Background

Eribulin is a non-taxane microtubule dynamics inhibitor that has been proven to prolong overall survival in patients with breast cancer. S-1, an oral anticancer drug, has demonstrated non-inferiority in overall survival (OS) to taxane as first-line chemotherapy for metastatic breast cancer (MBC). We previouly reported phase I trial results for the combination of these drugs with an overall response rate of 41.7% and median progression free survival (PFS) of 7.6 months. George W et.al (J Clin Oncol 2003) suggested that estrogen receptor negativity, the presence of three or more sites of disease, a short disease-free interval (1 to 24 months), and prior systemic therapy all predicted for impaired overall survival in their multivariate analysis. Considering these factors, we conducted a multicenter phase II study of this combination to further evaluate its safety and efficacy.

Background

Eribulin is a non-taxane microtubule dynamics inhibitor that has been proven to prolong overall survival in patients with advanced and recurrent breast cancer .S-1, an oral anticancer drug, composed of tegafur, gimestat and otastat potassium, has demonstrated non-inferiority in overall survival (OS) to taxane as first-line chemotherapy for metastatic breast cancer (MBC).We previouly reported phase I trial results for the combination of these drugs with an overall response rate of 41.7% and median progression free survival (PFS) of 7.6 months. George W et.al (J Clin Oncol 2003) suggested that estrogen receptor negativity, the presence of three or more sites of disease, a short disease-free interval (1 to 24 months), and prior systemic therapy all predicted for impaired overall survival in their multivariate analysis. Considering these factors, we conducted a multicenter phase II study of this combination to further evaluate its safety and efficacy.

Methods

Recurrent or advanced breast cancer patients previously treated with anthracycline or taxanes were enrolled from September 2014 to May 2016. Patients received Eribulin 1.4 mg/m² day1 and day8 intravenously and S-1 50 mg/m² from day1 to day14 orally. Primary objective was to investigate safety and efficacy. Secondary objectives were to evaluate PFS, OS and clinical benefit rate (CBR) using Response Criteria in Solid Tumors (RECIST).

Results

Thirty-two patients were enrolled this trial and 30 patients were evaluable. Objective response rate was 36.7%. There were 3 [10%] complete responses, 8 [26.7%] partial responses and 11 [36.7%] stable diseases. This combination therapy had a manageable safety profiles consistent with the known adverse effects of both drugs. The most common grade3-4 adverse events were neutropenia (22 [73.3%] of 32 patients), leukopenia (13 [43.3%] of 32 patients), febrile neutropenia (3 [9.4%] of 32 patients) and peripheral neuropathy (4 [12.5%] of 32 patients). CBR was 46.7%. The median overall survival and the median PFS was not reached.

Conclusions

We showed tolerability and clinical activity in this combination therapy in a subset of patients with poor prognosis. Eribulin in combination with S-1 may represent a promising treatment option for advanced or recurrent breast cancer patients.

Legal entity responsible for the study

Eisai

Funding

Eisai

Disclosure

All authors have declared no conflicts of interest.

Background

Some risk factors (RFs) in the management of ER-positive, HER2-negative metastatic breast cancer (ER+HER2-MBC), such as a shorter disease-free interval (DFI), visceral involvement or high tumor burden, have been identified in prospective clinical trials; however, the utility of those RFs in the real world has not been well discussed.

Methods

We reviewed our medical records from 2002 to present to assess the utility of RFs (DFI≤24 months [DFI≤24M]; visceral metastases [VIS]; prior (neo)adjuvant anthracycline and/or taxane [A/T]; or ≥ 3 metastatic organs [≥3 ORG]) defined in the TURANDOT risk factor analyses (Brodowicz T, Br J Cancer, 2014), a first-line bevacizumab trial of HR+HER2-MBC patients. According to the analysis, patients with ≥2 RFs were classified as “high-risk (HiR)”, and others were classified as “low-risk (LoR)”. Statistical analyses were performed using the Kaplan-Meyer method and a multivariate COX regression analysis.

Results

We identified 311 ER+HER2-MBC (224 recurrent, 87 advanced) patients who underwent chemotherapy (CTx). The most common RF at the initiation of first-line CTx was VIS (N = 186, 59.8%), followed by A/T, ≥3 ORG and DFI≤24M. The distribution of RFs was as follows: 0 in 89 (28.6%), 1 in 93 (29.9%), 2 in 94 (30.2%), 3 in 30 (9.6%), and 4 in 5 (1.7%). The survival from the initiation of CTx (OSCTx) was significantly poorer in HiR patients than LoR ones (median 815.0 vs. 1062.0 days, p < 0.001, log-rank) in all MBC patients, as well as in 87 advanced BC patients (median 825.0 vs. 1160.0 days, P < 0.05, log-rank). There was no significant difference in the OSCTx between patients with 0 and 1 RF (P = 0.90). In addition, in recurrent BC (rBC) patients, there was no significant difference in the OSCTx between patients with 2 and ≥3 RFs (P = 0.10). Multivariate analyses revealed ≥3 ORG and DFI≤24M as significant RFs (P < 0.05) for all rBC patients (hazard ratios 1.61 and 1.49, respectively).

Conclusions

Our review suggests that RFs such as high tumor burden and shorter DFI identified in prospective randomized studies are applicable to patients in the real world, even with heterogeneous backgrounds.

Legal entity responsible for the study

Junichiro Watanabe

Funding

None

Disclosure

J. Watanabe: Honoraria from AstraZeneca Japan, Chugai Pharmaceuticals, Eisai, Novartis Pharma Japan, Taiho pharmaceuticals, and advisory board member of AstraZeneca Japan, Eisai.

All other authors have declared no conflicts of interest.

Background

Breast cancer (BC) is the most frequently diagnosed disease and a leading cause of death in females globally. BC is also common in Pakistani females and one out of every nine female is at risk of developing BC. Information on the clinico-pathologic (CP) data of BC is limited especially from the northwest part of Pakistan. The purpose of this study was to profile the CP data of BC. This will clearly help us in assessing the CP characteristics of the disease and in public health intervention measures.

Methods

Data were extracted from consecutive medical files of BC patients at the IRNUM Hospital, Peshawar, Pakistan from 2014 to 2016. Demographic, clinical and pathological data were profiled. Data were analyzed for descriptive statistics, independent sample t test and Chi square test. Logistic regression was performed by stratifying patients according to the disease stage as early stage (stage I and II, ES) and late stage (stage III and IV, LS).

Results

Data of 362 patients with breast cancer was profiled. The mean age at diagnosis was 47.8 years. 8% of the patients were nulliparous and 5.2% of the patients had a positive family history of BC. The most common symptom was a lump in breast (82%), and left breast (54%) was the most common location of tumor. Most of the patients presented with LS disease (65%). ER+, PR+ and HER2+ cases were 62%, 47% and 49% respectively. The tumour was localized in 75% of the cases, while multifocal in 25% of the cases. The mean age (47.8 yrs) in the ES breast cancer is not statistically different from the mean age (47.7 yrs) in the LS breast cancer (p = 0.99). Lymph node positivity is associated with LS disease (p < 0.001) and it predicts LS disease (OR = 17.1, p < 0.001). Vascular invasion and HER2+ are also associated with LS disease (p = 0.06, p = 0.07, trending statistical significance).

Conclusions

Due to delayed consultation, patients present with late stage disease irrespective of age of patients. Thus, there is an urgent need for public health outreach programs directed towards awareness campaigns and the need for routine breast cancer screening. In addition, positive family history may be evaluated as potential risk factors in our population. Finally, a significant number of patients are ER+/PR+ and HER2+, which may promise targeted therapy options.

Legal entity responsible for the study

Office of Research, Khyber Medical University, Peshawar

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

Invasive triple-negative breast cancer accounts for 10-20% of breast cancers and is responsible for a high percentage of breast cancer-related deaths. It is indeed a very aggressive tumor that is associated with a poor prognosis with high risk of relapse and a short disease-free survival. It is treated by chemotherapy only and does not benefit from targeted therapy until now. The purpose of this study was to analyze progression-free survival (PFS) and overall survival (OS) after the change of therapeutic modalities, and the age at diagnosis of triple-negative breast cancer in Lebanese women and to compare the age distribution with a preceding Lebanese study and a recent American study of 38,813 patients nationwide.

Methods

Data were collected from hospitals and pathology laboratories across Lebanon. The collection was based on the following inclusion criteria: female diagnosed with an invasive TNBC between 2010 and 2016. PFS was studied in 193 cases, the overall survival analysis was done on 63 cases and the age at time of diagnosis on 387 cases. The statistical analysis was done using Student t tests.

Results

PFS improved from 19 to 35 months after the change of therapeutic protocols and the OS increased from 19 to 23 months (p < 0.001). The average age at time of diagnosis was approximately 56 years, compared with 52 years in the previous Lebanese study and there was a clear age disparity of the age at time of diagnosis between and Lebanese and American study when comparing patients of identical age groups. The age at diagnosis does not depend on the geographical area.

Conclusions

The new therapeutic protocols proved to be more effective, but screening programs must be done at an earlier age. The findings may be pertinent for the Lebanese patients and warrant further evaluation in different ethnic groups and populations.

Clinical trial identification

NA

Legal entity responsible for the study

Holy Spirit University of Kaslik

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

Palbociclib has been approved by the US FDA since 2015 yet safety and efficacy data among Asian patients is limited. This study reports the use of this drug in ER-positive HER2-negative MBC in Hong Kong as real world practice.

Methods

The demographic data, treatment response, and toxicity profile of patients received palbociclib were collected in a prospectively maintained database. Patients were from both the public and private sectors. The study is supported by the Hong Kong Breast Cancer Foundation.

Results

Fifty-four patients who have received palbociclib for the first time were recruited in the database. The median age was 51 year (range 34-81) and all patients were ethnic Chinese. All were post-menopausal by natural state (67%) or by ovarian suppression. Over half (55%) obtained palbociclib from the name-patient program prior to the launch of the drug in Hong Kong in Jan 2017. The proportion of first line use was 30% prior to- and 36% after the official launch of palbociclib. The partner endocrine therapy (ET) was aromatase inhibitor (39% letrozole, 11% exemestane) or fulvestrant (50%). Except for 4 patients, the majority (93%) were started on the standard dose of 125 mg/day. Of those started on 125 mg/day, 43% developed Gd 3 neutropenia, and 7% had Gd 4 neutropenia during the first cycle; 31% had dose reduction to 100 mg/day on second cycle. Other adverse events (AEs) included anemia (4%), thrombocytopenia (9%), stomatitis (5%), hand-foot syndrome (4%), fatigue (4%), and low appetite (4%). All these were Gd 1-2. No patient had neutropenic fever. Response assessment was available in 37 cases. The disease control rate was 70%. Many responded patients had visceral disease (54%) and were heavily pretreated (chemotherapy 1 line 15%, > =2 lines 35%; ET > =2 lines 27%; mTOR inhibitor 12%).

Conclusions

This is the first real world data reporting the preliminary efficacy and AEs of palbociclib among ER-positive HER2-negative MBC patients from Hong Kong. Palbociclib was well tolerated. The experience is consistent with published literature of Palbociclib. The use of palbociclib in Hong Kong is often in the second or later line setting and the cause remains to be elucidated.

Clinical trial identification

Not applicable

Legal entity responsible for the study

N/A

Funding

Pfizer

Disclosure

All authors have declared no conflicts of interest.

Background

Breast cancer has become the most common cancer in Thai women since 2005. Unfortunately two thirds of the patients were diagnosed at advanced breast cancer (ABC) stage. Furthermore, most of these women were under the Universal Coverage by the government which does not provide sufficient coverage for certain critical medical treatments for ABC patients. The cost of treatments is even more of a pressing issue in Thailand. This study aimed to evaluate the cost-effectiveness of exemestane (EXE), a steroidal aromatase inhibitor (SAI), as treatment therapy following adjuvant non-steroidal aromatase inhibitor (NSAI) for hormonal responsive ABC in Thailand.

Methods

A Markov model was used to estimate the relevant costs and health outcomes over the patients' lifetimes using a social cost and benefit perspective. All future costs and outcomes were discounted at a rate of 3% per annum. The efficacy and cost of EXE and chemotherapy were based on a clinical trial that included a total of 18 post-menopausal hormonal responsive ABC patients. Utility values were derived directly from all patients using EQ-5D. Primary outcomes of interest were lifetime costs, quality adjusted life-years (QALYs) gained, and the incremental cost-effectiveness ratio (ICER) in US ($) per QALY gained. One-way and probabilistic sensitivity analyses (PSA) were conducted to investigate the effect of parameter uncertainty.

Results

In base case analysis, the EXE group had better clinical outcomes and lower lifetime costs. The incremental cost per QALY gained was US $-2,747 per QALY. The acceptability curve showed that the probability of EXE being cost-effective was 97% at the willingness to pay of 1 time of Thai Gross National Income per capita (GNI per capita), approximately US $4,673 per QALY gained.

Conclusions

At a social cost of paying 1 GNI per capita, EXE is highly effective and cost-saving regimen for the first-line treatment of post-menopausal ABC with hormone positive receptor in Thailand. This study provides key relevant information aiding policy makers to make informed decision making regarding resource allocation to include EXE into reimbursement plan.

Legal entity responsible for the study

Faculty of Medicine, Chiang Mai University

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

Triple negative breast cancer (TNBC) is categorized by a lack in estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 receptor (HER2). TNBC is known to be more aggressive and lethal than other types of breast cancer because of their highly invasive and migratory ability. However, the mechanisms and main contributors of their metastatic ability are still unclear. ETS transcription factors are related with tumorigenesis in many tissues including breast epithelium. Among them, ELF3 (ESX/ESE1) is an epithelial-specific gene that is specifically associated with breast cancer and has been amplified in early breast cancer. The potential role of ELF3 in cytoplasm is presented, but the mechanism of ability to regulate tumor-associated gene expression and breast cell survival for ELF3 are not yet known. Several studies have suggested that the role of EMT is important in the aggressiveness and metastasis of TNBC. It is also known to play an important role in the formation of tumors in most invasive cancer. The main functions of EMT, such as down-regulation of E-cadherin and up-regulation of MMP, are known to be regulated by transcription factors including Snail, Slug and ZEB1.

Methods

For investigation of ELF3 ability in TNBC, we performed a series of assays; western blot, wound healing, invasion, soft-agar colony formation, flow cytometry, anoikis, CAM and immunofluorescence assays.

Results

In this study, we found that ELF3, an ETS transcription factor, was expressed low and high in mesenchymal and epithelial type of TNBC cell lines, respectively. Remarkably, overexpressed ELF3 in the highly invasive TNBC cell lines, MDA-MB-231 and BT549, suppressed EMT by attenuating the expression of several EMT-associated proteins (Vimentin, Slug and MMPs). Moreover, ELF3 overexpression reduced the tumor growth of BT549 in chick embryo chorioallantoic membrane (CAM) model.

Conclusions

Although high ELF3 expression has been known to be associated with tumorigenesis of other breast cancer types, overexpression of ELF3 in TNBC suppressed the metastatic potential of invasive TNBC cells. Our results suggest the important role for ELF3 in metastasis of TNBC.

Legal entity responsible for the study

Ewha Womans University

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

Recently several new chemotherapeutic agents have been developed and indicated for treatment of recurrent breast cancer. One of them, eribulin have improved overall survival (OS) in EMBRACE trials. On the other hand, bevacizumab has improved progression-free survival (PFS) in several clinical studies, but not extended OS in them. And there are few reports estimating these agents’ effects on OS and PFS of advanced or recurrent breast cancer patients in a real world setting.

Methods

Recurrent breast cancer patients who received chemotherapies in Toyama Breast Cancer Research Group (TBCRG) group institutes from January 2013 to March 2015 were reviewed. Kaplan-Meier method was utilized to estimate OS or PFS, and log-rank test was used to compare OS or PFS. Univariate and multivariate analyses were preformed to find significant factor(s) concerning OS.

Results

Of 208 patients who received chemotherapies in the period mentioned, there were 157 patients who received chemotherapies using both or either of eribulin (Eri), and bevacizumab (Bev). Median age of each group using Eri/Bev were 52.4/54.6. Disease status of Eri/Bev were as follows; 68.8%/79.0% ER positive, 18.8%/11.3% HER2 positive. Metastasis of each group using Eri/Bev were observed at; 51.0%/55.2% bones, 7.3%/8.1% CNS, 56.3%/47.2% lung, and 33.3%/49.6% liver. Response rates and PFS from the starting period of Eri/Bev were 21%/75%, and 387days/297days. Multivariate COX regression analysis disclosed negative HER2 status in Eri group, and liver involvement in Bev group influenced the response rates significantly. Earlier administration of Eri shows better survival durations from primary chemotherapies (1470 days), comparison with those of Bev (1076 days). Response rate/disease control rate of pre-line chemotherapies in Eri group were 32%/57%, and not significantly diffierent from 29%/65% in Bev group, but those of post-line chemotherapies were 21%/63% in Eri group and 6%/28% in Bev group.

Conclusions

According to our retrospective observation analyses of group data, eribulin did not reduce the effects of subsequent chemotherapies, and improved OS of advanced or recurrent breast cancer patients. We have to reassess the value of new chemotherapeutic agents continuously.

Disclosure

All authors have declared no conflicts of interest.

Background

In India, breast cancer is the second most common malignant condition among women. It is hereditary in 10% of cases, the majority related to mutations in the BRCA1 and BRCA2 genes. The presence of BRCA germline mutations in breast/ovarian carcinomas has been shown to have prognostic and therapeutic significance. Identification of tumours with BRCA defects has therapeutic and prognostic implications. Our objective was to assess whether immunohistochemical analysis (IHC) for BRCA is an effective method for the detection of BRCA dysfunction in hereditary breast carcinoma or not.

Methods

We have selected 231 patients for BRCA1/2 mutation detection during Aug.2010 to Oct.2015 from the breast cancer patients attended our hospital, NCRI. After taking written consent 4-5ml peripheral blood and/or operated tissue (where possible) were collected from BC patients. BRCA1/2 mutations were identified by ARMS-PCR, DNA sequencing and whole genome sequencing. We performed IHC staining with BRCA1 and BRCA2 antibody to distinguish tumour status between patients according to their indication of BRCA1 or BRCA2 mutation.

Results

Average age of the patients was 45.87±1.57 yrs. BRCA1/2 mutations were identified in 24 (10.38%) patientsthrough above mentioned methods. Tumour samples fromnine BRCA positive cases and 15BRCA negative cases were chosen for investigation of IHC. Out of 9 samples with BRCA mutations, 7were BRCA immunostainingnegative, with absence of nuclear or cytoplasmic staining. On the otherhand, from the 15 patients negative for mutations in both genes, 12 were positive for BRCA1immunostaining with a clear nuclear immunoreactivity in tumour cells. From ROCcurve analysis, it was found that IHC negativity (area- 0.211, CI: 0.011-0.411) isassociated (p = 0.02) with BRCA positivity.

Conclusions

In conclusion, we observed a high specificity for the prediction of BRCA1/2 carriers withimmunohistochemistry using BRCA antibody. Validation of this assay, using a larger sample, will allow using immunohistochemistry to decide which high-risk patients should be screenedfirst for the BRCA mutation gene.

Clinical trial identification

NA

Legal entity responsible for the study

Netaji Suibhas Chandra Bose Cancer Research Institue

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

It is unclear whether perioperative fluoropyrimidine (FP) use impacts the efficacy of capecitabine in advanced breast cancer treatment.

Methods

Medical records of patients with advanced breast cancer who received capecitabine between 2008 and 2016 at National Cancer Center Hospital (Tokyo, Japan) were reviewed. Progression-free survival (PFS), overall survival (OS), tumor response, and adverse events (AEs) were compared between a FP group (prior perioperative FP use) and a non-FP group (no prior FP use). To evaluate the effect of prior perioperative FP use on survival outcomes, hazard ratios (HRs) for PFS and OS were estimated for the FP group compared with the non-FP group.

Results

A total of 289 patients (FP group: n = 106; non-FP group: n = 183) were analyzed. Patient characteristics were similar between the two groups. The median recurrence-free interval (RFI) was 3.94 (range: 0.27-20.11) years in the FP group and 4.24 (range: 0.27-27.07) years in the non-FP group (p = 0.402). The FP group had poorer PFS than the non-FP group (univariate HR: 1.33; 95% confidence interval [CI]: 1.03-1.72, p = 0.028; multivariate HR: 1.33; 95% CI: 1.02-1.73; p = 0.034). However, OS was similar between the groups (univariate HR: 1.16; 95% CI: 0.84-1.62; p = 0.368; multivariate HR: 1.06; 95% CI: 0.74-1.51; p = 0.755). Multivariate HRs for PFS for the FP group with short RFI and long RFI (cutoff: RFI=4 years) separately were 1.56 (95% CI: 1.06-2.28; p = 0.025) and 1.20 (95% CI: 0.84-1.70; p = 0.326), respectively. With different cutoffs (RFI=3, 4, and 5 years), the ranges of adjusted HRs for PFS were 1.32-1.67 with short RFI, and 1.00-1.25 with long RFI. A trend for larger HR for the FP group with short RFI than with long RFI was also seen for OS with different cutoffs of RFI. The response rate (FP group vs. non-FP group) was 21.0% vs. 14.8% (p = 0.306), and the disease control rate was 59.9% vs. 54.5% (p = 0.422). There was no significant difference in AEs between the two groups.

Conclusions

Capecitabine can be used for patients with advanced breast cancer with FP use history, as OS does not correlate with prior FP use. For patients with FP use history, RFI may be a relevant factor for treatment selection.

Legal entity responsible for the study

National Cancer Center Hospital

Funding

None

Disclosure

All authors have declared no conflicts of interest.