Breast cancer (BC) is the most frequent malignancy among women worldwide, with an estimated 14 million new cases and 8 million mortalities in 2012, which is projected to rise by at least 70% by 2030 (1). It is most common in women aged >50 years (>75% of all cases), in contrast to those aged ≤40 years, who represent only 5–25% of all BC cases. Notably, BC in these younger women is generally considered to bear a more unfavorable disease outcome, with a substantially shorter overall survival as compared with older women (2,3).

Indeed, several multivariate analyses have shown that young age is an independent predictor of unfavorable disease outcome (4), and it has been suggested to be associated with a more aggressive tumor biology that potentially reduces the survival expectancy (5,6). This increased aggressiveness of BC among younger women has been attributed to mutations in the BC susceptibility proteins, breast cancer (BRCA)1 and 2 (5,6). In addition, BC in younger women is often diagnosed at more advanced stages than in older women. In addition, BC tumors in younger women are: i) More frequently negative for estrogen receptor (ER); ii) show extensive lymphovascular invasion (LVI); iii) exhibit increased cell proliferation (assessed by the Ki-67 marker); and v) demonstrate overexpression of p53 oncogene (6).

Molecular profiling has suggested that race and ethnicity may be other important factors associated with the development of BC, particularly with its poor prognosis among younger women, with those of African American origin being at the highest risk of increased mortality (7). All of the aforementioned evidence indicates that BC in younger women bears a worse disease outcome compared with older women. This difference is only partially explained by the fact that mammography screening and clinical breast examinations are targeted to women aged >40 years (8).

In Brazil, the incidence and mortality rates of BC are relatively high (9,10). Compared with North America, where the incidence of BC among younger women has plateaued (11), Brazil continues to present with relatively high incidence rates among women aged 30–39 years (12). Considering the increased BC mortality among young women of African origin (7), it is of note that Brazil is a country with a relatively high population of African descent, increasing the importance of assessing the characteristics of BC among young women in this country.

To the best of our knowledge, the present study analyzed the largest cohort of patients with BC aged ≤40 years (n=376) at a single institution to date, by comparing an extensive set of clinicopathological characteristics and other variables with a similarly sized cohort of BC patients aged 50–69 years (n=362). The aim of the present study was to determine whether disease outcome in younger women is poorer than that in the older women and, if supported, to estimate the significant determinants of this differential outcome in multivariate models.

The demographic characteristics of the patients in the two series are presented in Table I. The main clinical features are shown in Table II. The histopathological features and treatment characteristics are shown in Tables III and IV, respectively.

The two groups displayed significant differences in various characteristics. The older group showed a higher proportion of women with low educational level (up to 8 years of school) as compared with the younger group (77.1 vs. 55.9%, respectively; P<0.001) (Table I).

Table II shows that the groups had no differences in the presence of nodules or multicentric cancer at the first examination. The younger group had a higher proportion of multi-focal cancer and bilateral cancer as compared with the older group (6.1 vs. 2.5%, P=0.017 and 9.8 vs. 5.8%, P=0.037, respectively). Comorbidity was less frequent in the younger group than in the older group; one or two comorbidities were found in 30.3 vs. 48.3% of patients (P<0.001), respectively (Table II).

As indicated in Table III, no significant differences were identified between the groups in terms of histological types of the cancer or disease staging. The tumors in the younger group showed a greater frequency of a low degree of differentiation (23.1 vs. 16.6%; P=0.035), reduced blood vessel invasion (1.1 vs. 1.9%; P=0.003), reduced LVI (21.3 vs. 22.4%; P<0.001) and reduced perineural invasion (4.8 vs. 3.6%; P=0.055) as compared with the lesions in the older group (Table III).

The proportion of tumors that were positive for ER expression was significantly lower in the younger group than in the older group (33.5 vs. 42.8%; P=0.014). The two groups had similar negative rates of PR and C-erB-2 expression (Table III). Tumors classified as triple negative were more frequent among the younger women (10.1 vs. 6.4%; P=0.027) (Table III).

The two groups were similar in terms of the number of dissected lymph nodes. Although the younger group underwent radical mastectomy less frequently than the older group, the difference was not statistically significant (59.6 vs. 64.6%, respectively; P=0.078) (Table III). There was a higher proportion of breast reconstruction in the younger group as compared with the older group (20.7 vs. 3.9%; P<0.001) (Table IV). Furthermore, the groups had undergone similar neo-adjuvant treatments Table IV); adjuvant hormone therapy was used less frequently in the younger than in the older group, but this difference was only of borderline significance (27.7 vs. 36.2%; P=0.056) (Table IV).

The duration of follow-up ranged between 0 and 22.6 years, with a mean of 6.1 years and 8.5 months when mortality was excluded. The follow-up data were similar in the two groups (P=0.816). After 5 and 10 years, 4.9 and 10.5% of the patients, respectively, were lost to follow-up (data not shown). The OS rates were not significantly different between the groups (P=0.421) (Fig. 1).

Univariate analysis showed that the following characteristics were significantly associated with prognosis in the younger group: Second cancer (P=0.004), bilateral BC (P=0.100), familial history (P=0.086), menopause at diagnosis (P=0.026), associated diseases (P=0.077), tumor size (mastectomy) (P=0.075), T, N and M stage (P<0.001), degree of differentiation (P=0.127), perineural invasion (P=0.056), LVI (P=0.004), lymph node invasion (P<0.001), ER status (P=0.002), PR status (P=0.043), type of breast surgery (P<0.001), axillary surgery (P<0.001), number of lymph nodes dissected (P<0.001), breast reconstruction (P<0.001), neoadjuvant chemotherapy (P<0.028), chemotherapy (P<0.001) and hormone therapy (P<0.001) (Tables V–VIII).

In the older group, the following variables were significantly associated with prognosis: Period of treatment (P=0.002), ethnicity (P=0.129), marital status (P=0.170), palpable nodules (P=0.062), tumor size (mastectomy) (P=0.042), T, N and M stage (P<0.001), degree of differentiation (P<0.001), peri-neural invasion (P=0.095), blood vessel invasion(P<0.001), LVI (P=0.003), lymph node invasion (P<0.001), ER status (P=0.001), PR status (P=0.015), C-erB-2 expression (P=0.006), type of breast surgery (P<0.001), axillary surgery (P<0.001), number of lymph nodes dissected (P=0.005), neo-adjuvant chemotherapy (P=0.010), chemotherapy (P<0.001), hormone therapy (P<0.001), and radiotherapy (P=0.016). None of the other variables were statistically significant predictors of survival (Tables V–VIII).

When stratified by clinical stage, no significant differences in the stage-specific survival rates between the two age groups were found (P=0.421) (Fig. 1). However, when the groups were stratified by the period of treatment, significant differences in survival rates were observed between the two groups during the treatment period between 1997 and 2002 (young vs. old group, 40.7 vs. 60.0% survival, P=0.028) (Fig. 2).

In the multivariate analysis, second cancer [hazard ratio (HR), 2.20; 95% confidence interval (CI), 1.500–29.044; P=0.013] and bilateral BC (HR, 6.60; 95% CI, 1.228–3.930; P=0.008) were independent predictors of a poor outcome, with an increased risk of mortality in the younger group. C-erB-2 (HR, 1.97; 95%; CI, 1.003–3.869; P=0.049) was a positive predictor of a poor outcome in the older group, showing an increased risk of mortality. The ER status and TNM stage were significantly associated with disease prognosis in both groups (Tables IX and X).

The results described herein reveal important differences between the younger and older patients with BC. This is an almost unanimously accepted fact among BC investigators. Notably, however, the present study was unable to confirm the most controversial of these issues, the suggested worse survival rate of young patients with BC, and failed to identify any difference in disease outcome between the two study groups. This finding is of major importance, asthe OS (Kaplan-Meier) did not reveal significant differences between the two groups, despite several parameters indicating that a more aggressive tumor biology is confined to the younger patients. Only when calculated for the treatment period 1997–2002 were the OS rates significantly worse among young women. We propose that there are several explanations for this finding, with insights discussed herein.

Whether there are clinicopathological differences in BC between younger and older women remains a controversial issue. Typically, the young BC age group ranges from 35 (13,18,19) to 40 (2,14,20,21), however, there is no clear consensus supporting these strict age limits for young and old. However, BC is more frequent in women aged >50 years old. In a population-derived cohort from Brazil, the prevalence of BC was found to be 14% (12), 4.5% of these patients were aged ≤35 years (3) and 26.4% were aged ≤40 years (2).

Thus, in the present study, a 40-year cut-off was used to stratify the women as younger or older. This criterion was partially supported by epidemiological data demonstrating different tumor biology in different age groups (14,22). It is also important to emphasize that in Europe, regular mammography screening is a standard practice for women aged 50–69 years. This group is considered to be a biologically distinct group at high risk of developing BC with particular radiological characteristics (23). For this reason, women aged 50–69 years old were selected for comparison in the present study. As BC studies have different definitions regarding age groups, it is challenging to provide a reasonable comparison between different studies.

A number of reports also disagree regarding the importance of including different types of BC, for example, carcinoma in situ (CIS) (13,21) or metastatic disease (2,24). Other studies disagree regarding the pertinence of including patients with clinical stage I and II (25,26) or clinical stages I–III (2,20,24) cancer. The present study included TNM stage, and excluded cases of CIS due to their different histological features (27) and relatively favorable disease outcome.

The present study is based on robust parameters that were selected to reflect the true significance of the behavior of BC in young women. To the best of our knowledge, the current study includes the largest cohort of patients with BC aged ≤40 years (n=376) reported from a single institution to date. Worldwide, few institutions have studied larger samples (24,28) and the majority of large studies have been based on cancer registries (7,14,21).

The present study included a large number of patients with invasive BC presenting at advanced clinical stages. These features are not unusual and are inherent to the existing healthcare system in Brazil. Brazilian women have limited access to clinics that provide mammography examinations and organized population-based screening programs do not exist; consequently, the majority of the BC cases in Brazil are detected at advanced stages. This is in contrast to the situation in developed countries, where regular mammography screening enables the detection of the majority of cases of BC at an early stage (14,19,21). Indeed, prior to 2002, there was no formal recommendation from the Brazilian Health Authorities to provide mammography examinations in asymptomatic women. Therefore, as the presence of palpable and/or ulcerated lesions were a requirement for medical care, a substantial proportion of women exhibited these signs at their first examination. These characteristics are an inherent bias of the present study design resulting in a cohort enriched by BC patients with aggressive tumors at baseline. However, the overall relative survival rate of the older women (50–69 years old) improved between 1997 and 2002, attributable to improvements in treatment, such as chemotherapy and hormone therapy (29).

Mammography is undoubtedly an important diagnostic tool for non-palpable lesions, despite sensitivity limitations among women aged ≤40 years. It is speculated that regular programs for BC prevention could minimize the number of cases of advanced stage disease in Brazil (30). Hereditary BC associated with BRCA1/2 mutations have a prevalence of ~2.3% (31) in Brazil. Furthermore, studies of Latin American women have demonstrated that a family history of BC is less prevalent in Latin America than in the North American population (32). In the present study, mutations were not investigated, however, the familial history of BC was similar between the two study groups. However, the presence of second cancer was similar in the younger and older groups; this is consistent with the results of a previous study, where it was attributed to longer exposures to pathogenic factors (33).

The prevalence of bilateral disease was higher in the younger age group and is one of the indicators of more aggressive tumors, for example tumors with T stage II/III, grade III differentiation, negative ER/PR status and positive lymph node invasion are more aggressive (33). Conversely, the older women more frequently presented with other diseases associated with their BC, which can have an adverse influence on clinical outcome and contribute to a poor prognosis (34). However, the present results identified indicators of worse prognosis to be more common among the younger women.

Accordingly, younger women presented with a higher proportion of tumors with grade III differentiation (poorly differentiated), as reported in a previous study (33). Similarly, the present study observed significant differences between the two groups in terms of perivascular blood vessel invasion and LVI, with older women showing higher proportions of both types of invasion. Notably, this result conflicts with the previously reported data (35,36).

The present study also observed that a higher proportion of older women were positive for ER compared with younger women. This finding is consistent with the results of a previous study, in which advanced age was correlated with positive ER status and vice versa (36). This observation also agrees with the disease outcome data of the current cohort, as a negative ER status is typically associated with a more unfavorable prognosis. By contrast, PR expression did not significantly differ between the two age groups, in agreement with a previous report (26). Conversely, a previous study observed that a negative PR status occurs more frequently in the BC of younger women (35). However, the prognostic value of PR was visible only as a part of an algorithm, but not on its own (37). The present findings also revealed that triple negative BC, which are considered to predict a poor prognosis, were more common in younger women, as previously reported (13).

As anticipated, more important differences in factors that usually influence the efficacy of treatment were observed between the two groups, including tumor stage at the time of diagnosis, tumor characteristics and comorbidities. Of note, the present study included patients with follow-up times of up to 22 years (mean, 6.75 years). This is another important feature of the present study, as only a small number of studies have reported long-term follow-up data of 10 (20,25,36,38) or 15 years (2,14,24,28). In addition, BC treatment strategies have undergone rapid developments in the past two decades, and this development may have contributed to the prognostic differences between the two groups included in the current study. In the younger group, fewer patients received adjuvant hormone therapy and more women received palliative chemotherapy when compared with the older group. This is a clear limitation inherent to all retrospective studies where active intervention is no longer possible. However, the current observations clearly support proposals to also initiate monitoring programs for long-term BC patients.

Finally, the present results did not show significant differences in survival rates between the two study groups (Fig. 1). By contrast, a previous study conducted in central Brazil demonstrated a significant difference in survival rates between patients aged ≤40 years and those aged 40–50 years (P=0.0002) or those aged >50 years (P=0.03). However, this study excluded clinical stage IV disease and included far fewer patients than the present study (20). A previous study reported that BC mortality remains high among young patients, with an OS of ~60% over 5 years, compared with 85% among women aged >50 years (20). The equal survival rates between young and old women observed in the present study have been reported in previous studies (38,39), however, in general, the results have been highly variable among the published literature (40–43).

In conclusion, BC among young women is generally considered to be more aggressive and associated with a worse prognosis compared with BC in older women, whereas the prognostic value of age itself remains more controversial. The results of the present study suggest that BC in young women is associated with numerous pathological features of aggressiveness, including tumor grade, hormone receptor status and degree of differentiation, having been implicated as independent determinants of BC prognosis. However, the OS rates of the two age groups proved to be very similar, except when the data were stratified by the treatment period. For women treated during 1997–2002, the 10-year survival rate of the older women was ~60% compared with 40.7% in the younger cohort. The current study concludes that this increase in 10-year survival is due largely to improvements in treatment, increased early diagnosis and certain tumor characteristics, with the patient's age itself not being an independent prognostic factor. The present study indicates that medical advances associated with prevention of breast cancer may improve screening programs, which may therefore increase early diagnosis and subsequently lower mortality rates.