The current study, like other previously published studies (2
), showed a significantly higher breast cancer-specific mortality rate overall among women <40 years of age compared with women ≥40 years of age. In fact, 90% of women <40 years old who died during the study period, died due to their breast cancer, compared with only 49% of women ≥40 years old who died during the study period. By doing an age-group comparison for each stage at diagnosis, we found that the higher breast cancer mortality in younger women was attributed predominantly to poorer outcomes with early stage disease. Specifically, women <40 years of age were significantly more likely to die from breast cancer compared with women ≥40 years of age if diagnosed with Stage I or Stage II disease.
The younger women in our study were more likely to be diagnosed at more advanced stages of disease (II and III) compared with older women. For example, 45.1% of women <40 years old were diagnosed with Stage II disease while only 30.9% of women ≥40 years old were diagnosed with Stage II disease (see ). Given the lack of routine screening mammography guidelines for women <40 years of age, it is not surprising that women in this younger age group are more likely to present with a palpable mass and that their tumors tend to be larger and have more nodal involvement than breast cancers detected by screening (9
). Even if younger women undergo mammography screening, the imaging is less sensitive than breast imaging in postmenopausal women because the dense breast tissue in young women can obscure radiological features of early breast cancer (17
). Finally, there may be a greater likelihood for both patient and physician to contribute palpable masses to fibrocystic changes or other benign breast diseases in younger women. However, the increased breast cancer-specific mortality in younger women was not solely a result of advanced stage of disease at diagnosis, as evidenced by the significantly poorer outcomes in women <40 years of age with early stages of disease. In addition, greater breast cancer mortality in younger women also has been observed after controlling for tumor stage (3
The younger women in our study had tumors that were distinctly different from older women and were characterized by unfavorable biological parameters. This finding likely accounts for the significant within-stage disparity that we observed between the younger and older women. Younger women had tumors that were more likely to be higher grade, ER negative, and PR negative. All of these characteristics are associated with a more aggressive tumors and poorer prognosis. That there may be distinctly different breast cancer subtypes, with varying prognostic implications, has been reported previously (12
). Gene expression analysis has identified several breast cancer subtypes including basal-like, human epidermal growth factor receptor-2 positive/estrogen receptor negative (HER-2+/ER-), luminal A, and luminal B (18
). These subtypes of breast carcinoma differ in various ways, including the surface markers expressed, proliferative capacity, and ability to respond to certain therapies. The basal-like subtype has been associated with poor clinical outcome, possibly attributed to its high proliferative capacity, lack of estrogen receptors, and overexpression of HER-2, while luminal A subtype has been shown to have the best prognosis (19
). Recently, Anders et al (14
) performed a large-scale genomic analysis on breast cancers in young women and found 367 gene sets differentially expressed in young women’s tumors, whereas tumors arising in older patients did not share any common gene sets. His analysis also found that tumors in young women have lower ER positivity, higher HER-2/EGFR expression, and a trend toward inferior disease-free survival. All of these studies support the concept that tumors developing in younger women are biologically different from tumors in older women and tend to be more aggressive with unfavorable biological markers, which portend a poor prognosis.
While younger women were more likely to be diagnosed with late stage disease, our study is unique in that it demonstrated that significant survival disparities occur in younger women with Stage I and II disease compared with older women. Thus, the most significant within-stage disparities are not found in patients with late stage breast cancer. There are some possible explanations for this observation. The biological variability described previously is likely to be the main contributing factor responsible for the mortality disparities we observed, whereby younger women have tumors that have unfavorable features. Such biological variability would have the greatest impact in early stage, lymph node-negative disease. It is also possible that younger women with late stage disease (Stages III and IV) may be undergoing more aggressive treatment than older women diagnosed at these stages because of their younger age and presumed lack of comorbidities. Receipt of more aggressive treatment among younger breast cancer patients diagnosed with late stage disease might be the reason for the lack of a significant difference by age group in breast cancer-specific mortality in women with Stage III disease and a lower likelihood of death due to breast cancer in women with Stage IV disease. Because the SEER dataset does not include systemic therapy approaches or co-morbidity information, we cannot verify this hypothesis. Finally, when locally advanced disease is present, as with Stage III disease, the aggressiveness of the disease (and the presence of lymph node involvement) may be outweighed by any influence of younger age.
There are several limitations to our study, which are inherent to any retrospective cohort study. One limitation is the inability to control for selection bias. Younger women in our study were more likely than older women to have had mastectomies. Why this treatment was performed instead of breast-conserving surgery is unclear. Perhaps more mastectomies were performed on younger women due to the more advanced nature of their breast cancer, more nodal involvement, or even larger tumor size. Also, younger women may have had fewer comorbidities compared with older women and therefore were treated more aggressively, surgically or otherwise. Unfortunately, the public use SEER database does not contain information about comorbidities or other cancer treatments, such as chemotherapy and endocrine therapy. Types of systemic regimen, completion of the expected number of cycles, and delay in receiving the expected number of cycles could potentially account for the observed age disparities in survival. However, we are unable to determine whether younger patients were treated more aggressively than older women in this cohort. Socioeconomic status and access to health care, both of which could affect treatment options, are not available in the SEER data. Other data that might be associated with survival but are unavailable in the SEER data include genetic risk factors, such as BRCA 1 or BRCA 2 mutations and family history of breast cancer, as well as behavioral risk factors (e.g., physical activity, smoking, alcohol consumption, and use of hormone replacement therapy).
Despite the lack of some potentially relevant information, the SEER database provides high quality population-based data (20
), which makes for an effective large-scale cohort study. Our multivariate analyses, which controlled for potential confounders associated with survival, demonstrated significantly poorer survival in early stage disease (I and II) for women <40 years of age compared with women ≥40 years of age. Thus, advanced stage at diagnosis cannot solely explain the higher breast cancer mortality in younger women. However, the aggressive and unfavorable biological characteristics of the tumor subtypes seen in both histological and gene expression analysis suggests that younger women tend to have tumors with poor prognostic features. Therefore, further studies should focus on the specific tumor biology contributing to the increased mortality of young women with early stage breast cancer in order to determine more efficacious treatment strategies in this younger population.