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Journal of Clinical Oncology, Vol 26, No 20 (July 10), 2008: pp. 3303-3305 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.5621
Breast Cancer in Young Women: A New Color or a Different Shade of Pink?Duke University, Durham, NC
Dana-Farber Cancer Institute, Boston, MA
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 al1 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.2,3 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 However, in addition to exploring differences among these well-characterized 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 al1 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.6 Using this forest versus trees approach, Anders et al1 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.7 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.8 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."9 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,10,11 but studies demonstrating the potential for changes in receptor expression over time contributed to the notion that there was one underlying condition.12 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.13 This view began to change dramatically with exploration of differences among tumors through microarray studies evaluating gene expression in thousands of genes. In some of the seminal work in this area, Sorlie et al,14 focusing on 496 genes with differing levels of expression among 38 tumors and contrasting these with gene expression in normal breast tissue, identified five distinguishable molecular subtypes of breast cancer with similar gene expression patterns classified as basal-like, luminal A, luminal B, HER-2 positive, and normal. This work has been supported by other investigators and corresponds, albeit roughly, to IHC-based surrogates based on ER, progesterone receptor, and HER-2 staining that can be used to make distinctions and guide therapy in standard practice.15-17 Recognition of these seemingly distinct forms of breast cancer at the molecular level has begun to transform the way we view this disease and its treatment. A prime example is the recent retrospective evaluation of outcomes in Cancer and Leukemia Group B study 9344 based on breast cancer subgroups, as defined by IHC. The original publication documented the benefit of addition of paclitaxel to doxorubicin and cyclophosphamide adjuvant chemotherapy among patients with lymph node–positive disease.18 The recent study by Hayes et al19 found that this difference was largely confined to patients with either triple-negative or ER-negative, HER-2–positive disease. In fact, the magnitude of benefit seemed larger in these subgroups than appreciated in the original trial, with little to no additional benefit among patients with ER-positive, HER-2–negative disease. Consideration of breast cancer subtypes is also changing the way we view the course of this disease. We understand the natural history of basal-like breast cancer, which carries a high risk of early recurrence that rapidly diminishes after 5 years, to be quite different from the natural history of endocrine receptor–positive, HER-2–negative breast cancer, which carriers a lower but steady risk of recurrence persisting for 20 years and longer.10,20 An additional benefit of recognition of molecular subtypes has been to unlock some of the mystery behind health disparities affecting African American women with breast cancer. Many possible sociopolitical factors, including differences in health care access and behavior, and medical comorbidities have been evaluated and, in some cases, found to contribute to health disparities.21-23 However, recent work by Carey et al24 has demonstrated that at least some of the differences in outcome are likely to be related to differential incidence of breast cancer subtype by race/ethnicity as a function of age, with premenopausal African American women having more than twice the likelihood of developing basal-like breast cancer compared with both white women and older African American women and a substantially lower likelihood of having the most favorable breast cancer subtype, luminal A. However, not all recent progress in management of breast cancer has come through recognition of discrete subtypes of disease. Studies of gene expression have shown that we can refine prognosis and predict outcome among otherwise similar breast cancers through development of validated panels of genes, without specific regard to molecular subtypes.25,26 Emerging evidence is also suggesting that response to one class of therapy, anthracyclines, may vary largely based on overexpression of a particular enzyme, topoisomerase II.26a Does this define a unique subtype of breast cancer, or can this simply be viewed as a feature of the disease that can guide choice of therapy? Is there a meaningful difference?
Is breast cancer in young women a unique entity? There are several ways to address this question. In terms of defining biology that is truly unique to breast cancer in younger women compared with older women, this has yet to be established. The study by Anders et al1 demonstrated that there were statistically significant differences in expression of biologically meaningful gene sets between tumors of younger versus older patients, but this does not mean that all tumors from younger patients overexpressed any given gene set or that a given gene set could not be overexpressed in a tumor from an older patient. Differences in prevalence of recognized breast cancer subtypes are established, and although it is possible that there is an even more important fundamental feature of breast cancer in younger women at the molecular level, this has not yet been demonstrated. Furthermore, there is the challenge of where we draw meaningful cutoffs with regard to age. This study contrasted patients age Furthermore, if we define breast cancer among young women as a unique biologic entity, do we need to repeat all major clinical trials guiding breast cancer management to date to ensure that the risks and benefits we are assuming from trial data are valid? Although 96% of recent breast cancer randomized clinical trials report age, only 28% present evaluation of outcomes by age.27 Furthermore, the age categories most appropriate for evaluation have not been well defined, and the cutoffs examined differ among studies. Fortunately, for some recent advances such as adjuvant trastuzumab, age has been evaluated with consistent benefits seen across age groups.28,29 A larger concern might be that we could miss a beneficial impact of a given intervention if it was effective in this subgroup but not among breast cancer with different biology, and the beneficial effects would be swamped by the larger percentage of nonresponsive tumors. This concern is heightened for early-stage trials in which the representation of tumors with unique biology could be quite small. A similar concern holds true for population-based studies of cancer risks, where a factor that significantly increased the risk of a rare subtype could be missed. In terms of prognosis, breast cancer among young women has long been recognized as a somewhat unique entity, meriting an aggressive approach to both local and systemic therapy. This study helps define the biologic basis for these differences and highlights the importance of biology in determining outcomes, rather than classical prognostic factors such as tumor size and lymph node status. Most importantly, this study highlights a novel set of genes that seem to be overexpressed among breast cancers in younger women. Although much work remains to further explore, confirm, and define these gene sets and to determine which, if any, correlate with breast cancer outcomes, recognition that there are distinct additional differences at the molecular level is a good starting point. It can be hoped that further investigation may identify novel targets for therapy. It is of particular interest that some of the pathways identified as important in this study, such as MTOR/rapamycin and histone deacetylase, are potential therapeutic targets. It will also remain important to continue to investigate other factors that may contribute to inferior outcomes among younger women. How many subtypes of breast cancer are there? It depends in part on how and why we wish to define the disease and where we draw the lines among biologic differences. Biology in breast cancer, as in other areas, frequently exists along a continuum, rather than fitting neatly into discrete categories we may wish to define. For some purposes, generalization and consideration of breast cancer as one disease or several broadly defined diseases may be sufficient. However, as long as there are consistent differences in outcomes among patients, with some patients failing to respond to standard approaches and dying from disease, we will want to explore and define the reasons for these differences. Ultimately, we may move away from the concept of disease as a discrete entity that is largely comparable across patients to one in which the unique molecular features of each tumor and the biology of the patient, including pharmacogenomic differences, must be considered to guide a more personalized therapy. It is likely that we will continue to draw on evidence from large trials, particularly where similar effects are seen across subgroups, with fine tuning of treatment based on the unique circumstances of each patient. This at least is the goal, and studies of gene expression among young women, who to date face inferior outcomes for incompletely understood reasons, help point us in the right direction to refine our understanding of breast cancer biology and potentially improve outcomes for young and old patients alike. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Jeffrey Peppercorn, Ann H. Partridge Collection and assembly of data: Jeffrey Peppercorn, Ann H. Partridge Data analysis and interpretation: Jeffrey Peppercorn, Ann H. Partridge Manuscript writing: Jeffrey Peppercorn, Ann H. Partridge Final approval of manuscript: Jeffrey Peppercorn, Ann H. Partridge REFERENCES
1. Anders CK, Hsu DS, Broadwater G, et al: Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression. J Clin Oncol 26:3324-3330, 2008 2. Gajdos C, Tartter PI, Bleiweiss IJ, et al: Stage 0 to stage III breast cancer in young women. J Am Coll Surg 190:523-529, 2000[CrossRef][Medline] 3. Colleoni M, Rotmensz N, Robertson C, et al: Very young women (<35 years) with operable breast cancer: Features of disease at presentation. Ann Oncol 13:273-279, 2002 4. Ahn SH, Son BH, Kim SW, et al: Poor outcome of hormone receptor-positive breast cancer at very young age is due to tamoxifen resistance: Nationwide survival data in Korea—A report from the Korean Breast Cancer Society. J Clin Oncol 25:2360-2368, 2007 5. Bertheau P, Steinberg SM, Merino MJ: C-erbB-2, p53, and nm23 gene product expression in breast cancer in young women: Immunohistochemical analysis and clinicopathologic correlation. Hum Pathol 29:323-329, 1998[CrossRef][Medline] 6. Subramanian A, Tamayo P, Mootha VK, et al: Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102:15545-15550, 2005 7. Vogel M, Rosenberg C: The Therapeutic Revolution. Philadelphia, PA, University of Pennsylvania Press, 1979 8. Louis P: Research on the Effects of Bloodletting in Some Inflammatory Diseases. Boston, MA, C.G. Putnam, 1836 9. Holmes OW: Medical Essays (1842-1882). Boston, MA, Houghton, Mifflin and Company, 1891 10. Berry DA, Cirrincione C, Henderson IC, et al: Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:1658-1667, 2006 11. Dent R, Trudeau M, Pritchard KI, et al: Triple-negative breast cancer: Clinical features and patterns of recurrence. Clin Cancer Res 13:4429-4434, 2007 12. Holdaway IM, Bowditch JV: Variation in receptor status between primary and metastatic breast cancer. Cancer 52:479-485, 1983[CrossRef][Medline] 13. Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177-182, 1987 14. Sorlie T, Perou CM, Tibshirani R, et al: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869-10874, 2001 15. Yu K, Lee CH, Tan PH, et al: Conservation of breast cancer molecular subtypes and transcriptional patterns of tumor progression across distinct ethnic populations. Clin Cancer Res 10:5508-5517, 2004 16. Nielsen TO, Hsu FD, Jensen K, et al: Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10:5367-5374, 2004 17. Van Laere SJ, Van den Eynden GG, Van der Auwera I, et al: Identification of cell-of-origin breast tumor subtypes in inflammatory breast cancer by gene expression profiling. Breast Cancer Res Treat 95:243-255, 2006[CrossRef][Medline] 18. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003 19. Hayes DF, Thor AD, Dressler LG, et al: HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med 357:1496-1506, 2007 20. Saphner T, Tormey DC, Gray R: Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 14:2738-2746, 1996 21. Tammemagi CM, Nerenz D, Neslund-Dudas C, et al: Comorbidity and survival disparities among black and white patients with breast cancer. JAMA 294:1765-1772, 2005 22. Hershman D, McBride R, Jacobson JS, et al: Racial disparities in treatment and survival among women with early-stage breast cancer. J Clin Oncol 23:6639-6646, 2005 23. Griggs JJ, Sorbero ME, Stark AT, et al: Racial disparity in the dose and dose intensity of breast cancer adjuvant chemotherapy. Breast Cancer Res Treat 81:21-31, 2003[CrossRef][Medline] 24. Carey LA, Perou CM, Livasy CA, et al: Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295:2492-2502, 2006 25. Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004 26. Van’t Veer LJ, Dai H, van de Vijver MJ, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530-536, 2002[CrossRef][Medline] 26a. Pritchard KI, Messersmith H, Elavathil L, et al: HER-2 and topoisomerase II as predictors of response to chemotherapy. J Clin Oncol 26:736-744, 2008 27. Mitchell K, Carey L, Peppercorn J: Reporting of race and ethnicity in breast cancer research. Presented at the American Society of Clinical Oncology Breast Cancer Symposium, San Francisco, CA, September 7-8, 2007 28. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659-1672, 2005 29. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005 Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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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.
