bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCI 8609: Interim fluoro-3’-deoxythymidine (FLT) PET imaging findings from the phase I trial of PARP inhibitor veliparib (V) and carboplatin (C) in advanced breast cancer.
Authors: Ramaswamy Bhuvaneswari , Zhang Jun , Hall Nathan , Schregel Katharina , Lustberg Maryam B. , Wesolowski Robert , Mrozek Ewa , Layman Rachel M. , Olson Erin Macrae , Ottman Susan , Camp Andrea , Chalmers Jeffrey J. , Geyer Susan Michelle , Villalona-Calero Miguel Angel , Shapiro Charles L. , Grever Michael R. , Knopp Michael V. 
Published: March 2020

1023 Background: We are currently conducting a phase I trial of PARP inhibitor, V on an intermittent (7 or 14 day) or continuous (21 day) schedule in combination with C in patients (pts) with advanced breast cancer. We are using FLT PET/CT sequentially to assess DNA damage induced by varying dose schedules of PARP inhibitor, where uptake of FLT depends on the proliferation rate of the tumor. Methods: Eligible pts received C-AUC 5 Q 3weeks (except dose level 1-AUC 6) plus escalating doses of V, BID on 7, 14, or 21-day schedules based on a standard 3+3 dose escalation design. We performed FLT PET/CT at baseline, cycle 1 day 7 and 14 and after cycle 3. Lesions were track-matched with the FDG PET/CT and semi-quantitatively assessed using 2D ROI placement in a matched, blinded fashion. Results: 38 pts have been accrued to 7 dose levels and FLT-PET imaging was successfully obtained in all pts with the proliferative whole body mapping revealing expected bone-marrow, liver and RESuptake. FLT-PET uptake showed a significant (p < 0.001) decrease between baseline and day 7 (N = 25) with an overall trend to rebound nearly to baseline at day 14 for pts that did not show a significant decrease in FLT uptake reduction after cycle 3. The 14-day (n = 15) dosing schedule resulted in more pronounced day 14 reduction in FLT uptake when compared to those on the 7-day (n = 7) schedule. A FLT rebound to baseline level appeared to be associated with limited therapy response. There were no reported toxicities from FLT imaging. Conclusions: FLT-PET was consistently obtained with excellent whole body quality. All lesions revealed a FLT (proliferation) uptake that was different from the FDG (metabolism) uptake. FLT uptake indicated an initial reduction of proliferation at day 7, followed by a rebound at day 21 in all patients on the 7 or 14 day schema. The trial protocol was therefore amended to include a 21 day schema which is currently still ongoing. FLT appears to be a promising in-vivo imaging marker that may serve as a guiding tool to optimize dosing schema in addition to assessing/ predicting overall response. Study support- U01 CA076576 /Wright Center of Innovation ODSA TECH09-028. Clinical trial information: NCT01251874.
Effect of metformin versus placebo on weight and metabolic factors in initial patients enrolled onto NCIC CTG MA.32, a multicenter adjuvant randomized controlled trial in early-stage breast cancer (BC).
Authors: Goodwin Pamela Jean , Parulekar Wendy , Gelmon Karen A. , Shepherd Lois E. , Ligibel Jennifer A. , Hershman Dawn L. , Rastogi Priya , Mayer Ingrid A. , Hobday Timothy J. , Lemieux Julie , Thompson Alastair Mark , Pritchard Kathleen I. , Whelan Timothy Joseph , Mukherjee Som Dave , Chalchal Haji I. , Oja Conrad D. , Tonkin Katia Sonia , Bernstein Vanessa , Chen Bingshu E , Stambolic Vuk 
Published: March 2020

1033 Background: MA.32 investigates effects of Metformin vs. Placebo, in addition to standard care, on invasive disease free survival and other outcomes. Metformin may improve obesity and metabolic factors [insulin, glucose, leptin, C-reactive protein (CRP)] that have been associated with poor BC outcomes. Maintaining blinding of investigators to outcomes, we conducted a planned, DSMB approved, analysis of the effect of Metformin vs. Placebo on weight and metabolic factors at 6 months, including examination of interactions with baseline body mass index (BMI), in the first 498 subjects with paired fasting plasma samples. Methods: 498 non-diabetic subjects with T1-3, N0-3, M0 BC meeting defined entry criteria who had completed surgery and adjuvant chemo (if given) provided fasting blood samples at randomization and 6 months (while on study drug). Glucose was measured locally; blood was aliquoted, frozen and stored at -80°C then shipped to NCIC CTG (Kingston, Canada). Paired plasma aliquots were shipped to Mount Sinai Hospital (Toronto, Canada) for analysis of Insulin (Dako), hsCRP (Roche Elecsys) and leptin (Luminex). Statistical analysis used the Wilcoxon signed rank test. Results: Mean age was 52.4 ±9.2 years. Arms were balanced for ER/PgR (63% pos), BMI, prior adjuvant chemo (89%), T and N status, grade, mastectomy/lumpectomy and radiation. Conclusions: Metformin significantly improved weight, insulin, glucose, leptin and CRP at 6 months. Effects did not vary by baseline BMI. Funded by: NIH, CCSRI, CBCF, BCRF, Apotex Canada (drug & placebo - in kind). Clinical trial information: NCT01101438. [Table: see text]
Discordant ER, PR, and HER2 status between primary and metastatic breast cancer as prognostic factor.
Authors: Shin Hee-Chul , Han Wonshik , Moon Hyeong-Gon , Im Seock-Ah , Moon Woo Kyung , Park In-Ae , Park Sung Jun , Noh Dong Young 
Published: March 2020

1039 Background: The receptor status including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) of metastases may be different from that of the primary breast cancer. This discordance of receptor status may influence patient prognosis. We investigated discordance of receptor status between primary breast cancer and distant metastases in the same patients and its effect on prognosis. Methods: ER, PR, and HER2 status in metastases were available in 173 patients. The receptor status was compared between primary tumors and metastases. Tumors were classified as triple-negative breast cancer (TNBC) or non-triple-negative breast cancer (non-TNBC) according to receptor status and as concordant and discordant depending on the difference of receptor status between primary and metastatic breast cancer. Survival analysis was performed depending on concordant or discordant receptor status. Results: Discordance for ER, PR, and HER2 was 18.5%, 23.7%, and 10.4%, respectively. Concordant non-TNBC and TNBC between primary tumors and metastases was 69.9% and 17.9%, respectively. Discordant TNBC was 12.1%. On multivariate analysis, patients with discordant TNBC had unfavorable survival compared with patients with concordant non-TNBC (relative risk 2.544, 95% confidence interval, 1.220-5.303, p = 0.013). The median survival after recurrence was 41.8 months for patients with concordant non-TNBC, 20.7 months for patients with concordant TNBC, and 19.9 months for patients with discordant TNBC (p < 0.0001). Conclusions: The change of ER, PR, and HER2 status between primary and metastatic tumors occur and discordant TNBC is associated with poor survival.
Molecular biomarkers as predictive factors of pCR for early triple-negative breast cancer.
Authors: Ghanem Ismael , Castañeda Carlos , Perez-Campos Ana , Toldos Oscar , Sancho Perez Blanca , Manso Luis , Rodriguez-Peralto Jose Luis , Calderón Mónica , Cortes-Funes Hernan , Lora David , Garcia-Martin Rosa , Ciruelos Eva 
Published: March 2020

1041 Background: Early triple-negative breast cancer (TNBC) patients (p) without pathologic complete response (pCR) after neoadjuvant chemotherapy (NCT) have unsuccessful prognosis. Predictive factors for pCR are necessary in order to improve the treatment choice. The aims of the study are to determine the expression of different biomarkers (BM) in the initial biopsy (IB) of TNBC, to analyze the relationship between the BM expression and pCR, and to determine the expression changes of BM after NCT. Methods: We reviewed retrospectively the medical records of 49 TNBC p treated with NCT between 2001 and 2011 at two institutions. Expression of 14 BM in the IB and after NCT was independently analyzed by inmunohistochemistry by two pathology specialists. Staining intensity 0-1 + was considered as negative expression, and 2-3-4 + as positive. Ki 67>13% was interpreted as positive. Results: Forty-nine p with a median age of 47 years (27-79) were evaluated. Twenty-seven p (55%) had grade 3. Tumor stages were T1(2%), T2(26%), T3(39%), and T4(33%). 38p (77%) were node positive. Five p (10%) received anthracyclines and 42p (86%) anthracyclines plus taxanes. Fourteen p (29%) presented pCR, 27p (55%) partial response, 4p (8%) stable disease, 2p (4%) progressive disease, and 2p (4%) were not evaluable. The BM expression in the IB was: CD44 (88%), CK 5/6 (27%), EGFR ( 0%), Ki 67 (73%), Wt-1 (10%), p-Akt (24%), HER2 (19%), NY-ESO-1 (11%), MAGE A1 (0%), HER3 (14%), BRCA1 (84%), PTEN (12%), IGFR1 (12%) and AR (14%). Diferentially expressed BM in IB for p with and without pCR, respectively, were p-Akt 0/8(0%) vs 5/13(38%) p=0.11, CK 5/6: 4/9 (44%) vs 2/15 (13%) p=0.15 and Ki 67: 7/7(100%) vs 10/17(59%) p=0.06. The Table shows the BM expression before and after NCT for p without pCR. Conclusions: Tumor samples of TNBC show high expression of CD44, ki67, and BRCA1. Most of BM has a decrease in expression after NCT. CK 5/6, Ki 67, and p-Akt could be predictive factor for pCR, although larger prospective studies are needed. [Table: see text]
LMS-02: A phase II single-arm multicenter study of doxorubicin in combination with trabectedin as a first-line treatment of advanced uterine leiomyosarcoma (u-LMS) and soft tissue LMS (ST-LMS): First results in patients with u-LMS.
Authors: Pautier Patricia , Floquet Anne , Cupissol Didier , Lacas Benjamin , Bompas Emmanuelle , Chevreau Christine , Selle Frédéric , Weber Beatrice E. , Guillemet Cecile , Penel Nicolas , Duffaud Florence 
Published: March 2020

10505 Background: U-LMS and ST-LMS are rare tumours with poor prognosis when metastatic or locally advanced, presenting moderate chemosensitivity mainly to doxorubicine (doxo), ifosfamide (ifo), cisplatin, gemcitabine (gem) and trabectidine (trab). Response rates (RR) in combination therapies (1stline) does not exceed 50% for U-LMS and 35% for ST-LMS. The most active ones are doxo combinations (most of the time with ifo or dacarbazine) and gem + docetaxel (in particular in U-LMS) with a mean response durations of 3 to 6 months. Trab was demonstrated a definite activity on pre-treated LMS (RR of approximately 20% in LMS overall [U-LMS in particular]). In view of these encouraging results on LMS, a study combining trab with doxo as first line therapy for LMS is of interest. Methods: Patients (pts) received every 3 weeks, 6 cycles of doxo 60 mg/m2 followed by trab 1.1 mg/m23-h at day 1, and pegfilgrastim 6 mg on Day 2. Study primary objective: to determine the disease control rate (DCR) (ORR+SD). Secondary objectives: PFS 12 wks, RR by RECIST and duration, OS and toxicities. Patients were stratified into U-LMS (n=45) and ST-LMS (n=62) group. Herein, we report the first results in pts with U-LMS; mature data will be shown in ASCO Meeting. Results: 45 pts with U-LMS have been enrolled until November 2012. Median age is 58 years, 38 where of with data collected for at least 1 cycle, 85% had metastatic disease (mostly lung 30/33, liver and bone), and 26 pts have received 6 cycles. For 33 pts with at least 1 disease assessment (every 2 cycles), the ORR was 55% (18 PR) and 13 SD (39%) had SD disease for a DCR of 94% at that time. Presently, the median PFS at 12 weeks is 94,3% [95%IC:86-100]. Main grade 3-4 toxicities in 187 cycles were neutropenia (51%), febrile neutropenia (7%), thrombopenia (14%), anemia (7%), fatigue (5%), vomiting (6%) and transiet transaminase increase (22%). Conclusions: The combination of trab plus doxo seems to be an effective first-line treatment for pts with U-LMS, with meaningful clinical benefits and an acceptable and manageable safety profile. Clinical trial information: 2009-012430-70.
Discordance of oncologic surgical classifications in COG studies.
Authors: Morris Carol , Teot Lisa A. , Bernstein Mark L. , Marina Neyssa , Krailo Mark D. , Villaluna Doojduen , Gorlick Richard Greg , Randall R. Lor 
Published: March 2020

10528 Background: “Wide resection” (a cuff of normal tissue) versus “radical resection” (the entire compartment) indicate very distinct oncologic surgical procedures and hence potential margin status. Distinguishing between these two oncologic classifications is important for understanding oncologic outcomes. Methods: We examined the available data for COG AOST0331: A Randomized Trial of the European and American Osteosarcoma Study Group to Optimize Treatment Strategies for Resectable Osteosarcoma Based on Histological Response to Pre-Operative Chemotherapy. We reviewed the surgical and pathology reports of patients considered to have received a wide or radical resection according to the investigator at the patient’s institution. Results: In 956 patients, the overall discordance rate was 43%. Of those patients reported to have had a wide excision by the reporting institution, only 5% of patients were reclassified to radical resection. However, of those patients reported to have undergone radical resection, 75% were reclassified to wide. In the absence of this re-review of the data, 56% of the patients would have been reported to have had a radical resection when in fact only 17% met the criteria for true radical resection. The greater number of patient reclassified to wide from radical is likely indicative of the influence and limits of the CPT coding system currently used for billing by surgeons; only CPT codes for radical resection currently exist. Conclusions: These discrepancies complicate subsequent data analysis, particularly assessing predictors of local recurrence. While this reporting problem is not unique to COG studies, we aim to use this example to raise awareness among our colleagues about the importance of accurate data reporting. Providing better training to those individuals responsible for submitting data may decrease the incidence of erroneous data entry and is essential to the successful completion of study objectives.
Claudin-1 as a novel transcriptional target of hedgehog signaling and a predictor for outcome in breast cancer.
Authors: Warrier Sanjay , Sellinger Christina , Beith Jane McNeil , Cazet Aurelie , Swarbrick Alex , Carmalt Hugh , O'Toole Sandra 
Published: March 2020

1053 Background: Hedgehog signaling is important in the development of a number of malignancies. We have recently shown that the Hedgehog (Hh) signaling pathway is associated with a poor outcome and is a novel therapeutic target in triple negative breast cancer. Gene expression profiling of M6 murine cell line mammary xenografts overexpressing Hh ligand revealed a series of genes potentially regulated by Hh in breast cancer. We explored the expression patterns of one of the candidates, Claudin-1, an adhesion molecule, and its association with Hh pathway markers and outcome in 292 invasive ductal carcinomas. Methods: Immunohistochemistry for Claudin-1 was performed and scored by two observers for membranous and cytoplasmic localization. Membranous or cytoplasmic expression were scored and its associations with patient outcome were assessed using Kaplan Meier and Cox Proportional hazard model analyses. Correlations with clinicopathological features and Hh pathway protein expression were undertaken using chi squared analysis. Results: Claudin-1 was expressed both in the cytoplasm and at the plasma membrane of breast carcinoma cells. Cytoplasmic predominant expression of Claudin1 was associated with a favorable prognosis (HR 0.59 (95% CI: 0.36, 0.97), p = 0.039. In contrast, membranous predominant expression was associated with larger tumors, histological grade 3, a high Ki67 index and a poor outcome (HR 1.66 (95% CI: 1.064, 2.60), p = 0.026). Importantly, membranous Claudin-1 directly correlated with Hh ligand (p < 0.0001) and paracrine pathway activation as indicated by high epithelial Hh ligand expression (p < 0.0001) and high Gli1in the peritumoral stroma (p=0.027). There is a strong correlation between paracrine hh/gli (p = 0.001) and membrane predominant claudin confirming our in vivo findings. Conclusions: Claudin-1 is an important component of the tight junction in epithelial cells. We have shown for the first time that Claudin-1 is a direct target of Hh pathway activation. Furthermore, we report that the subcellular localization of Claudin-1 shows distinct association with outcome in breast cancer. These findings provide insight into potential mechanisms of metastatic spread of breast cancer.
Demonstration of gender-specific variability in a pharmacokinetic (PK) analysis of the PERSIST-5 trial of adjuvant imatinib (IM) for patients with primary gastrointestinal stromal tumor (GIST) at significant risk of recurrence.
Authors: Espat Joseph , Maki Robert G. , Raut Chandrajit P. , Staveley-O'Carroll Kevin F , Keir Christopher Hunt , Magley Andrea , DeMatteo Ronald P. 
Published: March 2020

10538 Background: ThePERSIST-5 phase II trial is evaluating 5 years of adjuvant IM therapy in patients with resected GIST at significant risk of recurrence. This analysis studied the effect of chronic therapy on steady-state trough levels in patients who received IM for up to 24 months to evaluate potential PK variations. Methods: Eligible patients were adults with KIT+ primary GIST who were considered to be at significant risk for recurrence (primary tumor any site ≥2 cm andmitotic rate ≥5/50 high-power fields, or non-gastric primary GIST ≥5 cm) without metastases. R0 resection of primary GIST was performed ≤12 weeks prior to the first IM dose. Patients are to receive oral IM 400 mg/day for up to 5 years or until progression, relapse, or intolerance. Plasma samples for PK analysis were collected at 1, 4, 12, and 24 months. IM plasma concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay. Results: In-study assay performance (%CV) was ≤9.6% and bias was -1.3% to 5.2%. IM concentrations ranged from below quantifiable limits to 4798 ng/mL. After daily IM doses for up to 12 months (or 24 months in 3 patients), IM trough levels remained constant over time. The range of IM trough levels (mean ± SD) was 957 ± 750 ng/mL to 1219 ± 822 ng/mL at month 1, and 727 ± 430 ng/mL to 996 ± 405 ng/mL at month 12. Inter-patient variability was 40.7-78.4%. There was no significant difference in IM trough levels between months 1 and 4, 1 and 12, or 4 and 12. Trough levels did not significantly differ by location of GIST. Most notably, mean IM trough concentrations were on average ~33% higher in females vs males. Conclusions: In this study,IM trough levels remained relatively unaltered in patients with high-risk GIST who received adjuvant IM for 1 year. The 33% higher mean trough levels in females warrants further study for clinical decision making. Clinical trial information: NCT00867113. [Table: see text]
Frequent mutations in MLH1, MET, KIT, PDGFRA, and PIK3CA genes in human gastrointestinal stromal tumors.
Authors: Xu Zhi , Huo Xinying , Tang Chuanning , Ye Hua , Lou Feng , Chen Si-Yi , Chen Jinfei 
Published: March 2020

10544 Background: Identifying mutations in individual tumor is critical to improve the efficacy of cancer therapy by matching targeted drugs to specific mutations. Gastrointestinal stromal tumor (GIST) is a stromal or mesenchymal subepithelial neoplasm affecting the gastrointestinal tract and it frequently contains an activating mutation in either the KIT or platelet-derived growth factor A (PDGFRA) gene. Although GIST is highly responsive to several selective tyrosine kinase inhibitors, combined use of inhibitors targeting other mutations is needed to further prolong survival. Methods: In this study, we aim to screen and identify genetic mutations in GIST for targeted therapy using the new Ion Torrent next-generation sequencing platform. Results: By utilizing the Ion Ampliseq Cancer Panel, we sequenced 737 loci from 45 cancer-related genes from DNA extracted from formalin-fixed and paraffin-embedded (FFPE) samples of 125 human gastrointestinal stromal tumors, set up stringent parameters for reliable variant calling by filtering out potential raw base calling errors, and identified frequent mutations in PDGFRA, KIT, APC, MLH1, MET, RET, and PIK3CA. Moreover, frequent missense mutations were detected in MLH1 (12%), MET (16.8%), KIT (51.2%), and PIK3CA (41.6%) genes. The mutations in MLH1 gene were frequently detected in the exon 14, while MET gene was frequently mutated in the exon 2. In addition, we identified missense mutations in other genes, including FLT3, KRAS, PDGFRA, and STK11, at lower frequencies. Conclusions: This study demonstrates the utility of using Ion Torrent sequencing to efficiently identify human cancer mutations. With the finding of the frequent mutations in MLH1 and MET genes, in addition to KIT, PDGFRA and PIK3CA, in GISTs, this study provides a molecular basis for clinically developing new drugs targeting these gene mutations for GIST therapy.
Predictors of complete response following disease recurrence in gastrointestinal stromal tumor (GIST) patient: A retrospective patient chart review analysis.
Authors: Conley Anthony Paul , Guérin Annie , Sasane Medha , Gauthier Geneviève , Schwiep Frances Annelies , Keir Christopher Hunt , Magestro Matt , Wu Eric Q. 
Published: March 2020

10545 Background: Adjuvant imatinib (IM) treatment reduces the risk of GIST recurrence and improves survival particularly when IM is used for a longer duration among moderate to high risk patients. However, among patients who recur, little is known about the factors impacting the probability of achieving complete treatment response (CR). This study identifies factors associated with the probability of achieving CR among patients who had a recurrence following cessation of initial adjuvant IM treatment for a KIT + GIST. Methods: An online tool was used to retrieve clinical data on 410 patients who were treated with adjuvant IM for ≥6 months for primary resectable KIT+GIST, discontinued, had a recurrence after discontinuation, and then restarted IM or initiated sunitinib. Tumor and treatment characteristics were collected at primary diagnosis and disease recurrence. Patient response status was assessed by physicians based on different measures (e.g., RECIST, Choi, other subjective measures). Predictors of CR were identified using logistic regression models. Results: Among the 410 (IM = 314, sunitinib = 96) patients treated for GIST recurrence, 22.4% achieved CR (25.2% of pts on IM and 13.5% of patients on sunitinib). On average, CR was achieved after 11 weeks of treatment and only 2% of patients had a subsequent disease progression/recurrence. RECIST criteria were most widely used for CR evaluation in 68% of patients followed by subjective measures (29%) and Choi criteria (17%), respectively. Patients with a unifocal tumor (Odds Ratio[OR]=2.61; p<.001 ), small tumor size (≤2cm) (OR=2.16; p=.023), lower mitotic rate ≤5/50 HPF (OR=1.87; p=.017) at recurrence, or tumor recurrence inside gastrointestinal system (OR=2.27; p=.036) were more likely to achieve CR. Conclusions: Among study patients, 22.4% achieved CR following disease recurrence. The main predictors of CR were tumor focality, size, location, and the mitotic rate at recurrence. This suggests that detecting recurrence at an early stage and managing disease with re-initiation of KIT inhibitor therapy may improve the probability of achieving CR following recurrence.