Li Xuefeng, Wang Hongxian, Lin Shuhui, Chen Tianwen
Day Surgery Care Unit, Shenzhen Nanshan People's Hospital, Shenzhen, Guangdong, China.
Department of Breast and Thyroid Surgery, Shenzhen Nanshan People's Hospital, Shenzhen, Guangdong, China.
Front Oncol. 2025 Jun 4;15:1556978. doi: 10.3389/fonc.2025.1556978. eCollection 2025.
This systematic review and meta-analysis aimed to evaluate the efficacy and safety of combination of Phosphatidylinositol 3-kinase (PI3K) inhibitors and fulvestrant in patients with advanced breast cancer (ABC) who are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-).
A systematic search was conducted across the PubMed, Cochrane Library, EMBASE databases and major conference websites (ASCO, ESMO, SABCS) to identify randomized controlled trials (RCTs) evaluating the combination of PI3K inhibitors and fulvestrant in the treatment of advanced breast cancer. Two independent reviewers systematically screened the literature, extracted data, and assessed the risk of bias for the included studies based on predefined criteria. Meta-analysis was subsequently performed using R software in accordance with the PRISMA guidelines.
A total of five randomized controlled trials (RCTs) involving 3,011 patients were included. The findings indicated that the combination of PI3K inhibitors and fulvestrant significantly improved progression-free survival (PFS) (HR = 0.74, 95% CI 0.67-0.80, P < 0.0001) and the objective response rate (ORR) (RR = 1.80, 95% CI: 1.39-2.35, P < 0.0001) compared to placebo plus fulvestrant. However, there was no statistically significant difference in clinical benefit rate (CBR) (RR = 1.10, 95% CI: 0.97-1.25, P = 0.1341). Subgroup analysis indicated that the predefined subgroup of PFS based on PIK3CA mutation status assessed by ctDNA was statistically significant (P = 0.0039), whereas the predefined subgroup of PFS based on PIK3CA mutation status assessed by tumor tissue was not statistically significant (P = 0.1514). In terms of adverse events, the incidence of grade ≥3 events was significantly increased in the PI3K inhibitors combined with fulvestrant group (RR=2.11, 95% CI: 1.73-2.58, P<0.0001), particularly hyperglycemia, rash, and transaminitis (ALT).
The combination of PI3K inhibitors and fulvestrant significantly improved PFS and ORR in patients with advanced breast cancer. However, substantial dose-limiting toxicities associated with this therapeutic regimen restrict its broader clinical application. In patients with PIK3CA mutations detected on ctDNA analysis, PFS was significantly improved compared to those with wild-type PIK3CA, suggesting that ctDNA-based PIK3CA mutation status may serve as a potential biomarker for treatment response.
PROSPERO, identifier CRD42023407466.
本系统评价和荟萃分析旨在评估磷脂酰肌醇3激酶（PI3K）抑制剂与氟维司群联合应用于激素受体阳性（HR+）、人表皮生长因子受体2阴性（HER2-）的晚期乳腺癌（ABC）患者的疗效和安全性。
在PubMed、Cochrane图书馆、EMBASE数据库和主要会议网站（美国临床肿瘤学会、欧洲肿瘤内科学会、圣安东尼奥乳腺癌研讨会）进行系统检索，以识别评估PI3K抑制剂与氟维司群联合治疗晚期乳腺癌的随机对照试验（RCT）。两名独立 reviewers 系统筛选文献、提取数据，并根据预定义标准评估纳入研究的偏倚风险。随后根据PRISMA指南使用R软件进行荟萃分析。
共纳入5项涉及3011例患者的随机对照试验。结果表明，与安慰剂加氟维司群相比，PI3K抑制剂与氟维司群联合应用显著改善了无进展生存期（PFS）（风险比[HR]=0.74，95%置信区间[CI]0.67-0.80，P<0.0001）和客观缓解率（ORR）（相对危险度[RR]=1.80，95%CI：1.39-2.35，P<0.0001）。然而，临床获益率（CBR）无统计学显著差异（RR=1.10，95%CI：0.97-1.25，P=0.1341）。亚组分析表明，基于循环肿瘤DNA（ctDNA）评估的PIK3CA突变状态的PFS预定义亚组具有统计学显著性（P=0.0039），而基于肿瘤组织评估的PIK3CA突变状态的PFS预定义亚组无统计学显著性（P=0.1514）。在不良事件方面，PI3K抑制剂联合氟维司群组≥3级事件的发生率显著增加（RR=2.11，95%CI：1.73-2.58，P<0.0001），尤其是高血糖、皮疹和转氨酶升高（谷丙转氨酶[ALT]）。
PI3K抑制剂与氟维司群联合应用显著改善了晚期乳腺癌患者的PFS和ORR。然而，与该治疗方案相关的大量剂量限制性毒性限制了其更广泛的临床应用。在ctDNA分析检测到PIK3CA突变的患者中，与PIK3CA野生型患者相比，PFS显著改善，这表明基于ctDNA的PIK3CA突变状态可能作为治疗反应的潜在生物标志物。
国际前瞻性系统评价注册库（PROSPERO），标识符CRD42023407466
