In this study, we curated promising impact of the HR expression on the heterogeneous outcomes of clinicopathological characteristics, metastatic patterns, and overall prognosis of HER2-positive breast cancer. To our knowledge, this was the first study that overall discussed the impact of HR status on the clinical characteristics and prognostic profiles of HER2-positive breast cancer based on a large-scale cohort, of which the findings could provide promising evidence for introduction of treatment strategies in clinical practice.
We firstly investigated the potential difference in the clinicopathological characteristics between the two subgroups of HER2-positive breast cancer. In accordance with previous data [15], the proportion of the white race was significantly advantageous in HR + subgroup, while the percentage of the black race was relatively higher in HR- breast cancer patients, which the individual risk factors comprising reproductive history, lactation, physical activity, mammography, and postmenopausal hormone use may explain this kind of ethnic disparity [16]. A consistent discrepancy was also detected in disease features, which HR−/HER2 + breast cancer exhibited a comparatively higher tumor grade and TNM stage, indicative of an increasing aggressiveness and progressive cancer behaviors. This proportion of results were in consistent with previous studies that reported the higher proportion of advanced stage and high-grade tumors among HR-/HER2 + cases when compared to HR + /HER2 + breast cancer patients [7, 11, 17,18,19,20]. Concerning treatment options, patients with HR + /HER2 + breast cancer held a climbing opportunity to receive locoregional therapeutics, such as surgery and radiotherapy, yet a less access to systemic delivery, which could be attributed to the distinctive disease factors of the two subgroups observed in the cancer course.
Notably, our investigation provided unique evidence of the associations between HR expression and metastatic patterns of newly diagnosed HER2-positive breast cancer. As expected, patients from HR + /HER2 + subgroup presented an overwhelming frequency of bone involvement with 62.1% of the entire HER2-positive cohort, while HR−/HER2 + tumors tended to metastasize in viscera including liver and lung. This kind of strong correlation between HR status and involved organs in HER2-positive disease was proposed early in 1991 [21] and confirmed in the following studies [11, 12, 22]. With an in-depth understanding of the modulated components in the various subgroups of breast cancer, there had been some studies emerging which could potentially interpret this phenomenon. For instance, the down-regulation of focal adhesion signaling in HR-negative patients was an important contributor of visceral involvement and the absence of Wnt/β-catenin signaling allowed for HR-positive tumors t metastasize in bone [23, 24]. In the current study, brain metastasis was more commonly occurred in the HR-negative population, which was also observed in several studies [11, 12, 22, 25] and could be the promoting profile of the conversely hyperactive Wnt/β-catenin signaling pathway [23]. These results suggest that clinicians should pay more attention to the organs liable to metastasis differing by HR status for de novo stage IV breast cancer patients.
Regarding prognostic profiles, our study revealed a great heterogeneity associated with HR expression in HER2-positive breast cancer, of which the HR + expression was in line with the mortality decrease of both OS and BCSS and this kind of correlation was inherently stable. It is undeniable that adjuvant treatment including targeted and endocrine therapy could affect the prognosis of HER2-positive and HR + /HER2 + breast cancer. Yet, the proportion of patients receiving adjuvant targeted and endocrine therapy were unavailable in SEER database. Trastuzumab, the first humanized monoclonal antibody against HER2, has been officially approved by the FDA for the treatment of HER-2-overexpressing breast cancers in 1998. Several real-world studies [26,27,28,29,30,31] demonstrated the percentage of adjuvant target therapy based on trastuzumab-containing regimens ranged from 65.6 to 88.8% among HER2 + breast cancer patients in the US. Previous literature has also reported that the majority of HR + patients (63.8–86%) treated with adjuvant endocrine therapy [32,33,34,35,36,37]. Thereby, we may suppose that patients identified from SEER database have received standard adjuvant treatments. This finding was in accordance with the previous outcomes, in which the HERA trial evaluated 1703 HER2 + early breast cancer patients underwent standard 1-year trastuzumab found a 3-year disease free survival (DFS) of 84.6% in HR + subgroup and 76.4% in HR- subgroup, respectively [38]. Likewise, a study included 3,177 patients with HER2 + breast cancer [39] showed a significantly favorable survival in patients with HR + /HER2 + subgroup compared with HR-/HER2 + subtype with the receipt of standard adjuvant therapeutics.
A potential reason for this sort of prognostic disparity could lie in the multiple therapeutic options in the course of cancer management, especially the contents of medication therapies after recurrence. Given the considerable advances in endocrine therapy, such as fulvestrant, CDK4/6 inhibitors (ribociclib, palbociclib, abemaciclib) and everolimus, the prognosis of HR + metastatic breast cancer has improved immensely [40], which could lead to a superior prognosis on HR + patients. In addition, molecular mechanisms might partly account for the distinct prognosis of HR + /HER2 + and HR−/HER2 + subtype population. Preclinical studies corroborated that PI3K, MAPK, and NOTCH were significantly overexpressed in HR−/HER2 + breast cancer, which could be potentially correlated to therapeutic resistance and lead to the poor survival outcome [41]. Indeed, the specific influence of HR status on the overall prognosis of HER2-positive breast cancer remained controversial [42], and this kind of inconsistency may due to the relatively limited volume of sample size, insufficient follow-up, and the discordance in inclusion criteria. Under this circumstance, this large-scale, population-based study provided strong evidence for the distinctive prognosis of HR-based HER2-poaistive breast cancer population. Considering the relative worse prognosis of HR−/HER2 + patients, physicians may increase the intensity of chemotherapy and targeted therapy such as the combination of trastuzumab and pertuzumab [43], and neratinib following adjuvant trastuzumab-based therapy [44] to reduce relapse rate and enhance survival in clinical practice.
As the mainstay consideration for breast cancer subtypes, the steroid hormone receptors ER and PgR are two critical biomarkers for assessing the intrinsic heterogeneity and introducing multidisciplinary therapeutics [45]. However, to date, the understanding of the clinical significance of ER and PgR status to HER2-positive breast cancer, especially regarding the HR-specific expression patterns, has been poorly investigated. Based on this cohort with extensive enrollment, we suggested that the prognosis of double-positive subtype was the most favorable in the entire population, and ER-negative exerted the foremost impact on the overall prognosis of HER2-positive breast cancer. Consistently, Bae and colleagues [46] indicated that ER + /PgR− and ER−/PgR + breast cancer were in associations with poorer DFS and OS than ER + /PgR + tumors and findings of Rakha et al. [47] adopting 1,944 breast cancer patients suggested that the single-positive patterns, including ER + /PgR− and ER−/PgR + , breast cancer exhibited an increasingly aggressive clinicopathological features than ER + /PgR + subtypes and an opposite profile in comparisons with the ER−/PgR− subtype. In this perspective, physicians could apply individual-based treatment in accordance with the varied HR-specific patterns.
The novel findings of this study lay in that the ER−/PgR + tumor tended to present an inferior prognosis, even to that of ER−/PgR− subtype breast cancer. This finding was in consistent with the previous study that the ER loss exerted a greater effect on the prognosis that PgR loss which could result in a poor survival of breast cancer patients [48]. In the routine practice, ER−/PgR + subtype breast cancer was considered as endocrine-related and would receive endocrine therapy and chemotherapy of which the protocol was with moderate strength given the estimated favorable prognosis. However, Kunc and colleagues [36] contended that patients with ER−/PgR + breast cancer would derive less benefit from the standard endocrine therapy than ER + /PgR + disease instead of chemotherapy. In this perspective, the insufficient therapies could be attributed to the poorer survival in comparisons with the other subtypes. Accordingly, practitioners are supposed to use more caution to introduce reasonable therapeutics towards different HR-specific subtypes of HER2-positive breast cancer. In particular, ER−/PgR + /HER2 + subtype that is relatively insensitive to endocrine therapy, should be treated with higher-intensity chemotherapy and targeted therapy in the adjuvant setting.
Inevitably, our study has several limitations. For starters, potential selection bias introduced by the missing data could not be fully avoided due to the retrospective nature of our study. Also, therapeutic information regarding endocrine therapy and anti-HER2 targeted therapy is not available in this database and these factors accordingly cannot be adjusted for the analysis, thereby leading to potential confounders and deviations in the study. This kind of dilemma also occurs in the absence of a few clinical parameters, such as Ki67 index, ECOG scores, and vascular invasion and part of the prognostic information in terms of recurrence-free and disease-free survival. Furthermore, although the PSM analysis were conducted to reduce the confounding factors, any bias due to the imbalance of the two groups cannot be totally excluded. Finally, the follow-up time could be insufficient by the year in which the complete information of receptor status became available in the SEER database.