| 摘要: | 背景：乳癌是女性癌症中發生率最高，也是癌症的主要死亡原因之一。乳癌依分子細胞型態大致分為荷爾蒙受體陽性、第二型人類上皮成長因子受體陽性、三陰性乳癌。其中荷爾蒙受體陽性且第二型人類上皮成長因子受體陰性，約佔所有乳癌60-70%。大部分的乳癌患者可經由輔助性化學治療及內分泌治療而有良好的治療效果，但仍有少數病患對內分泌治療產生抗藥性導致局部復發或是遠端器官轉移。近幾年多項臨床研究證實，細胞週期素激?4和6抑制劑可有效延長疾病無惡化存活期。然而，對於整體存活期的研究結果較不一致。因此，本研究主要透過系統性文獻回顧與統合分析，比較三種細胞週期素激?4和6抑制劑對荷爾蒙受體陽性且第二型人類上皮成長因子受體陰性的轉移性乳癌患者的治療效果及安全性。
材料與方法：搜尋電子資料庫包含：Pubmed，Embase，Cochrane Library， ClinicalTrials.gov中，使用關鍵字以breast cancer or metastatic breast cancer or advanced breast cancer and ‘CDK4/6 inhibitor’ or ‘abemaciclib’ or ‘ribociclib’ or ‘palbociclib’ and ’endocrine therapy’ and ‘progression free survival’ or ’overall survival’字串，進行搜尋相關的臨床試驗。使用RevMan (5.3 version) 進行統合資料分析，並使用評讀工具RoB1.0(risk of bias in randomized trials)進行「隨機對照試驗」過程中可能產生的偏差。
結果：本研究共納入11篇隨機對照試驗(randomized controlled trial, RCTs) ，共計5,572位女性乳癌患者。結果發現CDK4/6抑制劑合併內分泌治療可有效的延長疾病無惡化存活期(HR：0.55；95% CI：0.53-0.87；P<0.00001)及整體存活期(HR：0.79；95% CI：0.72-0.87；P<0.00001)，無論在治療意向 (Intention-to-treat, ITT)或可測量疾病(measurable disease)的分析中發現CDK4/6抑制劑在客觀緩解率(ORR, 1.59 [1.37, 1.86]; P <0.00001)或是臨床獲益率(CBR, 1.59 [1.37, 1.86]; P <0.00001)皆具有顯著的治療效果。另外，CDK4/6抑制劑合併內分泌治療組證實可有效降低疾病復發風險率(PD) (0.49 [0.41, 0.58]; P <0.00001)。關於安全性的部分，在接受CDK4/6抑制劑治療的患者中最常觀察到的3-4 級不良事件是中性粒細胞減少症(Risk Ratio: 26.87[9.63-74.97]; P <0.00001）。
結論：合併使用CDK 4/6抑制劑及內分泌治療證實可延長荷爾蒙受體陽性且第二型人類上皮成長因子受體陰性之轉移性乳癌患者的預後。然而，CDK 4/6抑制劑也會導致第3-4級的不良反應包括嗜中性白血球低下症。因此，使用CDK 4/6抑制劑合併內分泌治療轉移性乳癌患者時須特別觀察可能的副作用，及時做出個人化調整，以達到精準醫療的目標。
關鍵字：乳癌、CDK4/6抑制劑、內分泌治療、疾病無惡化存活期、整體存活期、客觀緩解率、臨床獲益率、疾病進展率、不良事件、系統性回顧、統合分析
Background: Breast cancer is the most common cancer and the leading cause of cancer death among women. Based on the molecular subtypes, breast cancer can be divided into three subtypes in general：hormone receptor-positive, human epithelial growth factor receptor-II positive, and triple-negative. Among them, the hormone receptor -positive and human epithelial growth factor receptor-II negative subtype accounts for 60%-70% of all breast cancers. Most breast cancer patients can be cured by endocrine therapy, and there are still a few patients who are resistant to endocrine therapy leading to local recurrence or distant metastasis. In recent years, a number of clinical studies have confirmed that cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitor) can effectively prolong the progression free survival period and replace traditional chemotherapy. This study mainly compares the therapeutic effects and differences of three cyclin-dependent kinase 4 and 6 inhibitors in clinical trials through systematic review and meta-analysis.
Objective:This study aims is investigation of the effects of endocrine therapy plus CDK 4/6 Inhibitors on prognosis of patients with HR-positive, HER2-negative metastatic breast cancer.
Materials and Methods: Search electronic databases including: Pubmed, Embase, Cochrane Library, ClinicalTrials.gov using keywords breast cancer or metastatic breast cancer or advanced breast cancer and 'CDK4/6 inhibitor' or 'abemaciclib' or 'ribociclib' or 'palbociclib' ' and 'endocrine therapy' and 'progression free survival' or 'overall survival' strings to search for relevant clinical trials.
Result: Eleven randomized controlled trials were eligible including 5572 breast cancer patients. Compared to the endocrine therapy alone group, adding CDK4/6 inhibitors to endocrine therapy had significantly improved progression free survival (HR：0.55；95% CI：0.53-0.87；P<0.00001) and overall survival (HR：0.79；95% CI：0.72-0.87；P<0.00001). According to our analysis of the intention-to-treat (ITT) group or measurable disease group, CDK4/6 inhibitors arms exhibited better overall response rate (ORR) as indicated by the relative risk (RR) (randomized-effect model, 1.50 [1.33, 1.70], ITT; P <0.00001) and higher clinical benefit rate (CBR) (randomized-effect model, ITT, 1.18 [1.09, 1.27]; P <0.0001). The combination regiment also proved to be effective in reducing the rate of progressive disease (PD) in the ITT group (randomized-effect model, 0.49 [0.41, 0.58]; 95% CI; P <0.00001). Nevertheless, more adverse events were observed in patients treated with CDK4/6 inhibitors. The most common grade 3-4 adverse events were neutropenia (Risk Ratio:26.87[9.63-74.97]; P <0.00001).
Conclusions: Combination of endocrine therapy and CDK4/6 inhibitors can improve the prognosis of patients with HR-positive, HER2-negative metastatic breast cancer. However, the addition of CDK4/6 inhibitors also increased the incidences of grade 3-4 adverse events.
Key words : Breast cancer, CDK4/6 inhibitor, Endocrine therapy, Progression free survival, Overall survival, Objective response rate, Clinical benefit rate, Systematic review, Meta-analysis. |
