Chaki Moumita, Benrashid Mona, Puri Subir, Sivakumar Smruthy, Sokol Ethan S, Briceno Josefa M
Breast Cancer, US Medical Affairs, AstraZeneca, Gaithersburg, MD, USA.
Computational Discovery, Foundation Medicine Inc, Cambridge, MA, USA.
Breast Cancer Res. 2025 Jul 1;27(1):122. doi: 10.1186/s13058-025-02055-0.
Based on the CAPItello-291 phase III trial results, capivasertib in combination with fulvestrant has been approved for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer harboring one or more PIK3CA, AKT1, and/or PTEN alterations. Given the growing interest in circulating tumor DNA (ctDNA) next-generation sequencing (NGS) to detect PIK3CA/AKT1/PTEN alterations, we retrospectively compared blood-based FoundationOne®Liquid CDx versus tumor tissue-based FoundationOne®CDx real-world data from patients with various breast cancer subtypes.
We utilized a database of patients profiled with FoundationOne®CDx and/or FoundationOne®Liquid CDx during routine clinical care. Analytical comparison of all pathogenic alterations in PIK3CA, AKT1, AKT2, AKT3, and PTEN, including alterations defined in the CAPItello-291 protocol (CAPItello-defined alterations), was performed in paired data from 289 patients with both tissue and liquid biopsies sampled within 90 days of each other.
Overall positive percent agreement (PPA) for short variants across ctDNA tumor fraction (TF) subgroups in paired biopsy samples was: ctDNA TF ≥ 10%: PIK3CA, 93.9%; AKT1, 100%; PTEN, 100%; ctDNA TF 1%-10%: PIK3CA, 96.3%; AKT1, 100%; PTEN, 100%; ctDNA TF < 1%: PIK3CA, 34.7%; AKT1, 50.0%; PTEN, 37.5%. PPA for CAPItello-defined alterations was: ctDNA TF ≥ 10%: 92.5%; ctDNA TF 1%-10%: 97.1%; ctDNA TF < 1%: 33.9%. For PTEN homozygous deletions, PPA was 50.0% in cases with ctDNA TF ≥ 10%. Overall PPA for AKT2 and AKT3 copy number variations (CNVs) was 66.7% and 0%, respectively.
Blood-based NGS could offer a minimally invasive option to identify clinically relevant PIK3CA/AKT1/PTEN short variants in cases with ctDNA TF ≥ 1%. Confirmatory tissue-based NGS should be performed when blood-based NGS results are negative, especially when ctDNA TF is < 1% and for enhanced detection of CNVs in general.
基于CAPItello - 291 III期试验结果，卡匹西利联合氟维司群已被批准用于患有激素受体阳性/人表皮生长因子受体2阴性晚期乳腺癌且携带一种或多种PIK3CA、AKT1和/或PTEN改变的患者。鉴于循环肿瘤DNA（ctDNA）下一代测序（NGS）在检测PIK3CA/AKT1/PTEN改变方面的兴趣日益增加，我们回顾性比较了不同乳腺癌亚型患者基于血液的FoundationOne®Liquid CDx与基于肿瘤组织的FoundationOne®CDx的真实世界数据。
我们利用了在常规临床护理期间接受FoundationOne®CDx和/或FoundationOne®Liquid CDx检测的患者数据库。对PIK3CA、AKT1、AKT2、AKT3和PTEN中的所有致病性改变进行分析比较，包括CAPItello - 291方案中定义的改变（CAPItello定义的改变），这些分析是在289例在彼此90天内采集了组织活检和液体活检的配对数据中进行的。
配对活检样本中跨ctDNA肿瘤分数（TF）亚组的短变体总体阳性百分比一致性（PPA）为：ctDNA TF≥10%：PIK3CA为93.9%；AKT1为100%；PTEN为100%；ctDNA TF 1% - 10%：PIK3CA为96.3%；AKT1为100%；PTEN为100%；ctDNA TF < 1%：PIK3CA为34.7%；AKT1为50.0%；PTEN为37.5%。CAPItello定义的改变的PPA为：ctDNA TF≥10%：92.5%；ctDNA TF 1% - 10%：97.1%；ctDNA TF < 1%：33.9%。对于PTEN纯合缺失，ctDNA TF≥10%的病例中PPA为50.0%。AKT2和AKT3拷贝数变异（CNV）的总体PPA分别为66.7%和0%。
基于血液的NGS可为ctDNA TF≥1%的病例提供一种微创方法来识别临床上相关的PIK3CA/AKT1/PTEN短变体。当基于血液的NGS结果为阴性时，应进行基于组织的确认性NGS，特别是当ctDNA TF < 1%时，以及一般用于增强CNV检测时。
