Breast Cancer in Young Women: A New Color or a Different Shade of Pink?

It has long been observed that young women with breast cancer are more likely to suffer from recurrence and death than older women after diagnosis. In this issue, Anders et al explore the potential biologic basis for differences in outcomes and argue that breast cancer in younger women is a unique biologic entity. Their study confirms prior work demonstrating that breast cancers in young women are characterized by lower levels of estrogen receptor (ER) expression and higher grade. In addition, through analysis of both immunohistochemistry (IHC) and mean mRNA levels, they found that breast cancers in younger women, defined in this study as age 45 years, have higher levels of human epidermal growth factor receptor 2 (HER-2) expression compared with women age 65 years, a correlation not found consistently in prior population-based studies. Although this work confirms that the distribution of breast cancer characteristics varies based on age at presentation, to this point, there would be little basis to claim that breast cancer in younger women is a separate disease. However, in addition to exploring differences among these wellcharacterized features of breast cancer, these investigators also explored differences in gene expression for thousands of genes that might distinguish one tumor from another in this combined data set. Using single-gene analysis and focusing on the 50 genes with greatest differences among tumor samples, they were unable to identify additional features that consistently distinguished tumors from younger versus older women. However, Anders et al also used gene set enrichment analysis, which is a technique specifically designed to evaluate groups of genes with common function or from common pathways to identify similarities that may not emerge with single-gene analysis. Using this forest versus trees approach, Anders et al found overexpression of multiple gene sets involved in immune function, cell signaling, survival, and several other pathways of interest that could reliably differentiate tumors in younger women at the molecular level from tumors of older women. On the basis of these admittedly exploratory findings, the authors contend that breast cancer in young women has unique biologic features and, by extension, deserves consideration as a distinct form of breast cancer. This research joins a rapidly expanding body of literature revealing the heterogeneity of breast cancer at the molecular level. Although there are many possible explanations for differences in outcomes among patients, it is clear that underlying differences in tumor biology play a large role. The question then becomes how we can best use this information to characterize the disease in individual patients to inform prognosis and choice of therapy, as well as to focus future research. This also raises more general questions confronting breast cancer clinicians and researchers regarding how many discrete forms of breast cancer exist and consideration of the value and potential costs in distinguishing them. It is important to note that initial progress in development of medical therapy arose from the recognition of discrete diseases that were fundamentally similar from patient to patient, allowing meaningful comparisons of outcomes and, later, development of clinical trials. The conceptual shift in viewing disease as a specific entity comparable across patients, rather than a personal state of underlying imbalance in humors or other elements varying from patient to patient, coupled with the rise of hospitals where similar patients were clustered and development of biostatistics, which provided the tools for comparison, was fundamental to what historian Charles Rosenberg has termed the Therapeutic Revolution. The pioneering work of Pierre Louis in 1836 in recognizing that blood letting was no more effective than diet and rest for treatment of pneumonia could not occur until pneumonia was recognized as sufficiently similar from one patient to the next to justify comparing outcomes. It should also be noted that much of the initial benefit from this conceptual advance was not in developing new therapies but, instead, in abandoning those that did not work. It was during this period of first evaluating established interventions in newly defined diseases that Oliver Wendell Holmes famously remarked to his students at Harvard that “if the whole materia medica [standard medical therapies] could be sunk to the bottom of the sea, it would be all the better for mankind and all the worse for the fishes.” Although recognition of discrete subtypes of breast cancer need not induce a similar state of therapeutic nihilism, it is important to consider how and when we know we are dealing with a distinct disease and what the consequences of this for both current practice and research may be. Until relatively recently, breast cancer was viewed as one disease, albeit with variable features that could affect prognosis and treatment options. Differences between ER-positive disease and ER-negative disease in terms of both natural history and response to therapy have been well documented, but studies demonstrating the potential for changes in receptor expression over time contributed to the notion that there was one underlying condition. Even when the importance of HER-2 overexpression leading to inferior outcomes in a subset of breast cancers was first recognized in 1987, this was essentially considered a poor-prognosis feature of the disease, rather than a discrete entity. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 20 JULY 1