An Analysis of PIK3CA Hotspot Mutations and Response to Neoadjuvant Therapy in Patients with Breast Cancer from Four Prospective Clinical Trials.

IF 10 1区医学 Q1 ONCOLOGY

Clinical Cancer Research Pub Date : 2024-09-03 DOI:10.1158/1078-0432.CCR-24-0459

Paul Jank, Thomas Karn, Marion van Mackelenbergh, Judith Lindner, Denise Treue, Jens Huober, Knut Engels, Christine Solbach, Kurt Diebold, Frederik Marmé, Volkmar Müller, Andreas Schneeweiss, Hans-Peter Sinn, Tanja Fehm, Christian Schem, Elmar Stickeler, Peter Fasching, Jan Budczies, Bärbel Felder, Valentina Nekljudova, Johannes Holtschmidt, Michael Untch, Carsten Denkert, Sibylle Loibl

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引用次数: 0

Abstract

Purpose: 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.

Experimental design: 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.

Results: 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.

Conclusions: 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.

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分析四项前瞻性临床试验中乳腺癌患者的PIK3CA热点突变和对新辅助治疗的反应。

目的：PI3K信号通路在乳腺癌（BC）中经常失调，PIK3CA突变与HER2阳性BC的耐药性有关。外显子9或外显子20的突变可能会对基于新辅助化疗的治疗方案产生不同的影响：我们调查了1691名早期BC患者的PIK3CA突变情况，这些患者是在四项新辅助多中心试验中随机抽取的：GeparQuattro（NCT00288002）、GeparQuinto（NCT00567554）、GeparSixto（NCT01426880）和GeparSepto（NCT01583426）。针对不同的分子亚组和抗 HER2 治疗程序，评估了不同的 PIK3CA 外显子和热点对新辅助化疗（NACT）后病理完全反应（pCR）和患者生存率的作用：在1691名患者中，共有302名患者（17.9%）的肿瘤存在PIK3CA突变，不同分子亚组的发生率不同：404名患者中有95名患者（23.5%）存在管腔/HER2neg突变，819名患者中有170名患者（20.8%）存在HER2pos突变，431名患者中有37名患者（7.9%）存在TNBC突变。我们发现PIK3CA第20外显子的突变与抗HER2治疗反应较差有关（OR=0.507，95%CI 0.320-0.802，p=0.004），尤其是在HR阳性的HER2阳性BC中（OR=0.445，95%CI 0.237-0.837，p=0.012）。相比之下，外显子9热点突变p.E452K和p.E545K在反应治疗响应方面没有发现显著差异。当PIK3CA发生突变时，Luminal/HER2neg患者的治疗反应有变差的趋势。有趣的是，PIK3CA突变时，新辅助治疗后有残留疾病的患者生存率更高：结论：PIK3CA热点突变p.H1047R与HER2阳性BC患者NACT后较差的pCR率有关，而外显子9的热点突变似乎影响较小。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical Cancer Research 医学-肿瘤学

CiteScore

20.10

自引率

1.70%

发文量

1207

审稿时长

2.1 months

期刊介绍： Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.