PIK3CA突变与原发性HER2阳性乳腺癌病理完全缓解率降低相关：来自五项研究拉帕替尼和曲妥珠单抗的前瞻性试验的967例患者的汇总分析
PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab.
作者信息
Loibl S, Majewski I, Guarneri V, Nekljudova V, Holmes E, Bria E, Denkert C, Schem C, Sotiriou C, Loi S, Untch M, Conte P, Bernards R, Piccart M, von Minckwitz G, Baselga J
机构信息
German Breast Group, Neu-Isenburg, Germany
The Netherlands Cancer Institute, Amsterdam, The Netherlands.
出版信息
Ann Oncol. 2016 Aug;27(8):1519-25. doi: 10.1093/annonc/mdw197. Epub 2016 May 13.
BACKGROUND
The predictive value of PIK3CA mutations in HER2 positive (HER2+) breast cancer treated with neoadjuvant anti-HER2 and chemotherapy has been reported, but the power for subgroup analyses was lacking.
PATIENTS AND METHODS
We combined individual patient data from five clinical trials evaluating PIK3CA mutations and associations with pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Patients received either trastuzumab (T), lapatinib (L) or the combination T/L in addition to a taxane-based chemotherapy. PIK3CA was genotyped in tumour biopsies taken before therapy.
RESULTS
A total of 967 patients were included in this analysis; the median follow-up is 47 months. Overall, the pCR rate was significantly lower in the PIK3CA mutant compared with the wild-type group (16.2% versus 29.6%; P < 0.001). Within the hormone-receptor positive (HR+) subgroup, the PIK3CA mutant group had a pCR rate of only 7.6% compared with 24.2% in the wild-type group (P < 0.001). In contrast, in the HER2+/HR- group, there was no difference in pCR (27.2% versus 36.4%; P = 0.125) according to PIK3CA mutation status (interaction test P = 0.036). According to treatment arm, the pCR rate for mutant versus wild-type was 20.3% versus 27.1% for T (P = 0.343), 11.3% versus 16.9% for L (P = 0.369) and 16.7% versus 39.1% for T/L (P < 0.001). In the HR+ T/L group, the pCR rate was 5.5% versus 33.9% (interaction between HR and PIK3CA genotype P = 0.008). DFS and OS were not significantly different by mutation status, though the incidence rate of events was low. However, HR+/PIK3CA mutant patients seemed to have significantly worse DFS {hazard ratio (HR) 1.56 [95% confidence interval (CI) 1.00-2.45], P = 0.050; Pinteraction = 0.021}. T/L tended to improve DFS compared with T in the wild-type cohort, especially in the HR- group [HR 0.72, 95% CI (0.41-1.25), P = 0.242].
CONCLUSION
Overall PIK3CA mutant/HER2+ tumours had significantly lower pCR rates compared with wild-type tumours, however mainly confined to the HR+/PIK3CA mutant population. No definite conclusions can be drawn regarding survival.
背景
已有报道称PIK3CA突变在接受新辅助抗HER2治疗和化疗的HER2阳性（HER2+）乳腺癌中的预测价值，但缺乏亚组分析的效能。
患者与方法
我们汇总了五项评估PIK3CA突变及其与病理完全缓解（pCR）、无病生存期（DFS）和总生存期（OS）相关性的临床试验的个体患者数据。患者除接受紫杉类化疗外，还接受了曲妥珠单抗（T）、拉帕替尼（L）或T/L联合治疗。在治疗前采集的肿瘤活检组织中对PIK3CA进行基因分型。
结果
本分析共纳入967例患者；中位随访时间为47个月。总体而言，PIK3CA突变组的pCR率显著低于野生型组（16.2%对29.6%；P<0.001）。在激素受体阳性（HR+）亚组中，PIK3CA突变组的pCR率仅为7.6%，而野生型组为24.2%（P<0.001）。相反，在HER2+/HR-组中，根据PIK3CA突变状态，pCR无差异（27.2%对36.4%；P=0.125）（交互检验P=0.036）。根据治疗组，突变型与野生型的pCR率在T组中为20.3%对27.1%（P=0.343），在L组中为11.3%对16.9%（P=0.369），在T/L组中为16.7%对39.1%（P<0.001）。在HR+T/L组中，pCR率为5.5%对33.9%（HR与PIK3CA基因型之间的交互作用P=0.008）。DFS和OS在突变状态方面无显著差异，尽管事件发生率较低。然而，HR+/PIK3CA突变患者的DFS似乎显著更差{风险比（HR）1.56[95%置信区间（CI）1.00 - 2.45]，P=0.050；P交互作用=0.021}。与野生型队列中的T相比，T/L倾向于改善DFS，尤其是在HR-组中[HR 0.72，95%CI（0.41 - 1.25），P=0.242]。
结论
总体而言，PIK3CA突变型/HER2+肿瘤的pCR率显著低于野生型肿瘤，但主要局限于HR+/PIK3CA突变人群。关于生存情况尚无明确结论。
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