这些新药已经或将改变乳腺癌精准治疗
2021年1月22日，《自然》子刊Nature Reviews Drug Discovery上的一篇综述《乳腺癌药物治疗市场》介绍了全球已经获批上市及正在研发的部分乳腺癌药物，虽然是一篇市场分析文章，不过可以了解乳腺癌治疗药物最新进展及未来趋势。笔者结合相关文献，梳理一下这些新型乳腺癌治疗药物。
https://www.nature.com/articles/d41573-021-00018-6
doi: https://doi.org/10.1038/d41573-021-00018-6
乳腺癌 全球第一大癌症
根据世界卫生组织国际癌症研究机构（IARC）发布的2020年全球最新癌症负担数据，2020年全球新发乳腺癌达到226万例，首次超过肺癌（221万例）成为全球第一大癌症。中国人口基数大，也是乳腺癌大国，2020年新发乳腺癌约42万例，并导致近12万人死亡。
2020年癌症新发病例数前十癌症类型
2020年中国女性癌症新发病例数前十癌症类型
https://www.iarc.fr/faq/latest-global-cancer-data-2020-qa/
Current treatments
现有疗法
1
HER2阳性乳腺癌
目前抗her2治疗药物可分为三大类别：
靶向HER2的单克隆大分子抗体
靶向HER2的抗体偶联药物(antibody-drug conjugate，ADC)
抑制HER2活性的特异性或激酶小分子抑制剂
Approximately 20% of breast cancers are HER2-positive. Trastuzumab 曲妥珠单抗 (Herceptin, Roche) was the first HER2-targeting agent to be approved (in 1998). Since then, a plethora of HER2-targeting agents have been approved, including pertuzumab帕妥珠单抗 (Perjeta, Roche), trastuzumab emtansine (T-DM1; Kadcyla, Roche),lapatinib拉帕替尼(Tykerb/Tyverb, Novartis), neratinib奈拉替尼(Nerlynx, Puma), trastuzumab deruxtecan (Enhertu，DS-8201), Daiichi Sankyo/AstraZeneca), tucatinib图卡替尼(Tukysa, Seagen/Pfizer) and margetuximab (MGAH22 Margenza, MacroGenics).
中国：吡咯替尼（小分子） 伊尼妥单抗（大分子）
2
HR阳性/HER2阴性乳腺癌
乳腺癌传统内分泌治疗药物：
1. 选择性雌激素受体调节剂(与雌激素竞争激素受体)
1） ER受体拮抗剂：代表药物：他莫昔芬（三苯氧胺）、托瑞米芬。
2） ER受体下调剂：代表药物:氟维司群。
2. 芳香化酶抑制剂(抑制雄激素向雌激素的转换，降低雌激素水平)
芳香化酶抑制代表药物:甾体类的来曲唑、阿那曲唑和非甾体类的依西美坦。
3. 黄体生成素释放激素类似物(又称卵巢去势药物\OFS）
代表药物:戈舍瑞林和亮丙瑞林。
Early-stage disease is treated with hormonal therapy, typically for 5–10 years. Patients with intermediate and high-risk disease may also receive chemotherapy prior to hormonal treatment. The first-line standard of care for metastatic disease is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor(CDK4/6抑制剂) :
palbociclib 哌柏西利 (Ibrance, Pfizer),
ribociclib 瑞博西林 (Kisqali, Novartis)
abemaciclib 阿贝西利 (Verzenio/Verzenios/Virginio, Eli Lilly)
— in combination with endocrine therapy. These therapies gained regulatory approval in 2015–2017 and have received successive label expansions; they are also being assessed in late-phase trials as adjuvant treatments for early-stage disease. The pivotal monarchE trial, assessing adjuvant abemaciclib, has met its primary end point of invasive disease-free survival.
In 2019, the FDA approved the PI3K inhibitor（PI3K抑制剂） alpelisib阿培利司 (Piqray, Novartis) for PIK3CA-mutated (approximately 40% of patients) advanced or metastatic disease following progression with an endocrine therapy. Everolimus/mTOR抑制剂/依维莫司(Afinitor, Novartis) with exemestane is also a treatment option for HR-positive/HER2-negative recurrent disease.
中国：西达本胺（HDAC抑制剂）
3
三阴性乳腺癌
In 2019, the PDL1 inhibitor（PDL1抑制剂） atezolizumab阿特珠单抗(Tecentriq, Roche) was granted FDA accelerated approval for PDL1-positive (approximately 40% of patients) advanced or metastatic disease, in combination with nanoparticle paclitaxel (Abraxane, Celgene). The approval of atezolizumab was based on progression-free survival data from a phase III trial (IMpassion130); however, in August 2020, atezolizumab (plus paclitaxel) failed to meet progression-free survival as a co-primary end point in another trial (IMpassion131), which treated the same population as in IMpassion130. Other phase III trials of atezolizumab are in early-stage triple-negative and HER2-positive disease.
The PD1 inhibitor（PD1抑制剂） pembrolizumab
帕博利珠单抗(Keytruda, Merck & Co.) in combination with chemotherapy was approved by the FDA in November 2020 for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer who express PDL1. Approval was based on the KEYNOTE-355 trial. A supplemental Biologics License Application is under FDA review for neoadjuvant pembrolizumab in combination with chemotherapy followed by adjuvant pembrolizumab for early-stage disease. The prescription drug user fee act (PDUFA) date is March 29, 2021. Pembrolizumab is also being assessed in early-stage ER-positive/HER2-negative disease.
Two poly-ADP ribose polymerase (PARP) inhibitors（PARP抑制剂） are approved for chemotherapy-pretreated, germline BRCA1/2-mutated, HER2-negative advanced or metastatic breast cancer. Prevalence of BRCA1/2 mutations in triple-negative (15%) and HR-positive/HER2-negative (3–4%) breast cancer is low. Olaparib 奥拉帕尼 (Lynparza, AstraZeneca) was first to market, followed by talazoparib他拉唑帕尼(Talzenna, Pfizer) (both FDA approved in 2018); Olaparib is also being assessed as an adjuvant treatment for high-risk BRCA1/2-mutated HER2-negative disease.
Sacituzumab govitecan (Trodelvy, Immunomedics) is a trophoblast cell surface antigen 2 (TROP2)-targeted antibody–drug-conjugate (ADC Trop-2导向抗体和拓扑异构酶抑制剂药物结合物). It gained FDA accelerated approval in 2020 for third-line and later-line metastatic triple-negative disease based on a single-arm phase II trial. A confirmatory phase III (ASCENT) trial is ongoing. It is also in phase III trials for pretreated advanced or metastatic HR-positive/HER2-negative disease (TROPICS-02 trial), and for early-stage HER2-negative disease regardless of HR status (SASCIA trial).
Emerging therapies
新兴治疗
AKT, protein kinase B; CXCR4, CXC chemokine receptor 4; HER2, human epidermal growth factor receptor 2, also known as ERBB2; MOA, mechanism of action; PARP, poly-ADP ribose polymerase; SERD, selective oestrogen receptor degrader; SERM, selective oestrogen receptor modulator.
经典信号通路——PI3K/AKT/mTOR信号通路
两款AKT抑制剂已经处于3期临床试验阶段，它们是罗氏的ipatasertib和阿斯利康的capivasertib。
CXCR4是一种趋化因子（chemokine）受体。它在多种癌症类型的癌细胞中高度表达，在癌症转移过程中起到重要作用。其在研疗法是Polyphor公司开发的潜在“first-in-class”选择性CXCR4抑制剂balixafortide。
HR阳性乳腺癌方面，目前至少有三款选择性雌激素受体降解剂（SERD）处于3期临床开发阶段。由于注射剂型可能限制这类疗法的使用范围，近年来研发的新一代SERD均为口服剂型，其中包括罗氏名为RG6171（又名GDC-9545）的第三代SERD。它不但能够有选择性地降解ER，而且在降解ER之前，通过与ER结合就能够防止ER激活它的靶点基因。
展望未来
从上面乳腺癌主要治疗药物的市场销售估计数图可以看出，HER2靶向治疗和CDK4/6抑制剂仍然是治疗乳腺癌的主要选择。其中CDK4/6抑制剂有望扩展适用范围，用于治疗早期HR阳性/HER2阴性乳腺癌。Enhertu (曲妥珠单抗deruxtecan，即DS-8201)可能进一步扩展其适应症，用于治疗HER2低表达乳腺癌和三阴性乳腺癌。
乳腺癌防治，任重而道远
注：本文旨在介绍乳腺癌医药研究进展学习，文中有些药物尚未在中国获批上市或乳腺癌治疗适应症，不作为目前国内临床治疗标准方案推荐。