Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China.
Lancet Oncol. 2024 Feb;25(2):184-197. doi: 10.1016/S1470-2045(23)00579-X. Epub 2024 Jan 8.
Triple-negative breast cancers display heterogeneity in molecular drivers and immune traits. We previously classified triple-negative breast cancers into four subtypes: luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). Here, we aimed to evaluate the efficacy and safety of subtyping-based therapy in the first-line treatment of triple-negative breast cancer.
FUTURE-SUPER is an ongoing, open-label, randomised, controlled phase 2 trial being conducted at Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China. Eligible participants were females aged 18-70 years, with an Eastern Cooperative Oncology Group performance status of 0-1, and histologically confirmed, untreated metastatic or recurrent triple-negative breast cancer. After categorising participants into five cohorts according to molecular subtype and genomic biomarkers, participants were randomly assigned (1:1) with a block size of 4, stratified by subtype, to receive, in 28-day cycles, nab-paclitaxel (100 mg/m, intravenously on days 1, 8, and 15) alone (control group) or with a subtyping-based regimen (subtyping-based group): pyrotinib (400 mg orally daily) for the LAR-HER2 subtype, everolimus (10 mg orally daily) for the LAR-PI3K/AKT and MES-PI3K/AKT subtypes, camrelizumab (200 mg intravenously on days 1 and 15) and famitinib (20 mg orally daily) for the immunomodulatory subtype, and bevacizumab (10 mg/kg intravenously on days 1 and 15) for the BLIS/MES-PI3K/AKT subtype. The primary endpoint was investigator-assessed progression-free survival for the pooled subtyping-based group versus the control group in the intention-to-treat population (all randomly assigned participants). Safety was analysed in all patients with safety records who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT04395989).
Between July 28, 2020, and Oct 16, 2022, 139 female participants were enrolled and randomly assigned to the subtyping-based group (n=69) or control group (n=70). At the data cutoff (May 31, 2023), the median follow-up was 22·5 months (IQR 15·2-29·0). Median progression-free survival was significantly longer in the pooled subtyping-based group (11·3 months [95% CI 8·6-15·2]) than in the control group (5·8 months [4·0-6·7]; hazard ratio 0·44 [95% CI 0·30-0·65]; p<0·0001). The most common grade 3-4 treatment-related adverse events were neutropenia (21 [30%] of 69 in the pooled subtyping-based group vs 16 [23%] of 70 in the control group), anaemia (five [7%] vs none), and increased alanine aminotransferase (four [6%] vs one [1%]). Treatment-related serious adverse events were reported for seven (10%) of 69 patients in the subtyping-based group and none in the control group. No treatment-related deaths were reported in either group.
These findings highlight the potential clinical benefits of using molecular subtype-based treatment optimisation in patients with triple-negative breast cancer, suggesting a path for further clinical investigation. Phase 3 randomised clinical trials assessing the efficacy of subtyping-based regimens are now underway.
National Natural Science Foundation of China, Natural Science Foundation of Shanghai, Shanghai Hospital Development Center, and Jiangsu Hengrui Pharmaceuticals.
For the Chinese translation of the abstract see Supplementary Materials section.
三阴性乳腺癌在分子驱动因素和免疫特征方面存在异质性。我们之前将三阴性乳腺癌分为四个亚型：亮氨酸受体阳性（LAR）、免疫调节型、基底样免疫抑制型（BLIS）和间充质样型（MES）。在这里，我们旨在评估基于亚型的治疗在三阴性乳腺癌一线治疗中的疗效和安全性。
FUTURE-SUPER 是一项正在进行的、开放性、随机对照的 2 期临床试验，在复旦大学附属肿瘤医院（上海）进行，中国。合格的参与者为年龄在 18-70 岁之间的女性，东部合作肿瘤学组（ECOG）表现状态为 0-1，组织学确诊的、未经治疗的转移性或复发性三阴性乳腺癌。根据分子亚型和基因组生物标志物，将参与者分为五个队列，然后根据亚型将参与者随机分为两组（1:1），接受 28 天周期的治疗，纳武利尤单抗（nab-紫杉醇）（100mg/m，静脉注射，第 1、8 和 15 天）（对照组）或基于亚型的方案（基于亚型的组）：LAR-HER2 亚型使用吡咯替尼（400mg 口服，每天一次），LAR-PI3K/AKT 和 MES-PI3K/AKT 亚型使用依维莫司（everolimus）（10mg 口服，每天一次），免疫调节亚型使用卡瑞利珠单抗（camrelizumab）（200mg 静脉注射，第 1 和 15 天）和法米替尼（famitinib）（20mg 口服，每天一次），BLIS/MES-PI3K/AKT 亚型使用贝伐珠单抗（bevacizumab）（10mg/kg 静脉注射，第 1 和 15 天）。主要终点是在意向治疗人群（所有随机分配的参与者）中，基于亚型的联合治疗组与对照组的研究者评估无进展生存期。安全性分析包括所有至少接受一剂研究药物并有安全性记录的患者。这项研究在 ClinicalTrials.gov（NCT04395989）注册。
2020 年 7 月 28 日至 2022 年 10 月 16 日期间，共招募了 139 名女性参与者，并随机分为基于亚型的组（n=69）或对照组（n=70）。在数据截止日期（2023 年 5 月 31 日），中位随访时间为 22.5 个月（IQR 15.2-29.0）。中位无进展生存期在基于亚型的联合治疗组（11.3 个月[95%CI 8.6-15.2]）明显长于对照组（5.8 个月[4.0-6.7]；风险比 0.44[95%CI 0.30-0.65]；p<0.0001）。最常见的 3-4 级治疗相关不良事件是中性粒细胞减少症（69 名患者中有 21 名[30%]，对照组中有 70 名患者中有 16 名[23%]）、贫血（5 名[7%]，对照组无）和丙氨酸氨基转移酶升高（4 名[6%]，对照组 1 名[1%]）。基于亚型的治疗组中有 7 名（10%）患者发生了治疗相关的严重不良事件，而对照组中没有。两组均未报告治疗相关死亡。
这些发现突出了在三阴性乳腺癌患者中使用基于分子亚型的治疗优化的潜在临床获益，为进一步的临床研究提供了依据。现在正在进行评估基于亚型的方案疗效的 3 期随机临床试验。
国家自然科学基金、上海市自然科学基金、上海市医院发展中心和江苏恒瑞医药。
