bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic variants of kinases suppressors of ras (KSR1) to predict survival in patients with ER-alpha positive metastatic breast cancer.
Authors: Zhang Wu , Benhaim Leonor , Yang Dongyun , Gerger Armin , Bohanes Pierre Oliver , Páez David , Loupakis Fotios , Wakatsuki Takeru , Labonte Melissa Janae , Ning Yan , El-Khoueiry Rita , Zhang Hua , Stebbing Justin , Giamas Georgios , Lenz Heinz-Josef 
Published: March 2020

e11018 Background: In addition to its activating role of MAPK pathway, the protein kinase suppressor of ras 1 (KSR1) has been identified as a novel modulator of estrogen receptor alpha (ERα), as silencing of KSR1 in ERα+ breast cancer (BC) cells lines resulted in dowregulation of ERα transcriptional activity in the presence of oestradiol. Our previously data revealed the existence of single nucleotide polymorphisms (SNPs) in EGFR and ERα pathway genes that may predict clinical outcome in ERα positive metastatic BC (mBC) patients. With respect to those findings we aimed to evaluate the clinical implication of KSR1 SNPs on survival in patients with primary ERα+ mBC treated with tamoxifen. Methods: Tumoral DNA was obtained from 222 patients treated with tamoxifen withERα+ invasive BC who had undergone surgery between 1981 and 2003 (median age 56 [28-90]). Three relevant KSR1 SNPs were selected based on public literature resources and databases, including 2 SNPs localised in the regulating 3’untranslated region (rs224190, rs 1075952) and 1 non-synonymous SNP localised in the coding exon 7 region (rs2293180). All SNP were analysed using DNA sequencing with OS and DFS as primary endpoint. Results: The overall median follow-up was 6.4 years.In univariate analysis the rs2241906 SNP was significantly associated with DFS and OS and patients with the TT genotypedemonstrated shorter DFS (2.1 vs. 7.1 months, p=0.005) and OS ( 2.6 vs. 8.4 months p=0.002) than patients with the x/C genotypes. The associations remained significant in the multivariate analysis adjusting age, lymph node status and HER2 status (HR (95%CI): 4.81 (2.00-11.59) and 5.74 (2.29-14.43), for DFS and OS, respectively). The same significant correlation was retrieved with the SNP rs1075952 in linkage disequilibrium with rs2241906 that was used as a control. No relationship was shown between rs2293180 and survival. Conclusions: Our findings demonstrated that KSR1 polymorphisms could arise as a potential marker to predict survival in patients with mBC treated with tamoxifen. The putative role of KSR1 as a modulator of ERα activity could functionally explain our results yielding insight for further studies.
Prognostic relevance of partial hormone receptor expression in stage I breast cancer.
Authors: Zwenger Ariel , Leone Julieta , Iturbe Julian , Perez Verdera Palmira , Leone Jose Pablo , Leone Bernardo Amadeo , Vallejo Carlos Teodoro 
Published: March 2020

e11021 Background: Patients whose tumors express only one hormone receptor (1HR) are usually considered hormone-sensitive regarding treatment decisions. However, certain retrospective analyses suggest that patients bearing ER+/PR- or ER-/PR+ tumors may have worse outcomes than those with ER+/PR+ (HR) phenotype. The aim of this study was to correlate partial expression of hormone receptors (ER+/PR- or ER-/PR+) with several well known prognostic factors and their possible influence on the incidence of local and distant failure, relapse free survival (RFS) and overall survival (OS) in women with early breast cancer treated at GOCS institutions. Methods: We evaluated 327 patients with stage I breast cancer (T1a,b,cN0M0; AJCC 2010) diagnosed between January 1991 and December 2009. Further analyses were conducted upon a cohort of 282 patients who were divided between those whose tumors expressed both HR and those with only 1HR. Results: The median age was 54.2 years (29-89). Median follow-up was 9.4±4.4 years (0.2-22.9). Both HR and 1HR were expressed in 242 and 40 patients respectively. Similar adjuvant treatment was administered in both groups although the number of mastectomies was higher in the subgroup with only 1HR (22.5% vs. 5.8%, P =. 0003). Univariate analyses showed no difference between both groups when correlated with age, body mass index, histologic type, T stage, histologic and nuclear grade, mitotic index, vascular invasion, necrosis and margin status. However, 1HR tumors had a higher rate of lymphovascular invasion (21.9% vs. 9.5%, P =.038) and HER2 expression (57.1% vs. 21.9%, P = .035). Treatment failure was more frequent in patients with only 1HR (12.5% vs. 5%, P =.064). Distant progression was also more common in this subgroup (80% vs. 58.3%, P =.334). There were no statistically significant differences in RFS and OS among groups. Conclusions: The expression of only 1HR constitutes a phenotype that could have a more aggressive biology and be associated with higher risk of recurrence than tumors with both receptors. Analysis of more patients, larger tumor size and N1 disease is warranted to confirm this hypothesis and have a better prognostic assessment.
Variations at HER2 and hormone receptor status in primary and metastatic sites of breast cancer patients.
Authors: Alhan Nurcan , Rahatli Samed , Kucukoztas Nadire , Yalcin Selim , Yagmurdur Mahmut Can , Dizdar Omer , Atilgan Alev , Ozdemir Handan , Altundag Ozden , Ozyilkan Ozgur 
Published: March 2020

e11023 Background: Evaluation of hormone receptors (ER/PR) and Her2-Neu is important for hormonal and anti-Her2 treatments. The parameters are generally estimated in primary tumors and it is unclear whether re-evaluation of metastatic lesions will be effective during follow-up. Methods: The primary aim of this study was the compare Her2 and HR (ER/PR) status in primary and metastatic tissues of breast cancer patients. HR and Her2 expression in biopsy specimens obtained from primary tumor and their metastatic lesions of 44 breast cancer patients, followed-up during 1995-2010 at Baskent University Hospital were analyzed. Results: Of 44 patients 29.5% were found Her2 (+), 54,5 % ER (+) and 45.4% PR (+) in primary site. Metastatic regions excised or biopsied as following: Bone 31.8% (14/44), liver 27.3% (12/44), skin 25% (11/44), lung 9.1% (4/44), brain 4.5% (2%44), bone marrow 4.5 (2/44), ovaries 4.5% (2/44), stomach, abdominal LAP and pelvic mass 2.3% (3/44). Positification rate of ER status in metastatic sites was detected as 4.5% (2/44), when positive in primary tumors, negatification rate was detected as 20.5%. The positification rate of PR status in metastatic sites, while being negative in primary tissue was 13.6% (6/44); and negativication rate in metastatic lesions, being positive in primary tumor was 27.3% (12/44). The positivication rate of Her2 expression in metastatic lesions while being negative in primary tissue was 4.5% (2/44); and negativication rate while being positive in primary tumor was detected as 13.6% (6/44). When the hormone receptor status and Her2 expression of the patients followed-up are evaluated, receptor variation was detected in 23 of 44 patients. Conclusions: Our study confirms that biological properties of breast cancer may vary among primary tumors and asynchronised metastatic lesions. Further prospective studies are needed to better define the discordance of Her2 or HR status at primary tissue and metastatic sites.
Outcome of breast cancer patients with stage I diesease: A retrospective analysis.
Authors: Ergun Aydin , Kucukoztas Nadire , Yalcin Selim , Rahatli Samed , Babacan Taner , Yagmurdur Mahmut Can , Ozyilkan Ozgur , Dizdar Omer , Altundag Ozden , Altundag Mustafa Kadri 
Published: March 2020

e11026 Background: Breast cancer is being diagnosed at earlier stages with the increasing use of screening mammography and public awareness. Treatment of stage I breast cancer is not established strictly and various prognostic and predictive factors are considered in treatment decisions. In this study, we aimed to determine feasible and reliable prognostic factors for using adjuvant chemotherapy in the treatment of stage I breast cancer. Methods: Patients with stage I breast cancer diagnosed in two centers, i.e. Baskent University and Hacettepe University, were retrospectively evaluated. Patient and tumor characteristics as well as patient outcomes in terms of DFS and OS were determined. Results: A total of 614 patients were identified. Median age was 50, and 44% were premenopausal. Patient characteristics were summarized in the table. Median follow-up was 38 months (6-369 mos). 38 patients relapsed on follow-up and 5 patients died. Seven of the relapses was locoregional, 29 were distant, including 10 with bone-only metastases, 19 with visceral metastases. Median DFS was 68 mos. Median OS was not reached. Five year DFS was 92% and 10 year DFS was 83%. 5 year OS was 96.8%. In multivariate analysis including age, hormone receptor status, cerbB2, grade, LV invasion, menopausal status and histological subtype, only grade 3 disease was shown to be associated with significantly increased relapse rate (OR 10, 95% CI; 1.15-86.9) Conclusions: In accordance with the pertinent literature, our findings suggest that tumor grade is strongly associated with higher risk of relapse. Further studies with molecular markers may provide beter prognostication and tailoring treatment according to the risk. [Table: see text]
FDG PET-CT in breast cancer: A single institution experience from India.
Authors: Rao Nalini K , Ajaikumar Basavalinga S , Kallur Kumar G , Sridhar P S , Somorat Bhattacharjee , Radheshyam Nayak , Govindarajan Mallarajapatna , Mahesh Bandemegal , Nagaraj Kanakapura Ramanna 
Published: March 2020

e11027 Background: Whole body FDG PET CT is a useful tool in diagnosis, staging and prognosis; and its timely use is critical for early intervention and achieving long term survival in patients with early and advanced breast cancer. Methods: In this observational retrospective study, we report FDG PET CT findings of all breast cancer patients enrolled in our hospital based cancer registry between the years 2008 to 2011. Results: One thousand and fifty three women underwent a total of 1638 scans. Two hundred and forty five scans (14.96%) were done for staging /restaging/diagnosis, 1208 (73.75%) were for response evaluation to chemotherapy and 185 (11.29%) were for surveillance. The median age at diagnosis was 53 years. We identified a possible synchronous breast primary in 28 (2.66%) women and a probable new or existing second non-breast primary in 21(1.99%) women. Internal nodal metastasis was identified in 76 (7.21%) women at diagnosis. There were 26 (2.47%) patients with multicentric tumors. There was an increased uptake in the thyroid gland in 49(2.99%) and in the adrenal in 41 (2.50%) women. There were other random ‘Incidental findings of concern’ in 7 (0.37%) of women, diagnosed either on the CT or PET-CT component. Findings on PET-CT, including- upstaging of the breast primary and unexpected new findings, unrelated to the breast primary, changed the treatment plan in approximately 7% -10% of the patients. We did find that PET-CT did not impact early tumors; however, it did contribute in, 1) the assessment of internal mammary nodes, 2) prognostication based on tumor burden and, 3) aggressive management of oligometastases. Conclusions: Whole body FDG PET CT is a useful tool for staging and prognostication in breast cancer patients. However, the timing of such scans for surveillance needs to be defined for early detection of progression to have an impact on survival.
Clinical and pathological comparison of patients with breast cancer under age 35 with those over age 70.
Authors: Dal Pinar , Rahatli Samed , Kucukoztas Nadire , Yalcin Selim , Dizdar Omer , Altundag Ozden , Ozyilkan Ozgur 
Published: March 2020

e11045 Background: Despite intensive treatment given to young breast cancer women, prognosis is stil poor in this group of population. However, older patients seem to have better prognosis. Methods: We performed the retrospective study for 50 women ≤35 yo compared with 50 women ≥70 yo, diagnosed and treated from 1991-2009 at Baskent University Hospitals. Results: Older women were more likely to have lower tumor grades and higher HR positivity, ≤35 years old women were more likely to have Her2 positivity, larger tumor size and metastatic lymph node involvement. Median follow up duration was 21.7 (2-91) months for ≤35 group, whereas it was 36.2 (4-195) months for ≥70 years group. Recurrence was observed in 34% of the young age group and 24% of the older age group. Three patients from the young group and 4 patients for ≥70 years age group died during the follow-up Young breast cancer patients have poor prognosis. Even after adjustment of the data, Overall survival and relapse free survival showed worse prognosis. Normal prognostic factors like tumor size, axillary lymph node involvement and grading can therefore be not the explanation for the more agressive disease progression alone. Older women were more likely to have lower tumor grades and higher hormone receptor positivity, ≤35 years old women were more likely to have Her2 positivity, larger tumor size and metastatic lymph node involvement. Median follow up duration was 21.7 (2-91) months for ≤35 age group, whereas it was 36.2 (4-195) months for ≥70 years group. Recurrence was observed in 34% of the young age group and 24% of the older age group. Three patients from the young group and 4 patients for ≥70 years age group died during the follow-up Young breast cancer patients have poor prognosis. Even after adjustment of the data, Overall survival and relapse free survival showed worse prognosis. Normal prognostic factors like tumor size, axillary lymph node involvement and grading can therefore be not the explanation for the more agressive disease progression alone. Conclusions: There are various reasons such as difficulty in diagnosing the patients the patients at earlier stage because of the higher density of breast tissue at younger age may be one of the reason.
Patient-reported outcomes (PRO) in patients with metastatic breast cancer (MBC) from the VIRGO observational cohort study (OCS).
Authors: Kaufman Peter Andrew , Mayer Musa , Dreyer Nancy A. , Yim Yeun Mi , Yu Elaine , Su Zhaohui , Mun Yong , Sloan Jeff A. , Cleeland Charles S. 
Published: March 2020

e11051 Background: Limited data exist on patient (pt) experience and work productivity (WP) in MBC. VIRGO is a prospective OCS following >1200 pts with locally advanced or MBC receiving 1st-line hormonal therapy (HT) or chemotherapy (CT) in a real-world setting. We report baseline characteristics of 277 pts from the VIRGO PRO substudy and correlations between health-related quality of life (HRQoL), symptoms, activities of daily living, and WP. Methods: Symptom severity and interference (MD Anderson Symptom Inventory [MDASI]), functional status (Activity Level Scale [ALS] from the Rotterdam Symptom Checklist) and WP (Work Productivity and Activity Impairment Questionnaire) were assessed. Pts rated their HRQoL during the past week on a scale of 0–10. Results: See table. The five most severe symptoms at baseline were fatigue, decreased sexual interest, disturbed sleep, drowsiness, and emotional distress; these were reported with less severity in the HT cohort (24%-37% vs 42%-59%). Overall MDASI severity and interference correlated with WP measures in the CT (R = 0.46 to 0.78) and HT cohorts (0.36 to 0.94). Mean of the five most severe symptoms also significantly correlated with WP indices (R = 0.47 to 0.66). HRQoL correlated (p < 0.05) with all WP measures (R = -0.46 to -0.56) in the CT cohort and with % impairment while working (R = -0.65) and % overall work impairment (R = -0.71) in the HT cohort. In univariate regression analysis, MDASI symptom interference score was the best predictor of reduced WP (R2 = 0.52 while working; R2 = 0.48 for nonwork activities). Conclusions: MBC pts receiving CT and HT report significant work impairment. Results indicate moderate correlations between WP indices, HRQoL and symptom burden. [Table: see text]
Effect of inhibition of ErbB2-tyrosine kinase domain with lapatinib on cardiac dysfunction compared to the antibody trastuzumab in mice.
Authors: Tocchetti Carlo G. , Coppola Carmela , Rea Domenica , Castaldo Noemi , Guarino Lorena , Barbieri Antonio , Palma Giuseppe , Gala Marianna , Luciano Antonio , Giudice Aldo , Piscopo Giovanna , Capasso Immacolata , Scala Stefania , Monti Maria Gaia , Cittadini Antonio , Iaffaioli Rosario Vincenz , De Lorenzo Claudia , Arra Claudio , Maurea Nicola 
Published: March 2020

e11052 Background: Lapatinib (L) inhibits ErbB2-tyrosine kinase domain and has been reported (in the few existing trials) to be associated with a low risk of cardiac dysfunction (2%), while the prototypical Trastuzumab (T) increases the frequency of asymptomatic ejection fraction decrease by 3-18%, and the risk of heart failure by 2-4%. Here, we characterize our L murine cardiotoxicity model. Methods: Cardiac function was measured with fractional shortening (FS) by M-mode echocardiography, and with radial myocardial strain (%) with speckle tracking (ST) in sedated C57BL6 mice (2-4 mo. old) at day 0, and after 2 and 7 days of daily administration of L (100mg/kg/day orally), and in control mice. For comparison we used our well-established models with T (2.25 mg/kg/day, ip), and Doxorubicin (D, 2.17 mg/kg/day ip) as positive control. On excised hearts, we evaluated TNFα and CD68 by immunohistochemistry. Results: FS was reduced with D at 2 days: 52±0.2%, p<.001 vs 60±0.4% (sham), while L and T decreased FS only at 7 days (56±2 and 49±1.5%, respectively, both p<.05 vs 60±0.5% for sham). Interestingly, FS reduction with L was milder (p=.01) than with T. By immunohistochemistry, all treatments increased cardiac inflammation significantly vs controls. In particular, with T more myocytes were positive for TNFα (6±1%), and there were more CD68 cells/mm2 (72±6) compared to L (2±.2% and 27±4, respectively, both p<.02 vs T). D-treated hearts exhibited the highest values. Importantly, from a diagnostic point of view, with ST-echocardiogaphy, myocardial strain was reduced early at 2 days with L and T, predicting cardiotoxicity: 34±7% for L, 44±7% for T (p=NS), both p<.05 vs sham (66±.6%). Conclusions: Specifically targeting the tyrosine kinase domain of ErbB2 with L is less cardiotoxic than T. Nevertheless, both dysfunctions occur later than D. Myocardial strain identifies systolic dysfunction earlier than conventional echo and can be useful to predict cardiotoxicity in these settings. From a clinical point of view, we plan to evaluate the impact of ST echocardiography in early prediction of anti-ErbB2 toxicity in patients, while dissecting myocardial toxicity mechanisms in our animal models.
Trastuzumab-induced cardiotoxicity in early breast cancer: Evaluation of possible risk and protective factors.
Authors: Farolfi Alberto , Melegari Elisabetta , Aquilina Michele , Scarpi Emanuela , Ibrahim Toni , Maltoni Roberta , Sarti Samanta , Cecconetto Lorenzo , Pietri Elisabetta , Fedeli Anna , Faedi Marina , Nanni Oriana , Amadori Dino , Rocca Andrea 
Published: March 2020

e11054 Background: Adjuvant trastuzumab improves survival in early breast cancer (EBC) patients (pts). However, trastuzumab-induced cardiotoxicity (TIC) renders it necessary to identify possible risk and protective factors. Methods: A retrospective study was conducted in which medical charts of pts treated with adjuvant trastuzumab were reviewed. Hypertension, smoking history, dysthyroidism, obesity, hypercholesterolemia, diabetes mellitus and anthracycline cumulative dose were considered as potential risk factors. The relationship between the use of beta-blockers (BB), angiotensin-converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB) (either started before or during adjuvant therapy) and TIC development was also evaluated. TIC was defined as an absolute left ventricular ejection fraction (LVEF) decrease ≥15 points from baseline or an absolute LVEF <50%. The term heart failure (HF) referred to the New York Heart Association classification III or IV. Logistic regression was used to assess relative risks. Results: A total of 179 HER2-positive EBC pts (median 54 years, range 30-84) were evaluated. 154 (86%) were treated with anthracycline-based adjuvant chemotherapy. 78 (44%) did not show any risk factors, whereas 101 (56%) had at least one: hypertension (24%), smoking habit (16%), dysthyroidism (18%), obesity (12%), hypercholesterolemia (9%) and diabetes mellitus (4%). Among the 179 EBC pts, 78 (44%, 95% confidence intervals (CI) 37-51%) experienced TIC during their 12-month trastuzumab treatment and only 4 (2%, 95% CI 0-4%) developed HF. 14 pts stopped trastuzumab due to TIC. None of the risk factors described above was correlated with TIC development. A previous anthracycline cumulative dose > 240 mg/m2 conferred an odds ratio of 3.07 compared with treatmemt with lower doses (95% CI 1.29-7.27, p=0.0011). BB, ACEI and/or ARB neither reduced nor increased the risk of TIC. Conclusions: TIC is a frequent, albeit generally mild, adverse event in clinical practice. Closer collaboration between cardiologists and oncologists is needed to better define risk and protective factors of cardiotoxicity in order to avoid trastuzumab-therapy discontinuation.
Mechanisms of resistance to trastuzumab as neoadjuvant therapy in women with HER2-overexpressing operable breast cancer.
Authors: Jinno Hiromitsu , Sato Tomomi , Hayashida Tetsu , Takahashi Maiko , Hirose Shigemichi , Kitagawa Yuko 
Published: March 2020

e11060 Background: Despite clinical usefulness of trastuzumab, intrinsic or acquired resistance is a common clinical phenomenon. Potential mechanisms of resistance include aberrant downstream signaling caused by loss of PTEN and/or PIK3CA mutation, alternative signaling from IGF-1R and masking with MUC4. Methods: Patients with operable breast cancer received 12 cycles of weekly paclitaxel (80 mg/m2 IV) plus weekly trastuzumab (4mg/kg loading dose followed by 2 mg/kg IV) before surgery. All tumors were HER2-positive by immunohistochemistry (IHC) or fluorescence in situ hybridization. Expressions of ER, PgR, Ki67, PTEN, phosphorylated IGF-1R (pIGF-1R) and MUC4 were performed by IHC in core needle biopsy samples at baseline. ER and PgR status was assessed using Allred score. For Ki67 labeling index, a total of 400 cells were counted from three consecutive high-power magnifications. PTEN, pIGF-1R and MUC4 expression level was scored semiquantitatively based on staining intensity. PIK3CA mutation status was evaluated by sequencing of PIK3CA exons 9 and 20 using PCR amplification and direct sequencing. Results: Thirty-seven patients were enrolled and assessable for clinical and pathologic responses. The pCR rate was 48.6% (18/37). ER and PgR were positive in 18 (48.6%) and 16 (43.2%) patients, respectively. Negative, moderate and strong membranous expression of MUC4 was observed in 3 (8.1%), 18 (48.6%) and 12 (32.4%) patients, respectively. Membranous staining for pIGF1-R was negative in 24 (64.9%) patients. PTEN loss was observed in 33.3% (8/24) of the tumor examined. PIK3CA sequence analysis of the 13 tumors identified 2 mutations in exon 20 and 2 mutations in exon 9, corresponding to a PIK3CA mutation frequency of 30.8%. MUC4 and pIGF1-R status did not affect the pCR rate. PTEN loss and/or PIK3CA mutation were not significantly associated with pCR rate. pCR rate was significantly correlated with PgR negativity (p=0.004) and higher Ki67 (p=0.01). Conclusions: These data indicate that aberrant downstream signaling caused by loss of PTEN and/or PIK3CA mutation, alternative signaling from IGF-1R and masking with MUC4 were not important mechanisms of resistance to trastuzumab.