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.
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.
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DOI：
10.1093/annonc/mdx803
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发表时间：
2018-10
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通讯作者：
S. Loibl;I. Majewski;V. Guarneri;V. Nekljudova;E. Holmes;E. Bria;C. Denkert;C. Schem;C. Sotiriou;S. Loi;M. Untch;P. Conte;R. Bernards;M. Piccart;G. von Minckwitz;J. Baselga
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作者：
S. Loibl;I. Majewski;V. Guarneri;V. Nekljudova;E. Holmes;E. Bria;C. Denkert;C. Schem;C. Sotiriou;S. Loi;M. Untch;P. Conte;R. Bernards;M. Piccart;G. von Minckwitz;J. Baselga
背景pik3突变在HER2阳性（HER2+）乳腺癌的新辅助抗HER2治疗和化疗中的预测价值已经有报道，但缺乏亚组分析的能力。患者和方法我们结合了来自5项临床试验的个体患者数据，评估pik3突变及其与病理完全缓解（pCR）、无病生存（DFS）和总生存（OS）的关系。患者接受曲妥珠单抗(T)，拉帕替尼(L)或T/L联合化疗，以及紫杉烷为基础的化疗。在治疗前的肿瘤活检中进行pik3ca2基因分型。结果共纳入967例患者；中位随访时间为47个月。总体而言，pik3camutant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，pik3camutant组的pCR率仅为7.6%，而野生型组为24.2% （P< 0.001）。相比之下，在HER2+/HR -组中，根据toPIK3CAmutation状态（相互作用测试P= 0.036）， pCR无差异（27.2% vs 36.4%， P= 0.125）。根据治疗组，突变型与野生型的pCR率分别为20.3%对27.1% (P= 0.343)， 11.3%对16.9% (P= 0.369)， 16.7%对39.1% （P< 0.001）。在HR+ T/L组，pCR率为5.5%比33.9% （HR与pik3cagenotype相互作用p = 0.008）。DFS和OS的突变状态差异不显著，但事件发生率较低。然而，HR+/PIK3CAmutant患者的DFS似乎明显更差{危险比（HR） 1.56[95%可信区间（CI） 1.00-2.45]，P= 0.050；Pinteraction = 0.021}。在野生型队列中，与T相比，T/L有改善DFS的趋势，尤其是在HR -组[HR 0.72, 95% CI (0.41-1.25)，P= 0.242]。结论总体而言，PIK3CAmutant/HER2+肿瘤的pCR率明显低于野生型肿瘤，但主要局限于HR+/PIK3CAmutant群体。关于生存，我们无法得出明确的结论。
BackgroundThe predictive value ofPIK3CAmutations 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 methodsWe combined individual patient data from five clinical trials evaluatingPIK3CAmutations 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.PIK3CAwas genotyped in tumour biopsies taken before therapy.ResultsA total of 967 patients were included in this analysis; the median follow-up is 47 months. Overall, the pCR rate was significantly lower in thePIK3CAmutant compared with the wild-type group (16.2% versus 29.6%;P< 0.001). Within the hormone-receptor positive (HR+) subgroup, thePIK3CAmutant 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 toPIK3CAmutation status (interaction testP= 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 andPIK3CAgenotypeP= 0.008). DFS and OS were not significantly different by mutation status, though the incidence rate of events was low. However, HR+/PIK3CAmutant 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].ConclusionOverallPIK3CAmutant/HER2+ tumours had significantly lower pCR rates compared with wild-type tumours, however mainly confined to the HR+/PIK3CAmutant population. No definite conclusions can be drawn regarding survival.