目前，蒽環(huán)類（例如表柔比星、多柔比星、多柔比星脂質(zhì)體）仍然是治療乳腺癌的基本藥物，被廣泛用于治療不同的乳腺癌，并且被作為早期乳腺癌手術(shù)前后的標(biāo)準(zhǔn)治療藥物。此外，蒽環(huán)類被推薦用于局部晚期或轉(zhuǎn)移性乳腺癌。多柔比星常被用于美國(guó)，而表柔比星較多被用于歐洲。表柔比星與多柔比星相比，分子結(jié)構(gòu)和治療效果相似，毒性（尤其心臟毒性）可能較少。雖然有效的抗癌治療越來(lái)越多，但是耐藥仍然是導(dǎo)致治療失敗的主要問題。蒽環(huán)類的療效似乎變化很大，緩解率為42%～79%。顯然大部分患者對(duì)蒽環(huán)類治療并未獲得任何好處，但是仍然經(jīng)歷不良反應(yīng)，此外延誤了啟動(dòng)更有效的治療。眾所周知，當(dāng)一線治療失敗時(shí)，二線治療以及其他治療獲益變得更為困難。因此，有必要對(duì)乳腺癌的蒽環(huán)類療效進(jìn)行預(yù)測(cè)。丹麥赫斯霍爾姆醫(yī)學(xué)預(yù)后研究所發(fā)明了一種基于細(xì)胞系和多基因信使核糖核酸（mRNA）的藥物療效預(yù)測(cè)法，根據(jù)藥物相關(guān)遺傳反應(yīng)特征，將體外敏感性和基因表達(dá)，結(jié)合3000多例臨床腫瘤標(biāo)本的臨床遺傳信息，計(jì)算藥物對(duì)特定腫瘤的可能療效。
2018年8月11日，施普林格·自然旗下《乳腺癌研究與治療》在線發(fā)表丹麥哥本哈根大學(xué)海萊烏醫(yī)院、哥本哈根大學(xué)王國(guó)醫(yī)院、哥本哈根大學(xué)北西蘭醫(yī)院、羅斯基勒大學(xué)醫(yī)院、奧爾堡大學(xué)醫(yī)院、奧胡斯大學(xué)醫(yī)院、西日德蘭地區(qū)醫(yī)院、瓦埃勒醫(yī)院、南日德蘭半島醫(yī)院、丹麥乳腺癌協(xié)作組、赫斯霍爾姆醫(yī)學(xué)預(yù)后研究所的研究報(bào)告，評(píng)估了藥物療效預(yù)測(cè)法對(duì)于晚期乳腺癌表柔比星療效的預(yù)測(cè)價(jià)值。
該丹麥乳腺癌協(xié)作組隊(duì)列回顧前瞻單盲研究于1997年5月～2016年11月連續(xù)入組140例患者接受表柔比星治療。患者知情同意后，從存檔福爾馬林固定石蠟包埋原發(fā)乳腺腫瘤組織分離mRNA，通過昂飛陣列進(jìn)行分析。主要研究終點(diǎn)為治療開始至疾病進(jìn)展時(shí)間，根據(jù)藥物療效預(yù)測(cè)法，結(jié)合患者醫(yī)療記錄回顧收集臨床病理學(xué)數(shù)據(jù)，分析表柔比星的療效。通過多因素比例風(fēng)險(xiǎn)回歸模型按幾線治療進(jìn)行統(tǒng)計(jì)學(xué)分析。
結(jié)果發(fā)現(xiàn)，治療開始至疾病進(jìn)展時(shí)間中位9.3個(gè)月，藥物療效預(yù)測(cè)法與進(jìn)展時(shí)間顯著相關(guān)（單側(cè)P=0.03）。藥物療效預(yù)測(cè)法評(píng)分75%與25相比，進(jìn)展時(shí)間分別為中位13個(gè)月、7個(gè)月，進(jìn)展風(fēng)險(xiǎn)減少45%（風(fēng)險(xiǎn)比：0.55，單側(cè)95%置信區(qū)間～0.93）。多因素比例風(fēng)險(xiǎn)回歸模型分析表明，藥物療效預(yù)測(cè)法與年齡和轉(zhuǎn)移數(shù)量無(wú)關(guān)。
因此，該研究前瞻驗(yàn)證了既往回顧分析證實(shí)藥物療效預(yù)測(cè)法對(duì)表柔比星療效的預(yù)測(cè)能力，可使那些被預(yù)測(cè)為療效不佳的患者較早選擇有效替代藥物，故有必要開展隨機(jī)前瞻研究證明該方法能否顯著改善總生存。
Breast Cancer Res Treat. 2018 Aug 11.
Predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort: a retrospective-prospective blinded study.
Anna Sofie Kappel Buhl, Troels Dreier Christensen, Ib Jarle Christensen, Knud Mejer Nelausen, Eva Balslev, Ann Soegaard Knoop, Eva Harder Brix, Else Svensson, Vesna Glavicic, Adam Luczak, Sven Tyge Langkjer, Soren Linnet, Erik Hugger Jakobsen, Jurij Bogovic, Bent Ejlertsen, Annie Rasmussen, Anker Hansen, Steen Knudsen, Dorte Nielsen, Peter Buhl Jensen.
Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Nordsjaellands Hospital, Copenhagen University Hospital, Hilleroed, Denmark; Zealand University Hospital, Roskilde, Naestved, Denmark; Aalborg University Hospital, Aalborg, Denmark; Aarhus University Hospital, Aarhus, Denmark; Regional Hospital West Jutland, Herning, Denmark; Vejle Sygehus, Vejle, Denmark; Hospital of Southern Jutland, Soenderborg, Denmark; The Danish Breast Cancer Cooperative Group, DBCG Secretariat, Rigshospitalet, Copenhagen, Denmark; Medical Prognosis Institute, Hoersholm, Denmark.
PURPOSE: Anthracyclines remain a cornerstone in the treatment of primary and advanced breast cancer (BC). This study has evaluated the predictive value of a multigene mRNA-based drug response predictor (DRP) in the treatment of advanced BC with epirubicin. The DRP is a mathematical method combining in vitro sensitivity and gene expression with clinical genetic information from >3000 clinical tumor samples.
METHODS: From a DBCG cohort, 140 consecutive patients were treated with epirubicin between May 1997 and November 2016. After patient informed consent, mRNA was isolated from archival formalin-fixed paraffin-embedded primary breast tumor tissue and analyzed using Affymetrix arrays. Using time to progression (TTP) as primary endpoint, the efficacy of epirubicin was analyzed according to DRP combined with clinicopathological data collected retrospectively from patients' medical records. Statistical analysis was done using Cox proportional hazards model stratified by treatment line.
RESULTS: Median TTP was 9.3 months. The DRP was significantly associated to TTP (P=0.03). The hazard ratio for DRP scores differing by 50 percentage points was 0.55 (95% CI -0.93, one-sided). A 75% DRP was associated with a median TTP of 13 months compared to 7 months following a 25% DRP. Multivariate analysis showed that DRP was independent of age and number of metastases.
CONCLUSION: The current study prospectively validates the predictive capability of DRP regarding epirubicin previously shown retrospectively allowing the patients predicted to be poor responders to choose more effective alternatives. Randomized prospective studies are needed to demonstrate if such an approach will lead to increased overall survival.
KEYWORDS: Epirubicin Advanced breast cancer Precision medicine Predictive biomarker
DOI: 10.1007/s10549-018-4918-4
聯(lián)系客服
