bluuebunny/crossref_metadata_2025 huggingface dataset:
Metronomic cyclophosphamide and capecitabine combined with lapatinib in heavily pretreated metastatic breast cancer (MBC) HER2-positive patients: 2-year update.
Authors: Cagossi Katia , Razzini Giorgia , Ferrari Alessia , Lazzaretti Maria Grazia , Leporati Meri , Silvestri Rosangela , Iadanza Manlio , Artioli Fabrizio
Published: March 2020

e11515

Background: Current therapeutic goals for MBC, as an incurable disease, are symptoms and prolonged disease control together with good quality of life. Metronomic chemotherapy has shown efficacy in patients with metastatic breast cancer. We evaluated the efficacy and tolerability of the combination of anti-angiogenetic activity of metronomic chemotherapy with a tyrosine kinase inhibitor such as lapatinib in heavily pre-treated MBC HER-2 positive patients. Methods: Metastatic breast cancer patients HER-2 positive with CEA or Ca15.3 elevated, prior systemic therapy for advanced disease, ECOG performance status < 1 and life expectancy longer than 3 months. MBC patients were treated with metronomic oral capecitabine (1500 mg daily) and cyclophosphamide (50 mg daily) plus lapatinib (1250 mg daily). The treatment was given until disease progression. Primary objective was time to progression (TTP) and safety. Results: Fifteenpatients were included. Median age was 52 years old (range 42-77). Median number of previous chemotherapy lines was 5 (range 2-10). Median time to tumor progression was 6 months (2-14). No complete response was observed. Eight out of fiftten patients (60%) with pre-existing only bone metastases achieved a stable disease and/or partial response and were still on treatment after 6 month of therapy. At the same time 100% of these patients exhibited significant reduction of serum marker concentrations. No grade 3-4 skin toxicity was reported. Hematological and gastro-intestinal toxicity was well tolerated (G1-2). No reduction of dose was needed. Conclusions: The combination of lapatinib with metronomic chemotherapy may lead to effective palliation despite extensive pretreatment at least in bone metastatic patients. The treatment appears to be less toxic than lapatinib and capecitabine at full dosage, especially in heavily pretreated MBC patients. The preliminary results suggest the need of a clinical trial to confirm a role of this combination to delay lapatinib resistance.
Evaluation of risk recurrence in early breast cancer assessed by Oncotype DX and tumor cell dissemination to blood and bone marrow.
Authors: Aktas Bahriye , Bankfalvi Agnes , Heubner Martin Leonhard , Kimmig Rainer , Kasimir-Bauer Sabine
Published: March 2020

e11516

Background: The OncotypeDX assay is a validated genomic test that predicts the likelihood of breast cancer (BC) recurrence, patients’ (pts) survival within 10 years of diagnosis and benefit of chemotherapy in early-stage, N0, ER-pos BC. In addition, disseminated tumor cells (DTC) in the bone marrow (BM) and circulating tumor cells (CTCs) in blood, especially stemness like tumor cells (slCTCs) including cells being able to perform epithelial-mesenchymal transition (EMT), have been associated with worse outcome in BC. Here we use OncotypeDX as well as the presence of DTCs, CTCs and slCTCs to evaluate the risk for recurrence in early BC pts. Methods: In total, 90 pts with newly diagnosed HER2-neg early stage BC received breast conserving surgery and sentinel lymphonodectomy. 17 pts were ER-/PR-, 12 pts ER+/PR-, 3 pts ER-/PR+ and 59 pts were ER+/PR+. Analysis of OncotypeDX and KI67 were performed. In case of G2 tumors, UPA and PAI1 were determined as further proliferation markers in tissue samples. Two BM aspirates from these patients were analyzed by immunocytochemistry for DTCs using the pan-cytokeratin antibody A45-B/B3. Furthermore, 2 x5 ml blood were analyzed for CTCs with the AdnaTest BreastCancer for the detection of EpCAM, MUC-1, HER-2, and beta-Actin transcripts. The recovered c-DNA was additionally multiplex tested for the presence of slCTCs using the AdnaTest EMT (multiplex RT-PCR for TWIST, AKT2, PI3K), and the AdnaTest TumorStemCell (ALDH1). Results: OncotypeDX was performed in 68/91 cases. 30/68 pts (44%) had a low RS, 29/68 pts (43%) an intermediate RS and 9/68 pts (13%) a high RS, respectively. BM aspiration could be performed in 70/91 pts with a positivity rate of 34% (24/70) for DTCs. CTCs were detected in 16/68 (25%) evaluable pts and slCTCs in 27/62 (44%) pts, respectively. In preliminary statistical analysis, KI67, PR and grading are showing association to RS as well as the presence of slCTCs. Tissue samples of patients with G2 tumors (N=65) underwent evaluation for UPA/PAI1analysis. Conclusions: Final statistical analysis for the complete data set including correlations to RS with all evaluable parameter will be available for presentation at the ASCO.
Benefit of chemotherapy after third line and evaluation of post-progression survival (PPS) in metastatic breast cancer (MBC): A single institution study.
Authors: Forcignano Rosachiara , Ciccarese Mariangela , Chiuri Vincenzo Emanuele , Cairo Giuseppe , Lupo Laura Isabella , Petrucelli Luciana , Gambino Abbondanza , Ronzino Graziana , Licchetta Antonella , Gnoni Antonio , Giannarelli Diana
Published: March 2020

e11517

Background: MBC remains an incurable disease with median survival of 2-3 years despite new drugs. The gain of benefit from third-line chemotherapy (CT3) in MBC is unknown. The validation of PPS as surrogate endpoint and its correlation to OS is under debate. Methods: From 2006-2012 we analyzed retrospectively consecutive 114 pts treated for MBC, 67 with at least 3 lines CT, to show the gain of benefit after CT3 and predictive factors of response to multiple lines of therapy. Moreover, we evaluated PPS for each line and its relation to OS. Results: Median age at M+ diagnosis was 58 years (29-87), median site of disease 2 (1-6), 66.7% visceral, HER-2+ pts 31.1%, median number of anti-Her-2 treatment 2 (1-6); 56.1% received a maintenance treatment (37% M1, 13% M2), median number of treatment 3 (1-8). Median OS for all pts was 47.1 (95%CI: 36.5-57.6). No difference in OS for pts with maintenance treatment vs not, respectively 49.1 vs 45.6 P=0.17. Multivariate Cox analysis showed that OS is related with ER/Pgr status (positive vs negative p=0.03) number of lines ( >3 vs ≤ 3) p< 0.0001 and number of metastatic sites (>2 vs ≤2) p=0.01. We evaluated relation between PFS and OS and PPS and OS until 6th line of therapy with a linear regression model. Conclusions: These results supported the use of chemotherapy after CT3. PFS and PPS are related to OS until 6th line of treatment. PPS as surrogate endpoint of OS is a valid hypothesis to be evaluated in prospective trials of MBC [Table: see text]
Correlation between body mass index and clinical and pathologic characteristics of breast tumor intrinsic subtypes.
Authors: Bas Murat , Yalcin Selim , Rahatli Samed , Kucukoztas Nadire , Dizdar Omer , Altundag Ozden
Published: March 2020

e11532

Background: In this study it is aimed to investigate the association between body mass index between the clinical and pathological characteristics of breast tumor intrinsic subtypes defined by ER, PR and HER-2 expression status. Methods: 885 breast cancer patients followed-up at the Medical Oncology Departments of Baskent University Faculty of Medicine from 1983- 2012 were evaluated. In accordance with the criteria of the WHO, patients with BMI (kg/m²) <18,5 were classified as underweight; 18.5-24.9 as normal; 25-29.9 as overweight, 30-34.9 as obese class I; between 35-39.9 as obese class II; and > 40 as obese class III (morbid). Results: Median age of the 885 patients included in the study was 53.9. The number of pre-menopausals were 348 (43.2%). Average BMI was 27.2 kg/m². Compared to Luminal B and HER-2 positive groups, the rate of T1 tumors were significantly higher (p=0.002 and p=0.006) in Luminal A group. There was a statistically significant (p=0.046) difference in LVI rates between the groups, with the Luminal B group showing a higher rate of LVI. There was a statistically significant difference in PR positivity between groups as PR positivity was more frequent in the group with BMI between 30.0-34.99 kg/m² compared to the groups with BMI less than 25 kg/m² and BMI between 25.0-29.99 kg/m² (p=0.035 and p=0.003). There was a statistically significant difference in HER-2 between groups as the rate of HER-2 negatives was significantly higher, and the rate of HER-2 positives were significantly lower in the group with 30.0-34.99 kg/m², compared to the group with BMI less than 25 kg/m² (p=0.002 and p=0.048). Conclusions: Our results indicate the association between body mass index and clinical characteristics of breast tumor intrinsic subtypes. Further research is needed to explore biological role of BMI on tumor intrinsic subtypes.
Identification of the activated form of the estrogen receptor (ER) in breast cancer (BC).
Authors: Gilles Erard M. , Bosq Jacques , Fuqua Suzanne A.W. , Zukiwski Alexander A. , Caillaud Jean-Michel , Gilles Barthelemy , Bonneterre Jacques
Published: March 2020

e11535

Background: : About 50% of ER positive (ERpos) BC are resistant to hormone treatment. In absence of ligand, ERs are evenly distributed in nuclei in normal tissue. Upon ligand binding, ERs dimerizes and form a discrete focal subnuclear distribution pattern (FDP), which are associated with transcriptional activation of ER. This ER FDP is observed in BC. We hypothesized that in BC that the presence/absence of ER in the FDP could predict antiestrogen activity. This study describes an immunohistochemistry (IHC) method, by which a biomarker could be developed to investigate this hypothesis. Methods: 37 paraffin embedded, formalin fixed archived BC samples were processed using 4 ER-alpha antibodies (Ab) under different IHC conditions to develop and refine this biomarker, the ER nuclear morphology was analyzed with standard microscopy at x1000. Interpretation of the IHC slides was done by an experienced pathologist. Standard ER, progesterone receptor (PR), and Ki67 testing were done. Tumor grade was obtained from the patients’ records. Analysis of the different Ab was with the kappa statistics. Comparison of the IHC technique to immunofluorescence (IHF) was done on 8 samples. Results: Consistent with prior research observations, tumors had two ER nuclear morphologies: 1. Diffuse pattern (D) where the ER was distributed evenly in a fine granular pattern, 2. Aggregate pattern (A) where the ER is distributed in distinct clumps or aggregates. This defined 3 tumor phenotypes: A cells only (A) 1% (4/37), D cells only (D) 65% (24/37), and a heterogenous mix of A + D cells (AD) 18% (7/37), ER Neg 14% (5/37). IHC and IHF analysis for ER nuclear morphology was concordant. The ER activation status (A/AD or D) was not correlated with staining ER intensity, ERpos %, PRpos%, but was correlated with % Ki67 staining (p=0.09) and tumor grade (0.035). Conclusions: ERpos early BC biopsies can be grouped in two categories based on ER nuclear morphology: A group with diffuse and homogenous nuclear staining, and a different group with heterogeneous area of cells having a nuclear pattern consistent with a functional or activated ER. These observations warrant clinical pathological studies to determine if this biomarker is potentially predictive of clinical outcomes.
An empirical assessment of breast cancer treatment charges by survival status.
Authors: Stenehjem David D. , Dahal Arati , Bellows Brandon Kyle , Brixner Diana I.
Published: March 2020

e11541

Background: Breast cancer treatment can be costly, but it remains unknown if charges differ between patients who die during treatment compared to survivors. The objective of this study was to assess annualized mean charges by survival status in patients with a diagnosis of breast cancer. Methods: The University of Utah Enterprise Data Warehouse was used to analyze patients ≥18 years with a diagnosis of breast cancer identified by ICD-9 code (initial diagnosis defined as index date) treated at the Huntsman Cancer institute (HCI) from 2002-2010. The HCI Tumor Registry was used to determine stage at diagnosis and other cancers. Cause and date of death was captured from the Utah Population Database. Cancer-related (CR) and non-CR charges were by ICD-9 codes from index date until death or end of the follow-up period, were weighted by the inverse probability of survival, and annualized. Generalized linear models (GLM) with gamma distribution and log link function were used to examine charges by survival status, while adjusting for baseline characteristics including demographics, stage, and comorbidities. Results: There were 1783 patients included, of which 296 (17%) died. Compared to survivors, deceased patients were older (mean age 62 vs. 56), more were diagnosed with stage IV disease (17% vs. 3%), and fewer with stage I (24% vs. 45%); all p<0.001. Mean unadjusted annualized CR charges were not different between groups (deceased $34,310 vs. alive $32,797; p=0.64), but non-CR charges were higher for deceased patients ($39,926 vs. $16,538; p<0.001). GLM results indicated deceased patients had 90% higher annualized CR charges relative to survivors (p<0.001) and higher charges for stages I, II, and III (125%, 86%, and 69%, respectively; all p<0.001). Deceased patients had 124% higher annualized non-CR charges relative to survivors (p<0.001) and higher charges for stages I, II, and III (174%, 146%, and 107%, respectively; all p<0.001). Charges did not differ between groups for stage IV patients. Conclusions: When adjusting for confounders, death was associated with higher CR and non-CR charges, except in patients with stage IV disease at diagnosis. Patients who died during treatment may have had more aggressive disease leading to higher charges.
Attitude of Italian oncologists toward fertilty preservation in patients with early breast cancer.
Authors: Frassoldati Antonio , Barni Sandro , Amoroso Domenico , Collovà Elena
Published: March 2020

e11547

Background: Patient’s desire for fertility preservation is a frequently underestimated problem in oncology clinical practice. Even if several different approaches have been suggested to maintain fertility in early stage breast cancer patients undergoing adjuvant chemotherapy, few women undergo to such procedures or are referred to a specialized team. Methods: Between April and July 2011, an electronic questionnaire regarding the treatment attitude in early breast cancer in premenopausal women was submitted to Italian oncologists, and 611 (female 52%, age range 25-65, 81% from general hospitals, 19% from research institute) filled in the questionnaire. Among the items, we explored also the issue of fertility preservation in women candidate for adjuvant chemotherapy and hormones. We compared the survey results (examined according to sex, age, working institution and geographic origin) with the recommendations available from guidelines of oncology and gynecology societies. Results: A pregnancy test before starting chemotherapy is considered mandatory only by 49.5% of oncologists, independently from age and type of treatment. In order to maintain fertility, several guidelines recommend eggs or embrio freezing, whereas the use of LHRH-analogs is recommended only in the contex of research trials. In our survey, the eggs freezing is considered the preferred method by 24,8% of Italian oncologists only, while 6% suggest cryopreservation of ovarian tissue. Embrio freezing is preferred by <1% of oncologist. However, the majority of Italian oncologists considers the administration of LHRH-analog the treatment of choice to maintain fertility (independently from the hormone receptor status of the tumor in 83% of cases). No significant differences as by type of institution, geographic location, and physician’s age has been observed. Conclusions: The use of LHRH-analog is the preferred method by Italian oncologists for fertility preservation. A recent analysis of literature regarding the use of LHRH-analogs by Italian Society for Medical Oncology using the GRADE method suggest an important role of this drugs, even if not yet conclusive for their efficacy (level of evidence 1+, Recommendation “slightly positive”).
Safety assessment of trastuzumab diluted in 100 ml of saline in the treatment of HER2-positive breast cancer patients.
Authors: Abe Hajime , Mori Tsuyoshi , Kawai Yuki , Tomida Kaori , Kubota Yoshihiro , Umeda Tomoko , Tani Tohru
Published: March 2020

e11555

Background: The infusion rate is considered to affect incidence and severity of infusion reaction (IR) caused by infusion of protein formulations. Trastuzumab (TRS) is approved for 90-minute infusion as the initial dose followed by 30-minute infusion with 250 ml saline. We evaluated the safety of TRS intravenously administered over 30minutes with 100 ml saline to reduce burden of patients although safety of infusion with 250 ml saline is established. Methods: Women with HER2 positive breast cancer, ≥18 years and ≥55% left ventricular ejection fraction (LVEF) were registered in the study. Patients received 8mg/kg of TRS 250 ml over 90 minutes diluted in 250 ml saline followed by 6mg/kg of TRS in 100 ml saline over 30 minutes in a three-week cycle. The primary endpoint of this study was the incidence of infusion reactions, and secondary endpoints were as follows: incidence of adverse events and effects on cardiac function. Results: Between June 2011 and June 2012, a total of 31 patients were recruited; 24 for adjuvant therapy and seven with metastases. The median age was 59 years (range, 39 to 82). Hormone receptor was positive in 18 patients (58%). Previous treatment with anthracyclines was reported in seven patients and radiation therapy in fourteen patients. The total number of TRS doses ranged from 5 to 17 with the median of 15. Mild IR occurred in two patients and rash occurred in one patient at the first dose. However, no IR and adverse events were observed after reducing to 100 ml saline. The average LVEF measured every 3 months was between 62.3% and 64.8%. No significant decrease in LVEF was reported with the largest decrease of 8% in one patient at the 12th month on treatment. Conversely, brain natriuretic peptide levels tended to decrease as the number of received doses increased. None of the subgroup analysis (age groups, adjuvant vs. metastatic setting, previous anthracycline treatment, and previous radiotherapy) showed statistical significance. Conclusions: Intravenous infusion of TRS with 100 ml saline over 30 minutes in breast cancer patients is considered safe based on results from the study. The safe treatment with shorter infusion time has benefit for both healthcare professionals and patients. Clinical trial information: UMIN000006710.
Role of hypertension on new onset congestive heart failure in patients receiving trastuzumab adjuvant chemotherapy for early breast cancer.
Authors: Maurea Nicola , Russo Giulia , Gori Stefania , Piscopo Giovanna , Cipresso Clemente , Coppola Carmela , Oliva Stefano , Cioffi Giovanni , Tuccia Fausto , De Laurentiis Michelino , Pacilio Carmen , Capasso Immacolata , Iaffaioli Rosario Vincenz , Tarantini Luigi
Published: March 2020

e11556

Background: Adjuvant trastuzumab therapy improves survival of Human Epidermal growth factor Receptor 2 (HER2)-positive women with early breast cancer (EBC). Trastuzumab-induced cardiotoxicity is not uncommon, occurring prevalently asymptomatic in the first three months of therapy. In the setting of community patients, the incidence, timing and phenotype of new onset congestive heart failure (CHF) is unknown. Methods: 499 consecutive HER2-positive women (mean age 55+11) with EBC treated with Trastuzumab between January 2008 and June 2009 at 10 Italian institutions were followed-up for 1 year. We evaluated incidence, time of occurrence, clinical features associated with CHF. Left ventricular ejection fraction (LVEF) was evaluated by echocardiography at baseline and 3-6-9-12 months during Trastuzumab therapy. Results: CHF occurred in 16 patients (3.2%), who were older and had a higher prevalence and higher degree of hypertension in comparison with patients who had not CHF. All CHF patients had a significant reduction in LVEF with a mean peak of – 12 points % detected at 3-month follow up. CHF occurred in 7 patients (44%) within 3-month follow-up, 4 patients (25%) between 3-6 months, 3 patients (19%) between 6-9 months and 2 patients (12%) between 9-12 months. Trastuzumab was discontinued in 10 of 16 patients and re-started in 5 after LVEF recovery. New onset CHF was predicted by the presence of hypertension (OR 2.9 [CI 1.1 – 7.9]. Conclusions: In clinical practice new onset CHF occurs seldom in HER-positive women with EBC, prevalently in the first six months of therapy. CHF is invariably associated with a significant reduction in LVEF and is predicted by a history of hypertension.
Lapatinib with trastuzumab for heavily treated HER2-positive metastatic breast cancer (mBC).
Authors: Sotelo Miguel J. , Manso Luis , Garcia Saenz José Ángel , Ciruelos Eva M. , Moreno Fernando , Mendiola Cesar , Callata Hector , Ghanem Ismael , Cabezas Santiago , Gonzalez-Larriba Jose-Luis , Diaz Rubio Eduardo
Published: March 2020

e11561

Background: Trastuzumab and lapatinib show complementary and non-cross resistant mechanisms of anti-HER2 action. Dual HER2 blockade has been preclinically and clinically assessed with encouraging results. Trastuzumab and lapatinib combination is effective in terms of survival in patients with heavily pretreated HER2-positive mBC. We aim to report our experience with lapatinib plus trastuzumab in this setting. Methods: Descriptive retrospective study of trastuzumab plus lapatinib activity in patients with HER2-overexpressing metastatic breast cancer treated in two institutions from 01/2007 to 12/2012. The objective of this analysis is to report the response rate (RR), progression-free survival (PFS) and toxicity. Results: 23 HER2-positive mBC patients previously treated with trastuzumab received trastuzumab plus lapatinib based therapy. 15 patients (65%) received 2 or more previous lines. 17 patients (74%) had visceral disease. Chemotherapy (CT) was added to the dual HER2 blockade treatment in 13 patients (56%) whereas hormonotherapy (HT) was added in 8 patients (35%) and 2 patients (9%) received lapatinib plus trastuzumab without any other agent. Chemotherapeutic drugs most used were: capecitabine (54%) and vinorelbine (15%). RR: partial response 22% (5/23), stable disease 39% (9/23). Median of follow-up was 11 months. PFS in the overall population was 4 months. PFS in patients with CT was 5 months, while PFS in patients with HT was only 2. PFS in hormone receptor positive and negative was 3 and 5 months respectively. The most common toxicities were: diarrhea (48%), anemia (39%), asthenia (39%) and hand-and-foot syndrome (17%). Grade ≥ 3 toxicity was diarrhea (26%) and hand-and-foot syndrome (9%). The incidence of cardiotoxicity was 9% (grade 2). Conclusions: These findings suggest that dual HER2 blockade in combination with CT is feasible and active in heavily pretreated HER2-positive mBC patients. However, further investigation is warranted to demonstrate superiority over sequential blockade with trastuzumab and lapatinib in this setting.
Prediction of benefit from treatment beyond the first line in patients with metastatic breast cancer (MBC).
Authors: Bonotto Marta , Gerratana Lorenzo , Minisini Alessandro , Poletto Elena , Russo Stefania , Andreetta Claudia , Mansutti Mauro , Fasola Gianpiero , Puglisi Fabio
Published: March 2020

e11565

Background: Despite the availability of several therapeutic options for MBC, palliative treatments beyond 1st line lack of predictive factors that could help clinical decision making. We aimed to determine which is the impact of benefit at 1stline into the benefit from subsequent therapeutic lines. Methods: We analyzed a consecutive series of 472 MBC patients treated with chemotherapy (CT) and/or endocrine therapy (ET) at the Department of Oncology of Udine, Italy, between 2004 and 2012. We evaluated Progression Free Survival at 1st (PFS1), 2nd (PFS2), 3rd (PFS3) and 4th (PFS4) line of treatment. Three distinct analyses were conducted: the first for the lines of CT, the second for the lines of ET and the third by considering both CT and ET as a line of treatment. A PFS longer than 6 months was defined as “6-month benefit". Results: Median Overall Survival was 34.5 mo (25th – 75th percentile: 14.5 – 58.8), median overall PFS1 and PFS2 was 8.9 mo and 4.3 mo respectively. Median PFS1 and PFS2 in CT lines only was 7 mo and 3.7 mo, respectively. Median PFS1 and PFS2 in ET lines only was 9.4 mo and 4.6 mo respectively. Overall, 289 patients (63.5%) presented 6-month benefit at 1st line, 128 (40.5%) at 2nd, 76 (33.8%) at 3rd and 34 (23.3%) at 4th. Not having a 6-month benefit in overall PFS1 was associated with a lack of benefit both at 2nd line (OR=0.48; p=0.0026) and at any line beyond the 1st (OR=0.39; p< 0.0001). Taking into consideration CT lines only, not having a 6-month benefit in CT PFS1 was associated with a lack of benefit both at 2nd line (OR=0.45; p=0.0072) and at any line beyond the 1st (OR=0.43; p=0.0026). A lack of benefit at the 1st ET line was not associated with further ET outcome neither in 2nd line nor in any line beyond the 1st. Stratification according to immunophenotype highlighted a statistical significance only among HER2 positive tumors (OR=0.2; p=0.0152 in 2nd line and OR=0.14; p=0.0036 beyond 1st line). Conclusions: Our results suggest that the absence of a “6-month benefit” in PFS1 predicts a lack of benefit in subsequent therapy lines, especially in HER2 positive disease. However, a lack of benefit at first line ET appears not to be detrimental to further anti-hormonal lines.
Relationship of anti-proliferative activity of TAS-108, a steroid anti-estrogen, and high expression of ERα in MCF7 cells.
Authors: Cheong Ye-Whang , Kim Young Choi , Kim Tae-Hoon
Published: March 2020

e11566

Background: TAS-108 is an anti-estrogen that binds to both ERα and ERβ and has potent anti-proliferative activity in vitro and in vivo assay. Recently, the phase II clinical study of TAS-108 showed that it has competitive clinical benefic with lower level of adverse effects. However, the effect of TAS-108 on molecular mechanism, including ER dimerization, remains largely uninvestigated. Methods: The plasmids containing ERα or ERβ fused with N- and C-terminal fragments of firefly luciferase were constructed for split luciferase complementation assays. The resulting plasmids were transfected in HEK293 cells for 24 hr and TAS-108 was added to the media for 6 hr. For RT-qPCR of AREG and TFF1 and proliferation assay, ERβ was transfected in MCF7 cells for 24hr. The proliferation level was determined by measuring the fluorescent level induced by Prestoblue reagent. Results: Using split luciferase complementation assay, we determined that TAS-108 induced ERα/β heterodimerization about 100-fold more potently than ERα/α homodimerization. Increasing the ERβ level by transfection in MCF7 cells (MCF7-ERβ), potency of TAS-108 was increased significantly; 30nM TAS-108 was suitable to block the E2 mediated increase of AREG and TFF1 expression and significantly decrease proliferation of MCF7-ERβ. Conclusions: Taken together, these data suggest that TAS-108 has a higher affinity for ERα/β heterodimerization than ERα/α homodimerization and TAS-108 shows more effective anti-proliferative activity by blocking the expression of E2-induced proliferative genes when coupled with increased levels of ERβ. These findings also underscore the molecular role of ERβ in the biology and suggest the possibility of the compound inducing ERα/β heterodimerization as anti-breast cancer drugs.
Coagulation assays in breast cancer: Correlation of plasma D-dimer with tumor load and invasiveness in breast cancer patients.
Authors: Karabulut Senem , Kilic Leyla , Ciftci Rumeysa , Yildiz Ibrahim , Sen Fatma , Keskin Serkan , Tastekin Didem , Tas Faruk
Published: March 2020

e11592

Background: Activated coagulation and fibrinolytic system in cancer patients is associated with tumor stroma formation and metastasis in different cancer types. The aim of this study is to explore the correlation of blood coagulation tests for various clinicopathologic factors in breast cancer patients. Methods: The study involves treatment-naive female breast cancer patients. Pretreatment blood coagulation tests including prothrombin time (PT), activated partial thromboplastin time (APTT), prothrombin activity (PTA), INR, D-dimer, fibrinogen levels and platelet counts were evaluated. Results: Between February 2010 and June 2011, 123 consecutive female patients with breast cancer were enrolled into the study. Median age of diagnosis was 51 years old (range: 26-82). 22 % of the group consisted of metastatic breast cancer patients. The plasma level of all coagulation factors revealed statistically significant difference between patient and control group except for PT (p<0.001 for all variables except for PT; p=0.08). Elderly age (>50 years) was associated with higher D-dimer levels (median 174 vs 345 U/ml, p=0.003). Metastatic patients exhibited significantly higher D-dimer values when compared with early breast cancer patients (median 205 U/ml vs 407.2 U/ml, p=0.049). Advanced tumor stage (T3&T4 vs T1&T2) was associated with higher INR (median 1.15 vs 1.09, p=0.05) and lower prothrombin activity (median: 82 % vs 70 %, p=0.025). Conclusions: Plasma D-dimer levels are elevated among metastatic breast cancer patients. Involvement of axillary lymph nodes and hormone receptor status does not seem to have an effect on coagulation parameters. For daily practice, D-dimer may be a suitable test for evaluation of disease extent before designing treatment strategy.
Tubular carcinomas of the breast: A comparison of features and survival outcomes versus low grade ductal and lobular carcinomas in the SEER database.
Authors: Romano Andrew Michael , Smolkin Mark E , Dillon Patrick Michael
Published: March 2020

e11596

Background: Tubular carcinoma of the breast (TC) is a rare histologic subtype of breast cancer considered to have a favorable prognosis relative to other histologies. TC is by definition low grade. TC is described to have clinical behavior similar to low grade ductal and lobular breast cancers, but due to its infrequent presentation, long-term follow-up studies of TC are lacking. Methods: The Surveillance, Epidemiology and End Results database was queried to include the years 1988-2009, selecting for patients with either grade 1 TC or grade 1 ductal and lobular breast cancer (G1BC). Data collected included age at diagnosis, race, stage, receptor status, overall survival, and surgery type. Two Cox proportional hazard models were assessed for differences between TC and G1BC, adjusting for age at diagnosis. Results: In SEER 18, 115,945 cases of TC+G1BC breast cancer are found, with 6.1% classified as TC. Of TC cases, 91% are stage 1, while 71% of GIBC are stage 1. Presenting stage 3 or 4 disease occurred in only 4.7% of G1BC versus 0.68% of TC cases. Due to the rarity of advanced disease, we analyzed early stage disease. For early Stage (1-2) breast cancer, mean age was 61.5 years for TC and 63.5 years for G1BC. The TC cases were 92% white, 4% black, 97% Estrogen Receptor (ER) positive, 82% Progesterone Receptor (PR) positive. Of G1BC cases, 88% were white, 5% black, 96% ER positive, 84% PR positive. Treatment differed with 76% of TC patients receiving lumpectomy versus G1BC where 65% received lumpectomy (p<0.001). There was no significant difference in overall survival between Stage I TC and G1BC (p=0.98), or between Stage II TC and G1BC (p=0.075), with the survival estimate higher for TC. Conclusions: In this large-scale analysis, TC was limited to early stage disease and there was no difference in overall survival between patients with early stage TC and early stage GIBC. There were similar receptor statuses and baseline characteristics, but more conservative surgical treatment in TC. Because no survival difference exists for early stage disease, the finding of tubular histology to guide treatment decisions may not be warranted.
Bevacizumab for advanced breast cancer: Hope, hype, and hundreds of headlines.
Authors: Fralick Michael , Fung Christina , Ray Monali , Booth Christopher M. , Mallick Ranjeeta , Burke Matthew , Clemons Mark
Published: March 2020

e11597

Background: On February 22, 2008, the Food and Drug Administration (FDA) granted accelerated approval for the use of bevacizumab (Avastin) in metastatic breast cancer. Based on the results of subsequent clinical trials this accelerated approval was revoked on November 18, 2011.In this study we categorize and analyze the newspaper reports related to bevacizumab use in advanced breast cancer. Methods: Using the FACTIVA media database, we reviewed all newspaper reports published in the United States and Canada from January 4,2002 to January 4, 2012 with the words “breast cancer” and “Avastin” or “bevacizumab”. Articles were classified as pre-approval (Jan 4 2002 – Feb 21 2012); approval (Feb 22 2008 – Nov 17 2011); or post-approval loss (Nov 18 2011 – Jan 4 2012). Information related to benefits, side effects, costs, interviewees, and article tone and theme were abstracted from each article by two independent reviewers. Differences between the 3 study phases were compared using the Chi square test. Results: 353 articles met our study inclusion criteria. The major article themes evolved over each study period. Reports having a positive headline tone (36%, 18%, 9%; p=0.0004) and/or positive article tone (42%, 19%, 9%; p<0.0001) declined with each study period. The proportion of articles discussing side effects (25%, 49%, 60%; p<0.0001) and financial costs (19%, 46%, 41%; p<0.0001) increased while those discussing efficacy decreased (82%, 59%, 15%; p<0.0001) with each study period. Drug representatives were most likely to be quoted in newspaper articles prior to bevacizumab’s approval (33%, 23%, 11%; p=0.015). Conclusions: Media reports are a common source of medical information for patients, practitioners, and policy-makers. Although we cannot discern cause from effect, we did observe substantial fluidity of media reports over time.
Comparative efficacy of everolimus versus fulvestrant for hormone-receptor–positive (HR+) advanced breast cancer (ABC) following progression/recurrence after first-line treatment: A network meta-analysis.
Authors: Bachelot Thomas Denis , Jerusalem Guy Heinrich Maria , Cikalo Maria , McCool Rachael , King Sarah , Duffy Steven , Glanville Julie , Varley Danielle , Zhang Jie
Published: March 2020

e11602

Background: Everolimus (EVE), an oral mammalian target of rapamycin (mTOR) inhibitor, is approved in combination with exemestane (EXE) to treat postmenopausal women (PMW) with HR+, human epidermal growth factor receptor-2–negative (HER2–) ABC that progressed after nonsteroidal aromatase inhibitor therapy. Fulvestrant (FUL), an estrogen receptor antagonist, is another treatment option for PMW previously treated with endocrine therapy. However, the comparative efficacy of EVE + EXE vs FUL is unknown. Methods: Six randomized, controlled trials in HR+, HER2–ABC patients were identified by systematic literature review (Cochrane library, National Horizon Scanning Centre, and NICE Web sites) that formed a network permitting indirect comparisons of EVE + EXE or EVE + tamoxifen (TAM) vs FUL: BOLERO-2, CONFIRM, EFECT, Paridaens (2008), SoFEA, and TAMRAD. All 6 trials had EXE, TAM, or FUL 250 mg as the common comparator to form the network. Relative efficacy of EVE and FUL was obtained using a Bayesian network meta-analysis based on these 6 trials. The primary endpoint was local assessment of progression-free survival (PFS) or time to progression (TTP). The hazard ratio (HR) of EVE + EXE relative to FUL and its 95% credible intervals (CrI) were calculated. Evidence of a difference between treatments is suggested by the 95% CrI not including 1. A HR <1 indicates that the hazard rate is higher in the comparator group and that the treatment is more effective. Results: EVE + EXE was found to be more efficacious for PFS/TTP than FUL 250 mg (HR = 0.47; 95% Crl, 0.38-0.58) and more efficacious than FUL 500 mg (HR = 0.59; 95% Crl, 0.45-0.77). EVE + TAM was found to be numerically better for PFS/TTP than FUL 250 mg (HR = 0.65; 95% Crl, 0.40-1.04) and numerically better than FUL 500 mg (HR = 0.81; 95% Crl, 0.49-1.33). Conclusions: The indirect evidence from this analysis suggests that EVE in combination with EXE is more efficacious than FUL 250 and 500 mg in PMW with HR+, HER2– ABC that progresses after endocrine therapy. These data should be interpreted with caution as there is no randomized trial that directly compares EVE + EXE vs FUL.
Safety and efficacy of dicarbamin in patients with early breast cancer receving DAC (docetaxel, doxorubicin, cyclophosphamide) chemotherapy in adjuvant setting.
Authors: Kopp Mikhail V. , Koroleva Irina , Mochalova Anastasia , Shaplygin Leonid
Published: March 2020

e12012

Background: One of the most serious potential side effects of chemotherapy is neutropenia. Grade 3 and 4 neutropenia is especially problematic because of increased incidence of infections, hospitalization, antibiotic treatment, necessity to reduce therapy intensity. The intensity of adjuvant chemotherapy is the key to successful treatment. Dicarbamin is agent for the prevention of chemotherapy-induced neutropenia. Dicarbamin therapy decreases dystrophic changes in myeloid progenitor cells and decreases the relative number of cells with signs of apoptosis. We conducted an analysis of efficacy of dicarbamin in patients during docetaxel-based chemotherapy. Methods: Between May 2011 and July 2012, 87 patients with early breast cancer were treated with adjuvant DAC regimens (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 every 3 weeks). All patients were female. All patients were treated with these regimens without prophylactic growth factor support. 42 patients of control (group A) were not given any prophylaxis of neutropenia. 45 patients (group B) were given dicarbamin 100 mg/day on day 5 before chemotherapy administration. Treatment with dicarbamin continued for all treatment period. Neutropenia was evaluated with Common Toxicity Criteria, Version 3.0. Results: Median age was 47 (29 – 55). Grade 4 neutropenia was reported in 13 (30.9%) patients treated without dicarbamin (A) and in 8 (17.7%) patients treated with dicarbamin (B). Grade 4 neutropenia was observed in 39 cycles in group A and in 22 cycles in group B (p=0.016). The beneficial effect of dicarbamin was also demonstrated by a quick recovery of granulocytes levels than in controls. In 17 (37.7%) patients treated with dicarbamin granulocytes levels were normal all period of chemotherapy. The dose intensity of chemotherapy was more in group with dicarbamin prophilaxis. The toxicity of dicarbamin was not observed. Conclusions: Dicarbamin is an active agent for prophylaxis of neutropenia without specific toxicity. The intensity of the DAC-chemotherapy was more in group with dicarbamin prophilaxis.
Hepatic trans-arterial chemoembolization (TACE) in metastatic breast cancer.
Authors: Damian Silvia , Tessari Anna , Capri Giuseppe , Mariani Paola , Bianchi Giulia Valeria , Mariani Gabriella , Ricchini Francesca , Sica Lorenzo , De Benedictis Elena , Cresta Sara , Lanocita Rodolfo , Spreafico Carlo
Published: March 2020

e12017

Background: Liver metastasis is one of the most frequent cause of death in breast cancer patients. Among loco-regional approaches available for solid tumor liver metastasis, TACE allows a prolonged intra-lesion exposure to chemotherapeutic agents. Initial studies have highlighted a benefit in terms of response rate (RR) and overall survival (OS) in breast cancer patients treated with TACE versus systemic chemotherapy. Methods: We have retrospectively evaluated 14 patients affected by breast cancer with liver metastasis. Patients had been selected for liver TACE according to the presence of liver metastasis as only site of disease, or in the event of further sites of metastasis that were stable or in response from the previous treatment. All the patients received one or more TACE with DC-Bead (Biocompatibles UK) 100-300 micron, loaded with a chemotherapeutic agent (doxorubicin, paclitaxel).The systemic therapy received by patients before TACE could be confirmed or changed according to disease response. Objective of the study was to evaluate the response rate to TACE and its correlation with the response to the very last treatment performed before it. As surrogate of efficacy, time to progression (TTP) and OS were analyzed. Results: Among the 14 treated patients (5 heavily pretreated, with more than three lines of chemotherapy) only one obtained a complete remission (RC). Four patients presented a partial remission (PR). Three of them were progressing from previous treatment and one had a PR. Stable disease (SD) after TACE was obtained in four cases: two of them had a progressive disease (PD) before TACE and two had a responsive disease. Five patients did not respond to TACE (one with PR from the previous line of therapy). Median TTP observed in responsive patients (CR + PR) was 4.5 times higher than non-responders (PD) (13.2 vs. 2.9 months). Patients with SD had a median TTP of 4.3 months. Median OS of responsive patients was 25.6 months vs. 17.5 and 19.2 months of patients with SD or PD respectively. Conclusions: In our experience, chemoembolization can represent a valid therapeutic option in breast cancer patients with liver metastasis, independently from the response to the previous systemic therapy, and may prolong survival.
Thirteen miRNAs involved in the response of breast cancer cells to doxorubicin.
Authors: Tormo Eduardo , Pineda BegoÃƒÂ±a , Ballester Sandra , Burgues Octavio , Serna Eva , Lluch Ana , Eroles Pilar
Published: March 2020

e12019

Background: Mature microRNAs (miRNAs) are a class of naturally occurring, small non-coding RNA molecules, about 21–25 nucleotides. Growing evidence shows that miRNAs exhibit a variety of regulatory functions related to cell growth, development, and differentiation, and are associated with a wide variety of human diseases. Several miRNAs have been linked to cancer; since expression analysis studies have revealed perturbed miRNA expression in tumors compared to normal tissues. As a consequence, human miRNAs are likely to be highly useful as biomarkers, especially for future cancer diagnostics, and are emerging as targets for disease intervention. Since doxorubicin (DOX) has been used for a long time in breast cancer treatment, and resistance mechanisms are not clear understood, the aim of this work was to find a miRNA expression profile that could explain the regulation in different breast cancer cell lines under DOX treatment. Methods: Three breast cancer cell lines (MDA-MB-231, MDA-MB-468, and MCF-7) were cultured in normal conditions and also treated with DOX. Total RNA containing small non-coding RNA was isolated and its expression profile was performed by using GeneChip miRNA 2.0 array. Real time PCR validation was carried out to confirm the results. Results: Principal Component Analysis (PCA) of the small non-coding RNA profiles showed different expression patterns between normal conditions and DOX treatment in each cell line separately. Taken together in a Heat Map, miRNA expression profiles of MDA-MB-231 and MDA-MB-468 cell lines were closer in both normal and DOX treatment conditions, while miRNA expression profile of MCF-7 cell line showed strong differences. Total of 13 common miRNAs between the three cell lines were found to be significantly affected by DOX treatment. PCR validation confirmed the results obtained. Conclusions: We conclude that 13 common miRNAs are responsables of changes compared to treatment with DOX in breast cancer cell lines MDA-MB-231, MDA-MB-468 and MCF-7. This miRNAs are mainly related with cellular processes such as cell differentiation, vascularisation, apoptosis and cell proliferation and also involved in other cellular processes, such as cell migration.
Is young age a poor prognostic factor in triple-negative breast cancer patients? Analysis of 363 patients from single institution registry.
Authors: Fayaz Mohamed Salah , Demian Gerges Attia , El-Sherify Mustafa , Abuzalouf Sadeq , George Thomas , Samir Suzanne , Eisa Heba El-Sayed , Nazmy Nashwa
Published: March 2020

e12023

Background: Young age is a known independent poor prognostic factor for breast cancer. Few data exist about validating such prognostic factor in triple negative subtype of breast cancer. In this study, we evaluate the prognostic value of young age presentation in triple negative breast cancer (TNBC) patients who were diagnosed in Kuwait Cancer Control Center. Methods: This is a retrospective analysis of 363 patients diagnosed with TNBC between July 1999 and June 2009. Of these, 27% were diagnosed at or below the age of 40. Chi-square test was used to correlate the age with other prognostic factors. Survival measurements were estimated using Kaplan-Meier analysis. Statistical significance was calculated using the log-rank test. Results: There was no correlation between young age at presentation and other prognostic factors including grade, T stage, lymph node status, lymphovascular invasion, and Ki67 positivity. Similarly, young age was not statistically associated with poorer 5-years overall survival (78% for patients < 40 years compared to 72% for those > 40 years; p = 0.13), disease free survival (66% vs. 61%; p = 0.5) or locoregional recurrence free survival (81% vs. 83%; p = 0.7). Conclusions: Young age does not seem to negatively impact the survival of TNBC patients nor associated with poor prognostic factors in our study population. Further studies are needed to define new prognostic factors, e.g. molecular markers, in this subtype of patients rather than the conventional clinicopathologic prognostic factors.
Epirubicin/cyclophosphamide followed by docetaxel as the primary systemic therapy for locally advanced breast cancer: The final analysis of a phase II study.
Authors: Hirano Akira , Kamimura Mari , Ogura Kaoru , Hattori Akinori , Okubo Fumie , Inoue Hiroaki , Kinoshita Jun , Fujibayashi Mariko , Shimizu Tadao
Published: March 2020

e12026

Background: The aim of this study was to evaluate the efficacy and safety of epirubicin/cyclophosphamide (EC) followed by docetaxel as the primary systemic therapy for locally advanced breast cancer. We previously reported pathological and objective response of patients receiving this treatment (Anticancer Res 28:4137-42, 2008). Another follow-up period of 5 years (5y) has since passed, and 5y overall survival (OS) and relapse-free survival (RFS) rates were determined. Methods: The primary endpoints were pathological and objective response in the breast and axilla, and toxicities. The secondary endpoints were the rate of breast-conserving surgery and the 5y OS and RFS rates. Patients with histologically diagnosed invasive breast cancer of T2-4 (>3 cm) or N1-3 were included in this study. The expected rate of pCR was 25%, and the sample size was calculated using the Simon method, with a type I error of 5% and a study power of 80%. The target enrollment was estimated to be 40 evaluable patients. pCR was defined as no evidence of residual invasive cancer, either in the breast or axilla. Patients received E (90 mg/m2) and C (600 mg/m2) every 3 weeks for 4 cycles followed by docetaxel (70 mg/m2) every 3 weeks for 4 cycles. Trastuzumab was not added to the regimen. Results: Forty-six patients were enrolled in this study. pCR were observed in 6 patients and the pCR rate was 13.0% (95% confidence interval, 3.4-22.7%). In particular, patients with HER2 positive tumor had a significantly higher rate of pCR than others (40.0% vs. 5.6%; p=0.0096). Overall, 5y OS was 93.2% and 5y RFS was 72.9%. According to ER, PgR, HER2 status, the following 4 subtypes were classified: luminal (ER and/or PgR+, HER2-; n=28), luminal-HER2 (ER and/or PgR+, HER2+; n=3), HER2 (ER and PgR-, HER2+; n=7) and triple negative (ER, PgR and HER2-; n=8). 5y OS and RFS were 96.4% and 70.6% in luminal type, 100% and 50% in luminal-HER2, 71.4% and 57.1% in HER2, 100% and 100% in triple negative, respectively. Conclusions: EC followed by docetaxel was an effective and well-tolerated treatment, and it is suggested that this treatment provides survival benefit especially for patients with triple-negative breast cancer.