Introduction

Breast cancer is one of the most common cancers and a leading cause of death among women worldwide. Numerous studies have demonstrated that breast cancer in young women (BCY) has unfavorable prognostic features. These cancers are more likely to be high nuclear grade (NG), estrogen receptor (ER) negative, progesterone receptor (PR) negative, and human epidermal growth factor-2 (HER-2) positive, have a high proliferation fraction, present with lymphovascular invasion (LVI), and be diagnosed at more advanced stage [1,2,3,4]. Furthermore, some studies demonstrate that young age is an independent unfavorable prognostic factor [5, 6].

The molecular subtype of breast cancer is associated with prognosis and response to treatment such as chemotherapy and endocrine therapy [7]. BCY tends to have a higher proportion of intrinsic breast cancer subtypes associated with a poorer prognosis such as triple-negative, HER-2, and luminal B subtypes [3, 8, 9]. Few studies have evaluated the effect of subtype disparities on breast cancer prognosis by age, especially BCY [10,11,12].

In the United States, approximately 230,000 women are diagnosed with breast cancer annually; among them, 4.7–4.9%, or approximately 11,000 patients, are diagnosed when they are younger than 40 years [13, 14]. According to the 2014 annual report of the Korean Breast Cancer Society Registry (KBCSR), of 21,484 patients diagnosed with new breast cancer, more than 10.5% were younger than 40 years [15]. We analyzed breast cancer mortality stratified by tumor subtype according to age among patients younger than 50 years using the KBCSR database, which has a higher proportion of BCY than Western populations.

Materials and methods

We identified 37,865 patients who were diagnosed at 20–49 years of age. We excluded male patients and patients who underwent neoadjuvant chemotherapy, had distant metastasis or inflammatory breast cancer at presentation, or had histopathology other than invasive ductal or invasive lobular carcinoma. We also excluded patients who lacked immunohistochemistry data (ER, PR, HER-2) or had short follow-up duration (<12 months).

Data collection

Data from an online breast cancer registration program collected by the KBCSR on patients diagnosed with invasive breast cancer between January 2003 and December 2010 were retrospectively reviewed. The database collected information on more than 50 demographic and clinicopathological characteristics including sex, age at diagnosis, method of surgical treatment, stage according to American Joint Committee on Cancer (AJCC) classification [16], histopathological characteristics, adjuvant therapy (chemotherapy, radiotherapy, and endocrine therapy), and date of death from the Ministry of Health and Welfare, Republic of Korea. The KBCSR has been described in detail previously [17]. We collected data on age at diagnosis, family history of breast cancer, type of operation, pathologic stage, NG, LVI, ER/PR/HER-2 status, and type of adjuvant treatment. Patient tumors were classified into four subtypes: luminal A (positive for ER and/or PR and negative for HER-2); luminal B (positive for ER and/or PR and HER-2); HER-2-enriched (negative for ER/PR and positive for HER-2); and triple-negative breast cancer (TNBC) (negative for ER/PR and HER-2). ER, PR, and HER-2 status in surgical specimens were assessed at each center using routine immunohistochemistry protocols.

Statistical analysis

Patient characteristics were compared using independent t tests for continuous variables and the Chi-square or Fisher’s exact test for categorical variables. Values are reported as mean ± standard deviation (SD) or median with ranges. Kaplan–Meier curves with the corresponding results of log-rank tests were constructed for overall survival (OS). Univariate and multivariate analyses for OS were conducted with a Cox proportional hazards model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Patients with any missing or unknown data were excluded from analysis by Cox models. OS was defined as the time between date of surgery and date of death from any cause. All tests were two sided, and p < 0.05 was considered significant. All statistical analyses used SAS version 9.4 (SAS Institute, Cary, NC, USA) and R3.2.1 (Vienna, Austria; http://www.R-project.org). This study adhered to the ethical tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Samsung Medical Center in Seoul, Korea (IRB number: 2017-04-021). The need for informed consent was waived because of the low risk posed by this investigation.

Results

Patient selection

A schematic diagram of patient selection is shown in Fig. 1. We identified 37,865 patients between 20 and 49 years of age with invasive breast cancer registered in the KBCSR database. Of these patients, we included only those eligible based on the following inclusion criteria: stage I–III breast cancer, no neoadjuvant chemotherapy, invasive ductal or invasive lobular carcinoma, follow-up longer than 12 months, and existing ER/PR/HER-2 data.

Fig. 1
figure 1

Schematic diagram for patient selection

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Baseline characteristics by age group

Among 30,793 patients eligible for analysis, 793 (2.6%) were aged 20–29 years, 8133 (26.4%) were 30–39, and 21,867 (71.0%) were 40–49. Among all eligible patients, 2471 (8.0%) died after undergoing an operation for breast cancer. Clinicopathological characteristics and adjuvant treatments according to age group are summarized in Table 1. Median follow-up duration was 84.8 (12.0–132.1) months. Mean age was 42.1 (±5.4) years. Patients in the 20s group were more likely to have cancers with advanced stage, higher NG, presence of LVI, and TNBC subtype than those in the 30s and 40s age groups (p < 0.0001 for all). In addition, patients in the 20s group were more likely to undergo chemotherapy than those in the 30s and 40s age groups (p < 0.0001).

Table 1 Baseline characteristics
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Association between age group/tumor subtype and overall survival

Patients in the 20s age group had worse OS than patients in the 30s and 40s age groups (p < 0.001; Fig. 2). Patients in the younger group had increased HR in univariate and multivariate analyses for OS (Table 2). In these analyses, patients with TNBC showed higher HR for OS than patients with HER-2, luminal B, or luminal A subtype: TNBC, 2.514 (2.075–3.045); HER-2 subtype, 2.262 (1.829–2.797), luminal B subtype, 1.437 (1.220, 1.692), and luminal A subtype (reference) (all p < 0.001) (Table 2).

Fig. 2
figure 2

Kaplan–Meier curve of overall survival according to age group

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Table 2 Univariate and multivariate analyses for overall survival
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Relationship of age group and overall survival stratified by tumor subtype

Patients with cancer of luminal A or B subtype showed significantly worse prognosis for the 20s age group than the 30s and 40s age groups (both p < 0.0001; Fig. 3). However, the prognosis of cancer of HER-2 subtype was not significantly different by age group (p = 0.440; Fig. 3), and the TNBC subtype also showed no significant difference between women in the age groups of 20s versus 30s, and 20s versus 40s (p = 0.445 and p = 0.592; Fig. 3). When stratified by tumor subtype, luminal A and B subtypes showed higher HRs in the 20s age group than in the 30s and 40s age groups, whereas HER-2 and TNBC subtypes were not significantly different among the age groups after additional adjustment for pathological stage, NG, LVI, tumor subtype, adjuvant chemotherapy, adjuvant radiotherapy, and adjuvant hormonal therapy (Table 3).

Fig. 3
figure 3

Kaplan–Meier curve of overall survival according to age group stratified by tumor subtype

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Table 3 Age and overall survival according to breast cancer subtype
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Discussion

We analyzed the relationship between mortality of breast cancer patients who were younger than 50 years and tumor subtype and age. We showed that patients diagnosed in their 20s tended to have unfavorable prognostic factors and worse prognosis than those in their 30s and 40s. However, when cancers were stratified by tumor subtype, no significant difference was observed for HER-2 and TNBC subtypes according to age group. Luminal subtypes showed worse prognosis in the 20s age group than in the 30s and 40s age groups.

Previous articles demonstrated that BCY is an independent risk factor for recurrence and mortality [5, 18, 19]. However, these studies did not consider the prognostic impact of age stratified by breast cancer subtype. A retrospective analysis of a randomized controlled trial of patients with early-stage HER-2-positive breast cancer who underwent chemotherapy followed by trastuzumab or no trastuzumab suggested that BCY is neither prognostic nor predictive of short-term oncological outcome [20]. For the TNBC subtype, Sheridan et al. [21] reported no differences according to age. Our study results were consistent with previous studies in which patients with HER-2 and TNBC subtype cancer showed no significant difference in mortality.

For luminal subtype, many studies report that BCY has a worse prognosis than breast cancer in older patients [21,22,23,24]. Partridge et al. [22] reported that age less than 40 years was associated with significant increases in risk of breast cancer-specific death from luminal A (HR 2.1, 95% CI 1.4–3.2) or luminal B (HR 1.4, 95% CI 1.1–1.9) subtype compared with older age groups. Of 17,575 patients with stage I–III breast cancer, 1916 were younger than 40 years and 1298 of them had luminal subtype cancer. BCY in western countries is relatively rare, and breast cancer in patients younger than 30 years is extremely rare, with an incidence lower than 1%. Furthermore, the proportion of luminal subtypes among BCY patients is lower than that of older patients with breast cancer. As precise analysis of this group is difficult, few studies show relationships between age and subtype for BCY. To the best of our knowledge, our study is the first to describe the characteristics of a large number of women in their 20s with breast cancer and the largest study on the relationships among breast cancer mortality, subtype, and age in BCY. More than 30,000 patients were included in our analysis, with approximately 9000 being younger than 40 years. We subgrouped the patients into 20s and 30s. Luminal A and B subtypes had higher risks of mortality in patients diagnosed at an earlier age (Fig. 3).

There are few potential hypotheses for why younger patients have worse prognosis than older patients with luminal breast cancer. In younger patients, the incidence of chemotherapy-induced amenorrhea is reduced, resulting in worse prognosis for hormone receptor-positive breast cancer [25,26,27]. Regan et al. [28] reported that weakly ER-positive and/or PR-positive tumors were less responsive to adjuvant endocrine therapy in the SOFT and TEXT randomized phase III trials. Viale et al. [29] also suggested that weakly ER-positive tumors are less responsive to adjuvant endocrine therapy in analyses using the Breast International Group 1-98 trial database. Sheffield et al. [30] reported that 90% of patients with weak ER positivity by immunohistochemistry (IHC) were classified as basal-like or HER-2-enriched subtypes by gene expression profiling using RT-qPCR. BCY was more likely to have weaker mRNA expression for ERα (p < 0.0001), ERβ (p = 0.02), and PR (p < 0.0001), but often had higher expression of HER-2 (p < 0.0001) and epidermal growth factor receptor (p < 0.0001), resulting in a lower response to adjuvant endocrine therapy [31]. Even though BRCA 1/2 mutations and other genetically related tumors are not clearly associated with breast cancer prognosis, BCY is more likely to have genetic mutations such as BRCA 1/2 than other genetic-related tumors [7, 32]. Finally, studies show that BCY is a risk factor for nonadherence and discontinuance of adjuvant endocrine therapy, resulting in worse oncological outcomes [33,34,35]. However, the issues of nonadherence and nonpersistence have many compound factors including age, increased out-of-pocket costs, social support, and treatment side effects [34].

A major strength of our study is the large number of BCY patients, at approximately 9000. This number allowed evaluation of the association of age and subtype for women in their 20s with breast cancer. We are about to use the eighth AJCC staging based on TNM anatomical factors and biological factors such as tumor grade, proliferation rate, and ER, PR, and HER-2 status in the staging system [36]. ER- and PR-positive breast cancer will be down-staged in the 8th AJCC staging. However, young patients with luminal subtype had worse prognosis so it should not be underestimated. Another change in the 8th AJCC staging system is that gene expression prognostic panels are incorporated into the staging system. Among the patients with luminal A subtype, node-negative cancers with tumor size less than or equal to 5 cm combined with low risk of multigene panels are expected to be categorized as stage I. However, gene expression prognostic panels are usually developed for postmenopausal patients and their applications in BCY patients are uncertain, especially for breast cancer patients in their 20s [37,38,39,40]. In the future, studies on gene expression prognostic panels validated for BCY are needed.

Our study had a few limitations. First, our study had a retrospective design based on analysis of the KBCSR database. We lacked information on detailed patient oncological outcome such as locoregional recurrence, distant metastasis, and contralateral recurrence. We also lacked information on proliferation markers such as Ki-67 and on administration of adjuvant treatment such as trastuzumab and goserelin. In addition, the database lacked information about adherence to adjuvant endocrine therapy, adjuvant chemotherapy, or goserelin. Adherence to adjuvant endocrine therapy is important for breast cancer of luminal subtype and could affect mortality from breast cancer. Second, the median follow-up of 84 months was relatively short, especially for luminal subtype cancer. Finally, we used IHC markers (ER, PR, and HER-2) as surrogates for gene expression. Although IHC profiles have been successfully used as surrogates, they can lead to misclassification. Despite these limitations, our study used a nationwide database linked to survival data officially confirmed by the KBCSR. All patients analyzed in the study were ethnically homogeneous (all patients were Korean), and the database had detailed clinicopathological characteristics including HER-2 status and treatment information. Our findings were consistent with results from the National Comprehensive Cancer Network Breast Cancer Outcomes Database Project [22].

In conclusion, breast cancer patients in their 20s had unfavorable characteristics and worse prognosis than patients in their 30s and 40s. When stratified by tumor subtype, women in their 20s with breast cancer of luminal subtype showed worse prognosis, while cancer of HER-2 and TNBC subtypes was not significantly different according to age.