Background
Breast cancer accounts for about a quarter of all cancers and 15% of cancer-specific deaths in women globally [
1]. It is the most frequently diagnosed and second leading cause of cancer mortality for women in the United States, with about 260,000 new incidences and approximate 40,000 deaths recorded each year [
2]. About 13–41% of patients with operable stage I, II and III breast cancer experience distant and local relapses, and eventually succumb to their disease [
3,
4]. Hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) are integrated into clinical management and lately prognostic staging of breast cancer [
5‐
7]. HR (estrogen receptor α, ER
+ and/or progesterone receptor, PR
+)-positive breast cancer is consisted of 65–80% of all breast cancers, which are routinely managed by 5 years of endocrine therapy that is extended up to 10 years in recent years [
8‐
10]. Patients with high risk factors such as HER2-positivity (HER2
+), HR-negative (HR
−) status or positive lymph nodes are recommended for cytotoxic chemotherapy [
8,
11]. Radiation therapy is recommended for all patients who undergo breast cancer conserving surgery and may be used for those either with a cancer larger than 5 cm or node-positive disease after mastectomy.
The intrinsic gene expression signatures in breast cancer were discovered by DNA microarray technology that classifies breast cancer into the molecular subtypes predominantly as luminal A, luminal B, HER2-enriched and basal-like [
12]. Largely in agreement with the gene expression profiling data, breast cancer is categorized into HR
+/HER2
− (ER
+, PR
+ and HER2
− or luminal-A), HR
+/HER2
+ (ER
+, PR
+ and HER2
+ or luminal-B), HER2
+ (HER2
+, ER
− and PR
− or HER2-enriched), and triple-negative breast cancer (TNBC or ER
−, PR
− and HER2
− or basal-like) subtypes by established immunohistochemistry (IHC) classifier [
13]. The IHC-based classification with joint HR and HER2 status is the mostly implemented method for establishing breast cancer subtypes in the clinic [
14]. The molecular subtypes were found to provide prognostic information, with luminal subtypes exhibiting better clinical outcomes [
15,
16]. The St. Gallen expert consensus panel has adopted a subtype-based approach in the context of current treatment modalities of early stage breast cancer [
17]. However, some studies revealed that intrinsic subtyping was not prognostic nor predictive of response to treatments [
18]. In a large cohort study, there was no significant difference in survival according to molecular subtype 5 years after diagnosis until ~ 20 years of clinical follow-up [
19]. The gene expression signature established from most of the patients receiving radiotherapy and conventional therapy cannot predict outcomes of untreated patients [
20,
21].
Currently, it remains unclear whether the molecular subtype has prognostic significance in patients who did not undergo any type of therapy including systemic treatments and radiation therapy except surgery. Thus, there is a heightened need to evaluate outcome by subtype in women with and without multimodality therapy within a population separately. In this investigation, our study objectives are the overall survivals (OS) by treatment status among breast cancer subtypes using Kaplan–Meier and multivariable Cox regression analyses adjusting for confounding factors.
Discussion
Molecular subtypes of breast cancer are extensively investigated surrounding the biological heterogeneity of breast tumors and prognostic relevance in the context of conventional care of management [
27]. However, its prognostic value has not been assessed in patients without any type of treatments including systemic and radiation therapy as an independent group. The subtype datasets of “the no systemic therapy” used in several previous studies had included breast tumor samples from patients with radiotherapy, indicative of heterogeneous treatment status [
28‐
30]. For example, a-76 gene signature in node-negative breast cancer was derived from the samples from which 87% of patients received radiotherapy. Mounting evidence indicates that radiotherapy may have systemic effect in addition to its locoregional management [
31]. In the participants represented by the CBCTR network, about one-third of patients did not receive systemic treatments nor radiation therapy. Such dataset allows us to assess the biomarkers for bona fide prognosis. The estimate by both Kaplan–Meier and multivariable analyses adjusting for patient and clinicopathologic factors did not detect any significant survival difference among subtypes in untreated patients. van de Vijver et al. had discussed a 70-gene prognosis signature could not predict metastasis-free survival and OS of untreated node-positive patients [
20]. Of 97 sporadic breast cancer patient samples that were used to develop the 70-gene prognosis signature, 62 patients received radiation therapy, three received chemotherapy and two with hormonal therapy, which indicated a heterogeneous treatment status [
21]. Together, these data are important regarding their potential broad implication in understanding the interplay between treatment outcome and biology of breast cancer subtypes and may have implications in other cancer types [
32].
Our results show that patients with HR
+ subtypes had better outcome with conventional therapy, corroborating with large amount of data in the literature [
13,
15,
27,
33]. In the meta-analyses conducted by the Early Breast Cancer Trialists’ Collaborative Group (Oxford Overview), patients with ER
+ disease significantly benefited from adjuvant endocrine therapy with tamoxifen as well as polychemotherapy with either CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) regimen or anthracycline/taxane-based regimens [
3,
34]. In addition, by the Oxford Overview, a greater benefit from radiotherapy was observed in the ER
+ group [
35,
36]. A recent systemic review and meta-analysis in a total of 3798 patients demonstrated that the rate of local–regional control is higher in patients with luminal A subtype than in HER2+ or TNBC patients who received breast conservation therapy followed by radiotherapy [
37]. Therefore, HR
+ or HR
+/HER2
− tumors are not only sensitive to endocrine therapy but also to radiotherapy and chemotherapy. It is the established therapies lasting about 5 years that had led to the better clinical outcome in patients with HR
+ and/or HR
+/HER2
− disease. Despite these, the risk of breast cancer mortality persists throughout 24 years after primary treatment of ER
+ breast cancer by a large dataset analysis of clinical trial patients, consistent with our results [
38]. Of note, there is no data to directly compare the endocrine therapy alone and chemotherapy alone in HR+ early stage breast cancer since endocrine therapy is given upfront due to its low toxicity and effectiveness. In the context of combination of endocrine treatment and chemotherapy, little (additional) benefit was observed from endochemotherapy compared with endocrine therapy alone in women with low and intermediate Oncotype recurrence scores [
39,
40].
We found substantial drops in the survival rates at 5 years in treated relative to untreated women with TNBC and HER2
+ subtypes (Fig.
1a, b). The worse outcomes within 5 years in basal-like and HER2
+ subtypes were initially reported in a subgroup of 49 patients with locally advanced tumors and no distant metastases who were treated with neoadjuvant chemotherapy and adjuvant tamoxifen [
15]. The subtype phenotype was subsequently confirmed, with variation in significance, by many other studies either with endocrine therapy, chemotherapy or radiotherapy alone, and/or by endochemotherapy, chemoradiotherapy or endo-chemoradiotherapy [
27,
28,
38,
41,
42]. A historic cohort study also showed the outcome difference that was mostly observed within the first 5 years of follow-up among breast cancer subtypes [
19]. Further, HER2
+ and TNBC subtypes were less effectively responded to radiation therapy relative to the luminal subtypes by a recent systemic review and meta-analysis in four clinical breast cancer subtypes, and this phenomenon was observed in other studies as well [
37,
43]. Moreover, despite initial sensitivity to neoadjuvant chemotherapy, patients with basal-like and HER2
+ tumors paradoxically had early relapse, and worse overall and distant disease-free survivals [
44]. Altogether, these data may have prompted a need for re-examination of treatment approaches for certain breast cancer subtypes such as TNBC. On the other hand, HER2-targeted therapy likely has shifted the outcome of patients with HER2
+ subtype, which the population-based estimate is ongoing [
45].
It has been shown that triple-negative and HER2
+ primary breast tumors exhibited higher frequency of expression of γH2AX, a component in the ATM/H2AX DNA damage response complex that facilitates the DNA damage repair [
23]. The data that constitutive expression of γH2AX at diagnosis was associated with worse survival in patients who received chemotherapy provided a molecular mechanism of action of resistance [
46]. In addition, a large decrease versus minor reduction of γH2AX was associated with better response to neoadjuvant chemotherapy in TNBC [
44].
It is worth to note that the size of this investigation population was relatively small, compared to those of a similar type. Despite the limitation, our research represents a first step, with significance, to address the question of the molecular subtypes of breast cancer for prognosis in patients with and without conventional treatments as distinct entities. Validation of the association between the breast cancer subtypes and treatment outcomes is warranted in other retrospective studies and clinical trials.
Acknowledgements
Supported in part by the Division of Cancer Treatment and Diagnosis of the National Cancer Institute, National Institutes of Health. We would like to thank patients who participated the program, gave their consent and donated their breast cancer specimens to research. We are grateful to the physicians, nurses, pathologists, statisticians and research staff who designed, established, and maintained the database at each participating sites, CBCTR and the Cancer Diagnosis Program at the National Cancer Institute.
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