背景:在靶向治疗期间,HER2阳性乳腺癌总是失去HER2DNA扩增。相比之下,有趣的是,HER2蛋白可能丢失或获得。为了纵向和系统地了解HER2DNA/蛋白质化学计量的复杂/不一致变化,HER2DNA拷贝数和可溶性血液蛋白(aHER2/sHER2)平行测试,非侵入性(通过液体活检),在二维中,因此HER2-2D。
方法:在使用抗体-药物偶联物(ADC)曲妥珠单抗-emtansine(T-DM1)对晚期HER2阳性乳腺癌患者(n=37)进行标准治疗之前和之后,通过数字PCR和ELISA评估aHER2和sHER2。
结果:如预期,aHER2总是被T-DM1抑制,但这种损失令人惊讶地反映了sHER2增益,有时是相当大的实体,在大多数(30/37;81%)患者中。HER2致癌剂量的这种非正统分裂在两个代表性病例中得到了aHER2/sHER2动力学的支持。和免疫组织化学高状态,尽管4/5的T-DM1肿瘤后可再活检sHER2患者的拷贝数中性。此外,通过T-DM1体外处理的垂死的乳腺癌细胞系优先释放sHER2。最后,sHER2增加与比sHER2损失更长的PFS相关(平均PFS282天vs133天,95%CI[210-354]对[56-209],对数秩检验p=0.047),特别是当排除在T-DM1治疗期间出现循环HER2旁路改变的病例(n=11)时(平均PFS349vs139天,95%CI[255-444]vs[45-232],对数秩检验p=0.009)。
结论:HER2增益是在肿瘤组织中适应性选择的,并通过sHER2增益在血液中概括。可能,在用裸抗体抗HER2治疗期间,增加致癌剂量对肿瘤有益,但在用强细胞毒性ADC如T-DM1治疗期间对宿主有利。在后一种情况下,HER2-gain肿瘤可以暂时保持在检查,直到替代致癌驱动因素,液体活检显示,绕过HER2。无论哪种解释,HER2-2D可能有助于定制/优先考虑抗HER2治疗,尤其是对低aHER2/低sHER2肿瘤有活性的ADC。
背景:NCT05735392于2023年1月31日回顾性注册https://www。
结果:gov/search?term=NCT05735392。
BACKGROUND: During targeted treatment, HER2-positive breast cancers invariably lose HER2 DNA amplification. In contrast, and interestingly, HER2 proteins may be either lost or gained. To longitudinally and systematically appreciate complex/discordant changes in HER2 DNA/protein stoichiometry, HER2 DNA copy numbers and soluble blood proteins (aHER2/sHER2) were tested in parallel, non-invasively (by liquid biopsy), and in two-dimensions, hence HER2-2D.
METHODS: aHER2 and sHER2 were assessed by digital PCR and ELISA before and after standard-of-care treatment of advanced HER2-positive breast cancer patients (n=37) with the antibody-drug conjugate (ADC)
Trastuzumab-emtansine (T-DM1).
RESULTS: As expected, aHER2 was invariably suppressed by T-DM1, but this loss was surprisingly mirrored by sHER2 gain, sometimes of considerable entity, in most (30/37; 81%) patients. This unorthodox split in HER2 oncogenic dosage was supported by reciprocal aHER2/sHER2 kinetics in two representative cases, and an immunohistochemistry-high status despite copy-number-neutrality in 4/5 available post-T-DM1 tumor re-biopsies from sHER2-gain patients. Moreover, sHER2 was preferentially released by dying breast cancer cell lines treated in vitro by T-DM1. Finally, sHER2 gain was associated with a longer PFS than sHER2 loss (mean PFS 282 vs 133 days, 95% CI [210-354] vs [56-209], log-rank test p=0.047), particularly when cases (n=11) developing circulating HER2-bypass alterations during T-DM1 treatment were excluded (mean PFS 349 vs 139 days, 95% CI [255-444] vs [45-232], log-rank test p=0.009).
CONCLUSIONS: HER2 gain is adaptively selected in tumor tissues and recapitulated in blood by sHER2 gain. Possibly, an increased oncogenic dosage is beneficial to the tumor during anti-HER2 treatment with naked antibodies, but favorable to the host during treatment with a strongly cytotoxic ADC such as T-DM1. In the latter case, HER2-gain tumors may be kept transiently in check until alternative oncogenic drivers, revealed by liquid biopsy, bypass HER2. Whichever the interpretation, HER2-2D might help to tailor/prioritize anti-HER2 treatments, particularly ADCs active on aHER2-low/sHER2-low tumors.
BACKGROUND: NCT05735392 retrospectively registered on January 31, 2023 https://www.
RESULTS: gov/search?term=NCT05735392.