This Focus article presents a debate between two experts to try to understand more about why younger women with breast cancer tend to have a poorer prognosis than their older counterparts.
Breast cancer in young women frequently presents with an aggressive phenotype, leading to a poorer prognosis than in older women. The critical issue centres on whether the drivers of this ‘poor-prognosis’ phenotype in young women represent a distinct biology or reflect an over-representation of molecular and cellular processes that underpin aggressive disease in all women with this common malignancy. Addressing whether or not the biology of breast cancer in young women is truly unique is an important question, as it increases our understanding of the disease process, while informing the provision of appropriate optimal quality care for the young breast cancer patient. Here, Marco Colleoni, from the European Institute of Oncology in Milan, Italy, and Carey Anders, of the Lineberger Comprehensive Cancer, in North Carolina, USA, offer alternative viewpoints, which they originally presented in a live debate conducted during the European School of Oncology’s conference on Breast Cancer in Young Women (BCY1, November 2012, Dublin, Ireland).
Breast cancer at a young age has been reported to pursue a more aggressive clinical course and to be associated with a poorer prognosis compared with disease in older women. Factors influencing poor prognosis in this patient group include higher tumour grade at diagnosis, high tumour proliferation, pronounced vessel-invading disease, increased expression of HER2 (ErbB2) and reduced expression of both oestrogen (ER) and progesterone receptor (PR).
Both immunohistochemical (IHC) and molecular classifications have been employed to address whether cancer biology defines a unique disease in young women with breast cancer[3–6]. Previous research has identified four subtypes: luminal A (less-aggressive subtype), and luminal B, HER2-enriched, and triple negative (more-aggressive subtypes), which have prognostic relevance[6,7]. Evaluation of these four subtypes in a cohort of 2970 young patients, which included a subset of ‘very young women’ (<35 years) with breast cancer, indicated that there were significantly more patients with triple-negative subtypes and significantly fewer luminal A subtypes in the ‘very young’ cohort when compared with the ‘less young’ women. Other studies have also identified luminal subtypes in older patients, with triple-negative subtypes over-represented in women younger than 40 years of age. The finding that ‘very young’ patients with tumours classified as luminal B, HER2-enriched and triple-negative subtypes were at increased risk of relapse, when compared with older patients with the same subtype, suggests that younger patients with breast cancer may exhibit a unique biology.
Further evidence for a unique biology in breast cancer in young women comes from molecular studies. Young women with breast cancer have a significantly increased prevalence of the more-aggressive subtypes, in particular the ‘basal-like’ tumours[9,10]. Meta-analysis of prognostic signatures and gene classifiers from 20 data sets, representing over 3500 patients aged ≤40 years, indicated that distinct molecular processes, including those related to immature mammary epithelial cells and growth factor signalling, are over-represented in breast cancer arising at a young age. Particular genes/processes that were enriched included RANKL, c-Kit, BRCA1-mutated phenotype, mammary stem cells, luminal progenitor cells (immature mammary epithelial cell phenotype), mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)-related pathways (growth factor signalling phenotype). A prognostic effect of stromal-related gene signatures was also observed, suggesting a role for the microenvironment in mediating breast cancer growth and proliferation in young women, leading to a more-aggressive phenotype.
Thus, both IHC-defined subtype and molecular classification data indicate that breast cancer that develops at a young age is different biologically from that arising in older premenopausal and postmenopausal women.
There is no question that breast cancer arising in young women is unique in many aspects. Challenges faced by young women diagnosed with breast cancer are often quite different from those experienced by older women. These unique challenges may include disruption of career in its early phase, child-bearing and ongoing family responsibilities, impact of therapy on sexuality and body image, and the psychosocial toll of facing a life-threatening illness at a young age. Historically, multiple studies have shown that younger women tend to experience worse breast cancer outcomes as compared to their older counterparts[1–3]; however, the reason for this observation is not entirely understood.
Immunohistochemical (IHC) and gene expression profile studies have also shown that the more-aggressive subtypes of breast cancer (i.e. basal-like and HER2-enriched) are over-represented among younger women as compared with older women[4,5]. Analysis of 784 early-stage breast cancers, which included women aged ≤45 years (n=200) and women aged ≥65 years (n=211) identified distinct clinical-pathological features (low IHC oestrogen receptor [ER] expression, high IHC HER2 expression, larger tumours and higher tumour grade) in younger women. Gene expression analysis indicated a significantly lower expression of ER and progesterone receptor mRNA and a significantly higher expression level of HER2 and epidermal growth factor receptor (EGFR) mRNA in younger women.
A more detailed view of the biology of young women’s breast tumours, obtained by analysing microarray data from several large, publicly available data sets in a non-subtype-dependent manner, indicated that breast tumours arising in younger women were enriched for 367 biologically relevant gene sets when compared with older women, suggesting, with the IHC data, a unique biology for breast cancer in younger women. Independent analysis of a second pooled data set, which included women aged ≤45years and women aged ≥65 years confirmed the increased incidence of the more-aggressive basal-like and HER2-enriched subtypes in younger women. However, when correcting for significant clinical-pathological and histopathological features, including grade, nodal status, ER status and intrinsic breast cancer subtype, adjusted models yielded negligible gene differences between breast tumours arising from defined age groups of ≤45 versus ≥65 years[6,7]. As is standard in the field, this finding was replicated in an independent data set as part of this analysis, further confirming these results.
Based on these results, age alone does not appear to offer an additional layer of biological complexity above that of breast cancer subtype and grade. These data support the argument that the biology of young women’s breast tumours may not be unique, but rather an over-representation of aggressive, biologically driven subtypes is accounting for the disparities observed in outcome by age.
While the information generated by gene expression profiling is compelling, many unanswered questions remain, including: (1) why are younger women more prone to aggressive subtypes of breast cancer? (2) what is the role of the microenvironment? (3) how does breast density and/or other factors (e.g. breastfeeding, parity) contribute to these findings? and (4) will disparities in outcome persist in the era of modern targeted therapies? – all areas deserving of further research.
The question as to whether younger patients with breast cancer exhibit a unique biology is a controversial one. All of the data presented both in favour of and against this hypothesis indicate an increased incidence of more-aggressive molecular subtypes in young women with breast cancer. It may be that factors such as the cut-off age for younger patients need to be considered – perhaps a different biology underpinned by basal-like or HER2-enriched molecular subtypes is implicated in very young patients (i.e. younger than 35 years of age). A precise consideration of the role of the stromal microenvironment may also be relevant and should be pursued. In any case, it is clear that our increased understanding of breast cancer tumour biology in younger women is starting to inform a new scientific rationale (e.g. targeting of genes like RANKL or growth factor pathways like PI3K), that may be of particular benefit to this poor-prognosis cohort of patients.
This article was first published in The Oncologist vol. 18, no.4, and is republished with permission. © 2013 Alpha Med Press doi:10.1634/theoncologist.2013-0118
References (In Favour – Marco Colleoni)
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6. Perou CM, Sorlie T, EisenMBet al. Molecular portraits of human breast tumours. Nature 2000;406:747–52.
7. 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 2008;26:3324 –30.
8. Cancello G, Maisonneuve P, Rotmensz N et al. Prognosis and adjuvant treatment effects in selected breast cancer subtypes of very young women (35years) with operable breast cancer. Ann Oncol 2010;21:1974–81.
9. Carey LA, Perou CM, Livasy CA et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006;295: 2492–2502. 28.
10. Bauer KR, BrownM,CressRDet al. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative,andHER2-negative invasive breast cancer, the so-called triple-negative phenotype: a populationbased study from the California cancer Registry. Cancer 2007;109:1721–172.
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References (Against – Carey Anders)
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2. Chung M, Chang HR, Bland KI et al. Younger women with breast carcinoma have a poorer prognosis than older women. Cancer 1996;77:97–103.
3. Bharat A, Aft RL, Gao F et al. Patient and tumor characteristics associated with increased mortality in young women ( 40 years) with breast cancer. J Surg Oncol 2009;100:248 –51.
4. Bauer KR, Brown M, Cress RD et al. Descriptive analysis of estrogen receptor (ER)-negative,progesteronereceptor(PR)-negative,andHER2-negativeinvasive breast cancer, the so- called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer 2007;109:1721–8.
5. Cancello G, Maisonneuve P, Rotmensz N et al. Prognosis and adjuvant treatment effects in selected breast cancer subtypes of very young women (35years) with operable breast cancer. Ann Oncol 2010;21:1974–81.
6. 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 2008;26:3324 –30.
7. Anders CK, Fan C, Parker JS et al. Breast carcinomas arising at a young age: unique biology or a surrogate for aggressive intrinsic subtypes? J Clin Oncol 2011;29:e18–e20.