Nerone Marta, Rossi Lorenzo, Condorelli Rosaria, Ratti Vilma, Conforti Fabio, Palazzo Antonella, Graffeo Rossella
Service of Medical Oncology, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale (EOC), 6500 Bellinzona, Switzerland.
Oncology Unit, Humanitas Gavazzeni, 24125 Bergamo, Italy.
Cancers (Basel). 2023 Jun 23;15(13):3305. doi: 10.3390/cancers15133305.
We explored the outcomes of germline pathogenic/likely pathogenic variants (PVs/LPVs) in the endocrine-sensitive disease treated with first-line standard of care cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Three studies retrospectively showed a reduction in the overall survival (OS) and progression-free survival (PFS) in gm patients compared to both the germinal wild type (gwt) and the untested population. Regarding the efficacy of PI3Kα inhibitors, there are no subgroups or biomarker analyses in which germinal BRCA status was explored. However, the biological interactions between the PIK3CA/AKT/mTOR pathway and at a molecular level could help us to understand the activity of these drugs when used to treat BC in PVs/LPVs carriers. The efficacy of trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC) targeting HER2 for HER2-low and HER2-positive (HER2+) BC, has been increasingly described. Unfortunately, data on T-DXd in HER2+ or HER2-low metastatic BC harboring germinal PVs/LPVs is lacking. Including germinal status in the subgroup analysis of the registration trials of this ADC would be of great interest, especially in the phase III trial DESTINY-breast04. This trial enrolled patients with HER2-negative (HER2-) and both HR+ and HR- metastatic disease, which can now be categorized as HER2-low. The HER2-low subgroup includes tumors that were previously classified as triple negative, so it is highly likely that some women were germline PVs/LPVs carriers and this data was not reported. Germline status will be available for a higher number of individuals with BC in the near future, and data on the prognostic and predictive role of these PVs/LPVs is needed in order to choose the best treatment options.
我们探讨了在接受一线标准护理细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂治疗的内分泌敏感疾病中，生殖系致病/可能致病变异（PVs/LPVs）的结果。三项回顾性研究表明，与生殖系野生型（gwt）和未检测人群相比，gm患者的总生存期（OS）和无进展生存期（PFS）有所缩短。关于PI3Kα抑制剂的疗效，尚未进行探索生殖系BRCA状态的亚组或生物标志物分析。然而，PIK3CA/AKT/mTOR通路之间在分子水平上的生物学相互作用，有助于我们了解这些药物用于治疗PVs/LPVs携带者的乳腺癌时的活性。曲妥珠单抗德鲁昔单抗（T-DXd）是一种针对HER2低表达和HER2阳性（HER2+）乳腺癌的抗体药物偶联物（ADC），其疗效已得到越来越多的描述。遗憾的是，缺乏关于携带生殖系PVs/LPVs的HER2+或HER2低表达转移性乳腺癌患者使用T-DXd的数据。在该ADC注册试验的亚组分析中纳入生殖系状态将非常有意义，尤其是在III期试验DESTINY-breast04中。该试验纳入了HER2阴性（HER2-）以及HR+和HR-转移性疾病患者，这些患者现在可归类为HER2低表达。HER2低表达亚组包括以前被归类为三阴性的肿瘤，因此很可能一些女性是生殖系PVs/LPVs携带者，但这一数据未被报告。在不久的将来，更多乳腺癌患者将能够获得生殖系状态信息，为了选择最佳治疗方案，需要有关这些PVs/LPVs的预后和预测作用的数据。
