摘要:研究背景 三重陰性乳癌(Triple-negative breast cancer, TNBC),其病理特徵為缺乏雌性激素接受體,黃體素接受體及第二型人類表皮生長因子接受體。三重陰性 乳癌因具有其獨特的分子和組織學特徵,雖對化學治療有較高之緩解率,但其 臨床方面卻容易復發,其預後也較其它乳癌類型有較不好。基於上述原因,實 有必要立即發展獨創性及有效之治療策略,來增加三重陰性乳癌治癒率和提高 存活率。 研究緣由: 因表皮細胞生長因子(EGFR/ErbBI)之過度表現及表皮細胞生長因子的基因 突變,已被證實與三重陰性乳癌有高相關性,因此使用表皮生長因子接受體阻 抗劑來抑制表皮細胞生長因子,是很適合作為治療三重陰性乳癌的治療標的。 Afatinib是表皮生長因子接受體之阻抗劑,可藉由抑制ErbB家族之相關訊息傳 遞來治療癌症。同時,Afatinib在三重陰性之乳癌細胞株及轉殖動物模式的前期 臨床實驗及第一期臨床試驗均證實有效性,因此我們推測可能未受控制ErbB 之訊息傳遞可能直接造成三重陰性乳癌之致癌機轉,若能藉由Afatinb來做為 術前治療三重陰性乳癌,不僅有學術研究的重要性,也能提供獨創性的治療策略。 研究目的: 主要療效指標是評估合併afatinib和每週paclitaxel用來術前治療三重陰 性乳癌之病理完全緩解率。次要療效指標是評估單獨afatinib來治療三重陰性 乳癌空窗期之臨床療效,及評估單獨afatinib及合併afatinib和每週paclitaxel 之藥物副作用和安全性。同時,探討afatinib藥物所可能影響之下游訊息傳遞路徑,是否找出可能預測單獨afatinib和合併afatinib和每週paclitaxel之療效 生物標記。 研究方法: 三重陰性之可開刀乳癌病人,若能符合下列條件(clinical T2-T3, N0-N1, M0; clinical T1-3, N1-2, M0; or any T4a tumor)及願意接受術前治療,均可進入此第II 期開放臨床試驗。我們研究流程如下,單獨afatinib每天40mg,連續14天後, 使用乳房超音波評估其療效,並做粗針核心切片術。之後再進入合併afatinib和每週paclitaxel之治療的療程:接受合併afatinib和每週paclitaxel之4個療程 後,再用核磁共振檢查評估療效,若完全緩解則直接進行手術;若部分完全緩解, 則繼續接受2個療程後再接受手術。除了臨床評估(乳房超音波,磁核共振檢 查)外,我們也將評估預測afatinib和合併afatinib及每週paclitaxel之治療效的生物標記,及可能受afatinib治療後所可能影響之分子標記的動態變化影響之分子標記的動態變化(收集時間點為治療前,兩週時間點為治療前,兩週 afatinib治療後,及手術標本)。並藉由組織學免疫染色, 基因突變分析mRNAmRNA mRNA表現變化及 EGFREGFR EGFR螢光原位雜交法和基因圖譜等方法,進一步釐清這些生物標記(例如 : EGFR, EGFR-signaling, FGFR, FGFR-signaling, ERK, p53, NF-κB) 及釐清 afatinib有效性和無效性之可能分子機制。預期成果 :我們預期 單獨使用 afatinib或合併 afatinib和每週paclitaxel,其 高臨床療效性及高病理完全緩解率,和可接受性之副作用,以及可預測療效之生物標記,將在接受術前治療之三重陰性乳癌病人可被證實及發現。並以此第二期開放臨床研究成果 ,幫助我們建立及設計第三期臨床試驗的基礎,同時進一步證實和確認這研究基礎的可行性。
Abstract: Triple-negative breast cancer (TNBC) is defined by a lack of expression of both estrogen and progesterone receptor as well as human epidermal growth factor receptor 2 (HER-2). TNBC is characterized by distinct molecular, histological and unfavorable clinical features despite the high rates of response to chemotherapy. Based on the above reasons, it is important to emergently develop novel therapies and/or treatment strategies to increase treatment efficacies and the survival rate of TNBC. [Rationale]: Overexpression of epidermal growth factor receptor (EGFR/ErbB1) and EGFR mutation have been reported in TNBC and may therefore be a valid target for antitumor therapy in TNBC. Afatinib (BIBW 2992) is an ErbB-family blocker that irreversibly inhibits signaling from all relevant ErbB-family dimers. Afatinib has demonstrated preclinical activity in triple-negative breast cancer cell lines and xenograft models of breast cancer, and clinical activity in phase I studies. Based on the assumption that uncontrolled ErbB-signaling is directly related to an increased oncogenic potential in TNBC, the studying afatinib in the neoadjuvant treatment of TNBC patients is important and provides a novel therapy. [Aims] The primary endpoint is to evaluate the pathologic complete response of the combination of afatinib and weekly paclitaxel in TNBC patients receiving neoadjuvant treatment. The secondary endpoints are to evaluate the clinical response and safety of afatinib with and without paclitaxel, and to explore the different afatinib-affecting downstream molecular pathways as well as potential biomarkers predicting the response of afatinib with and without paclitaxel. [Patients and methods]: Patients with TNBC (clinical T2-T3, N0-N1, M0; clinical T1-3, N1-2, M0; or any T4a tumor) and received neoadjuvant treatment will included in this open, label, multicenter phase II study. Our schema is as follows: (1) Afatinib 40 mg per day for 14 days, then evaluation, every subject will go into the following phase no matter whether she had response or not (2) the following phase (the combination with afatinib and paclitaxel): Afatinib 40 mg per day, day 1 to day 21, in combination with paclitaxel 80 mg/m² on days 1, 8, 15 in a 3-weekly course. In addition to the clinical assessment, we will evaluate the potential predictive biological markers of activity of Afatinib with and without paclitaxel and dynamic changes of molecular makers ([serum and tissue samples: before treatment, 2 weeks after treatment, and operation timing]; potential molecules, such as EGFR, EGFR-signaling, FGFR, FGFR-signaling, ERK, p53, NF- ?B, and etc. were evaluated through the immunohistochemical stains, mutation analysis, mRNA [RT-PCR], single nucleotide polymorphism analysis, and FISH analysis). In addition, the genetic expression profiles will be compared between afatinib-responsive and afatinib-unresponsive samples. [Expected Results]: The promising clinical activity, tolerable toxicity, and potential biomarkers of afatinib with and without paclitaxel in TNBC patients receiving neoadjuvant setting will be demonstrated. The results from this study can be used to conduct a larger trial that would allow us to confirm or validate the hypotheses generated.