lesion-based analysis, 21 of 30 (70%) pts had more malignant lesions identified on 18F-NaF than on TcBS. The mean number of additional malignant lesions per patient on 18F-NaF vs TcBS was 4. Eight of the 30 pts had same number of malignant lesions identified in both studies. One of 30 pts had one less malignant lesion identified on 18F-NaF than on TcBS. CT correlation by 18F-NaF PET/CT of this particular lesion did not confirm osteoblastic feature. Malignant lesion distribution on 18F-NaF included: spine (28%), thorax (26%), pelvis (24%), long bones (13%) and skull (10%). In the patient-based analysis, 24 pts (80%) were POS by 18F-NaF, of whom 14 pts were POS, 8 were IND, and 2 were NEG by corresponding TcBS; in the 4 pts with NEG 18F-NaF, zero were POS, 2 were IND and 2 were NEG by corresponding TcBS. Conclusions: 18F-NaF identified more malignant lesions than TcBS. 18F-NaF may also add useful information in the management of advanced prostate cancer pts with and without known bone metastases.
Next-generation sequencing (NGS) to identify actionable genomic changes in common and rare solid tumors: The FMI experience with the initial 50 consecutive patients.
Authors: Palmer Gary A. , Miller Vincent A. , Curran John , Ross Jeffrey S. , Lipson Doron , Yelensky Roman , Stephens Philip , Lancelotta Mary Pat , Cronin Maureen T. 
Published: March 2020

10590 Background: Solid tumor (ST) oncology has been transformed by the linkage of genomic changes with targeted therapeutics. Unfortunately, most STs still have no alteration detected with currently available assays. Thus, more informative testing platforms are needed to analyze genomic changes in FFPE biopsy samples often limited by tumor size, heterogeneity and ploidy. Methods: We reviewed the genomic profiles of the first 50 clinical specimens received by our CLIA lab (Foundation Medicine) and analyzed by our NGS assay (Ross J. ASCO 2011). 182 genes known altered in STs and 14 genes known rearranged in STs were included. Genomic alterations were categorized as “actionable” if linked to an approved therapy in the ST under study or another ST (e.g. ALK rearrangement in lung or breast cancer, respectively), a known or suspected contraindication to a given therapy (e.g. KRAS G12D in colorectal cancer) or a clinical trial linked to the alteration (e.g. mTOR inhibition in a tumor with STK11 loss). Results: Fifty tumor specimens were received from 50 patients (median age 54, F/M=30/20) representing 35 sites. Two samples failed analysis and 6 had no detectable genomic alteration. Among 16 primary tumor types, lung (n=15), colorectal (n=7), sarcoma (n=5), breast and esophageal/gastric (n=4 each) were most common. We reported 135 genomic alterations (mean 2.8, range 0-6) unequivocally involved in oncogenesis and 69 actionable alterations. At most, 29 of these (42%) would have been detected by current assays (138% increase with NGS). Thirty seven patients had one or more actionable alterations (range 1-4) detected by NGS (74%, 95% CI 60-85%) versus only 21 (42%, 95% CI 28-57%) in whom changes would have been detected by current assays. Conclusions: Use of a broad, comprehensive NGS assay identifies an unprecedented number of actionable genomic alterations across a variety of STs from routine FFPE samples. This assay can serve as a paradigm for improving access to approved therapies in STs, minimizing use of ineffective therapies and enhancing enrollment in rationally chosen trials. Ongoing and planned trials will study the impact on several efficacy endpoints.
Role of proliferation in response to neoadjuvant chemotherapy in GEICAM/2006-03 and GEICAM/2006-14 breast cancer patients.
Authors: Alba E. , Albanell Joan , Chacon Lopez-Muniz Jose Ignacio , Calvo Lourdes , De la Haba- Rodriguez Juan , Sanchez Rovira Pedro , Plazaola Arrate , Barnadas Agust , Seguí-Palmer Miguel Angel , Arcusa Lanza Angels , Ramos Vazquez Manuel , Rojo Federico , Burgues Octavio , Pajares Bella , Bermejo Begoña , Sanchez-Muñoz Alfonso , Casas Maria Isabel , Caballero Rosalia , Carrasco Eva Maria , Lluch Ana ,   Spanish Breast Cancer Research Group GEICAM
Published: March 2020

10616 Background: Ki67 proliferation biomarker determined by immunohistochemistry (IHC) has been studied as a prognostic and predictive factor in Operable Breast Cancer (OBC). Ki67 modifications after neoadjuvant endocrine therapy have been correlated with long term outcome. However, there is no robust data about its predictive role in Neoadjuvant Chemotherapy (NC). In this study, we investigated Ki67 value as predictor of NC efficacy. Methods: 193 patients (pts) from 2 GEICAM phase II randomized trials (2006-03 and 2006-14) were included: 78 (40%) received epirubicine plus cyclophosphamide followed by docetaxel (EC-D), 41 (21%) EC-D plus carboplatin, and out of the 74 HER2+ pts, 37 (19%) received EC-D plus tratuzumab and 37 (19%) EC-D plus lapatinib. Median age was 49 years. From series, 87% were invasive ductal carcinoma, 58% premenopausal, 50% grade III, 23% luminal , 39% basal and 38% HER2+. Ki67 was centrally assessed by IHC (MIB1 clone) and median score was 40% (range 1-100%). Pathological Complete Response (pCR), defined as absence of invasive cells in breast and lymph nodes, was achieved in 56 pts (29%). Univariate and multivariate logistic regression models were used to study the association of each clinical-pathological variable with pCR. ROC curves were used to determine the most accurate ki67 cut-off for predicting NC response. Results: Ki67≥50% was defined as the most accurate threshold to select patients obtaining benefit from NC. In the univariate analysis, histological grade (p=0.01), treatment (P=0.006), ER (p<0.0001), PR (p<0.0001), HER2 (p=0.01), and Ki67≥50% (p=0.0003) were statistically associated with pCR. A multivariate logistic regression showed that only Ki67≥ 50% (p=0.0003; OR=5.4 CI95% 2.1-13.4), ER (p=0.0001; OR=0.2 CI95% 0.1-0.4), and HER2 status (p<0.0001; OR=8.8 CI95% 3.3-23.6) were predictive for pCR (AUC=0.7812). Conclusions: These results suggest that a high proliferation in breast cancer measured by Ki67 marker is an independent predictive factor for pCR in an unclassified HER2 population of OBC patients treated with NC.
Biomarkers that predict sensitivity to heat shock protein 90 inhibitors (HSP90i).
Authors: Jhaveri Komal L. , Iyengar Neil M. , Corben Adriana , Patil Sujata , Akram Muzaffar , Towers Russell , Sakr Rita , Hudis Clifford , King Tari A. , Rosen Neal , Chandarlapaty Sarat , Modi Shanu 
Published: March 2020

10618 Background: HSP90 is an attractive target in tumors as it mediates the maturation and stabilization of client oncoproteins. HSP90i are potentially active in a variety of tumors, but therapeutic benefit is confirmed in only a small subset to date. Predictive biomarkers could identify patients (pts) and/or tumors with sensitivity to HSP90i improving the therapeutic index. We explored potential biomarkers across multiple studies of HSP90i. Methods: Archived pre-treatment tumor specimens from pts treated with any of several HSP90i (17-AAG, 17-DMAG, CNF2024, retaspimycin & ganetespib) on 8 phase I/II trials at MSKCC from 1999 to 2011 were identified. The following antibodies were validated at MSKCC and tumor tissue was tested by immunohistochemistry (IHC) with results defined for each as: ER, PR & AR: >1% pos & <1% neg; HSP90 & HSP70: 0, 1+ neg & 2+, 3+ pos; PTEN: 0, 1+ neg & 2+ pos; HER2: 0, 1+ neg, 2+ equivocal, 3+ pos; EGFR: 0 neg & 1+, 2+, 3+ pos. Clinical response was correlated with IHC using Fisher’s exact test. Results: Of the 164 pts identified, adequate tissue was available for 51, including 11 different solid tumors & 1 CML. Breast (N=31), melanoma & prostate (N=4 each) were most frequent. The mean age at primary diagnosis was 50 yrs (24-81). The median no. of lines of prior chemotherapy for metastatic disease was 2 (0-8). The mean duration of HSP90i therapy was 79 days (0-411). There were 19 responses (5 PR; 14 SD); 14/19 responses strongly correlated with HER2+ status (p = 0.001); 1 pt with ER+/HER2-/EGFR- & 4 with EGFR +/HER2-/ER- disease also responded. A correlation for ER & EGFR with response was not excluded (p=0.07 & p=0.086 respectively). Conclusions: Our findings confirm HER2 as a sensitive client and an effective biomarker for sensitivity to HSP90 inhibitors. ER & EGFR did not meet statistical significance but may warrant further exploration in prospective settings.
Current patterns of chemotherapy and supportive care for early-stage breast cancer (ESBC).
Authors: Lyman Gary H. , Dale David C. , Tomita Dianne , Whittaker Sadie , Crawford Jeffrey 
Published: March 2020

1062 Background: ESBC is commonly treated with myelosuppressive chemotherapy, and high relative dose intensity (RDI) correlates with improved overall survival. A retrospective analysis of patients with ESBC treated from 1997–2000 showed that 56% received an RDI < 85% (Lyman et al. JCO. 2003;21:4524-4531). To determine current practice, we evaluated ESBC treatment patterns at 24 US community- and hospital-based oncology practices. Methods: Data were abstracted from medical records of 532 patients with ESBC treated from January 2007–December 2009. Inclusion criteria included surgically resected ESBC (stage I-IIIA); ≥ 18 years old; and completion of at least 1 standard chemotherapy cycle on an every 2 or 3 week schedule. The primary endpoint was RDI over planned cycles. Other endpoints were incidence of dose delays ≥ 7 days, dose reductions ≥ 15% from standard, grade 3/4 neutropenia (SN), febrile neutropenia (FN), FN-related hospitalization, granulocyte-colony stimulating factor (G-CSF) use, and antimicrobial therapy. Descriptive statistics were generated for all endpoints. Results: In this study, mean (range) age was 55 (29–85) years. Relative to previously published results, chemotherapy regimens have shifted from mainly doxorubicin + cyclophosphamide (AC) (previously 35%) to docetaxel + cyclophosphamide (TC; n = 221; 42%) and AC followed by paclitaxel (AC-T; n = 163; 31%). Mean RDI is now higher (93% for both TC and the most common AC-T schedule [dose dense AC-T; n = 84] vs 79% previously); the incidence of dose delays (16% vs 25% previously) and dose reductions (21% vs 37% previously) have decreased; and primary prophylactic use of G-CSF has increased (76% vs 3% previously). In this study, 40% of patients had SN, 3% had FN, 2% had an FN-related hospitalization, and 30% received antimicrobial therapy. These measures were not available in the previously published results. Conclusions: The observed changes between the two studies are noteworthy though inferential comparisons are limited by changes in treatments and other factors. RDI has improved over time, but 16% of patients in this study received an RDI < 85%. Further evaluation is needed to identify factors associated with lower RDI and determine outcomes for these patients.
Using CHFR expression to predict response and survival after first line treatment with carboplatin-paclitaxel in NSCLC.
Authors: Pillai Rathi Narayana , Brodie Seth Aaron , Li Ge , Herman James Gordon , Brock Malcolm , Owonikoko Taofeek Kunle , Ramalingam Suresh S. , Khuri Fadlo Raja , Brandes Johann Christoph 
Published: March 2020

10625 Background: The identification of resistance mechanisms for conventional chemotherapy in lung cancer is of fundamental importance not only for personalization of chemotherapy but also for the subsequent development of novel targeted approaches to overcome this resistance. Currently, there is no clinically validated test for the prediction of response to tubulin-targeted agents in NSCLC. Our previous preclinical work identified Checkpoint with Forkhead and Ringfinger domain” (CHFR) as a predictor of taxane cytotoxicity in in vitro models. The current work assessed the translational significance of this finding in a cohort of US veterans treated at a single-institution. Methods: We studied a cohort of patients with advanced NSCLC treated with taxane-containing frontline regimens at the Atlanta VA Medical Center between 2000 and 2009. Archived paraffin-embedded tissue was retrieved and stained for CHFR expression using standard immunohistochemical techniques. Level of protein expression was assessed by light microscopy and scored for intensity of CHFR staining. Intensity of staining was correlated with clinical outcome including objective response and median overall survival using Chi-Square test and Cox proportional models. Results: We analyzed tumor samples from 45 eligible patients with median age 62.6 years, M/F (44/1). In this cohort, high expression of CHFR is strongly associated with adverse outcomes: the risk for progressive disease (PD) after first-line chemotherapy with carboplatin-paclitaxel was 54% in patients with CHFR-high vs. only 18% in those with CHFR-low tumors (HR 3.1; 95% CI 1.09-9.04; p=0.02). Median overall survival was strongly correlated with response to first-line therapy (clinical benefit: 9.24 months; PD: 4.7 months; p<0.001) and with CHFR expression status (CHFR low: 10 months; CHFR high: 5.6 months; p =0.01). Conclusions: CHFR expression is a novel predictive marker of response and overall survival in NSCLC patients treated with taxane-containing chemotherapy.
DNA damage responses in relation to late effects following radiotherapy for early breast cancer.
Authors: Chua Melvin 
Published: March 2020

10626 Background: In this study, we assessed if induction of apoptosis in G0 blood lymphocytes following ex vivo irradiation correlated with clinical radiosensitivity and DNA double-strand (DSB) repair in breast radiotherapy (RT) patients. Using small molecule inhibitors, we examined the relationship between DSB repair and radiation-induced apoptosis. Methods: Breast cancer patients with minimal (controls) or marked late RT changes (cases) were selected. DSB were quantified by γH2AX/53BP1 immunostaining 0.5 and 24 h after exposure of lymphocytes to 0.5 and 4 Gy, respectively. Induction of apoptosis was assessed 48 h after 8 Gy using a fluorochrome inhibitor of caspases (FLICA) assay. Apoptotic cells were defined by small cell size and positive FLICA signal, measured using flow cytometry. Small molecule DNA-PK (Nu7441) and ATM (Ku55933) inhibitors were used at concentrations of 1 µM and 10 µM, respectively. Results: Despite similar foci induction at 0.5 h, residual foci levels 24 h after 4 Gy differed significantly between cases and controls (Foci per cell = 12.7 in cases, n = 8 vs 10.3 in controls, n = 8, p = 0.002). In contrast to residual foci levels, comparable levels of apoptosis were observed between cases and controls 48 h after 8 Gy. Mean proportion of apoptotic cells was 37.2% in cases and 34.7% in controls (p = 0.413). Residual foci levels were not correlated with levels of apoptosis in lymphocytes of the same patients (R = -0.059, p = 0.785). To determine if apoptosis is modulated by DSB repair, apoptosis measurements were repeated in lymphocytes treated with Nu7441 to inhibit non-homologous end-joining. We observed that Nu7441-treated cells had higher levels of residual foci and apoptosis compared to mock-treated cells, 48 h after 1 Gy. This effect was wholly dependent on an active ATM function as cells treated simultaneously with Nu7441 and Ku55933 had extremely low levels of apoptosis, comparable to levels observed in cells treated with Ku55933 alone. Conclusions: Higher levels of residual DSB observed among radiosensitive patients suggest a role for DSB repair in the pathogenesis of late radiation-induced effects. Induction of apoptosis appears to be dependent on DSB end-joining following exposure to ionising radiation.
In silico identification of an epithelial core signature in human tumors.
Authors: Goswami Chirayu Pankaj , Cano Oscar D. , Gokmen-Polar Yesim , Badve Sunil S. 
Published: March 2020

10628 Background: Gene expression analysis is performed on grossly selected specimens often without any microscopic analysis of tumor content. In studies where histological analyses have been performed, cases having 80% or more tumor content are used for microarray analysis. The variability in amount of epithelial and stromal cells may generate to misleading differential expression analysis and selection for wrong targets for therapeutics. It is also often unclear, whether the genes identified are stromal or epithelial in origin. The goal of this study was to identify genes that define core epithelial phenotype; these genes could provide means of normalization of expression data. Methods: The CABIG GSK microarray (HG-U133_plus_2) data consisting of 950 cell lines from carcinoma (n=562), non-carcinoma (n=385) and normal tissue (n=3) was analyzed to identify epithelial specific genes. 10 carcinomas each from 11 sites (n=110) and an equal number of non-carcinomas were randomly selected. In silico analyses were performed by 1) identifying genes differentially expressed between carcinoma and non-carcinoma samples using a one way ANOVA; 2) identifying gene signature associated with carcinoma using Predictive Analysis of Microarrays (PAM) and 3) a weighted gene coexpression network analysis (WGCNA) was performed to identify co-expression modules. A similar analysis was also performed on tissue samples (E-GEOD-12360) from carcinomas and non-carcinomas. Venn-diagram was generated to identify intersecting set. Results: Comparison of the carcinoma and non-carcinoma samples using ANOVA identified 1455 differential expressed gene probes in cell lines and 540 gene probes in tissues (FDR=1E-10). The cell lines analysis identified 5 modules and a 65-gene signature (43 core and 22 accessory set) that was specific for epithelial cells. In the tissue analysis a 188-gene signature was similarly identified. Cross-comparison identified a smaller 31 gene intersecting set; this was not associated with loss of discriminatory power. Conclusions: A 31 geneset which can be used to determine the epithelial content of heterogeneous tumors, was identified. This study has the potential to significantly impact the use of microarray based gene expression data.
Patient-reported pain and other symptoms as prognostic factors for overall survival (OS) in a phase III clinical trial of patients with advanced breast cancer.
Authors: Shen Wei , Wang Ping , Smyth Emily Nash , Bowman Lee , Peterson Patrick , John William J. , Melemed Allen S. 
Published: March 2020

1068 Background: The safety and efficacy of gemcitabine plus paclitaxel versus paclitaxel in advanced breast cancer after anthracycline-based adjuvant therapy has been reported previously (Albain et al. 2008). This post-hoc analysis evaluates the prognostic effect of baseline scores of the Brief Pain Inventory short form (BPI-SF) and the Rotterdam Symptom Checklist (RSCL) on OS. Methods: Patients completed theBPI-SF and the RSCL. BPI “worst pain” item and BPI interference subscale scores range from 0 (no pain or interference with daily living) to 10. Four RSCL subscales were transformed to 0-100, with 100 as best score. Univariate Cox models were used to determine the prognostic effect of each measure on OS. Multivariate Cox models were used to determine the prognostic effect of each measure in the presence of 11 demographic/clinical variables, including Karnofsky performance status, age, and estrogen and progesterone receptor status. Kaplan-Meier curves and log-rank tests were used to compare OS among patient groups categorized using clinically meaningful thresholds and the sample median of the BPI and RSCL scores. Results: Randomized patients were evaluable for this analysis (n=529). In the univariate analysis, significant prognostic effects on OS were observed for baseline scores of both BPI measures (worst pain and interference) (HRs, 1.07 for 1-point increase; all p≤0.0042) and three out of four RSCL subscales (activity level, physical distress, quality of life) (HRs, 0.86-0.91 for 10-point increase; all p≤0.0120). In the multivariate Cox models, BPI worst pain remained as a significant prognostic factor (p=0.0245), as did RSCL activity level (p=0.0004). The median OS for patients with BPI worst pain score 0 (no pain) was 23.8 months (mos) versus 17.9 mos and 14.8 mos for scores 1-4 (mild) and 5-10 (moderate/severe) (log-rank p=0.0066). The median OS was 23.8 mos for patients with RSCL activity scores greater than or equal to the sample median (≥95.2) versus 14.6 mos for patients with scores <95.2 (log-rank p<0.0001). Conclusions: This retrospective analysis resulted in strong evidence that BPI-SF and RSCL provide distinct prognostic information for OS.