Aging and Cancer Immuno-oncology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Endocrinology. 2021 Oct 1;162(10). doi: 10.1210/endocr/bqab153.
The lethality of estrogen receptor alpha positive (ER+) breast cancer, which is often considered to have better prognosis than other subtypes, is defined by resistance to the standard of care endocrine treatment. Relapse and metastasis are inevitable in almost every patient whose cancer is resistant to endocrine treatment. Therefore, understanding the underlying causes of treatment resistance remains an important biological and clinical focus of research in this area. Growth factor receptor pathway activation, specifically HER2 activation, has been identified as 1 mechanism of endocrine treatment resistance across a range of experimental model systems. However, clinical trials conducted to test whether targeting HER2 benefits patients with endocrine treatment-resistant ER+ breast cancer have consistently and disappointingly shown mixed results. One reason for the failure of these clinical trials could be the complexity of crosstalk between ER, HER2, and other growth factor receptors and the fluidity of HER2 activation in these cells, which makes it challenging to identify stratifiers for this targeted intervention. In the absence of stratifiers that can be assayed at diagnosis to allow prospective tailoring of HER2 inhibition to the right patients, clinical trials will continue to disappoint. To understand stratifiers, it is important that the field invests in key understudied areas of research including characterization of the tumor secretome and receptor activation in response to endocrine treatment, and mapping the ER-HER2 growth factor network in the normal and developing mammary gland. Understanding these mechanisms further is critical to improving outcomes for the hard-to-treat endocrine treatment-resistant ER+ breast cancer cohort.
雌激素受体阳性（ER+）乳腺癌的致死率通常被认为比其他亚型预后更好，但这种肿瘤对标准的内分泌治疗具有耐药性。几乎每个对内分泌治疗耐药的癌症患者，其肿瘤都会不可避免地复发和转移。因此，了解治疗耐药的根本原因仍然是该领域生物学和临床研究的重要重点。生长因子受体通路激活，特别是 HER2 激活，已被确定为一系列实验模型系统中内分泌治疗耐药的 1 种机制。然而，为了测试针对 HER2 是否有益于内分泌治疗耐药的 ER+乳腺癌患者而进行的临床试验，结果却一直令人失望，好坏参半。这些临床试验失败的原因之一可能是 ER、HER2 和其他生长因子受体之间的串扰以及这些细胞中 HER2 激活的流动性非常复杂，这使得确定针对这种靶向干预的分层因素变得具有挑战性。在没有可以在诊断时进行检测以允许前瞻性地将 HER2 抑制作用适用于合适患者的分层因素的情况下，临床试验将继续令人失望。为了了解分层因素，该领域必须投资于一些关键的研究领域，包括肿瘤分泌组学的特征以及对内分泌治疗的受体激活的研究，以及在正常和发育中的乳腺中绘制 ER-HER2 生长因子网络。进一步了解这些机制对于改善难以治疗的内分泌治疗耐药的 ER+乳腺癌患者的预后至关重要。
