原发性HER2阳性乳腺癌PIK3CA突变与病理学完全缓解率降低相关

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　　PIK3CA突变对于抗HER2疗法和化疗新辅助治疗HER2阳性乳腺癌的预测价值已有报道，但是亚组分析的把握度不足。

　　2016年8月，欧洲肿瘤内科学会（ESMO）官方期刊、牛津大学出版社旗下的《肿瘤学年鉴》第27卷第8期正式发表了德国乳腺癌研究组织（GBG）、荷兰癌症研究所、意大利帕多瓦大学、英国苏格兰前沿科学、意大利维罗纳大学、柏林大学夏里特医学院附属医院、德国癌症联盟、德国基尔大学医院、比利时布鲁塞尔自由大学朱尔·博尔代研究所、澳大利亚彼得·麦卡勒姆癌症中心、荷兰赫利俄斯医院、美国纽约纪念斯隆-凯特琳癌症中心的汇总分析研究报告。

　　该研究汇总分析了来自调查拉帕替尼和曲妥珠单抗的5项前瞻研究967例患者，中位随访47个月，发现PIK3CA突变与野生型相比，显著降低原发性HER2阳性乳腺癌病理学完全缓解率（16.2%比29.6%，P＜0.001），尤其对于激素受体阳性（7.6%比24.2%，P＜0.001）、拉帕替尼＋曲妥珠单抗（16.7%比39.1%，P＜0.001）、激素受体阳性且拉帕替尼＋曲妥珠单抗（5.5%比33.9%，激素受体与PIK3CA基因型之间P=0.008）人群亚组，但是在HER2阳性/激素受体阴性（27.2%比36.4%，P=0.125，PIK3CA突变状态之间P=0.036）、曲妥珠单抗单药（20.3%比27.1%，P=0.343）、拉帕替尼单药（11.3%比16.9%，P=0.369）人群亚组中无显著差异。突变状态对无病生存和总生存无显著影响，但是激素受体阳性且PIK3CA突变患者无病生存降低（风险比：1.56，95%置信区间：1.00～2.45，P=0.050，激素受体与PIK3CA基因型之间P=0.021）。曲妥珠单抗＋拉帕替尼与曲妥珠单抗单药相比，略可改善PIK3CA野生型队列的无病生存，尤其对于激素受体阴性组（风险比：0.75，95%置信区间：0.41～1.25，P=0.242）。

　　总之，PIK3CA突变与野生型相比，显著降低HER2阳性肿瘤病理学完全缓解率，尤其对于激素受体阳性、拉帕替尼＋曲妥珠单抗治疗、激素受体阳性且拉帕替尼＋曲妥珠单抗治疗人群。PIK3CA突变对于生存的影响无法得出明确结论。

Ann Oncol. 2016 Aug;27(8):1519-25.

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.

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.

German Breast Group, Neu-Isenburg, Germany; The Netherlands Cancer Institute, Amsterdam, the Netherlands; University of Padua, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy; Frontier Science Scotland, Kincraig, United Kingdom; Medical Oncology, University of Verona, Verona, Italy; Charité Universitatsmedizin Berlin, and German Cancer Consortium (DKTK) Berlin, Germany; University Hospital Kiel, Kiel, Germany; Institut Jules Bordet, Université Libre de Bruxelles, Belgium; Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Helios-Klinikum, Berlin-Buch, Germany; Memorial Sloan-Kettering Cancer Center, New York, USA.

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.

KEYWORDS: HER2+ breast cancer; PIK3CA; double anti-HER2 treatment; neoadjuvant; pathological complete response; survival

PMID: 27177864

PII: mdw197

DOI: 10.1093/annonc/mdw197