蒙娜利莎：乳腺癌三大研究汇总分型

　　蒙娜丽莎（MONA LISA）是意大利文艺复兴时期博学家达·芬奇的代表作之一，又被诺华用于命名周期蛋白依赖性激酶CDK4和CDK6抑制剂瑞博西利（LEE011）联合内分泌药物治疗激素受体阳性HER2阴性晚期乳腺癌的随机双盲安慰剂对照三期临床系列研究：

• MONALEESA-2：瑞博西利或安慰剂＋来曲唑一线治疗绝经后女性666例，中位无进展生存25.3比16.0个月（风险比：0.57，P<0.001）

• MONALEESA-3：瑞博西利或安慰剂＋氟维司群一或二线治疗男性或绝经后女性726例，中位无进展生存20.5比12.8个月（风险比：0.60，P<0.001），中位总生存未达终点比40.0个月（风险比：0.72，P=0.005）

• MONALEESA-7：瑞博西利或安慰剂＋戈舍瑞林＋他莫昔芬或非甾体芳香酶抑制剂治疗绝经前女性672例，中位无进展生存23.8比13.0个月（风险比：0.55，P<0.001），中位总生存未达终点比40.9个月（风险比：0.71，P=0.01）

　　不过，瑞博西利并非对全部乳腺癌患者都有效，乳腺癌基因亚型对于瑞博西利＋内分泌药物治疗激素受体阳性HER2阴性晚期乳腺癌的生存预后和疗效预测价值尚不明确。

　　2021年3月26日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表西班牙乳腺癌研究协作组、巴塞罗那大学、巴塞罗那医院、奥古斯特苏尼尔生物医学研究所、凯龙肿瘤研究所、美国诺华、瑞士诺华的MONALEESA三大研究生物标志汇总分析报告，探讨了乳腺癌基因亚型与无进展生存的相关性。

• MONALEESA-2 (NCT01958021): A Randomized Double-blind, Placebo-controlled Study of LEE011 in Combination With Letrozole for the Treatment of Postmenopausal Women With Hormone Receptor Positive, HER2 Negative, Advanced Breast Cancer Who Received no Prior Therapy for Advanced Disease

• MONALEESA-3 (NCT02422615): A Randomized Double-blind, Placebo-controlled Study of Ribociclib in Combination With Fulvestrant for the Treatment of Men and Postmenopausal Women With Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer Who Have Received no or Only One Line of Prior Endocrine Treatment

• MONALEESA-7 (NCT02278120): A Phase III Randomized, Double-blind, Placebo-controlled Study of LEE011 or Placebo in Combination With Tamoxifen and Goserelin or a Non-steroidal Aromatase Inhibitor (NSAI) and Goserelin for the Treatment of Premenopausal Women With Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer

　　该回顾探索研究利用50基因检测（PAM50）对MONALEESA三大研究的肿瘤标本进行分析。通过多因素比例风险回归模型，对年龄、既往化疗、体力状态、内脏病变、仅骨转移、组织学分级、转移部位数量、既往内分泌治疗、初诊时已转移病变等其他影响因素进行校正后，分析PAM50亚型与无进展生存的预后相关性、不同亚型和不同治疗的疾病进展风险。

　　结果，对1160例肿瘤标本完成了PAM50亚型，其中瑞博西利组672例、安慰剂组488例。

　　各治疗组与各研究的基因亚型分布基本一致：

• 管腔A型：46.7%

• 管腔B型：24.0%

• 正常样型：14.0%

• HER2过表达型：12.7%

• 基底样型：2.6%

　　两个治疗组基因亚型与无进展生存的相关性都有统计学意义（P<0.001）。

　　与管腔A型相比，疾病进展风险：

• 管腔B型：高1.44倍

• HER2过表达型：高2.31倍

• 基底样型：高3.96倍

　　瑞博西利与安慰剂相比，除了基底样型，其余基因亚型进展或死亡风险都显著较低：

• HER2过表达型：低61%（风险比：0.39，P<0.0001）

• 管腔B型：低48%（风险比：0.52，P<0.0001）

• 管腔A型：低37%（风险比：0.63，P=0.0007）

• 正常样型：低53%（风险比：0.47，P=0.0005）

• 基底样型：相似（风险比：1.15，P=0.77）

　　因此，该回顾探索研究结果表明，对于激素受体阳性HER2阴性晚期乳腺癌，除了基底样型，瑞博西利对各种基因亚型都可带来无进展生存获益，故有必要进一步开展前瞻研究进行验证。

相关链接

• 新英格兰医学杂志：MONALEESA-2研究无进展生存结局

• 美国临床肿瘤杂志：MONALEESA-3研究无进展生存结局

• 新英格兰医学杂志：MONALEESA-3研究总生存结局

• 英国柳叶刀肿瘤学：MONALEESA-7研究无进展生存结局

• 新英格兰医学杂志：MONALEESA-7研究总生存结局
  

J Clin Oncol. 2021 Mar 26. Online ahead of print.

Correlative Biomarker Analysis of Intrinsic Subtypes and Efficacy Across the MONALEESA Phase III Studies.

Prat A, Chaudhury A, Solovieff N, Paré L, Martinez D, Chic N, Martínez-Sáez O, Brasó-Maristany F, Lteif A, Taran T, Babbar N, Su F.

Hospital Clínic of Barcelona, Barcelona, Spain; SOLTI Breast Cancer Research Group, Barcelona, Spain; Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; University of Barcelona, Barcelona, Spain; Institute of Oncology (IOB) Quiron, Barcelona, Spain; Novartis Institutes for BioMedical Research, Cambridge, MA; Novartis Pharmaceuticals Corporation, East Hanover, NJ; Novartis Pharma AG, Basel, Switzerland.

PURPOSE: The prognostic and predictive value of intrinsic subtypes in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated with endocrine therapy and ribociclib (RIB) is currently unknown. We evaluated the association of intrinsic subtypes with progression-free survival (PFS) in the MONALEESA trials.

METHODS: A retrospective and exploratory PAM50-based analysis of tumor samples from the phase III MONALEESA-2, MONALEESA-3, and MONALEESA-7 trials was undertaken. The prognostic relationship of PAM50-based subtypes with PFS and risk of disease progression by subtype and treatment were evaluated using a multivariable Cox proportional hazards model, adjusting for age, prior chemotherapy, performance status, visceral disease, bone-only metastases, histological grade, number of metastatic sites, prior endocrine therapy, and de novo metastatic disease.

RESULTS: Overall, 1,160 tumors from the RIB (n = 672) and placebo (n = 488) cohorts were robustly profiled. Subtype distribution was luminal A (LumA), 46.7%; luminal B (LumB), 24.0%; normal-like, 14.0%; HER2-enriched (HER2E), 12.7%; and basal-like, 2.6% and was generally consistent across treatment arms and trials. The associations between subtypes and PFS were statistically significant in both arms (P < .001). The risks of disease progression for LumB, HER2E, and basal-like subtypes were 1.44, 2.31, and 3.96 times higher compared with those for LumA, respectively. All subtypes except basal-like demonstrated significant PFS benefit with RIB. HER2E (hazard ratio [HR], 0.39; P < .0001), LumB (HR, 0.52; P < .0001), LumA (HR, 0.63; P = .0007), and normal-like (HR, 0.47; P = .0005) subtypes derived benefit from RIB. Patients with basal-like subtype (n = 30) did not derive benefit from RIB (HR, 1.15; P = .77).

CONCLUSION: In this retrospective exploratory analysis of hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer, each intrinsic subtype exhibited a consistent PFS benefit with RIB, except for basal-like.

PMID: 33769862

DOI: 10.1200/JCO.20.02977