bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extracellular matrix and breast cancer cells' response to trastuzumab: The role of glycosaminoglycans, heparanases, and syndecan-1.
Authors: Pinhal Maria Aparecida Silva , Suarez Eloah Rabello , Nader Helena Bonciani , Del Giglio Auro 
Published: March 2020

10568 Background: Trastuzumab is an antibody anti-epidermal growth factor 2 receptor (HER2), which improves disease-free and overall survival in HER2 positive breast cancer. Nevertheless, many patients become resistant to this treatment. Heparanase (HPSE) is an enzyme that is responsible for removal of heparan sulfate (HS) chains from proteoglycans, generating free oligosaccharides that modulate many physiopathological functions, including tumor developing. We have analyzed whether some extracellular matrix components influence trastuzumab efficacy. Methods: Heparanase-1 (HPSE-1) overexpression effect was analyzed using MCF7 cells stable transfected with HPSE-1 cDNA (MCF7-HPSE-1). HPSE-1, HPSE-2, Syndecan-1 (Syn-1) and HER2 expression, HPSE-1 activity and cell viability were evaluated in different breast cancer cells treated or not with trastuzumab. The glycosaminoglycans synthesis and shedding were also evaluated. Trastuzumab and HS binding were analyzed by confocal microscopy and Fluorescence Resonance Energy Transfer (FRET). Results: MCF7 transfected with HPSE-1 cDNA becomes completely resistant to trastuzumab. HS affinity by Trastuzumab was then tested, showing that they bind in high levels and this binding is necessary to antibody activity. In MCF7 cells, trastuzumab decreases HPSE-1, HPSE-2, HER2 and Syn-1 mRNA expression, while in MCF7-HPSE-1 the antibody increases the expression of these molecules. Conclusions: Our results have demonstrated that an ideal concentration of HS in cell surface, regulated by trastuzumab, is necessary to its action, beyond HER2 high levels. High HS concentration at cell surface enhances the antibody amount disposable to interact with HER2 in cell surface, determining breast cancer cells susceptibility to trastuzumab. These new insights could be useful when devising strategies for overcoming trastuzumab resistance in HER2 positive cancers. Supported by FAPESP, CNPq, CAPES.
Accuracy of microRNA-based classification of metastases of unknown primary.
Authors: Pavlidis Nicholas , Pentheroudakis George E. , St. Cyr Brianna , Spector Yael , Meiri Eti , Fountzilas George , Gousia Anna , Benjamin Hila , Malamou-Mitsi Vassiliki , Kotoula Vassiliki , Stoyianni Aikaterini , Krikelis Dimitrios , Sanden Mats Olot , Ashkenazi Karin ,   Hellenic Cooperative Oncology Group
Published: March 2020

10575 Background: Identification of the tissue of origin of metastatic tumors is important for estimation of prognosis and patient management. Carcinoma of unknown primary (CUP) is not uncommon in oncology, representing 3-5% of all newly found malignancies. We used a microarray-based test that uses the expression of 64 microRNAs to retrospectively evaluate tumors from CUP patients. Methods: A cohort of resected metastatic lesions from patients diagnosed with CUP was studied blindly on the microRNA-based test. The cohort included 93 samples (from 92 patients) with tissue adequate for the test. Eight samples failed due to inadequate RNA quality; 85 samples (84 patients) were processed successfully. Test results were compared with clinical presentation including imaging, pathological data (histology and IHC) at initial CUP diagnosis and with clinical management and outcome data at the completion of each patient`s follow up. Results: The test results were fully concordant with the diagnosis based on all the clinical and pathological information available including follow-up and outcome in 92% of patients compared to ~70% agreement with the patients’ diagnosis at initial presentation, before additional data gathered throughout patient management. Two different metastases from the same patient yielded the same result. The microRNA test assigned a single tissue of origin for 51 patients and two tissues of origin in 33 patients, with the first being the more likely diagnosis. When comparing only the first (or single) diagnosis, a concordant level of 88% was achieved. Conclusions: In a retrospective, well studied cohort of metastases from CUP patients, a previously developed test based on the expression profile of 64 microRNAs allowed accurate identification of tissue of origin in 92% of the cases. This study validates the high accuracy of the test on real CUP patients. The high concordance of the test results to the final tissue of origin diagnosis of the patient, even in cases where the initial diagnosis at CUP presentation was discordant, demonstrates the importance of the test in yielding additional data valuable for patient management at an early stage of the patient’s treatment plan.
Defining a FISH chromosomal aneusomy panel for predicting lung cancer in the setting of CT-detected lung nodules.
Authors: Franklin Wilbur A. , Skokan Margaret , Lewis Marina T , Feser William , Wolf Holly J , Miller York E , Merrick Daniel , Barón Anna E , Varella-Garcia Marileila 
Published: March 2020

10580 Background: Early detection of lung cancer by CT is supported by the National Lung Screening Trial; but while sensitivity of CT is high, specificity is low. Biomarkers to predict the malignant nature of CT detected lung nodules would have great clinical utility. We previously found in a nested case-control study that a 4-target chromosomal aneusomy (CA) FISH panel exhibited sensitivity/specificity of 76%/88% in sputum samples of heavy smokers obtained within 18 months of lung cancer diagnosis. We hypothesized that CA-FISH may be an effective biomarker to assist with clinical decisions in the setting of CT detected lung nodules of indeterminate etiology and attempted to identify a more effective reagent. Methods: Homebrew probes encompassing genomic sequences of EGFR, NXK2-1, PIK3CA, MYC, BRF2, SOX2, PPMID, FGFR1 and the commercial reagent LSI D5S721/D5S23 (Abbott Molecular) were combined in 2-4-target FISH assays to investigate tissue copy number in early stage lung squamous cell carcinoma (SCC, N=19) and adenocarcinoma (AC, N=20). Logistic regression models were used to estimate predictive discrimination [sensitivity, specificity, area under the ROC curve (AUC)]. Results: Copy number gain was largely detected for all markers (mean range 3.39 - PPMID to 4.67 - MYC). Mean copy number of PI3CA, BRF2, SOX2 and FGFR1 were significantly higher in SCC than AC, while NKX2 and MYC were marginally higher in AC than SCC. Gene amplification was detected for all 9 markers, most frequently for SOX2 and FGFR1 (6 and 5 cases) with significant overlap between FGFR1/BRF2 and SOX2/PIK3CA. Based on the AUC results and the existence of targeted inhibitors, the probe set EGFR/FGFR1/MYC/PIK3CA was selected as a candidate for further development as an adjunct to CT screening for early detection. For this selected set,the optimal cutoff based in the linear predictor from logistic regression yields a sensitivity and specificity of 0.85. Conclusions: A highly sensitive/specific CA-FISH probe set was identified which may well complement CT screening in the early diagnosis of lung cancer. This probe set will be tested in the setting of CT detected lung nodules. (Supported by LUNGevity and NCI-Lung Cancer SPORE grants).
89 Zr-bevacizumab PET imaging in metastatic renal cell carcinoma patients before and during antiangiogenic treatment.
Authors: Oosting Sjoukje , Brouwers Adrienne H. , Van Es Suzanne C. , Nagengast Wouter B. , Oude Munnink Thijs H. , Lub-de Hooge Marjolijn N. , Hollema Harry , De Jong Johan R , de Jong Igle J. , de Haas Sanne , Scherer Stefan , Sluiter Wim J. , Dierckx Rudi A , Bongaerts A. H.H. , Gietema Jourik A. , De Vries Elisabeth 
Published: March 2020

10581 Background: Renal cell cancer (RCC) is characterized by high VEGF production leading to excessive angiogenesis. To visualize VEGF, we performed serial 89Zr-bevacizumab-PET scans before and during antiangiogenic treatment in RCC patients. Methods: Metastatic (m) RCC patients who received sunitinib (50 mg once daily, 4 out of 6 weeks) or bevacizumab (10 mg/kg every 2 weeks) plus interferon (IFN 3-9 MU 3x/week), underwent 89Zr-bevacizumab-PET scans at baseline and after 2 and 6 weeks, and CT scans at baseline and every 3 months. Tracer uptake in tumor lesions was quantified with maximum Standardized Uptake Value (SUVmax). Relationship between baseline and Δ SUVmax and time to progression (TTP) was analyzed. Wilcoxon test was used to compare scans, Kaplan-Meier method for survival analysis. Results: 22 out of 26 patients were evaluable, 11 per treatment. On 89Zr-bevacizumab-PET, 131 out of 231 lesions ≥ 10 mm (detection limit) were visible and 125 quantifiable. Mean SUVmax at baseline was 10.1 (SD 8.4; range 2.3 - 46.9). During bevacizumab/IFN treatment, SUVmax consistently decreased (mean decrease 47.0% 95% CI 39.1-54.9, P<0.0001) at 2 weeks with a further decrease of 9.7% (95% CI 0.86-18.5, P=0.016) at 6 weeks. After 2 weeks sunitinib, there was only a modest decrease in mean SUVmax (14.6%, 95% CI 1.57-27.63, P=0.0064) with a wide range (-80.4% to +269.9%) and an overshoot of 84.4% (95% CI 47.8-120.9, P=0.0001) after 2 drug free weeks. TTP was longer in (n=15) patients with baseline SUVmax > 11.1 (highest normal tissue uptake) in the 3 most intense lesions than in those with a lower value (median 89.7 vs 22.8 weeks, HR 0.16, 95% CI 0.04 - 0.70). TTP was longer in patients (n=11) with an absolute Δ SUVmax >6.00 in the most intense lesion at 2 weeks (HR 0.25, 95% CI 0.06-0.98). Conclusions: 89Zr-bevacizumab-PET visualizes tumor lesions in mRCC patients. Different changes in tumor tracer uptake after start of bevacizumab/IFN versus sunitinib indicate that these drugs induce different angiogenic responses. High baseline SUVmax and large change in SUVmax corresponded with longer TTP, suggesting that 89Zr-bevacizumab-PET may help to identify patients who benefit the most from antiangiogenic treatment.
Serum HER2 in the context of circulating tumor cells in patients with metastatic breast cancer.
Authors: Mueller Volkmar , Riethdorf Sabine , Rack Brigitte Kathrin , Janni Wolfgang , Fasching Peter A. , Solomayer Erich , Aktas Bahriye , Kasimir-Bauer Sabine , Pantel Klaus , Fehm Tanja N. ,   on behalf of the DETECT Study Group
Published: March 2020

10599 Background: Circulating tumor cells (CTC) reflect an aggressive tumor behavior by hematogenous tumor cell dissemination. Overexpression of HER2 in breast cancer (BC) is associated with increased angiogenesis and therefore potentially linked to increased hematogenous tumor cell spread. The aim of the analysis was to investigate whether concentrations of serum HER2 (sHER2) deliver prognostic information in the context of CTC detection in metastatic BC patients. Methods: Blood was obtained in a prospective multicenter setting from 254 patients with metastatic BC at the time of disease progression. sHER2 was determined using a commercial ELISA-kit (Wilex). CTC were detected with the CellSearch system (Veridex). Patients received systemic treatment according to national and international guidelines including HER2-targeted treatment. Results: Five or more CTC were detected in 122 of 245 evaluable patients (49.8%).119 of 251 (47%) metastatic patients had serum sHER2 levels above 15ng/mL. Median PFS was 9.2 months (95%-CI: 9.9 – 13.0 mths) with elevated sHER2 versus 11.4 mths (9.9 – 13.0 mths) with non-elevated levels (p=0.07). OS was 17.4 mths (14.6 – 20.3 mths) vs. 26.5 mths (23.1-29.8 mths; p<0.01). In patients with 5 or more CTC, serum levels were above the cut-off for sHER2 in 61% vs. 33% in those with less than 5 CTC (p< 0.01). Patients with elevated sHER and 5 or more CTC hat a PFS of 9.1 mths (7.2 – 11.1 mths) and a OS of 14.5 mths (11.8 – 17.2 mths), those with non-elevated sHER2 and less than 5 CTC a PFS of 12.1 (10.1 – 14.1 mths) and a OS of 29.5 month (25.4 – 33.6 mths) (p=0.15 for PFS and p< 0.01 for OS). Including sHER2, CTC and established prognostic factors in the multivariate analysis, the presence of CTC, line of therapy, ER and HER2 status of the primary tumor remained independent predictors of OS. Conclusions: Elevated serum levels of sHER2 are associated with the presence of CTC and indicate poor clinical outcome. However, sHER2 has no independent prognostic value when presence of CTC were taken into account.
Isolation and expansion of circulating tumor cells (CTC) from melanoma patients using a novel cell culture technique.
Authors: McGregor John R. , Samlowski Wolfram E. , Tharkar Shweta , Donepudi Sreekanth , Ferrone Soldano 
Published: March 2020

10614 Background: Identification of rare (>2-5) circulating tumor cells (CTC) in 7.5 ml blood by immunofluorescence assay (IFA) correlates with a poor prognosis in colon, breast, prostate and lung cancer. Changes in CTC count during treatment also predict the eventual patient progression and survival in these cancers. Existing assays do not detect melanoma CTC, however. In addition, isolation of viable CTC remains problematic. To overcome these limitations we attempted to develop novel melanoma CTC assays, using IFA and cell culture approaches. Methods: Blood samples were obtained from patients and controls following informed consent. The buffy coat (white cells + tumor) was isolated by Ficoll/Hypaque centrifugation, and split into 6 replicate cultures in proprietary TrueCells medium. After 21 days in culture, tumor colonies were counted, and stained for melanoma and leukocyte markers. Buffy coat cells from parallel blood samples were stained with a panel of CSPG4-specific mAb (a pan-melanoma marker) on ultraclean glass slides for analysis by immunofluorescence microscopy. Results: Blood samples were obtained from 16 melanoma patients, ages 28-87. Eight patients were men and 8 were women. CSPG4+ events (>2) were detected in 8/16 patients by IFA (range 0-52). In contrast, tumor cell colonies of >50 cells grew in 12 out of 16 patients with Stage 3 or 4 melanoma (range 0-1054), shown in Table. Cells isolated from CTC colonies produced melanin, stained for CSPG4 and other melanoma markers, but not for leukocyte markers. Control cultures grew no tumor colonies. Conclusions: Our pilot study shows that melanoma CTC can be identified by both IFA and cultured from blood in many patients with stage 3 or 4 melanoma. These CTC exhibited cytologic characteristics diagnostic of melanoma. The culture assay may represent a useful means of enumerating, isolating, and expanding viable melanoma CTC for further molecular study. [Table: see text]
Phase II trial of sorafenib (S) and vinorelbine (V) in metastatic breast cancer (mBC) with pharmacokinetics (PK) analysis.
Authors: Ferrario Cristiano , Miller Wilson H. , Charamis Helen , Langleben Adrian , Batist Gerald , Scarpi Emanuela , Nanni Oriana , Panasci Lawrence C. 
Published: March 2020

1099 Background: S inhibits pathways involved in cancer resistance to treatments (Raf, VEGFR, PDGFR). This phase 2 trial aimed to define tolerability and efficacy of full doses of S and V in mBC. Toxicity data were previously reported: frequent dose reductions were noted, for which we investigated a possible PK interaction. Indeed, the metabolism of both S and V depends on hepatic CYP3A isoenzymes. Methods: Patients with measurable (RECIST), HER2 negative mBC received first-line therapy with V (30 mg/m2 days 1, 8 every 21) + S (400 mg bid). After 8 cycles patients could be switched to S alone. For PK analysis 6 patients started S on day 4 of cycle 1, to compare plasma levels of V, S and M2 (N-oxide active metabolite of S) when V and S were administered apart from each other versus concomitantly. Plasma samples were collected at time 0 (oral intake of S or right before V infusion), at completion of V infusion and after 0.5, 1, 2.5, 5, 7, 24, 48 and 72 hours from time 0 (cycle 1 day 1 for V and day 21 for S+M2; cycle 2 day 1 for both). Samples were analyzed using validated LC-MS/MS assays. Results: 27 patients (median age 57, 35-71) received a median of 8 cycles (1-28), with one patient still on treatment. With repeated cycles 48% of patients required at least 1 dose reduction and 3 patients discontinued therapy for toxicity. 30% of patients had a partial response, 85% had clinical benefit (including stable disease ≥ 4 cycles). Median progression-free survival was 5.7 months (95% CI 4.4-7.6). Plasma levels of V were influenced by S, with a mean Cmax right after the infusion of 1301 ng/mL for V administered alone (cycle 1 day 1) versus 2039 ng/mL with concomitant S (cycle 2 day 1; paired t-test, p=0.004). Plasma levels of S and M2 showed a greater degree of interpatient variability, with no significant difference observed in the presence or absence of concomitant V. Conclusions: Combining S with V at full doses is feasible, but not devoid of toxicity. A PK interaction may contribute to the frequent dose reductions. A reasonable option in clinical practice is to start therapy at lower doses of both agents, with a gradual dose increase if well tolerated. Promising efficacy of this combination is documented, with a very high rate of disease control.
Prognostic impact of local therapy of the primary tumor in metastatic breast cancer.
Authors: Himsl Isabelle Katrin , Ditsch Nina , Lenhard Miriam Susanne , Engel Jutta , Untch Michael , Bauerfeind Ingo , Friese Klaus , Harbeck Nadia , Kahlert Steffen 
Published: March 2020

1114 Background: MBC is an incurable disease and the treatment aims are palliative. It is not known whether the difference in OS is the result of a selection bias or caused by dissemination of tumor stem cells in pat. without surgery. Methods: To identify the impact of surgical therapy of the primary tumor, a mono-institutional retrospective review from 1990-2006 was done in primary MBC pts. Results: We identified 269 pts. with primary MBC, 63 of whom had received no surgical local treatment. Mean follow up is 65 m for pts., observed mortality 87%. Location of metastases were bone only (36%), visceral or soft tissue (one organ only, 19%), multiple organs (40%) and including CNS metastases (5%). 50% had G3 tumors, 25% negative receptor status, 7% non-resectable local disease and 57% symptomatic metastases. In univariate analysis, pat. without local treatment had a median OS of 14.4m, pts. with local therapy 28.1m (p<0.001). Pts. not receiving local treatment were significantly more likely to have multiorgan or CNS involvement (p< 0.001), symptoms at diagnosis (p=0.009), non-resectable tumor (p<0.001) and were more likely to die within the first 30d after diagnosis (p< 0.001). In multivariate analysis, local treatment had no significant impact on OS. The only significant variables were: number of involved organs, symptoms at diagnosis, receptor status, grading, and size of the local tumor. The effect of local treatment on OS was not homogenous across subgroups. Local treatment was a significant factor in tumors with only one involved organ or asymptomatic disease. In all other groups, local treatment did not result in an OS benefit. Conclusions: Our cohort showed significantly improved OS in univariate analysis if the breast primary tumor had been removed in metastatic disease. Yet, the decision for local treatment was biased by the extent and presentation of metastatic disease. Pts. with more advanced MBC seem not to benefit from removal of the primary tumor. However, we see significant influence in pts. with limited and asymptomatic MBC. The potential dissemination of tumor stem cells from the breast primary in metastatic but locally untreated disease may only influence prognosis in pts. with limited disease.
Patient factors and satisfaction in the choice of contralateral prophylactic mastectomy.
Authors: Arrington Amanda Kathleen , London Karin , Chen Steven L. , Vito Courtney , Yim John H , Nelson Rebecca A. , Kruper Laura 
Published: March 2020

1117 Background: The percentage of women undergoing contralateral prophylactic mastectomy (CPM) has more than doubled in recent years. The underlying reasons patients choose CPM have not been fully evaluated. Our objective was to survey patients who have undergone a unilateral mastectomy with or without CPM to identify reasons surrounding their decisions. Methods: After obtaining IRB approval, a 30-question cross-sectional validated survey was mailed to 691 patients who underwent mastectomy from 1972 to 2011 and are receiving treatment or surveillance at City of Hope. The questionnaire queried the factors behind the choice of surgery for each patient. Demographic questions were included and patient charts were also reviewed. Results: The overall response rate was 53% (N=368). Patients were classified into those who underwent mastectomy with CPM (N=139, 38%) and those who underwent mastectomy without CPM (no-CPM) (N=229, 62%). Of returned surveys, the median age was 50; 24% of patients reported a family history of breast cancer (42% CPM vs. 13% no-CPM, p<0.0001) and 80% of patients had education beyond the high school level (87% CPM vs. 77% no-CPM, p=0.013). PM patients reported being “very concerned” about breast cancer more often than no-CPM patients (46% vs. 34%, p=0.033).The primary reasons for CPM were: concern of recurrence (55%), cosmetic symmetry (27%), physician recommendation (17%), and unclear pre-operative imaging (9%). When questioned about regrets, the top response was decreased sensation (26%). Although 81% of CPM patients were “very satisfied” with their decision, 32% of no-CPM patients reported the same level of satisfaction with their decision (p<0.0001). For no-CPM patients, the primary reasons for the choice of no-CPM was physician advice and “monitoring is sufficient”; with 18% of the responders still considering a CPM. Conclusions: Patients’ perceived risk of contralateral breast cancer is the primary reason for CPM. CPM patients tend to be more satisfied with their decision compared to no-CPM patients. This may be related to the active decision-making thought processes and education necessary to choose CPM. Further patient education is warranted to minimize the risk of regret in making this decision.