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如何避免乳腺癌内分泌治疗耐药？

2022年10月09日

来源：SIBCS

　　晚期乳腺癌最常见的类型为雌激素受体阳性HER2阴性，通常无法治愈，但是最新的一线治疗标准方案（芳香化酶抑制剂＋细胞周期蛋白依赖性激酶CDK4/6抑制剂）可能长期控制病情。不过，大多数患者最终对一线治疗继发耐药，随后内分泌治疗＋化疗效果较差，也更容易耐药。临床前研究和临床数据回顾分析表明，芳香化酶抑制剂继发耐药通常源于雌激素受体α编码基因ESR1突变，而该突变可能对选择性雌激素受体降解剂氟维司群敏感。那么，如果发现ESR1突变时，就把芳香化酶抑制剂换成氟维司群，能否避免内分泌治疗耐药？

　　2022年9月29日，英国《柳叶刀》肿瘤学分册在线发表法国综合癌症中心联盟的PADA-1研究报告，探讨了雌激素受体阳性HER2阴性晚期乳腺癌芳香化酶抑制剂＋哌柏西利一线治疗期间ESR1突变水平升高患者改用氟维司群＋哌柏西利的有效性和安全性。

PADA-1 (NCT03079011): PAlbociclib and Circulating Tumor DNA for ESR1 Mutation Detection (Randomized, Open Label, Multicentric Phase III Trial to Evaluate the Safety and Efficacy of Palbociclib in Combination With HT Driven by ctDNA ESR1 Mutation Monitoring in ER+, HER2-negative Metastatic Breast Cancer Patients)

　　该多中心非盲随机对照三期临床研究于2017年3月22日至2019年1月31日从法国83家医院入组年龄≥18岁、美国东部肿瘤学协作组（ECOG）体力状态评分0～2的雌激素受体阳性HER2阴性晚期乳腺癌女性1017例，给予哌柏西利＋芳香化酶抑制剂（来曲唑或阿那曲唑或依西美坦）一线治疗并通过循环肿瘤DNA分析监测血液ESR1突变水平。随后，279例（27%）血液ESR1突变水平升高，其中病情尚未进展且签署知情同意书的172例（17%）按1∶1随机分组进行治疗：88例改用氟维司群＋哌柏西利，84例继续芳香化酶抑制剂＋哌柏西利。根据有无内脏转移、从入组到血液ESR1突变水平升高时间<12个月或≥12个月对患者进行分层。共同主要终点为研究者评定的意向治疗人群随机分组后无进展生存，以及全部患者≥3级血液学不良事件。

　　结果，截至2021年7月31日数据库锁定时，172例随机分组患者入组后中位随访35.3个月（四分位：29.2～41.4）、随机分组后中位随访26.0个月（四分位：13.8～34.3）。

　　氟维司群组88例与芳香化酶抑制剂组84例患者相比，随机分组后：

中位无进展生存：11.9个月比5.7个月（95%置信区间：9.1～13.6、3.9～7.5）
进展或死亡风险：显著减少39%（分层风险比：0.61，95%置信区间：0.43～0.86，P=0.0040）
≥3级中性粒细胞减少：35例比39例（41.7%比44.3%）
4级严重中性粒细胞减少：1例比1例（1.1%比1.2%）
≥3级淋巴细胞减少：3例比4例（3.6%比4.5%)
3级严重疲劳：0例比1例（0比1.2%）

　　1017例入组患者≥3级不良事件：

中性粒细胞减少：715例（70.3%）
淋巴细胞减少：66例（6.5%）
血小板减少：20例（2.0%）
治疗相关严重不良事件：31例（3.1%）
治疗相关肺栓塞致死亡：1例（0.4%）

　　亚组分析表明，无论年龄≤60岁或＞60岁、体力状态评分0或1～2份、有无内脏转移、既往有无芳香化酶抑制剂治疗、从入组到血液ESR1突变水平升高时间<12个月或≥12个月，氟维司群组与芳香化酶抑制剂组相比，无进展生存都有优势。

　　因此，该前瞻随机对照研究首次通过循环肿瘤DNA分析证实大规模实时连续监测耐药相关突变的可行性，还首次证实血液ESR1突变水平升高时，内分泌治疗换药后，无进展生存显著延长一倍，而毒性反应并未增加，针对血液ESR1突变的早期换药可能带来显著临床获益。这些结果表明，当耐药肿瘤细胞负荷仍然较低时，循环肿瘤DNA监测可用于针对耐药相关突变，该结果可能与ESR1突变相关。由于芳香酶抑制剂＋CDK4/6抑制剂耐药后，选择性雌激素降解剂活性较低，故维持CDK4/6抑制同时，在耐药发生前对耐药相关突变进行监测并及时换药，是有效且耐受性良好的治疗选择。此外，该研究探索的原创设计可能有助于在将来的研究中解决新药继发耐药问题。

Lancet Oncol. 2022 Sep 29. IF: 54.433

Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial.

Francois-Clément Bidard, Anne-Claire Hardy-Bessard, Florence Dalenc, Thomas Bachelot, Jean-Yves Pierga, Thibault de la Motte Rouge, Renaud Sabatier, Coraline Dubot, Jean-Sébastien Frenel, Jean Marc Ferrero, Sylvain Ladoire, Christelle Levy, Marie-Ange Mouret-Reynier, Alain Lortholary, Julien Grenier, Camille Chakiba, Laetitia Stefani, Jérome Edouard Plaza, Florian Clatot, Luis Teixeira, Véronique D'Hondt, Hélène Vegas, Olfa Derbel, Claire Garnier-Tixidre, Jean-Luc Canon, Barbara Pistilli, Fabrice André, Laurent Arnould, Anne Pradines, Ivan Bièche, Céline Callens, Jérome Lemonnier, Frédérique Berger, Suzette Delaloge; PADA-1 investigators.

Institut Curie, Université Versailles Saint-Quentin, Université Paris-Saclay, Saint-Cloud, France; Institut Curie, Paris, France; Institut Curie and Université de Paris, Paris, France; Institut Curie, PSL University, Saint-Cloud, Paris, France; Centre Armoricaind'Oncologie, Plérin, France; Institut Claudius-Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France; Centre Léon Bérard, Lyon, France; Centre Eugène Marquis, Rennes, France; Institut Paoli Calmettes, Aix-Marseille Université, Marseille, France; Institut de Cancérologie de l'Ouest, Nantes, France; Centre Antoine Lacassagne, Nice, France; Centre Georges Francois Leclerc, Dijon, France; Centre Francois Baclesse, Caen, France; Centre Jean Perrin, Clermont Ferrand, France; Hopital Privé du Confluent, Nantes, France; Institut Sainte Catherine, Avignon, France; Institut Bergonié, Bordeaux, France; Centre Hospitalier Annecy Genvoi, Pringy-Metz-Tessy, France; UNEOS Site Hopital Robert Schuman, Vantoux, France; Centre Henri Becquerel, Rouen, France; Hopital Saint Louis, Paris, France; Institut du Cancer de Montpellier Val d'Aurelle, Montpellier, France; Centre Hospitalier de Tours, Hopital Bretonneau, Tours, France; Hopital Privé Jean Mermoz, Lyon, France; Institut Daniel Hollard, G H Mutualiste de Grenoble, Grenoble, France; Grand Hopital de Charleroi, Charleroi, Belgique; Gustave Roussy, Villejuif, France; Cancer Research Center of Toulouse, Toulouse, France; Claudius Regaud Institute, Toulouse University Cancer Institute, Toulouse, France; UNICANCER, Paris, France.

BACKGROUND: In advanced oestrogen receptor-positive, HER2-negative breast cancer, acquired resistance to aromatase inhibitors frequently stems from ESR1-mutated subclones, which might be sensitive to fulvestrant. The PADA-1 trial aimed to show the efficacy of an early change in therapy on the basis of a rising ESR1 mutation in blood (bESR1mut), while assessing the global safety of combination fulvestrant and palbociclib.

METHODS: We did a randomised, open-label, phase 3 trial in 83 hospitals in France. Women aged at least 18 years with oestrogen receptor-positive, HER2-negative advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited and monitored for rising bESR1mut during first-line aromatase inhibitor (2.5 mg letrozole, 1 mg anastrozole, or 25 mg exemestane, orally once per day, taken continuously) and palbociclib (125 mg orally once per day on days 1-21 of a 28-day cycle) therapy. Patients with newly present or increased bESR1mut in circulating tumour DNA and no synchronous disease progression were randomly assigned (1:1) to continue with the same therapy or to switch to fulvestrant (500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1) and palbociclib (dosing unchanged). The randomisation sequence was generated within an interactive web response system using a minimisation method (with an 80% random factor); patients were stratified according to visceral involvement (present or absent) and the time from inclusion to bESR1mut detection (<12 months or ≥12 months). The co-primary endpoints were investigator-assessed progression-free survival from random assignment, analysed in the intention-to-treat population (ie, all randomly assigned patients), and grade 3 or worse haematological adverse events in all patients. The trial is registered with Clinicaltrials.gov (NCT03079011), and is now complete.

FINDINGS: From March 22, 2017, to Jan 31, 2019, 1017 patients were included, of whom 279 (27%) developed a rising bESR1mut and 172 (17%) were randomly assigned to treatment: 88 to switching to fulvestrant and palbociclib and 84 patients to continuing aromatase inhibitor and palbociclib. At database lock on July 31, 2021, randomly assigned patients had a median follow-up of 35.3 months (IQR 29.2-41.4) from inclusion and 26.0 months (13.8-34.3) from random assignment. Median progression-free survival from random assignment was 11.9 months (95% CI 9.1-13.6) in the fulvestrant and palbociclib group versus 5.7 months (3.9-7.5) in the aromatase inhibitor and palbociclib group (stratified HR 0.61, 0.43-0.86; p=0.0040). The most frequent grade 3 or worse haematological adverse events were neutropenia (715 [70.3%] of 1017 patients), lymphopenia (66 [6.5%]), and thrombocytopenia (20 [2.0%]). The most common grade 3 or worse adverse events in step 2 were neutropenia (35 [41.7%] of 84 patients in the aromatase inhibitor and palbociclib group vs 39 [44.3%] of 88 patients in the fulvestrant and palbociclib group) and lymphopenia (three [3.6%] vs four [4.5%]). 31 (3.1%) patients had grade 3 or worse serious adverse events related to treatment in the overall population. Three (1.7%) of 172 patients randomly assigned had one serious adverse event in step 2: one (1.2%) grade 4 neutropenia and one (1.2%) grade 3 fatigue among 84 patients in the aromatase inhibitor and palbociclib group, and one (1.1%) grade 4 neutropenia among 88 patients in the fulvestrant and palbociclib group. One death by pulmonary embolism in step 1 was declared as being treatment related.

INTERPRETATION: PADA-1 is the first prospective randomised trial showing that the early therapeutic targeting of bESR1mut results in significant clinical benefit. Additionally, the original design explored in PADA-1 might help with tackling acquired resistance with new drugs in future trials.

FUNDING: Pfizer.

DOI: 10.1016/S1470-2045(22)00555-1