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

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

Postmastectomy radiotherapy (PMRT) has been strongly considered for patients with 1-3 positive axillary nodes (ALNs). In addition, the indications for PMRT are expanding to patients with negative ALNs but have multiple high-risk recurrence factors. However, For patients with isolated tumor cells. We aimed to determine the effects of PMRT on survival of patients with ITCs or ALNs micrometastases of breast cancer.

Methods

We identified patients with ITCs or ALNs micrometastases after mastectomy from the Surveillance, Epidemiology, and End Results database from 2004 to 2014. Overall survival (OS) and breast cancer-specific mortality (BCSM) were compared among patients received PMRT or not, using propensity score-matched analyses. Cox proportional hazards models and competing-risk models were performed in OS and BCSM analyses, respectively.

Results

We identified 11,622 eligible cases. PMRT was administered to 1,728 patients. Treatment was less frequent among patients who were older, patients with high-income, and patients with right-side tumor. OS at 5 years and 10 years were 88.1% and 74.2% in PMRT group, and were 87.8% and 77.3% in non-PMRT group, respectively. Five-year and 10-year cumulative BCSM rate were 6.4% and 12.3% in PMRT group, and were 6.6% and 14.1% in non-PMRT group, respectively. OS and BCSM were unaffected by PMRT after adjusting for multiple confounders (OS, hazard ratio, 0.92; 95% CI, 0.74 to 1.16; BCSM, subhazard ratio, 0.89; 95% CI, 0.67-1.18).

Conclusions

To our knowledge, this is the largest study to date of the effect of radiotherapy on survival in breast cancer with ITCs or ALN micrometastases. In this population-based study, we do not find survival benefit of PMRT on patients with ITCs or ALN micrometastases.

Legal entity responsible for the study

Sun Yat-sen University Cancer Center

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

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

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

As treatment outcomes for mTNBC are poor, new treatment options are needed. We present a subgroup analysis for the safety and antitumor activity of pembrolizumab (PEM) as a therapy for Japanese patients (pts) with mTNBC in Cohorts A and B of KEYNOTE 086.

Methods

Pts with centrally confirmed mTNBC, at least one systemic treatment (Cohort A) or no prior systemic therapy (Cohort B) for metastatic disease, ECOG PS 0-1, and regardless of tumor PD-L1 expression (Cohort A) or with a tumor PD-L1 combined positive score (CPS) ≥1% (Cohort B), received PEM 200 mg IV every 3 weeks (wk) for 24 months (m) or until disease progression, intolerable toxicity, or investigator or patient (pt) decision. Tumor imaging was performed Q9W for 12 m and Q12W thereafter. Clinically stable pts with PD could remain on PEM until PD was confirmed on subsequent assessment. Primary endpoints were ORR (RECIST, central review) in Cohort A and safety in Cohorts A and B. Secondary were ORR in Cohort B, disease control rate (CR + PR + SD ≥ 24 wk), PFS and OS in Cohorts A and B.

Results

Of 20 pts in Cohort A, 12 had PD-L1 (+) tumors and 8 had PD-L1 (-) tumors. The median age was 53.5 y, 11 pts had elevated LDH and 13 pts had visceral metastases. Of 9 pts in Cohort B, median age was 38.0 y, 1 pt had elevated LDH, 5 pts had visceral metastases. As of Nov 10, 2016, the best overall response was PR in 1 pt and SD in 2 pts in Cohort A, and CR in 1 pt and SD in 2 pts in Cohort B. Median PFS was 2.0 m (95% CI, 1.7 – 2.1) in Cohort A, and 2.1 m (95% CI, 1.6 – 4.2) in Cohort B. Median OS was 8.3 m (95% CI, 4.6 – 10.3) in Cohort A, and was not reached in Cohort B. Drug-related AEs (DRAEs) occurred in 20 pts (67.0%) in Cohorts A and B; the most common DRAEs were pruritus (4 pts), fatigue, pyrexia, anemia, rash, and diarrhea (3 pts each). Grade (Gr) 3-4 DRAEs were diarrhea, nausea, and bacteraemia (1 pt each), all in Cohort A. Infusion reaction (1 pt, Gr 2), interstitial lung disease (1 pt, Gr 1), hypersensitivity (1 pt, Gr 2) and hyperthyroidism (1 pt, Gr 1) were seen as irAE. No pts died or discontinued PEM due to AEs.

Conclusions

Data from 29 Japanese pts in Cohorts A and B suggest that PEM monotherapy has a well tolerated safety profile and anti-tumor activity which are similar to those reported in the overall populations.

Clinical trial identification

NCT02447003.

Legal entity responsible for the study

Merck & Co., Inc., Kenilworth, NJ, USA

Funding

Merck & Co., Inc., Kenilworth, NJ, USA

Disclosure

H. Mukai: Received personal fees as honoraria from AstraZeneca, Novartis Pharma, Daiichi Sankyo, and Taiho Pharmaceutical, and received research funds from Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Nippon Kayaku, Novartis Pharma, Pfizer Japan, and MSD.K.K. N. Masuda: Honoraria: Chugai, Astrazeneca. H. Ishiguro: Advisory board: MSD.K.K. T. Shimamoto, K. Yamamoto: Employees of MSD.K.K. Y. Ding, G. Aktan, V. Karantza: Employees of Merck

All other authors have declared no conflicts of interest.

Background

MONALEESASIA is an ongoing Phase Ib dose-escalation/-expansion study evaluating RIB + LET in a subset of Asian pts from Hong Kong and Singapore with HR+, HER2–ABC.

Methods

Postmenopausal pts from Hong Kong and Singapore with HR+, HER2– ABC and no prior systemic therapy for ABC received RIB (400 or 600 mg/day; 3-weeks-on/1-week-off) + LET (2.5 mg/day; continuous). Dose escalation used a Bayesian Logistic Regression Model with overdose control. The primary endpoint was to determine the maximum tolerated dose (MTD)/recommended Phase II dose (RP2D); secondary endpoints included safety and pharmacokinetic (PK) profile. Blood samples for PK non-compartmental analysis were collected on Days 1 and 21 of Cycle 1 from pre-dose to 24 h post-dose.

Results

At data cut-off (Jan 16, 2017), 26 pts were enrolled (RIB 400 mg: n = 6; 600 mg: n = 20). One dose-limiting toxicity was observed at 600 mg (Grade 3 increased alanine transaminase [ALT]); the MTD/RP2D was RIB 600 mg/day (3-weeks-on/1-week-off) + LET 2.5 mg/day (continuous). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 4/6 pts at 400 mg and 17/20 pts at 600 mg during the dose-escalation and -expansion parts. The most common Grade 3/4 TRAEs (≥20% in either cohort; 400 mg vs 600 mg) were decreased neutrophil count (n = 3 vs n = 7), neutropenia (n = 1 vs n = 6), increased ALT (n = 1 vs n = 4), and increased aspartate transaminase (n = 0 vs n = 4). After a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21), absorption of both RIB and LET was rapid (Table); increases in RIB exposure were dose dependent.

Conclusions

The MTD/RP2D was declared as RIB 600 mg/day (3-weeks-on/1-week-off) + LET 2.5 mg/day (continuous) in Asian pts from Hong Kong and Singapore with HR+, HER2– ABC. Preliminary safety and PK data are consistent with prior observations in non-Asian pts.

Clinical trial identification

CLEE011A2115C/NCT02333370.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation

Funding

Novartis Pharmaceuticals Corporation

Disclosure

Y-S. Yap: Received honoraria and provided consultancy for Novartis. Y. Ito: Yoshinori Ito reports grants from MSD, AstraZeneca, Novartis, Parexel, Chugai, and Lilly. O. Bornstein: Orna Bornstein is an employee of Novartis Pharmaceuticals Corporation. Y. Han: Yu Han is an employee at Novartis Pharmaceuticals Corporation. T. Samant: Tanay Samant is an employee of Novartis Pharmaceuticals Corporation and owns stocks/shares in Novartis Pharmaceuticals Corporation. X. Liu: Xiaochun Liu is an employee of Novartis Pharmaceuticals Corporation and owns stocks in Novartis Pharmaceuticals Corporation. J. Chiu: Dr. Chiu served on advisory boards for Novartis and Pfizer.Table: 94O

Summary of RIB and LET PK profiles

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.