Background

Eribulin mesylate (ERI) demonstrated a survival benefit in patients with locally recurrent or metastatic breast cancer who previously received 2 or more chemotherapy regimens. Recently, we conducted Phase II study about the efficacy of ERI with trastuzumab (ERI+TRA) as late-line therapy for locally advanced or metastatic HER2-positive breast cancer (UMIN000012350), and reported that objective response rate (ORR) and median progression-free survival (mPFS) were 17% and 4.6 months. However, some patients who received prior pertuzumab (PER) and/or T-DM1 were enrolled in that study, there are limited data on the efficacy of ERI+TRA in those patients. The aim of this study was to assess the efficacy of this combination therapy based on prior PER and/or T-DM1 use.

Methods

In primary phase II study, patients with locally advanced or metastatic HER2 positive breast cancer who previously received at least one chemotherapeutic regimen, received ERI at 1.4 mg/m² intravenously (I.V.) on days 1 and 8 of each 21-day cycle with an initial TRA dose of 8 mg/kg I.V. on day 1, followed by 6 mg/kg of TRA on day 1 of each subsequent cycle. ORR, clinical benefit rate (CBR) and PFS were assessed in patients who had and had not received prior PER and/or T-DM1.

Results

Thirty-six patients (median age: 60.5 years) received ERI+TRA. 69.4% (n = 25) had previously treated with prior PER and/or T-DM1, defined as ‘prior’ patients. Remaining 30.6% (n = 11) without both agents were defined as ‘non-prior’ patients. In prior patients compared with non-prior patients, median number of prior treatment regimens was 4 (range, 1‐8) versus 3 (range, 1-7), respectively; ORR was 12.0% versus 27.3%, respectively; CBR was 24.0% versus 54.5%, respectively; mPFS was 4.3 versus 9.7 months, respectively.

Conclusions

ERI+TRA demonstrated lower efficacy than in non-prior patients, but CBR and PFS were 24.0% and 4.3 months, which was considered to be a clinically relevant treatment option in patients who received prior PER and/or T-DM1.

Clinical trial identification

UMIN000012350.

Legal entity responsible for the study

Nagoya Surgical Oncology Group

Funding

Eisai

Disclosure

All authors have declared no conflicts of interest.

Background

Varlitinib, a tyrosine kinase inhibitor of the ErbB family (EGFR, HER2 and HER4), showed anti-tumor activity in trastuzumab-resistant models and in patients with trastuzumab-resistant, chemotherapy-refractory MBC in a phase 1 study. This study compared the efficacy and safety of varlitinib plus capecitabine (VC) versus lapatinib plus capecitabine (LC) in HER2⁺ MBC patients who failed prior trastuzumab therapy.

Methods

The primary objective was to assess percentage change in tumor size at week 12. Objective response rate (ORR), safety and drug exposure were also assessed. Patients who received at least one dose of study treatment were included in primary analysis. Sensitivity analysis for primary objective and ORR were performed in patients who remained on study for more than 30 days.

Results

From Dec 2014 to Aug 2016, 24 patients were randomized to the VC arm (400mg BID) and 26 to the LC arm (1250mg QD) in 16 sites in 6 countries. Percentage of tumor size reduction was numerically higher in VC than LC (-31.00% vs. -19.37%, one-sided p = 0.132). ORR in the VC arm (40.9%) was similar to LC arm (45.5%), p = 1.000. Sensitivity analysis showed numerically superior ORR and statistically significant higher reduction of tumor size in VC compared to LC (60% vs. 45.5%, p = 0.508; mean, -34.6% vs.-19.4%, one-sided p = 0.075) All patients had at least 1 AE. Severe AE(s) were observed in 13 patients (54.2%) in the VC arm and 11(42.3%) in the LC arm. The most common AE was diarrhea (66.7%) in the VC arm and were diarrhea and palmar-plantar erythrodysaesthesia syndrome (both 50%) in the LC arm. Median intended exposure and percentage of intended dose were lower in the VC arm (115.5 days, 74.6%) indicating more frequent dose interruption, dose reduction and treatment discontinuation than the LC arm (135.0 days, 99.05%).

Conclusions

Sensitivity analysis showed greater tumor size reduction and improved ORR for VC arm when the combination was administrated for more than 30 days. Reduced intended exposure and dose intensity for the VC arm suggests a dose reduction of varlitinib may be considered when combined with capecitabine for the 2nd line treatment of HER2⁺ MBC.

Clinical trial identification

NCT02338245.

Legal entity responsible for the study

ASLAN pharmaceuticals

Funding

ASLAN pharmaceuticals

Disclosure

All authors have declared no conflicts of interest.

Background

The standard therapy for primary treatment of HER2-positive metastatic breast cancer (MBC) is combination therapy of pertuzumab (PER), trastuzumab (HER) and docetaxel (DTX). Although the effectiveness of trastuzumab emtansine (T-DM1) after HER treatment has been reported, there are few reports on the effectiveness of T-DM1 for patients treated with PER. We retrospectively investigated the effectiveness of T-DM1 on HER2-positive MBC previously treated with PER.

Methods

Between October 2013 and June 2017, 79 patients with HER2-positive MBC were treated with PER. 44 patients were investigated the subsequent treatment. 34 patients received T-DM1, and 10 patients received treatment other than T-DM1 after PER treatment.

Results

Median treatment line was 3.0 (1-9) vs 4.0 (1-9) in the T-DM1 treatment and other than T-DM1 treatment, respectively. The response rate was CR 0% vs 0%, PR 36.0% vs 25%, SD 32.0% vs 62.5%, PD 32.0% vs 12.5%, respectively. The objective response rate was 36.0% vs 20.0%. The clinical benefit rate was 48.0% vs 50.0%. Median time to treatment failure was 6.6 months vs 2.9 months, respectively. There was a significant difference in median overall survival; median not reached vs 19.6 months (p = 0.04).

Conclusions

OS was significantly better with administration of T-DM1 after PER treatment. Based on the results of this study, it was confirmed that efficacy of T-DM1 in patients with HER2-positive metastatic breast cancer previously treated with PER.

Legal entity responsible for the study

Koshi Matsui

Funding

None

Disclosure

All 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

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

The subanalysis of prospective randomized trials of E suggested E suppressed development of new lesion [NL] and it led to improvement of overall survival (Twelves, BCRT, 2015), however, behaviors of disease in real-world patients (pts) have not been well discussed.

Methods

Outcomes of HER2-MBC pts who received E at our institute from November 2011 to present were reviewed. Statistical analyses were performed using the chi-square test, the Kaplan-Meyer method.

Results

We identified total 128 (90 ER+, 38 ER-) HER2-MBC who received E at least 2 cycles in our institute. Median age at the initiation of E were as follows; overall, 58 (range 30-77); ER+, 60 (30-77); ER- 55.5 (32-71). Median number of regimens prior to E were as follows; overall, 1 (range 0-8); ER+, 1 (0-6); ER-, 2 (0-8). While all pts had a history of anthracycline and/or taxane in ER- subset, Number of involved organ were 2 (1-5) in overall and both subsets and no significant difference was seen in the pattern of visceral involvement. Most of (122/128, 95.5%) the pts was discontinued E therapy, and median time-to-treatment failure (TTF) were as follows; overall, 125.0 days (95% confidence interval [CI] 43.0-328.0); ER+, 134.0 days (95%CI 62.0-314.0); ER-, 104.0 (95%CI 42.0-230.0). Reasons for the discontinuation of E were as follows; progression of known lesion(s), 77 (63.1%); development of NL, 27 (22.1%), decrease of performance status, 11 (9.0%); intolerable toxicity, 6 (4.9%); other, 1 (0.9%). In ER- subset, development of NL was more frequently seen compared to ER+ subset, however, it was not statistically significant. (7/20 vs 10/67, P = 0.12, chi-square). Multivariate cox regression analyses disclosed some risk factors for TTF as follows; liver metastasis, hazard ratio [HR] 0.39, P < 0.05; soft tissue metastasis, HR 0.53, P < 0.05; ≥3 involved organs, HR 2.99, P < 0.05; taxane for early breast cancer, HR 2.50, P < 0.05. When limited to ER+ pts who received E as 2nd-line therapy (N = 40), only one (2.5%) pt developed NL and there was a positive relationship between TTF and OS after E (Spearman's roh=0.64, p < 0.0001).

Conclusions

Our single institutional review with some limitations disclosed eribulin monotherapy revealed equivalent effect shown in prospective studies.

Legal entity responsible for the study

Junichiro Watanabe

Funding

None

Disclosure

J. Watanabe: Advisory board member of Eisai Co., Ltd. Honoraria from Eisai Co., Ltd.

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

In this study, we observe the patterns initial palliative treatment for premenopausal patients with HR-positive/HER2-negative MBC and determine if non-adherence to clinical guidelines are associated with worse clinical outcomes in terms of progression-free survival (PFS) and overall survival (OS) in the South Korean population.

Methods

A retrospective review was performed for premenopausal patients diagnosed with HR-positive MBC between October 1997 and May 2016 who received palliative systemic treatments at a large tertiary medical center. Survival outcomes were analyzed according to the palliative treatment received prior to disease progression.

Results

The review identified a total of 272 premenopausal patients with HR-positive/HER2-negative MBC. The patients were young (median age, 39 years), as per the premenopausal criteria. Chemotherapy alone was first-line palliative treatment in 78 patients, with endocrine therapy as the initial treatment in 133 patients. In 57 patients, the first line treatment was switched from chemotherapy to endocrine treatment prior to any disease progression. Both progression free survival and overall survival were significantly longer for chemotherapy-endocrine therapy (median PFS 18.2 months and OS 85.2 months) than for chemotherapy-alone (median PFS 12.6 months and OS 45.5 months) or endocrine therapy-alone (median PFS 7.0 months and OS 57.3 months) (all P values < 0.01). In multivariate analysis, chemotherapy-endocrine therapy was an independent predictive value for improved PFS and OS (hazard ratio [HR] 0.33, 95% CI 0.20-0.52, P < 0.001; HR 0.38, 95% CI 0.19-0.73, P = 0.004).

Conclusions

In our study population, chemotherapy alone was not objectively inferior to endocrine therapy as the initial palliative treatment. In addition, chemotherapy followed by endocrine therapy was associated with objective higher response rate than endocrine therapy alone. Further studies should explore the relationship between non-adherent treatment patterns and patient outcomes across the largely premenopausal breast cancer populations across Asian countries.

Legal entity responsible for the study

Prof. Yeon Hee Park

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

Differential efficacy of newly registered therapies in subgroups of metastatic breast cancer (mBC) is an important consideration for their subsequent use in clinical practice. In a systematic literature review, we evaluated differences in outcome regarding progression free survival (PFS), time to progression (TTP), overall survival (OS) and visceral versus non-visceral disease. The impact of HER2- and hormone receptor-status was also considered.

Methods

A systematic literature search (6362 hits) in the meta-Database PubMed was performed for the last 20 years. 257 studies (n = 126,291) were included for further analysis. 69 studies had published data for visceral vs non visceral disease including phase III trials. Out of these 69 studies we selected n = 16 studies (n = 13,083) which looked at the endpoints mentioned above. In order to achieve comparability, we extracted the information of hazard ratios (HR), confidence intervals (CI) and times in weeks (if available) for PFS, TTP, OS of the entire study population, which was divided into three groups: HER2-positive, HER2-negative, unknown HER2 status.

Results

No statistically significant difference in treatment response was found in mBC patients looking at HRs and CIs. Relevant, yet not statistically significant differences were found in the specific response of visceral metastases to modern combination therapies, especially in HER2-positive breast cancer: There was a benefit regarding OS using lapatinib combined with trastuzumab or trastuzumab and docetaxel combined with pertuzumab. Additionally, in two chemotherapy trials, there was a numerical difference between therapy response in visceral vs. non-visceral metastases regarding PFS in the unknown HER2 group, and regarding OS in the HER2 negative group.

Conclusions

In the subgroup analyses, we did not find any significant differences in response rates for visceral vs. non-visceral metastasis. There seems to be a beneficial effect of combination therapies regarding OS in visceral disease. At the present time, metastasis localization should not be used as a predictive marker for choice of systemic therapy in mBC.

Legal entity responsible for the study

Tahir Mehmood

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

There are many reports suggesting that the levels of bone turnover markers (BTM) might be correlated with skeletal-related-events and disease progression in breast cancer patients with bone metastases (BM). We therefore evaluated the correlations OS with the changes in urinary N-telopeptide of type I collagen (u-NTX) in breast cancer patients with BM treated with denosumab (Dmab).

Methods

34 patients were enrolled in this study. All patients received Dmab 120 mg subcutaneously every month and u-NTX was checked at baseline and 1 month after Dmab was administered. We calculated the percentage change of u-NTX level (u-NTX%) [(baseline u-NTX level – 1-month u-NTX level)/baseline u-NTX level] and established a cut-off value by using receiver operating characteristic analysis. OS was defined as the time interval from Dmab administration to the date of death. The patients were divided into two groups by using the cut-off value, and OS was evaluated using the Kaplan-Meier method and analyzed by a log-rank test.

Results

According to the immunohistochemical analysis, estrogen receptor positive and human epidermal growth factor receptor 2 negative (ER+/HER2-) profile was observed in 22 patients, while ER+/HER2+, ER-/HER2+, and ER-/HER2- profiles were observed in 4, 2, and 6 patients, respectively. 2 patients had oligo-BM and 32 patients had multiple-BM. The mean u-NTX% was 0.63 and the established cut-off value was 0.669. The u-NTX% in 19 patients was >0.669 (high u-NTX group) while the remaining 15 patients had u-NTX% under 0.669 (low u-NTX group). OS in the high u-NTX group (n = 19) was significantly longer than in the low u-NTX group (n = 15) (24 months(M) vs 15 months(M), p = 0.005). In 22 ER+/HER2- patients, OS in the high u-NTX group (n = 12) was significantly longer than in the low group (n = 10) (34 M vs 16 M, p = 0.002). Moreover, in 20 patients without other organs metastases, OS in the high u-NTX group (n = 12) was significantly longer than in the low group (n = 8) (24 M vs 15 M, p < 0.001).

Conclusions

High u-NTX% in early phase of treatment could be a promising finding for OS in breast cancer patients with BM treated with Dmab.

Legal entity responsible for the study

Department of Breast Surgery, Yokkaichi Municipal Hospital

Funding

None

Disclosure

All authors have declared no conflicts of interest.