Institute of Pathology, Philipps University Marburg and Marburg University Hospital (UKGM), UCT Frankfurt-Marburg, Marburg, Germany.
Department of Gynecology and Obstetrics, University of Frankfurt, UCT Frankfurt-Marburg, Frankfurt, Germany.
Clin Cancer Res. 2024 Sep 3;30(17):3868-3880. doi: 10.1158/1078-0432.CCR-24-0459.
The PI3K signaling pathway is frequently dysregulated in breast cancer, and mutations in PIK3CA are relevant for therapy resistance in HER2-positive (HER2pos) breast cancer. Mutations in exons 9 or 20 may have different impacts on response to neoadjuvant chemotherapy-based treatment regimens.
We investigated PIK3CA mutations in 1,691 patients with early breast cancer who were randomized into four neoadjuvant multicenter trials: GeparQuattro (NCT00288002), GeparQuinto (NCT00567554), GeparSixto (NCT01426880), and GeparSepto (NCT01583426). The role of different PIK3CA exons and hotspots for pathologic complete response (pCR) following neoadjuvant chemotherapy (NACT) and patient survival were evaluated for distinct molecular subgroups and anti-HER2 treatment procedures.
A total of 302 patients (17.9%) of the full cohort of 1,691 patients had a tumor with a PIK3CA mutation, with a different prevalence in molecular subgroups: luminal/HER2-negative (HER2neg) 95 of 404 (23.5%), HER2pos 170 of 819 (20.8%), and triple-negative breast cancer 37 of 468 patients (7.9%). We identified the mutations in PIK3CA exon 20 to be linked with worse response to anti-HER2 treatment (OR = 0.507; 95% confidence interval, 0.320-0.802; P = 0.004), especially in hormone receptor-positive HER2-positive breast cancer (OR = 0.445; 95% confidence interval, 0.237-0.837; P = 0.012). In contrast, exon 9 hotspot mutations p.E452K and p.E545K revealed no noteworthy differences in response therapy. Luminal/HER2neg patients show a trend to have worse treatment response when PIK3CA was mutated. Interestingly, patients with residual disease following neoadjuvant treatment had better survival rates when PIK3CA was mutated.
The PIK3CA hotspot mutation p.H1047R is associated with worse pCR rates following NACT in HER2pos breast cancer, whereas hotspot mutations in exon 9 seem to have less impact.
PI3K 信号通路在乳腺癌中经常失调，PIK3CA 的突变与 HER2 阳性（HER2pos）乳腺癌的治疗耐药性有关。外显子 9 或 20 的突变可能对基于新辅助化疗的治疗方案的反应有不同的影响。
我们研究了 1691 例早期乳腺癌患者的 PIK3CA 突变，这些患者被随机分配到四项新辅助多中心试验中：GeparQuattro（NCT00288002）、GeparQuinto（NCT00567554）、GeparSixto（NCT01426880）和 GeparSepto（NCT01583426）。评估了不同 PIK3CA 外显子和新辅助化疗（NACT）后病理完全缓解（pCR）和患者生存的热点对不同分子亚群和抗 HER2 治疗程序的作用。
在 1691 例患者的全部队列中，共有 302 例（17.9%）患者的肿瘤存在 PIK3CA 突变，在不同的分子亚群中存在不同的发生率：管腔/HER2 阴性（HER2neg）404 例中有 95 例（23.5%），HER2pos 819 例中有 170 例（20.8%），三阴性乳腺癌 468 例中有 37 例（7.9%）。我们发现 PIK3CA 外显子 20 的突变与抗 HER2 治疗的反应较差有关（OR=0.507；95%置信区间，0.320-0.802；P=0.004），尤其是在激素受体阳性 HER2 阳性乳腺癌中（OR=0.445；95%置信区间，0.237-0.837；P=0.012）。相比之下，外显子 9 的热点突变 p.E452K 和 p.E545K 显示在反应治疗方面没有显著差异。管腔/HER2neg 患者在 PIK3CA 突变时表现出治疗反应较差的趋势。有趣的是，在新辅助治疗后有残留疾病的患者，当 PIK3CA 发生突变时，其生存率更高。
HER2pos 乳腺癌中 PIK3CA 热点突变 p.H1047R 与 NACT 后 pCR 率较低相关，而外显子 9 中的热点突变似乎影响较小。
