ReviewFrom bench to bedside: What do we know about hormone receptor-positive and human epidermal growth factor receptor 2-positive breast cancer?
Introduction
Since breast cancers are heterogeneous, targeted medicine improves the therapeutic effectiveness of breast cancer treatment care. Currently, the estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) and Ki67 are used as routine biomarkers to diagnose and guide the use of adjuvant treatment options for breast cancer patients [1].
ER and PgR are grouped together into the class of hormone receptors (HRs). ER expression presents in approximately 75% of breast cancer patients [2]. ER-positive (ER+) breast cancers are susceptible to endocrine therapies (e.g., tamoxifen, aromatase inhibitors [AIs], luteinizing hormone releasing hormone analogues and bilateral oophorectomy), to interfere with ER signaling and/or block estrogen synthesis. A positive relationship between the ER Allred score and the response rate to endocrine therapies suggests that breast cancers patients with a higher ER level have better prognoses when they are subjected to endocrine therapies [3]. PgR expression is regulated through the transcriptional activity of ER. Therefore, PgR positivity is an indicator of ER signaling pathway integrity and good prognosis to endocrine therapy [4], [5], [6]. Ki67 is a nuclear protein that expresses throughout all phases of the cell cycle in the proliferating cells [7], [8]. High Ki67 expression is often associated with poor recurrence-free and disease-specific survival in HR-positive (HR+) breast cancers [9]. The Ki67 level can predict whether HR+ breast cancer patients would benefit from chemotherapeutic regimens: only high Ki67 tumors in ER+ patients receive clinical benefit from chemotherapy [10], [11], [12]. Also, the Ki67 level can be utilized as a pharmacodynamic endpoint to assess tumor response in a neoadjuvant setting.
Approximately 15–20% of breast carcinoma is HER2-positive (HER2+) [13]. Systemic treatment for HER2+ breast cancers involves a combination of chemotherapies and HER2-targeted blocking agents (e.g., trastuzumab, trastuzumab estansine [T-DM1], lapatinib and pertuzumab), regardless of HR status [14]. The Surveillance, Epidemiology and End Result Registry (SEER) conducted an assessment of incident rates of the major subtypes of breast cancer, based on 28% of the US population [15]. According to this study, 73% (36,810) are HR+ HER2-negative (HER2−), 5% (2328) are HR-negative (HR−) HER2+, 12% (6912) are HR− HER2− and the remaining 10% (5240) are HR+ HER2+. Although it comprises one tenth of the total breast cancer population, the HR+ HER2+ subtype has drawn limited attention within the research community, compared to other subtypes.
Based on the transcriptional signature, breast carcinomas are classified as luminal A, luminal B, HER2-enriched or basal-like [16], [17]. HR+ carcinomas are classified as luminal type. This type is further subdivided into low-risk luminal A type, with high ER-regulated gene expression, and high-risk luminal B type, with low ER-regulated gene expression. In addition to ER activity, HER2 overexpression and high Ki67 proliferation index are also considered to be molecular characteristics of luminal B type [18]. The luminal A type is responsive to endocrine therapy, whereas the luminal B type is more aggressive and refractory to endocrine therapy. In luminal A breast cancers, the PgR positivity indicates that the ERα signaling pathway is active and predicts a good prognosis for endocrine therapy [4]. HER2+ and triple negative breast cancers (ER-negative [ER−] PgR-negative [PgR−] HER2− or HR− HER2−) are classified as HER2-enriched and basal-like, respectively. Gene expression profiling tools have become available commercially to provide predictive information to guide individualized treatment; these tools include the PAM50 (a 50-gene prediction analysis for microarrays), Oncotype DX (a 21-gene recurrence score) and MammaPrint (a 70-gene DNA microarray assay) [8], [19], [20], [21], [22]. Despite the availability of comprehensive genetic profiling assays, the immunohistochemistry of ER, PgR, HER2 and Ki67 remains the gold standard to guide treatment plans.
HR+ HER2+ breast cancers are less characterized than other subtypes. About one eighth of the HR+ population are HER2+ and more than half of the HER2+ patients are HR+ [14], [15], [23]. Approximately 50% of luminal B type breast cancers are HR+ HER2+, which are more likely to be ER+ PgR− HER2+ [24], [25]. In clinical studies, the HR+ HER2+ subgroup displays a wider range of clinical endpoints (e.g., PFS and pCR) than other subtypes, implying the heterogeneity of this subtype. The five-year overall survival (OS) and disease free survival (DFS) of HR+ HER2+ patients are worse than that of HR+ HER2− but better than that of HR− HER2+ or HR− HER2− [19], [26], [27]. HR+ HER2+ breast cancers have higher chances of being diagnosed in younger populations and as higher-grade diseases, compared to other subtypes [15], [28]. These findings support the hypothesis that, not only the clinicopathological, but also biological characteristics of HR+ HER2+ tumors, are different from other subtypes of breast tumors. Therefore, HR+ HER2+ breast cancers should be recognized as a distinct subcategory of breast cancers. It is important to understand the molecular features of HR+ HER2+ breast cancers and tailor therapeutic strategies specific to this subtype.
In this review, we will summarize the molecular circuits and functional signaling units of the ER and HER2 signaling pathways. We will further illustrate how the coexistence of active ER and HER2 pathways affects the molecular characteristics of HR+ HER2+ breast cancers and will clarify the potential for drug resistance that occurs due to the signaling crosstalk between ER and HER2. In addition, we will describe preclinical studies that dissect the molecular features and etiology of this subtype of breast cancers and elaborate strategies for optimizing the treatment of HR+ HER2+ breast cancer patients.
Section snippets
ER signaling pathway
In ER+ breast cancer cells, estrogen stimulates cell proliferation and survival via the genomic and non-genomic action of ERs. These actions involve the two classical nuclear receptors, ERα and ERβ, as well as G-protein coupled receptor GPER, which is also as known as GPR-30 [29], [30]. ERα and ERβ are encoded by ESR1 and ESR2, respectively. Among the ERs, ERα is the major player contributing to breast malignancies, whereas ERβ plays a prominent role in prostate cancer [29], [31]. In breast
HER1-4 family of receptor tyrosine kinase (RTK)
Overexpression and/or amplification of HER2, also known as HER2/neu or epidermal growth factor receptor ErbB-2, results in aggressive tumor growth and poor clinical outcomes [64]. HER2 encodes a transmembrane RTK that perceives extracellular signals (e.g., growth factors) to initiate a signaling cascade that mediates cell proliferation and survival.s RTK family members are generally composed of an extracellular ligand binding domain, a transmembrane domain and a functional intracellular
The signaling cross-talk between ERα and HER2 in HR+ HER2+ breast cancers
ERα action can regulate the activity of the HER2 signaling pathway at multiple levels: (1) At the genomic level, activated ERα induces the expression of growth factor receptor ligands, such as TGFα and AR, and RTK HERs (e.g., HER1 and HER2) to augment the activity of the HER2 signaling pathway (Fig. 1a) [42], [101], [102]. (2) At the non-genomic level, the estrogen-activated membrane ERα can interact with and activate HER2 to initiate the downstream signaling cascade (Fig. 1b) [51], [103], [104]
Preclinical tools for HR+ HER2+ breast cancers
The low success rate for translating research hypotheses into clinical success has been a problematic issue. Oncology drug discovery has one of the highest failure rates on clinical trials among all the therapeutic areas [117]. So far, approximately only one-third of the drugs tested in preclinical models show activity in phase II clinical trials [118]. In order to deliver accurate preclinical data to support late stage clinical trials, early findings should be reproduced in multiple research
The clinical implications of HR+ HER2+ breast cancers
Regardless of HR status, patients with HER2 overexpression/amplification are subjected to a combination of HER2-targeted therapies and chemotherapy as the standard first-line therapy [14], [126]. Clinical studies of NeoALTTO, TBCRC and NeoSphere have reported that HR+ HER2+ patients have a lower pathological complete response (pCR) rate to neoadjuvant anti-HER2 agents plus chemotherapy, compared to HR- HER2+ patients [100], [127], [128]. These results reinforce the need for improvements to the
Perspectives on HR+ HER2+ breast cancers
Although the combination of endocrine therapies and HER2 blocking agents is recommended for the HR+ HER2+ subtype, the standard treatment regimen that uses HER2 blocking agents plus chemotherapy is preferred in the current clinical setting [14]. In HR+ HER2+ breast cancer, the crosstalk between the ER and HER2 signaling pathway results in new regulatory mechanisms that require targeted treatment. Major concerns have been raised regarding the biology and treatment of HR+ HER2+ breast cancers:
(a)
Acknowledgements
We thank Dr. Nancy Linford providing us suggestions on manuscript writing and proofreading. The research was supported by the City of Hope Excellence Award and the National Cancer Institute (P30CA033572).
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