当前位置:肿瘤瞭望>资讯>研究>正文

观点·SIBCS特辑丨Virginia Kaklamani教授:HR+晚期乳腺癌后CDK4/6i时代的MD安德森诊疗策略

作者:  Jiang  Ying   日期:2024/10/22 14:06:06  浏览量:1255

肿瘤瞭望版权所有,谢绝任何形式转载,侵犯版权者必予法律追究。

2024年10月18日,第十八届全国乳腺癌会议暨第十九届上海国际乳腺癌论坛盛大开幕,汇聚了全球乳腺癌重要进展。如今,激素受体阳性(HR+)乳腺癌已经入后CDK4/6抑制剂时代,基于PIK3CA/AKT1/PTEN通路的靶向内分泌治疗为患者带来了新的希望。此次大会中,得克萨斯大学MD安德森癌症中心Virginia G.Kaklamani教授分享了“HR+转移性乳腺癌治疗进展”重要讲题,并做客《肿瘤瞭望》“观点·SIBCS特辑”栏目,探讨后CDK4/6抑制剂时代HR+晚期乳腺癌的诊疗策略及临床实践经验。

编者按:2024年10月18日,第十八届全国乳腺癌会议暨第十九届上海国际乳腺癌论坛盛大开幕,汇聚了全球乳腺癌重要进展。如今,激素受体阳性(HR+)乳腺癌已经入后CDK4/6抑制剂时代,基于PIK3CA/AKT1/PTEN通路的靶向内分泌治疗为患者带来了新的希望。此次大会中,得克萨斯大学MD安德森癌症中心Virginia G.Kaklamani教授分享了“HR+转移性乳腺癌治疗进展”重要讲题,并做客《肿瘤瞭望》“观点·SIBCS特辑”栏目,探讨后CDK4/6抑制剂时代HR+晚期乳腺癌的诊疗策略及临床实践经验。
 
01
肿瘤瞭望:当前美国对激素受体阳性(HR+)晚期乳腺癌的诊疗现状如何?存在哪些未满足临床需求?
 
Oncology Frontier:What is the current status of diagnosis and treatment for HR+advanced breast cancer in the United States?what are the unmet clinical treatment needs?
 
Virginia Kaklamani教授:HR+乳腺癌是最常见的分子亚型,近年来涌现的新治疗方法为临床实践带来了诸多改变。既往HR+晚期乳腺癌多以芳香化酶抑制剂(AI)、氟维司群等内分泌治疗为主,如今CDK4/6抑制剂、口服SERD、PIK3CA/AKT1/PTEN通路抑制剂等带来了更多的治疗选择,为患者带来了福音。在此背景下,HR+晚期乳腺癌治疗所面临的最大挑战是内分泌耐药,其耐药机制包括了多种不同通路的改变,比如PIK3CA/AKT1/PTEN通路不同位点的变异、缺失都有可能导致内分泌耐药,进而带来更差的预后。
 
Dr.Virginia Kaklamani:HR+breast cancer is the most common molecular subtype,and the emergence of new treatment methods in recent years has brought many changes to clinical practice.In the past,HR+advanced breast cancer was mainly treated with endocrine therapies such as aromatase inhibitors(AI)and fulvestrant.Nowadays,CDK4/6 inhibitors,oral selective estrogen receptor downregulators(SERDs),and PIK3CA/AKT1/PTEN pathway inhibitors have provided more treatment options,bringing good news to patients.Against this backdrop,the biggest challenge in the treatment of HR+advanced breast cancer is endocrine resistance,whose resistance mechanisms include changes in various different pathways.For instance,mutations or deletions at different sites of the PIK3CA/AKT1/PTEN pathway can lead to endocrine resistance,resulting in a poorer prognosis.
 
02
肿瘤瞭望:请您介绍一下PIK3CA/AKT1/PTEN通路在HR+晚期乳腺癌患者治疗中的价值。目前针对该通路国际上已有阿培利司(Alpelisib)、卡匹色替(Capivasertib)、伊那利塞(Inavolisib)获批,三者在HR+晚期乳腺癌的治疗中应如何选择?在临床应用中的安全性表现如何,有哪些需要特别注意的地方?
 
Oncology Frontier:What is the therapeutic value of the PIK3CA/AKT1/PTEN pathway in HR+advanced breast cancer?Alpelisib,capivasertib,and inavolisib have been approved for targeting this pathway.How should these three drugs be selected for the treatment of HR+advanced breast cancer?What are their safety profiles?
 
Virginia Kaklamani教授:内分泌耐药的主要机制之一即为PIK3CA/AKT1/PTEN通路激活上调。若癌细胞存在PI3K、AKT或PTEN变异,则会对内分泌治疗反应不佳,预后变差。因此,针对该通路开发的AKT抑制剂或PI3K抑制剂非常重要。当前美国已商业上市的内分泌精准靶向药物包括PI3K抑制剂阿培利司(Alpelisib)和AKT抑制剂卡匹色替(Capivasertib),此外PI3K抑制剂伊那利塞(Inavolisib)刚在FDA获批,其中卡匹色替可用于PI3K/AKT/PTEN变异患者,适用范围更广。三者的副作用并不一致,其共性不良反应包括腹泻、皮疹、口腔炎、高血糖等。其中阿培利司和伊那利塞存在更严重的高血糖,往往会因此导致剂量限制。卡匹色替会导致更高比例的腹泻,但高血糖的发生率相对更低。卡匹色替的另一个优势在于不仅仅可以用于PI3K变异的患者,同时也可以让发生AKT和PTEN变异的患者获益,相比于其他两个药物,靶点抑制更多更全。
 
众所周知,HR+晚期乳腺癌多以CDK4/6抑制剂联合内分泌治疗为主,在存在PI3K变异时可进一步联合伊那利塞。那么二线治疗应如何决策呢?若一线CDK4/6抑制剂联合内分泌治疗6个月内进展,则会采用化疗或抗体偶联药物(ADC);若一线治疗缓解时间超过6个月,则会在基因检测的指导下开展精准靶向治疗。我们首先会实施下一代基因测序(NGS)以确定是否存在特定变异。若存在PIK3CA/AKT1/PTEN通路变异,我们会选择阿培利司或卡匹色替。虽然post-MONARCH研究在CDK4/6抑制剂跨线治疗中取得了些许进展,但对患者的获益非常有限,PFS仅提升0.7个月,且PIK3CA/AKT1/PTEN通路变异人群的HR值为0.86,所以我一般不会在临床中二线治疗考虑CDK4/6抑制剂跨线方案。阿培利司和卡匹色替均会改善患者预后,但需要综合考虑前述不良反应。若选择阿培利司,则可预防性使用二甲双胍等药物以避免高血糖的发生,以及使用苯海拉明预防皮疹;若选择卡匹色替,则无需预防用药,仅需在治疗前告知患者潜在的腹泻风险,如果出现不良反应后再积极治疗。如无变异,则会优先考虑依维莫司,其次考虑CDK4/6抑制剂跨线治疗。
 
Dr.Virginia Kaklamani:One of the main mechanisms of endocrine resistance is the activation and upregulation of the PIK3CA/AKT1/PTEN pathway.If cancer cells have mutations in PI3K,AKT,or PTEN,they will respond poorly to endocrine therapy and have a worse prognosis.Therefore,the development of AKT inhibitors or PI3K inhibitors targeting this pathway is very important.Currently,in the United States,the marketed drugs include the PI3K inhibitors Alpelisib and Inavolisib,as well as the AKT inhibitor Capivasertib.Among them,Capivasertib can be used for patients with PI3K/AKT/PTEN mutations and has a broader range of applications.The side effects of the three are not the same;their common adverse reactions include diarrhea,rash,stomatitis,hyperglycemia,etc.Alpelisib and Everolimus have more severe hyperglycemia,which often leads to dose limitation.Capivasertib can cause a higher proportion of diarrhea,but the incidence of hyperglycemia is relatively lower.Another advantage of Capivasertib is that it is not only effective for patients with PI3K mutations but also benefits patients with AKT and PTEN mutations.Compared to the other two drugs,it has more comprehensive target inhibition.
 
It is well known that hormone receptor-positive(HR+)advanced breast cancer is primarily treated with CDK4/6 inhibitors combined with endocrine therapy,and in cases with PI3K mutations,the treatment can be further combined with alpelisib.So,how should we decide on second-line treatment?If the disease progresses rapidly with first-line CDK4/6 inhibitor combined endocrine therapy,chemotherapy or antibody-drug conjugates(ADCs)will be adopted;if the first-line treatment has a remission time of more than 12 months,treatment will be guided by genetic testing.We first perform next-generation sequencing(NGS)to determine if there are specific mutations.If there are PIK3CA/AKT1/PTEN pathway mutations,we will choose alpelisib or capivasertib.Although the post-MONARCH study has made some progress in the cross-line treatment of CDK4/6 inhibitors,the benefit to patients is very limited,with a progression-free survival(PFS)increase of only 0.7 months,and a hazard ratio(HR)of 0.86 for the PIK3CA/AKT1/PTEN pathway mutation population,so I generally do not consider CDK4/6 inhibitor cross-line therapy in clinical second-line treatment.Alpelisib and capivasertib can both improve patient prognosis,but the aforementioned adverse reactions need to be considered comprehensively.If alpelisib is chosen,metformin and other drugs can be used prophylactically to avoid hyperglycemia,and diphenhydramine can be used to prevent rash;if capivasertib is chosen,no prophylactic medication is needed,only the potential risk of diarrhea should be informed to the patient before treatment,and active treatment should be taken if adverse reactions occur.If there are no mutations,everolimus will be considered first,followed by cross-line treatment with CDK4/6 inhibitors.
 
03
肿瘤瞭望:PIK3CA/AKT1/PTEN通路相关的基因突变在HR+乳腺癌的发生率有多少?临床实践中应该如何把握好PIK3CA/AKT1/PTEN通路变异的检测时机和检测方法?
 
Oncology Frontier:What is the incidence of gene mutations related to the PIK3CA/AKT1/PTEN pathway in HR+breast cancer?In clinical practice,how should the timing and methods for detecting PIK3CA/AKT1/PTEN pathway alterations be properly managed?
 
Virginia Kaklamani教授:基因检测是治疗乳腺癌最重要的事情之一。临床需要通过对HR+乳腺癌血液中的循环肿瘤DNA(ctDNA)或肿瘤组织进行基因检测以确定治疗决策,包括对ESR1变异、PI3K变异、AKT变异、PTEN变异等的检测。在美国,PI3K变异的概率约为30%·-40%,AKT变异或PTEN变异约占5%-10%,邵志敏教授团队的研究数据显示在中国人群这一比例会更高,因此进行基因检测非常重要。
 
由于相关基因变异会存在于原发灶及转移灶,且会在内分泌敏感向内分泌耐药发展的过程中发生,所以在有能力开展多靶点的基因检测时,应做到晚期复发患者应检尽检,以识别可以在AKT抑制剂等靶向治疗中获益的患者。在临床实践中,我会对所有HR+晚期乳腺癌患者实施NGS检测,具体的实施时机是在一线治疗前,以确定后续治疗策略;若因为特殊原因患者未在一线治疗时接受NGS检测,我也会在二线治疗时及时安排相关检测,以期为患者提供针对性的个体化精准治疗。
 
Dr.Virginia Kaklamani:Gene testing is one of the most important things in treating breast cancer.Clinically,it is necessary to make treatment decisions by testing circulating tumor DNA(ctDNA)in the blood or tumor tissue of HR+breast cancer,including testing for ESR1 mutations,PI3K mutations,AKT mutations,and PTEN mutations.In the United States,the probability of PI3K mutations is about 30%-40%,and AKT mutations or PTEN mutations account for about 5%-10%.Research data from Professor Zhimin Shao’s team shows that this proportion is even higher in the Chinese population,so conducting gene testing is very important.Since related gene mutations can exist in both the primary lesion and the metastatic lesion,and can occur during the development from endocrine sensitivity to endocrine resistance,multi-target gene testing should be performed for advanced recurrent patients whenever possible,to identify patients who can benefit from targeted therapies such as AKT inhibitors.In clinical practice,I will implement NGS testing for all HR+advanced breast cancer patients,and the specific timing is before the first-line treatment to determine subsequent treatment strategies;if for some special reasons the patient did not receive NGS testing during the first-line treatment,I will also arrange the relevant testing in a timely manner during the second-line treatment,in order to provide targeted,personalized,and precise treatment for the patients.
 
04
肿瘤瞭望:PIK3CA/AKT1/PTEN通路抑制剂等新型药物的问世对乳腺癌临床实践带来了怎样的变革?在乳腺癌领域,此类新型靶向治疗还有哪些研究方向或应用前景?
 
Oncology Frontier:What changes have the advent of PIK3CA/AKT1/PTEN pathway inhibitors brought to breast cancer clinical practice?What are the research directions or application prospects for these novel targeted therapies?
 
Virginia Kaklamani教授:针对PIK3CA/AKT1/PTEN通路已经获批了三种靶向治疗药物。其一是PI3K抑制剂阿培利司。SOLAR-1研究显示,阿培利司联合氟维司群较氟维司群可改善患者无进展生存期(PFS),但仅限于PI3K变异患者。其二是目前唯一一款获批的AKT抑制剂卡匹色替。CAPItello-291研究中入组了约70%的CDK4/6i经治患者,显示PIK3CA/AKT1/PTEN通路变异人群卡匹色替联合氟维司群mPFS是对照组的2.5倍,为7.3个月vs 3.1个月,HR值为0.5,且总体生存期(OS)也有改善的趋势,并因此在美国获批上市。其三是FDA刚刚批准的另一款PI3K抑制剂伊那利塞,INAVO120研究显示伊那利塞联合哌柏西利和氟维司群一线治疗对具有PI3K变异的内分泌耐药患者具有较好疗效,但入组标准明确规定了是内分泌辅助治疗中进展或完成辅助治疗12个月内进展的人群,这部分人群临床中占比很小,可能仅有约10%的患者。
 
上述研究已经改写了HR+乳腺癌的治疗方式,更是提示我们采用基因检测结果指导精准治疗已成为重要的治疗策略。展望未来,更多针对PIK3CA/AKT1/PTEN通路的抑制剂以及更多联合用药方案正在不断探索,将为HR+乳腺癌的治疗带来更多可能。
 
Dr.Virginia Kaklamani:Three targeted therapy drugs have been approved for the PIK3CA/AKT1/PTEN pathway.The first is the PI3K inhibitor Alpelisib.The SOLAR-1 study demonstrated that Alpelisib combined with fulvestrant improved progression-free survival(PFS)compared to fulvestrant alone,but only in patients with PI3K mutations.The second is Capivasertib,the only approved AKT inhibitor to date.In the CAPItello-291 trial,which enrolled about 70%of patients previously treated with CDK4/6 inhibitors,Capivasertib combined with fulvestrant approximately doubled the median PFS compared to fulvestrant alone,at 7.2 months versus 3.6 months.The PIK3CA/AKT1/PTEN mutation group and the Intent-to-Treat(ITT)population showed consistent results,reaching 7.3 months,and there was also a trend of improvement in overall survival(OS),leading to its approval in the United States.The third is Inavolisib,another PI3K inhibitor recently approved by the FDA.The INAVA120 study showed that Inavolisib combined with palbociclib and fulvestrant as a first-line treatment had good efficacy in patients with PI3K mutations who were resistant to endocrine therapy.However,the inclusion criteria strictly defined this as a population progressing during or within 12 months after completing adjuvant endocrine therapy,a group that constitutes a small proportion of the clinical population,possibly only about 10%of patients.These studies have rewritten the treatment approach for HR+breast cancer and highlight the importance of using genetic testing results to guide precision treatment as a significant therapeutic strategy.Looking to the future,more inhibitors targeting the PIK3CA/AKT1/PTEN pathway and more combination therapy regimens are being continuously explored,which will bring more possibilities for the treatment of HR+breast cancer.
 
Virginia Kaklamani教授
得克萨斯大学圣安东尼奥健康科学中心血液学/肿瘤内科学医学教授
医学博士、教授
得克萨斯大学圣安东尼奥临床研究副主任、癌症遗传学项目联合主任、
得克萨斯大学MD安德森癌症中心梅斯癌症中心乳腺癌项目负责人
圣安东尼乳腺癌癌研讨会联合主席
A.B.Alexander肿瘤学杰出主席
 
更多精彩内容,
请扫码关注“观点”专栏
 

 

版面编辑:张靖璇new  责任编辑:无医学编辑

本内容仅供医学专业人士参考


乳腺癌

分享到: 更多