bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I dose escalation study of oral lapatinib in combination with docetaxel in patients with HER2-positive locally advanced or metastatic breast cancer (LAMBC): Initial safety and tolerability results.
Authors: Fumoleau Pierre , Dalenc Florence , Mailliez Audrey , Veyret Corinne , Bonneterre Jacques , Guillemet Cecile , Zanetta Sylvie , Moldovan Cristian , Guiu Séverine , Skrzypski Jeremy , Gauthier Mélanie , Coudert Bruno P. , Isambert Nicolas
Published: March 2020

e11529

Background: Previous studies evidenced that the combination docetaxel (D) (75 mg/m²) + lapatinib (L) (1,250 mg/d) is well tolerated in heavily pretreated HER2-positive metastatic breast cancer patients (pts) in association with systematic G-CSF. This phase I study was conducted to assess safety, optimal tolerated regimen (OTR) and clinical activity of D + L in naïve treatment pts with HER-2 positive LAMBC without primary use of growth factor. Methods: Women with HER2+ LAMBC, naïve of treatment for advanced or metastatic disease, ECOG PS 0-2, were eligible for this study. Pts received once daily oral dosing of L with intravenous D on day 1 of every 3 week cycle. Initial dose was D (75 mg/m²) + L (1,250 mg/d) escalating up to D 100 mg/m² and L 1,500 mg/d until the Maximal Tolerated Dose (MTD) was reached. An expansion cohort of 6 pts was treated at the OTR level. Primary use of G-CSF was not permitted. Results: From Aug 2008 to Nov 2011, 17 pts were enrolled: median age 54.4 years [34.6-77], 59% were PS 0. All patients have metastatic disease with lung (29,4%), bone (41,2%), liver (76.5%) and lymph nodes (35.3%) metastasis. 7 pts received previously chemotherapy in adjuvant setting, 5 pts hormonotherapy and 7 pts radiotherapy. All but two pts were evaluable for dose limiting toxicities (DLT). 1 DLT/6 pts (FN) was observed at dose level (DL) 1 (D 75 mg/m² + L 1,250 mg/d) and 2 DLT/3 pts (gr 3 diarrhoea; gr4 neutropenia >7 d) at DL2 (D 75 mg/m² + L 1,500 mg/d). Only one DLT (FN) was observed in expansion cohort at OTR (D 75 mg/m² + L 1,250 mg/d; 6 pts). Over all C1, other significant toxicities (% pts) included gr4 neutropenia 53%, gr3 transaminase increase 6%, gr2 skin rash 36%, gr2 nausea/vomiting 18%, gr2 diarrhoea 12%, gr2 stomatitis 12%, gr2 hand-foot syndrome 6%; no decrease of cardiac function occurred. Conclusions: OTR for D and L was 75 mg/m² once every 3 weeks and 1,250 mg once daily respectively. This study demonstrates that this combination could be administered without systematic use of G-CSF in non pretreated pts with LAMBC. Additional safety data and preliminary evidence of activity are anticipated to be available at the time of presentation. Clinical trial information: NCT01044485.
Association of extreme age with worse survival in advanced breast cancer.
Authors: Pulido Gema , de la Haba-Rodriguez Juan , Gomez M.Auxiliadora , Jimenez Jeronimo , Cano Maria Teresa , Ortiz Maria Jose , Aranda Enrique
Published: March 2020

e11530

Background: Age has been associated with survival in advance breast cancer. In the ALAMO Register prognostic index, older age was associated with mortality. Although recent reports suggest that age below 35 was also associated with worse prognosis. We analysed the impact of extreme ages in survival in an advance breast cancer cohort. Methods: Survival analysis of patients followed in the Advance Breast Cancer Cohort at the Reina Sofia Hospital between 1996-2006. Patients were classified in 4 groups of age: I (< 35), II (35-50), III (51-75) and IV (>75 years). Log-rank test was used to compare survivals between groups. Cases were censored after 5 years of follow-up. A uni and multivariate stepwise regression model was used to estimate factors associated with survival. Results: 212 cases of advance breast cancer were included. Patients’ main characteristics, distributed by age groups, are reported in the Table. Median (IQR) survival was shorter (p=0.01) in group I 12.4 (4.7-25.4) and group IV 10.8 (5.1-19.8) compared to groups II 23.5 (17-29.5) and group III 20.2 (15.2-23.7). Factors independently associated with survival were age groups 1-4 versus 2-3 (p=0.02), histologic grade II-II versus I-unknown (<0.01), disease free interval <24 months versus >24 months (p<0.01) and visceral versus non-visceral metastatic location (p<0.01). Conclusions: Extreme ages (<35 or >75 years) at the diagnosis of the advance breast cancer are associated with worse survival. This factor in addition with the histologic grades, the disease free interval and metastatic location were associated with survival. [Table: see text]
A gene expression profile indicative of early stage HER2 tyrosine kinase inhibitor response.
Authors: O'Neill Fiona , Madden Stephen F. , Clynes Martin , Doolan Padraig , Crown John , Aherne Sinead , O'Connor Robert
Published: March 2020

e11536

Background: Lapatinib, afatinib and neratinib are tyrosine kinase inhibitors (TKIs) of HER2 and EGFR growth receptors. A panel of breast cancer cell lines was treated with these agents and gefintib (EGFR inhibitor) and the expression pattern of a specific panel of genes investigated as a potential marker of early drug response. Methods: RNA was extracted from breast cancer cell lines (BT474, SKBR3 and MDAMB453) with differing HER2 expression patterns and sensitivity to lapatinib before and 12hrs after treatment with 1 µM of lapatinib, 150nM of afatinib, 150nM of neratinib or 1µM of gefitinib. Gene expression changes were measured by Taqman RT-PCR and RQ values were determined using the comparative cycle threshold (Ct) method. Results: The expression of RB1CC1, ERBB3, FOXO3a, NR3C1 was directly correlated with the degree of sensitivity of the cell line to lapatinib and was observed to “switch” from up-regulated to down-regulated in the HER2 expressing lapatinib insensitive cell line (MDAMD453). The CCND1 gene (functionally linked to the other four genes) demonstrated an inversely proportional response to drug exposure; showing a trend of strong down-regulation in lapatinib-sensitive lines. A similar expression pattern was observed following the treatment with both neratinib and afatinib. In contrast, gefitinib treatment, resulted in a completely different expression pattern change. Conclusions: In these HER2-expressing cell models, lapatinib, neratinib and afatinib treatment generated a common, characteristic and specific gene expression response, proportionate to the sensitivity of the cell lines to the HER2 inhibitor. Characterisation of changes in these genes shortly after drug treatment may therefore give a valuable predictor of the likely extent and specificity of tumour HER2 inhibitor response in patients, potentially guiding more specific use of these agents.
The relationship between tumor markers and histopathologic and demographic features of patients with breast cancer and their distinctive role in metastatic process.
Authors: Aydin Kubra , Uygur Meliha Melin , Odabas Hatice , Korkmaz Taner , Yasar Nurgul , Dinc Nur , Aydin Dincer , Yuksel Sinemis , Balvan Ozlem , Guven Aslihan , Mayadagi Alparslan , Aliustaoglu Mehmet , Gumus Mahmut
Published: March 2020

e11540

Background: Tumor marker monitoring is generally performed by the physicians, although in many guidelines, it has not been recommended for breast cancer. In this study, we aimed to research the role of CEA and CA15.3 levels in metastatic process. Methods: In between years 2000 January and 2011 August, the documents of 482 female patients followed by breast cancer diagnosis in Medical Oncology and Radiation Oncology clinics of Kartal Dr. Lutfu Kirdar Education and Research Hospital, were evaluated retrospectively. Results: To determine the role of CEA and CA15.3 levels in evaluation of metastatic process, ROC analysis was performed and its cut-off values were 1.3 ng/ml and 14 U/ml, respectively. Sensitivities of CA15.3 and CEA levels were detected as 83.33% and 87.50%; specificities were 40.80% and 41.14%, respectively. Evaluation of the relationship between CEA and CA15.3 levels and the status of hormone receptors by ROC analysis showed the cut-off values as 26 U/ml and 1,6 ng/ml, respectively. In determination of endocrine sensitivity, the sensitivities of tumor markers elevation were 88.17% and 54.12%, respectively. Their specificities were 26.92% and 73.08%. CEA level elevation in hormone sensitive patients was statistically significant (p: 0.007). When sensitivity and specificity of CA15.3 and CEA levels on detection of c-erbB2 positivity were evaluated by ROC analysis, cut-off values were determined as 17 U/ml and 1,7 ng/ml. Sensitivities of these distinctive cut-off values were found as 58.8% and 71.15% and specificities were 60% and 51.67% (p: 0.017). When the relation between CA15.3 and CEA levels and node involvement was evaluated by ROC analysis, cut-off values were respectively 16 U/ml and 0.9 ng/ml. Their sensitivities were 53.45% and 87.93% and specificities were 55.56% and 51.67%, respectively. Conclusions: The levels of tumor markers have been suggested to have a significant role in prognosis of the disease with respecttothe correlation between different histopathological and clinical features and tumor markers. Randomised controlled prospective studies planned and performed in this issue may clarify this uncertainity.
Biologic subtypes and first relapse pattern in curative surgery performed breast cancer patients: Study of Anatolian Society of Medical Oncology.
Authors: Kaplan Muhammet Ali , Yalçintas Arslan Ülkü , Isikdogan Abdurrahman , Oksuzoglu Berna , Inanc Mevlude , Akman Tulay , Inal Ali , Cankir Havva Yesil , Kucukoner Mehmet , Budakoglu Burcin , Ozkan Metin , Yilmaz Ugur , Baykara Meltem , Yazilitas Dogan , Ersoy Ugur , Bilici Mehmet , Cubukcu Erdem , Yazici Ozan , Suner Ali , Demirci Umut
Published: March 2020

e11559

Background: Relapse is one of the most important risk factors in overall survival, and distant recurrence is related to a complex biologic interaction of seed and soil factors. The aim of the study was to investigate the association between the molecular subtypes and patterns of relapse in patients with curative surgery performed breast cancer. Methods: We retrospectively evaluated clinical data from 1126 breast cancer patients with relapses after their curative surgery between 1998 and 2012 from referral centers of Turkey. Study population was divided into four biological subtypes according to their hormone receptor status and HER2 expression.Patients were divided into four biological subtypes according to IHC: triple negative (ER negative, PR negative, and HER2 negative), HER2 overexpressing (ER negative, PR negative, and HER2 positive), luminal B (ER and/or PR positive, HER2 positive), and luminal A (ER and/or PR positive, HER2 negative). Results: The proportion of patients with luminal A, Luminal B, HER2-overexpressing, and triple negative breast cancer was 42.0% (n=473), 23.0% (n=259), 13.3% (n=150), and 21,7% (n=244), respectively. Median time to relapse was 26.6 months. 22.5% of the patients (n=253) had multiple relapse sites. The incidence of first distant recurrence site was significantly different among the subtypes. Liver (31.8% vs. 22.4%, p=0.008), bone (42.2% vs 37.0%, p<0.001), and lung metastases (30.9% vs. 22.2%, p=0.019) were increased in HER2 overexpressing, luminal A and triple negative group as first relapse site compared with other groups, respectively. Brain metastasis was increased in HER2 overexpressing and triple negative groups (17.7%), compared with Luminal A and B groups (8.0%, p<0.001). Conclusions: Organ-specific metastasis may depend on the molecular subtype of breast cancer. Tailored strategies against distant metastasis concerning the molecular subtypes in breast cancer may be considered.
Prognostic value of Ki67LI in HER2-negative luminal (HNL) early breast cancer (EBC): A 14-year single institution experience with long follow-up.
Authors: Ferro Antonella , Russo Lucianna , Eccher Claudio , Caldara Alessia , Triolo Renza , Barbareschi Mattia , Cuorvo Lucia Veronica , DiPasquale MariaChiara , Pellegrini Marco , Bernardi Daniela , Cantaloni Chiara , Maines Francesca , Galligioni Enzo
Published: March 2020

e11569

Background: Several studies have emphasized the biologic and prognostic value of Ki67LI and its role in routine practice, particularly to define prognostic subgroups of luminal tumors. Methods: Ki67LI was identified by immunohistochemical staining in 3760 consecutive EBC pts followed from 1995 to 2008. Median age was 61 y. The relationship with clinic-pathological parameters and the prognostic significance of KI67LI were investigated in all EBCs and in 2380 HER2 negative luminal (HNL) cases, stratified on homogeneous grading (594 G1, 1282 G2, 504 G3). Results: Median Ki67LI values were 22% in all cases, 20% in HNL and 10%, 20% and 35% in HNL- G1,G2,G3 respectively. Ki67LI > 22% (1873 pts) was significantly (p<0.001) associated with younger age, ductal type, greater size, positive N, poor G, absent or low ER /PR, positive HER-2, triple negative subtypes. Local and Distant Relapses were 138 (7.3%) and 355 (18.9%) in < or > 22% Ki67LI respectively. Median time to first event was 31.7 ms in > 22% vs 50.1 ms in < 22% Ki67. At a median f-up of 77 months EFS and OS were 91.9 and 92.1% in < 22% vs 78.9% and 81% in > 22% Ki67 respectively (p <0.001). The prognosis was consistently worse for > 22% Ki 67 in all clinical-pathological subsets, except in negative ER group. In multivariate analysis, KI67 maintained an independent prognostic significance for DFS and OS. In HNL, EFS and OS were 93.7 and 92% in < 20% vs 81.7 and 83.3% in >20% Ki67(p <0.001). Using median ki67LI value for different homogenous HNL-GG as cutoffs, we stratified these populations in low and high risk. Results are summarized in the Table. Conclusions: Our study confirms the prognostic value of Ki67LI in EBC,as well as other clinical pathological characteristics such as age, tumor size, histological type, nodal and hormonal receptors status. Cutoffs are different into HNL.They could identify different biological entities in each grading group providing additional prognostic information in outcome prediction. [Table: see text]
Health care utilization and costs among HER2-negative, HR-positive, elderly women with metastatic breast cancer in the United States.
Authors: Pawaskar Manjiri , Karve Sudeep , Dalvi Tapashi , Davis Keith L. , Deeter Robert
Published: March 2020

e11571

Background: Limited data exist on the cost burden of elderly women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer (MBC). We therefore assessed this cost burden in a retrospective analysis of the Surveillance, Epidemiology and End Results-Medicare database (2000-2009). Methods: Women aged ≥65 years diagnosed with MBC or early-stage breast cancer who progressed to MBC with HER2 negative, HR positive status were selected. MBC diagnosis date or date of progression to MBC was the index date. The study included non-HMO patients who had continuous Medicare (Part A and B) enrollment for ≥12 months before index date to death or end of database (2009). All-cause and MBC-related (claims for MBC diagnoses or MBC-related treatments) healthcare utilization and costs were assessed descriptively and then annualized based on follow-up duration. Results: In total, 13,170 women met the inclusion criteria (mean [SD] age 76.7 [7.0] years, 88% white, 77% both ER and PR positive). Mean [SD] post-index follow-up duration was 38.5 [28.1] months. On average, patients had 2.5 hospitalizations (mean length-of-stay: 16 days) and 3 emergency department (ED) visits. Mean [SD] annual all-cause costs (in 2011 $) per patient were $34,264 [$33,429], half of which $16,397 [$18,284] were attributable to MBC. Hospitalizations, hospital outpatient visits, and physician office visits accounted for over three-quarters of total all-cause costs (mean [SD]: $13,804 [$22,589] $4,171 [$6,509], and $8,676 [$11,065], respectively) and 75% of MBC-related costs (mean [SD]: $4,449 [$9,436], $2,844 [$5,383], and $5,799 [$9,945], respectively). Within MBC-related costs, mean [SD] annual costs of chemotherapy, radiation, and hormone therapy were $1,442 [$4,095], $1,872 [$4,086], and $579 [$1,197], respectively. Conclusions: Our findings indicate that HR positive, HER2 negative elderly women with MBC have a substantial economic burden on the Medicare system with primary costs drivers being inpatient, hospital outpatient and physician office visit costs.
Metastatic breast cancer subtypes and central nervous system metastases.
Authors: Aversa Caterina , Geuna Elena , Martinello Rossella , Milani Andrea , Rossi Valentina , Redana Stefania , Valabrega Giorgio , Aglietta Massimo , Montemurro Filippo
Published: March 2020

e11581

Background: The relapse pattern, survival and response to therapy are known to be different between breast cancer (BC) subtypes defined by combining hormone-receptor (HR) and HER2 status. Our aim was to study incidence and predictors of central nervous system metastases (CNS-M) and the outcome after CNS-M according to tumor subtype. Methods: 488 patients (pts) treated with at least one line of chemotherapy for metastatic BC were retrospectively evaluated. According to the combination of HR and HER2 status, tumors were grouped in: Luminal (Lum): HR+/HER2-, Luminal/HER2+ (Lum/HER2+): HR+/HER2+, pure HER2 positive (pHER2+): HR-/HER2+, and triple negative (TN): HR-/HER2-. All HER2+ patients received treatment with Lapatinib or Trastuzumab in addition to chemotherapy for metastatic disease. Median follow up was 34 months. Results: 133 pts (27%) developed CNS-M, with a median time to CNS progression of 43 months. The rate of CNS-M by subtype was: Lum 18%, Lum/HER2+ 37%, pHER2+ 49%, TN 25% (p <0.001). Multivariate analysis confirmed that, compared with Lum tumors, Lum/HER2+ ( HR 2.556, p<0.001), pHER2+ (HR 4.444, p<0.001) and TN (2.249, p=0.011) subtypes were at higher risk of CNS-M. Median overall survival (OS) CNS-M was 8.8 months in the whole series (IC 95% 6.6-11.0). Median OS in months by subtype was: Lum 9, Lum/HER2+ 18, pHER2+ 7, TN 7 (p<0.001). Multivariate analysis revealed that belonging to the Lum/HER2+ subtype (HR 0.528 compared with the Lum subtype, p<0.001) and having isolated CNS (HR 0.398, compared with CNS-M plus systemic progression, p<0.001) predicted significantly reduced risk of death. Conclusions: Among pts with a known increased risk of brain metastases, the Lum/HER2+ subtype appears associated with the longest OS after CNS-M, probably due to different biology and better extracranial disease control by chemotherapy, hormonal therapy and target agents. These results suggest that these patients may benefit from a more aggressive treatment of CNS-M and, possibly, from the screening for asymptomatic CNS lesions.
Assessment of treatment response with fulvestrant (F) 500 mg in standard clinical practice through a retrospective study: NCT01509625.
Authors: Blancas Isabel , Ruiz-Borrego Manuel , Salvador Bofill Javier , Conde Veronica , Carabantes Francisco , Bayo Juan L. , Jaen Ana , Perez Ruiz Elisabeth , Santiago María del Mar , Baena Jose Manuel , Villareal Vicente , Martinez Guisado Antonia , de la Cruz Merino Luis , Rodriguez Pedro , Reyes Evelyn , Cajal Rosana , Delgado Mayte , Gonzalez Flores Encarnacion , Inoriza Angel , Sanchez Rovira Pedro
Published: March 2020

e11583

Background: The CONFIRM study showed greater efficacy of F500 as compared to F250.Based on these results a dosage change was authorized in Spain.The aim of this study is to describe the efficacy of F500 (progression free survival(PFS) and clinical benefit rate(CBR) in Spanish patients (P) with estrogen receptor (ER+) Metastatic Breast Cancer (MBC) through a retrospective data collection. Methods: After written informed consent, data collection was recorded from clinical records of P who previously had progressed on hormonal treatment and who received at any time F 500 from 1st January 2010 to 31st October 2011. Results: 102 P in 14 centers were included in the study, 93 P were evaluable.Median age was 65 (39-88). Histology: 80.6% ductal ;15% lobulillar. Hormonal receptors: ER+/ PgR+ 77.4%; ER+/PgR- 21.6 %. HER2 status was documented in 80P, 15% of them were HER2+. 45.4% were Ki67 +. Mean from diagnosis to metastatic disease:3.7 years, 19.3% of P had de novo metastatic disease. 21.5% of P had visceral metastases.82.8% of P had good PS (0-1) when F started.F received as 1st line in 7.5%, as 2nd line in 52.7% and 3rdor more in 39.8% of the P. Average cycles administered: 10(3-48). With a median follow up of 16 months (m) since F treatment (1.4-34.4), median PFS was 10.6 m[8.3-13.0]. CBR was 59.1% (12.9%CR, 12.9 PR and 33.3% SD≥ 24 weeks). Median PFS in P with or without CB was 23.3 m and 5.6 m respectively. Median PFS in P with F in 1 st line was 10.3 m, 11.6 m in 2nd line and 9 m in 3rd line or more. No significant differences in CBR were observed between P with or without visceral metastases (58.9 vs 60%). There was a trend in the CBR between HER –ve and +ve groups (64.7% vs 33.3% p = 0.0565). 1-year survival rate was 86% (77.3-92.3). Median Overall Survival was not calculated because only 20 P had died when data were analyzed. More frequent toxicities were: local injection site pain (11.8%), hot flushes (11.8%) and gastrointestinal disorders (8.6%). Conclusions: F500 in real life setting showed a PFS of 10.6 m and got CB in 2/3 of P with a good toxicity profile, in line with phase III trials. In P who achieve a CB the median PFS was almost two years. P with visceral metastases may benefit from F same as those with non visceral involvement.
Magnetic resonance imaging with concentric shrinkage as a prognostic factor in patients with luminal breast cancer during neoadjuvant chemotherapy.
Authors: Fukada Ippei , Takahashi Shunji , Tanabe Masahiko , Araki Kazuhiro , Kobayashi Takayuki , Kobayashi Kokoro , Gomi Naoya , Horii Rie , Akiyama Futoshi , Iwase Takuji , Ito Yoshinori
Published: March 2020

e11587

Background: The important characteristics of breast cancer is its tumor heterogeneity and response to neoadjuvant chemotherapy (NAC). We analyzed the patterns of tumor shrinkage as a prognostic indicator after NAC for luminal breast cancer. Methods and Results. Methods: Of 854 patients who had received NAC in the single institute between January 2000 and December 2009, 265 luminal breast cancerwere retrospevively examined. Luminal breast cancer was defined as ER and/or PgR positive in more than 10% of cancer cells and HER2 negative (IHC 0, 1+ or FISH <2.0). Before and after NAC, the primary lesion was evaluated by enhanced MRI in 235 patients. Results: The median follow-up period was 51.4 months. 38 patients(16.2%) experienced recurrence after a median DFI of 49.1 months. The median age was 50 and 232 patients received anthracycline containing chemotherapy and 179 patients received taxane. 120 out of 235 patients exhibited concentric shrinkage pattern. Multivariate analysis for DFS identified Age(49>), strong ER/PgR positivity and concentric shrinkage as significantly favorable, and lymph node metastases as significantly unfavorable prognostic factors. Multivariate analysis for OS identified tumor size as significantly unfavorable prognostic factors(p=0.012). Conclusions: the tumor shrinkage pattern could be an important prognostic factor for luminal breast cancer and this suggests that a concentric shrinkage pattern of response may be infrequently associated with chemotherapy-resistant residual cancer cells.
The effect of anastrozole on bone mineral density during the first 5 years of adjuvant treatment in postmenopausal women with early breast cancer.
Authors: Inoue Hiroaki , Hirano Akira , Ogura Kaoru , Hattori Akinori , Kamimura Mari , Okubo Fumie , Kinoshita Jun , Kimura Kiyomi , Shimizu Tadao
Published: March 2020

e11604

Background: Adjuvant therapy with aromatase inhibitors (AI) is associated with increased bone loss in postmenopausal women. We assessed changes in bone mineral density (BMD) from baseline to 60 months of treatment in patients receiving anastrozole (ANA) as initial adjuvant therapy with/without oral bisphosphonates (Bis). Methods: Postmenopausal women with endocrine responsive breast cancer receiving ANA as adjuvant therapy at our hospital since 2004 were enrolled in this study. BMD was assessed by dual-energy X-ray absorptiometry at baseline and after 6, 12, 24, 36, 48 and 60 months. Oral Bis (risedronate or alendronate) treatment was initiated when patients were diagnosed as having osteoporosis with a T-score of -2.5 or lower. Results: Fifty-seven patients were enrolled in the study between 2004 and 2011. Patients’ median age was 65 years (range 50~85) and the median follow-up period was 46.3 months (9.6~83.8). Thirty-five patients were administered Bis (risedronate in 27 patients, alendronate in 8 patients). Within 6 months of hormone therapy, BMD decreased by 0.3% from baseline at the lumbar spine and BMD decreased by 1.2% at the femoral neck. However, BMD increased by 2.8% at the lumbar spine and BMD decreased 0.5% at the femoral neck for 60 months of treatment. In patients treated with upfront Bis (n=24), 4.9% BMD increase from baseline was noted at the lumbar spine whereas in those without Bis (n=20) BMD decreased by 4.6% from baseline within 24 months (p=0.0002). Fractures were observed in 4 patients (7.0%), and 1 patient (1.8%) had fragility fracture. Conclusions: Oral Bis prevented ANA-induced bone loss, and upfront treatment of Bis significantly increased BMD at the lumber spine.
Mediation of HER2 expression-dependent antiproliferative and pro-apoptotic effect of pan-HER2-specific TKIs on breast cancer cells through STAT5 and JNK.
Authors: Gschwantler-Kaulich Daphne
Published: March 2020

e11606

Background: HER-targeted tyrosine kinase inhibitors (TKIs) have demonstrated pro-apoptotic and antiproliferative effects in vitro and in vivo. The exact pathways through which TKIs exert their antineoplastic effects are, however, still not completely understood. Methods: Using Milliplex assays, we have investigated the effects of the three panHER-TKIs lapatinib, canertinib and afatinib on signal transduction cascade activation in SKBR3, T47D and Jurkat neoplastic cell lines. The growth-inhibitory effect of blockade of HER and of JNK and STAT5 signaling was measured by proliferation- and apoptosis-assays using formazan dye labeling of viable cells, Western blotting for cleaved PARP and immunolabeling for active caspase 3, respectively. Results: All three HER-TKIs clearly inhibited proliferation and increased apoptosis in HER2 overexpressing SKBR3 cells, while their effect was less pronounced on HER2 moderately expressing T47D cells where they exerted only a weak antiproliferative and essentially no pro-apoptotic effect. Remarkably, phosphorylation/activation of JNK and STAT5A/B were inhibited by HER-TKIs only in the sensitive, but not in the resistant cells. In contrast, phosphorylation/activation of ERK/MAPK, STAT3, CREB, p70 S6 kinase, IkBa, and p38 were equally affected by HER-TKIs in both cell lines, irrespective of their sensitivity against the HER-TKIs. Moreover, we demonstrated that direct pharmacological blockade of JNK and STAT5 abrogates cell growth in both HER-TKI-sensitive as well as -resistant breast cancer cells, respectively. Conclusions: We have shown that HER-TKIs exert a HER2 expression-dependent effect on proliferation and apoptosis in cancer cell lines in vitro, which is at least partially mediated by blockade of JNK and STAT5A/B. Despite slight differences in their specificity towards individual members of the HER family all three inhibitors had comparable antiproliferative and proapoptotic effects in vitro.
Prognosis of pT1a,bN0 breast cancer: Perception from the French oncology community—Results from the EURISTIC survey.
Authors: Spielmann Marc , Azria David , Classe Jean Marc , Dalenc Florence , Dromain Clarisse , Facchini Thomas , Goncalves Anthony , Liegeois Philippe , Namer Moise , Pivot Xavier B. , Pointreau Yoann , Vincent-Salomon Anne , Mahe Mercedeh
Published: March 2020

e11607

Background: Although most early-stage breast tumors have a favourable outcome, some subgroups carry a higher recurrence risk. The objective of the EURISTIC Survey was to evaluate the perception French physicians have of the prognostic risk associated with the biopathological characteristics of tumors in pT1a,b N0 breast cancer. Methods: This 38 item postal survey was developed by an expert panel. 2,000 physicians involved in breast cancer treatment were contacted. Specialities involved were medical and radiation oncologists, surgeons, radiologists and pathologists. Results: The survey was conducted between September and December 2012. A total of 663 physicians responded (response rate = 33%). They stated treating an average of 50 breast cancer patients per month. 58% of physicians reported that tumour size was not considered a major parameter in this clinical setting. In the absence of an adjuvant treatment, the prognosis of T1a,bN0 carcinoma was perceived better if HR-positive rather than HER2-positive or triple-negative with a "positive" prognosis perception rated by 83%, 21% and 8% of physicians respectively. For pT1a,bN0 tumors, the criteria with the highest perceived prognostic risk were ranked as follows: HER2+ (29%), HR- (20%) elevated tumor grade (20%) and triple negative tumor (14%). The average size threshold for a "negative" prognostic rated tumor was 18 mm. This threshold was scaled up for HR-positive carcinoma (22 mm) and scaled down for HER2-positive (10mm) or triple negative carcinoma (7mm). Between 4 and 17 mm, there was a linear correlation between tumor size and perceived risk of recurrence with HER2-positive tumors always carrying a worse prognostic than HR-positive tumor (Table). Conclusions: French physicians have the perception that HER2-positivity and triple negative tumor biology strongly impact the prognosis of pT1a,b N0 carcinoma, independent of tumor size. [Table: see text]
Low-dose metronomic cyclophosphamide/methotrexate (LDCM) and aspirin for patients who fail to achieve pathologic complete response (pCR) after neoadjuvant treatment for stage II-III breast cancer.
Authors: Burdette-Radoux Susan , Holmes Chris E. , Khan Farrah B. , Dittus Kim , Wilson Karen M. , Wood Marie E.
Published: March 2020

e12000

Background: Patients (pts) who fail to achieve pCR after neoadjuvant chemotherapy have a 20% risk of recurrence at two years. Data for effective postsurgical chemotherapy in this population is lacking. LDCM is an all-oral chemotherapy regimen with anti-angiogenic activity and acceptable toxicity in metastatic breast cancer. Aspirin is associated with a lower risk of breast cancer recurrence in retrospective studies and has anti-angiogenic activity. Here we combine LDCM and aspirin for high risk pts with poor response to neoadjuvant chemotherapy. Methods: Pts with stage II-III HER-2 negative breast cancer who had residual invasive cancer after neoadjuvant chemotherapy were eligible. Pts completed surgery and radiotherapy prior to enrolment and began study treatment within 180 days of surgery. Pts received four 28-day cycles of LDCM (cyclophosphamide 50 mg po daily, and methotrexate 2.5 mg po twice daily on days 1 and 2 each week ). Aspirin 325 mg daily was added on cycles 3 and 4. Pts were evaluated for the primary endpoint of toxicity and safety every 28 days. Secondary endpoint was 2 year relapse free survival. Results: 10 of 13 planned pts were evaluable for toxicity as of Jan 24, 2013. Pathologic stage ranged from T2N0 to T3N3. 70% of tumors were chemoresistant (stable or upstaged at time of surgery). 60% of pts had hormone receptor positive tumors and received concurrent hormonal therapy. Median age was 59 years (range 38-76). All pts completed 4 cycles of study treatment without dose reduction. There were no grade 3 or 4 related toxicities. Worst hematologic toxicity was grade 2 leukopenia. Worst nonhematologic toxicity was grade 2 fatigue; all other related toxicities were grade 1. 9 pts were evaluable for recurrence and none had recurred at a median followup of 13 months (range 7-23). Conclusions: This antiangiogenic regimen is well tolerated in patients at high risk for recurrence after neoadjuvant chemotherapy, resulting in no recurrences at 13 months followup, and suggesting it may be a candidate for future trials in this setting. Subsequent analyses will include longer term followup and biomarkers for angiogenesis. Clinical trial information: NCT01612247.
Feasibility study of cationic liposome-encapsulated paclitaxel in combination with paclitaxel followed by FEC as induction therapy in HER2-negative breast cancer.
Authors: Ignatiadis Michail , Lemort Marc , Wilke Celine , Vanderbeeken Marie-Catherine , D'hondt Veronique , Gombos Andrea , De Azambuja Evandro , Lebrun Fabienne , Dal Lago Lissandra , Maetens Marion , Ameye Lieveke , Veys Isabelle , Michiels Stefan , Paesmans Marianne , Larsimont Denis , Sotiriou Christos , Nogaret Jean-Marie , Piccart-Gebhart Martine J. , Awada Ahmad
Published: March 2020

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Background: Cationic liposome-encapsulated paclitaxel , a tumor endothelial targeting agent (composition of paclitaxel combined with neutral and cationic lipids) has shown activity in metastatic triple-negative breast cancer (BC) in combination with paclitaxel (Awada et al. ESMO2010). No data exist in the non-metastatic setting. Methods: HER2-negative BC candidates for neoadjuvant chemotherapy were scheduled to receive 12 cycles of weeklycationic liposome-encapsulated paclitaxel 22mg/m2 plus paclitaxel 70mg/m2 followed by 3 cycles of FEC (Fluorouracil 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2) every 3 weeks followed by surgery. Primary endpoint was percent (%) reduction in Magnetic Resonance Imaging (MRI) estimated tumor volume at the end of cationic liposome-encapsulated paclitaxel plus paclitaxel administration as compared to baseline. Safety, pathological complete response (pCR) defined as no residual tumor in breast and axillary nodes at surgery and correlation between % reduction in MRI estimated tumor volume and pCR were also evaluated. Results: Six patients with estrogen receptor (ER)-negative/HER2-negative and 9 with ER-positive/HER2-negative BC were included. Nine patients completed treatment as per protocol. Despite premedication and slow infusion rates, grade 3 hypersensitivity reactions to cationic liposome-encapsulated paclitaxel were observed during the 1st, 2nd, 3rd and 6th weekly infusion in 4 patients, respectively and required permanent discontinuation of the cationic liposome-encapsulated paclitaxel . Two patients stopped cationic liposome-encapsulated paclitaxel plus paclitaxel after 8 and 9 weeks due to clinical disease progression, two patients had grade 3 increase in transaminases and 1 patient grade 4 neutropenia. PCR was observed in 5 of the 6 ER-/HER2- and in none of the 8 ER+/HER2- BC patients. The median % reduction in MRI estimated tumor volume at the end of cationic liposome-encapsulated paclitaxel plus paclitaxel treatment was 90% (95% Confidence Interval: 69-99%), (p<0.001, sign test) for the 14 patients that underwent surgery; 99% (CI:87-100%) for patients with pCR and 84% (CI:50-95%) for patients with no pCR. Conclusions: The cationic liposome-encapsulated paclitaxel and paclitaxel combination showed promising preliminary activity as preoperative treatment, especially in ER-/HER2- patients. Further studies are warranted with need of premedication optimization. Clinical trial information: NCT01537536.
An examination of medical and economic outcomes of U.S. veteran breast cancer patients.
Authors: Wang Li , Fritschel Elyse , Li Lu , Huang Ahong , Baser Onur
Published: March 2020

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Background: While a breast cancer diagnosis is common in many medical settings, it is still uncommon in the U.S. Department of Veterans Affairs (VA) population, namely due to the minority of female veterans and infrequent diagnosis among men (Neumayer L, Schifftner TL, Henderson WG, et al. Breast cancer surgery in Veterans Affairs and selected university medical centers: results of the patient safety in surgery study. J Am Coll Surg. 2007; 204(6): 1235-41.). Currently, few studies describe the outcomes of breast cancer patients in the VA population. Methods: Using the Veterans Health Administration (VHA) datasets, a retrospective, observational study of patients diagnosed with breast cancer during the study period from October 1, 2005 to September 30, 2010 was conducted. Mortality, health care resource use, and costs were assessed for the 12-month follow-up period. Patients' clinical characteristics were assessed descriptively, and mortality rates were calculated using the Kaplan-Meier method. Results: In patients identified with breast cancer (n=11,719), the total follow-up mortality rate reached 17.04% (n=1,993). Mortality by age stratum totaled 26.07% for patients 65 years and over (n=1,192), 10.64% for those age 40 to 64 years (n=711), and 20.22% (n=90) for patients under 39 years. Nearly one-fifth of all breast cancer patients had follow-up inpatient visits (19.00%), which translated into an average inpatient cost of $22,220 annually per patient. While a similar percentage of patients had follow-up emergency room (ER) visits (18.79%), the average ER cost per patient totaled $140.53 annually. Conclusions: Mortality rate is the lowest for U.S. veteran breast cancer patients between ages 40 and 64 and more than doubles for those over age 65. The mortality rate of patients under age 39 years also exceeded the rate of the 40-64 age group, leading to more years of potential life lost. Additionally, inpatient utilization contributes to a high average annual cost incurred by U.S. veteran breast cancer patients. This information may further aid physicians and researchers as the number of female veterans increases.
Type of surgery for early breast cancer and predictive factors an institutional review: A regression model.
Authors: Muzaffar Mahvish , Mohamed Iman , Gaba Colette , Khuder Sadik
Published: March 2020

e12016

Background: Breast conserving surgery (BCS) is the preferred surgical management for most early-stage breast cancer, given the equivalent survival after BCS plus radiation and mastectomy (M). Clinical reports of an increasing trend in mastectomy from some institutional reviews have been published. The aim of this study was to assess correlation of type of surgery with different factors in our cancer registry database. Methods: We retrospectively reviewed the cancer registry data at UTMC for early breast cancer stage I/II from 2006-2010. Patient demographics, tumor characteristics, institution of surgery, academic versus private surgeon were identified and compared. We used univariate analysis to select factors for entry into a multivariate analysis. Multinomial logistic regression analysis was performed to predict the type of surgery (cancer side mastectomy (CSM) versus BCS, bilateral mastectomy (BM) versus BCS based on the above variables. A p-value of < 0.05 was significant and comparisons were two tailed. Results: We identified 506 eligible patients with stage I/II breast cancer. 306(60.5%) had undergone breast conservative surgery (BCS), 91 (18%) patients had cancer side mastectomy (CSM) and 109 (21.5%) patients had bilateral mastectomy (BM). 298 (59%) patients were stage I and 208 (41%) had stage II, 218 (42%) had undergone surgery at academic center versus 298 (58%) at nonacademic institution. Predictors o CSM were stage II (p =0.0193), high-grade tumor (p=0.015), surgeon from academic institution (p=0.64), age (p=0.61). Predictors of BM were surgeon from academic institution (p=0.060), age (p=0.07). Conclusions: This study confirms some known factors like stage, surgeon expertise, as influencing factors in type of local surgery, while at the same time did not show impact of race and other tumor characteristics. Further research of these factors need to confirm the influence on decision making prospectively.
Efficacy and safety of first-line bevacizumab combined with paclitaxel in 220 patients with metastatic breast cancer: The Hungarian AVAREG observational study.
Authors: Dank Magdolna , Budi Laszlo , Landherr Laszlo , Piko Bela , Mangel Laszlo , Erfán Jozsef , Cseh Jozsef , Ruzsa Agnes , Nagy Andras
Published: March 2020

e12022^

Background: First-line bevacizumab (Bev) combined with paclitaxel (Pac) significantly improves progression-free survival (PFS) and response rate vs. Pac alone in HER2-negative metastatic breast cancer (mBC), as shown in the E2100 study. The efficacy and safety of first-line Bev-Pac treatment was investigated in a non-interventional study in routine oncology practice in Hungary. Methods: Patients (pts) who had received no prior chemotherapy for mBC received Bev–Pac combination therapy according to the EU label. The primary endpoint was PFS. Efficacy and safety were documented until progression, death, or Bev discontinuation, whichever occurred first. Subgroup analyses of efficacy were conducted in pts with triple-negative mBC (TNBC). Results: Efficacy and safety data were available from 220 treated pts. Baseline characteristics were: median age 56 years (range 30–79; 13% ≥65 years; 4% ≥70 years); 18%/23% stage III/IV disease at first diagnosis; 36% disease-free interval ≤2 years; 46%/44%/30% bone/lung/liver metastases; 75%/21%/3% ECOG status 0/1/2; 45% ER positive; 48% TNBC. The Bev schedule was 10 mg/kg q2w (median 14 q2w Bev cycles) in 51% of pts and 15 mg/kg q3w (median 10 q3w Bev cycles) in 49%. The median duration of follow-up was 12.2 months (range: 0.9–36.5). Median PFS was 9.3 months (95% CI 7.8–10.8) in the total population (events in 63%), 8.3 months (95% CI 7.8–8.8) in the TNBC subgroup, and 13.3 months (95% CI 10.9–15.6) in the non-TNBC subgroup (log-rank p=0.001 between the TNBC and non-TNBC subgroups). Median time to treatment failure was 7.0 months (95% CI 6.1–8.0). The 1-year survival rate was 68%. Median OS was not reached. Adverse events (AEs) occurred in 36% of pts, and were classified as serious in 8% (20 events). The most common AEs (any grade) were hypertension, neuropathy, proteinuria, and anemia. There were three deaths, from pulmonary embolism, venous thromboembolism, and cardiomyopathy, on Bev therapy. No new safety signals were seen. Conclusions: These data in the real-life setting reconfirm that first-line Bev–Pac therapy is an effective and well-tolerated treatment option for mBC pts, with notable activity in pts with TNBC. Clinical trial information: NCT01777932.
Pneumocystis pneumonia incidence in metastatic solid tumor and lymphoma patients from an administrative health care claims database.
Authors: McCusker Margaret Elizabeth , Huang Jian , Walls Robert
Published: March 2020

e12500

Background: Pneumoncystis jiroveci pneumonia (PJP) causes severe, often life-threatening illness in immunocompromised patients, including patients with cancer. PJP incidence estimates have been reported for several different cancer types based on case series from single institutions. In order to obtain incidence estimates from a larger pool of patients, we studied PJP claims among patients with metastatic solid tumors (MSTs) or lymphomas in a large administrative healthcare claims database. Methods: Adults diagnosed with MSTs or lymphomas between January 1999-September 2011 were identified in the MarketScan commercial, Medicare supplemental and Medicaid databases based on ICD-9 diagnosis codes. First PJP after cancer diagnosis was defined by PJP ICD-9 code (136.3) associated with an inpatient hospital stay of at least 1 day. Patients with a PJP claim before their cancer diagnosis were excluded. PJP incidence proportions and rates (with 95% CIs) were calculated by age group, sex, HIV status, and tumor type. Results: There were 158 PJP cases (0.04%) among 392,369 HIV-negative MST patients, an incidence rate of 3.0/10,000 pt-yrs (95% CI 2.6-3.5). Incidence rates by metastatic cancer type were 6.8/10,000 pt-yrs for lung, 5.4/10,000 pt-yrs for pancreas, 4.1/10,000 pt-yrs for prostate, 3.0/10,000 pt-yrs for breast, and 0.9/10,000 pt-yrs each for colorectal and ovary. There were 337 PJP cases (0.21%) among 162,799 HIV-negative lymphoma patients, an incidence rate of 9.4/10,000 pt-yrs (95% CI 8.5-10.5). Incidence was higher among males compared to females in both MST and lymphoma patients. PJP incidence rates in HIV-positive patients were approximately 14 times higher than in HIV-negative patients. Conclusions: PJP is a rare occurrence among patients with MSTs or lymphomas. In this analysis of a large administrative healthcare claims database, PJP incidence was higher among lymphoma patients compared to MST patients. Incidence estimates were lower than reports from institutional case series, but patterns of occurrence were consistent in terms of higher incidence in patients with lymphomas or HIV. Differences in incidence by tumor type were also observed among MST patients.
Retrospective analysis of breast cancer patients in an Asian-majority community clinic.
Authors: Hu Adriana , Keung Yi-Kong , Lau Ryan A , Keung Lap-Woon , Hu Eddie
Published: March 2020

e12502

Background: Incidence of breast cancer in Asian countries is about one third to one half of that of the US. Asian immigrants have a higher risk of developing breast cancer in the US presumably by adopting more westernized lifestyles. We conduct a retrospective analysis of breast cancer patients (pts) in an Asian-majority community in Southern California. Methods: Unselected consecutive female breast cancer pts were studied. Clinical data were review and statistical analysis was conducted by SPSS 16.0. Results: 501 pts, 334 Asians (incl. Chinese 84%) and 167 non-Asians (incl. Caucasian 47% and Hispanic 45%) were studied. Conclusions: This study raised several intriguing findings: 1. Asian pts are significantly younger and have lower BMI than non-Asians. 2. Asian pts are more likely to undergo mastectomy than breast conserving surgery. 3. Asian pts tend to have denser breasts which may potentially limit the sensitivity of mammogram. Since the ratio of DCIS to invasive cancer is comparable between Asian and non-Asian pts in this study, mammogram is probably effective in detecting early cancer in Asians. 4. Significantly fewer Asian pts are diagnosed by screening mammogram. It is probably due to lower utilization of mammogram in the Asian population. 5. BRCA1/2 mutation is not significantly different between Asians and non-Asians. Due to inherent limitations of retrospective study, these findings need to be confirmed in a larger prospective study. [Table: see text]