Risk reduction of distant metastasis in hormone-sensitive postmenopausal breast cancer

Adjuvant endocrine therapy remains the principle strategy to reduce recurrence risk in postmenopausal women with early breast cancer. Studies of the natural history of breast cancer have shown that, while not reaching zero at any time point, the risk of recurrence is highest in the first 5 years following initial diagnosis and treatment. Within this initial 5 years, there is a peak of recurrence at the 2- to 3-year mark. Among the types of breast cancer recurrences observed at this early peak, distant metastasis (DM) predominates over local or contralateral relapse. DM recurrences are most strongly linked to breast-cancer-related death, and it has been suggested that adjuvant endocrine therapies that are most effective in minimizing the early peak of DM recurrence may have the most favorable impact on survival in women with early breast cancer. Aromatase inhibitors (AIs) including anastrozole, letrozole, and exemestane have gained popularity in the past few years as alternatives to 5 years of adjuvant tamoxifen, the previous standard of care. However, clinicians have not yet resolved how best to integrate AIs into breast cancer treatment; both upfront therapy (i.e., in lieu of tamoxifen) and a sequential/switch strategy (i.e., after some period of prior tamoxifen) have been proposed. The benefits and drawbacks of these approaches to AI treatment, particularly with respect to reducing early DM recurrences, are reviewed

Phase Ib/II study of nivolumab combined with palliative radiation therapy for bone metastasis in patients with HER2-negative metastatic breast cancer

Radiation therapy (RT) can enhance the abscopal effect of immune checkpoint blockade. This phase I/II study investigated the efficacy and safety of nivolumab plus RT in HER2-negative metastatic breast cancer requiring palliative RT for bone metastases. Cohort A included luminal-like disease, and cohort B included both luminal-like and triple-negative disease refractory to standard systemic therapy. Patients received 8 Gy single fraction RT for bone metastasis on day 0. Nivolumab was administered on day 1 for each 14-day cycle. In cohort A, endocrine therapy was administered. The primary endpoint was the objective response rate (ORR) of the unirradiated lesions. Cohorts A and B consisted of 18 and 10 patients, respectively. The ORR was 11% (90% CI 4–29%) in cohort A and 0% in cohort B. Disease control rates were 39% (90% CI 23–58%) and 0%. Median progression-free survival was 4.1 months (95% CI 2.1–6.1 months) and 2.0 months (95% CI 1.2–3.7 months). One patient in cohort B experienced a grade 3 adverse event. Palliative RT combined with nivolumab was safe and showed modest anti-tumor activity in cohort A. Further investigations to enhance the anti-tumor effect of endocrine therapy combined with RT plus immune checkpoint blockade are warranted

ヒト シボウ ソシキ ユライ stroma サイボウ ワ エンキセイ センイガ サイボウ ゾウショク インシ オ イデンシ ドウニュウスル コト デ コウカテキ ニ ゾウショクシ ブンカスル

京都大学0048新制・課程博士博士(医学)甲第10453号医博第2652号新制||医||845(附属図書館)UT51-2003-T279京都大学大学院医学研究科外科系専攻(主査)教授 今村 正之, 教授 中尾 一和, 教授 田中 絋一学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

Clinical Predictive Factors for the Efficacy of Everolimus in Patients With Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer: A Multicenter Retrospective Cohort Study in Japan

Purpose: To investigate the clinical predictive factors for the efficacy of everolimus (EVE) for advanced/metastatic breast cancer (AMBC). Methods: Routine practice data of consecutive patients with AMBC who received EVE at 5 institutions in western Japan were retrospectively analyzed in this cohort study (study registration no.: UMIN 000032569). The correlation among time to treatment failure (TTF), overall survival (OS), and clinical background was investigated via univariate and multivariate analyses using Cox hazards model for the clinically important variables. Results: A total of 134 patients were included in the analysis. The median TTF and OS were 5.2 months (95% confidence interval [CI]: 4.1-6.4) and 27.3 months (95% CI: 23.7-30.9), respectively. Multivariate analysis showed that dose reduction of EVE from any initial dose was associated with a longer TTF (hazard ratio [HR]: 0.52; 95% CI: 0.32-0.84, P  = .007). Meanwhile, very low hormone sensitivity (ie, relapse within the first 2 years during adjuvant endocrine therapy or progression within 3 months of endocrine therapy immediately before EVE) was associated with a shorter TTF (HR: 2.48; 95% CI: 1.49-4.10, P  < .001). In the analysis of stratified treatment outcomes, TTF was longer in the group with <3 liver metastases and in groups other than the very low hormone sensitivity group, regardless of the treatment line of EVE. Conclusions: Low hormone sensitivity and ⩾3 liver metastases were important prognostic factors for the efficacy of EVE. EVE may be less effective in patients with AMBC with these factors, and as such, chemotherapy should be administered instead

Adipogenesis Induced by Human Adipose Tissue-Derived Stem Cells

Adipose tissue-derived stem cells (ASCs), including preadipocytes, may play an important role in de novo adipogenesis and are expected to be a useful external source of cells for adipose tissue engineering. In this study, we examined in vivo adipogenesis up to 24 weeks after implantation, induced by human ASCs that were isolated from adipose tissues and expanded in vitro. ASCs proliferated in vitro in the presence of basic fibroblast growth factor (bFGF), and the number of cells increased by more than 1000-fold at the fourth passage. The ability to differentiate into mature adipocytes was maintained up to the third passage. We incorporated designated numbers of third-passage-expanded cells into a type I collagen scaffold and implanted them into the back of nude mice with or without controlled-release bFGF. After the implantation of 2 x 10(6) ASCs with controlled-release bFGF, the greatest cross-sectional surface area of adipose tissue in the scaffold was 1.19 mm(2) at 12 weeks and 2.14 mm(2) at 24 weeks. About 2 x 10(6) ASCs with controlled-release bFGF was the best condition for total adipogenesis. Immunohistochemical analysis with antihuman vimentin antibody showed that the area of human-origin adipose tissue was maximum in the group with 8 x 10(6) ASCs incorporated in a scaffold at both 12 and 24 weeks. The amount of human-origin adipose tissue increased in all groups with implanted ASCs from 12 to 24 weeks. Only trace of human-origin adipose tissue was observed in other groups implanted ASCs. Our results show that human ASCs not only function as progenitor cells for in vivo adipogenesis, but also induce de novo adipogenesis for long period