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Research ArticleExperimental Studies

Antitumor Activity of Eribulin After Fulvestrant Plus CDK4/6 Inhibitor in Breast Cancer Patient-derived Xenograft Models

YUKI NIWA, MAKOTO ASANO, TAKAYUKI NAKAGAWA, DAMIEN FRANCE, TARO SEMBA and YASUHIRO FUNAHASHI
Anticancer Research December 2020, 40 (12) 6699-6712; DOI: https://doi.org/10.21873/anticanres.14693
YUKI NIWA
1Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan;
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MAKOTO ASANO
1Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan;
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TAKAYUKI NAKAGAWA
1Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan;
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DAMIEN FRANCE
2Oncodesign, Dijon, France
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TARO SEMBA
1Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan;
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YASUHIRO FUNAHASHI
1Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan;
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  • For correspondence: y-funahashi@hhc.eisai.co.jp
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    Subtypes of 4 luminal-type breast cancer patient-derived xenograft models. Representative immunohistochemical images show the expression of estrogen receptor (ER), progesterone receptor (PGR), human epithelial growth factor receptor 2 (Her2) and Ki67. Magnification, ×100.

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    Figure 2.

    Antitumor activity of CDK4/6 inhibitor, endocrine therapy and chemotherapy in 4 luminal-type breast cancer patient-derived xenograft (PDX) models. PDX tumor-bearing mice were randomized into each treatment group (n=2 to 4 per group), and treated with 5 mg/mouse fulvestrant (Flv; purple) on a Q7D×3; 100 mg/kg palbociclib (Palb; green) on a Q1D×21; a combination of Flv plus Palb (orange); 0.5-0.57 mg/kg of eribulin (Eri-L; pink), and 2.0-2.26 mg/kg of eribulin (Eri-H; red) on a Q4D×3; or 250 mg/kg capecitabine (Cape; blue) on a Q1D×14. Untreated control is shown in black. The same control group data are shown in the upper (CDK4/6 inhibitor and endocrine therapy) and lower (chemotherapy) panels. (A) Relative tumor volumes are shown for days after treatment initiation. Minimum relative tumor volumes (RTVs) for individual mice, which were lower than 0.01 are shown as 0.01. (B) Survival of mice. Kaplan–Meier estimates of mouse survival combined across the 4 PDX models are shown (n=8 to 12 per treatment group). Mouse survival was defined as the number of days t until the tumor volume reached four times the initial tumor volume. Differences in survival were examined by using the log-rank (Mantel–Cox) test. *p<0.05 vs. Control by log-rank test. #p<0.05 vs. Cape by log-rank test. (C) Waterfall plots. The best overall response as percentages from baseline across the 4 PDX models are shown. The best overall response was determined by comparing the tumor volume change at day t with the baseline tumor volume at day 0 for t≥21 (after end of treatment period). Maximum values of best percentage change from baseline are shown as 200%. Best percentage changes from baseline that exceeded 200% are represented as 200%. The same control data are used in the left (CDK4/6 inhibitor and endocrine therapy) and right (chemotherapy) panels.

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    Figure 3.

    Molecular profiles of the 4 luminal-type breast-cancer patient-derived xenograft (PDX) models. RNA was extracted and purified from resected tumor tissues from untreated mice (n=1 per model). After synthesis of cDNA, quantitative RT-PCR was performed, and mRNA expression levels of genes relative to ones in the OD-BRE-0438 model were calculated. Ct values for each sample were measured in duplicate and mean Ct values were used for analysis. nd: Not detected.

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    Figure 4.

    Antitumor activity of endocrine therapy plus CDK4/6 inhibitor combination treatment in the OD-BRE-0438 model. (A) Scheme of treatment with fulvestrant (Flv), palbociclib (Palb), or Flv plus Palb in the 1st and 2nd experiments. (B) Antitumor activity of Flv, Palb, or Flv plus Palb combined for an initial 2 weeks, days 0 and 14 (1st experiment). OD-BRE-0438 tumor-bearing mice were treated with Flv (purple, 5 mg/mouse, Q7D×2), palbociclib (green, 100 mg/kg, Q1D×14), or their combination (orange). Untreated control is shown in black. n=6 per group. Data shown are means+SEM. *p<0.05 vs. control by repeated measures Dunnett’s multiple comparisons test using log-transformed values. (C) Antitumor activity of Flv plus Palb for 2 weeks, days 14 and 28 (2nd experiment). Mice treated with Flv plus Palb for 2 weeks were randomized into two groups (n=6 per group). One group continued treatment with Flv plus Palb (Flv+Palb→Flv+Palb, orange) and the other group received no further treatment (Flv+Palb→no treat, black). Data shown are means+SEM. (D–G) Tumor samples were collected on day 14 (untreated (control) or Flv+Palb) or on day 28 (Flv+Palb→Flv+Palb or Flv+Palb→no treat). Representative immunohistochemical images of estrogen receptor (ER) (D) and E-cadherin (F) expression, and quantification of ER in tumor cells (E) and E-cadherin on cell membranes of tumor cells (G). ER expression in tumor cells (E) or E-cadherin expression on membranes of tumor cells (G) was classified into levels that were high (3+), moderate (2+), low (1+) or negative (0+) and H-scores were calculated. n=6 per group. Data shown are means±SEM. *p<0.05 vs. Control by Dunnett’s multiple comparisons test. #p<0.05 vs. Flv+Palb by Dunnett’s multiple comparisons test.

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    Figure 5.

    Antitumor activity of chemotherapy after endocrine therapy plus CDK4/6 inhibitor combination treatment in the OD-BRE-0438 model. (A) Scheme of sequential treatment with eribulin (Eri) and capecitabine (Cape) after fulvestrant (Flv) plus palbociclib (Palb) treatment. Flv plus Palb combination therapy was conducted for 2 weeks between days 0 and 14, and mice treated with Flv plus Palb for 2 weeks were randomized into two groups (n=6 per group, day 14) and treated with either Eri or Cape for an additional 2 weeks. (B) Antitumor activity of Eri and Cape after Flv plus Palb combination treatment. Relative tumor volume (upper) and relative body weight (lower) compared with tumor volume and body weight on day 14 (after Flv+Palb therapy for 14 days and before chemotherapy treatments) from days 14 to 28 (chemotherapy period) are shown. Data shown are means+SEM. (C) Comparison of antitumor activity of Eri and Cape (day 28). Data shown are means±SEM. Statistical analysis was conducted by unpaired t-test using log-transformed values. (D-G) Tumor samples were collected on day 28 (initial 2 weeks of treatment with Flv plus Palb, followed by an additional 2 weeks of treatment with Eri or Cape, each at two doses. Representative immunohistochemical images of estrogen receptor (ER) (D) and E-cadherin (F) expression, and quantification of ER in tumor cells (E) and E-cadherin on cell membranes of tumor cells (G). ER expression in tumor cells (E) or E-cadherin expression on membranes of tumor cells (G) was classified into levels of high (3+), moderate (2+), low (1+) and negative (0+) and H-scores were calculated. n=6 per group. Data shown are means±SEM. Dotted lines in graphs indicate mean H-scores of Flv+Palb (day 14). *p<0.05 by two-way ANOVA with Sidak’s multiple comparisons test.

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Anticancer Research: 40 (12)
Anticancer Research
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December 2020
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Antitumor Activity of Eribulin After Fulvestrant Plus CDK4/6 Inhibitor in Breast Cancer Patient-derived Xenograft Models
YUKI NIWA, MAKOTO ASANO, TAKAYUKI NAKAGAWA, DAMIEN FRANCE, TARO SEMBA, YASUHIRO FUNAHASHI
Anticancer Research Dec 2020, 40 (12) 6699-6712; DOI: 10.21873/anticanres.14693

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Antitumor Activity of Eribulin After Fulvestrant Plus CDK4/6 Inhibitor in Breast Cancer Patient-derived Xenograft Models
YUKI NIWA, MAKOTO ASANO, TAKAYUKI NAKAGAWA, DAMIEN FRANCE, TARO SEMBA, YASUHIRO FUNAHASHI
Anticancer Research Dec 2020, 40 (12) 6699-6712; DOI: 10.21873/anticanres.14693
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Keywords

  • CDK4/6 inhibitor
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  • luminal-type breast cancer
  • patient-derived xenograft model
  • reversal of epithelial-mesenchymal transition
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