Approximately 70% of human breast tumors express hormone receptors (HRs), comprising the estrogen receptor (ER) and/or progesterone receptor (PR). The ER is the primary transcription factor driving oncogenesis in HR-positive (HR+) breast cancers; it is both a target of, and predictor of response to, anti-estrogen therapy. Unlike in other breast cancer subtypes, more than half of all disease recurrences in HR+ breast cancer occur 6 years or more after diagnosis, particularly following 5 years of adjuvant anti-estrogen therapy. Late relapses in HR+ breast cancer thus represent a significant clinical challenge. There is considerable molecular and clinical heterogeneity underlying HR+ breast cancers, and a limited understanding of the mechanisms underlying treatment resistance and late relapse. In this review, we describe the long natural history of HR+ breast cancer and discuss relapse patterns in relation to their clinicopathological and molecular characteristics. We highlight the relationship between tumor relapse and anti-estrogen therapy resistance, and we describe the concept of tumor dormancy. Finally, we review novel translational research strategies utilizing preclinical models and patient tumor samples, and current clinical strategies that address this increasingly common challenge in breast cancer.
Approximately 70% of human breast tumors express hormone receptors (HRs)—the estrogen receptor (ER) and/or the progesterone receptor (PR); these are the primary transcription factors driving oncogenesis in HR-positive (HR+) breast cancers. Both are targets of and predictors of response to anti-estrogen therapy.[1,2] Upon stimulation by estrogen, ER is recruited to specific sites across the genome in a highly organized manner through specific epigenetic events that restrict its recruitment to a subset of its potential binding sites. ER signaling can be effectively targeted by antagonizing the binding of estrogens to the ER with tamoxifen, blocking estrogen biosynthesis with aromatase inhibitors (AIs) and luteinizing hormone–releasing hormone (LHRH) agonists, and down-regulating ER with fulvestrant (Faslodex). However, a significant minority of patients relapse despite adjuvant anti-estrogen therapy. Most patients with metastatic disease ultimately develop resistance to anti-estrogen therapies. HR+ tumors do not represent a single disease entity, and there is considerable molecular and clinical heterogeneity. Unlike other breast cancer subtypes, HR+ breast cancer is commonly associated with late recurrences,[1,5,6] with an annual risk of distant recurrence following adjuvant anti-estrogen therapy of 1% to 4%, depending on the extent of initial disease. The use of adjuvant AIs and the addition of chemotherapy to anti-estrogen regimens may benefit some patients,[8,9] but these seem to have little impact on the risk of late recurrence. At present little is known about the predictive markers for late relapse and underlying mechanisms of treatment resistance and late relapse, for which alternative treatment strategies are clearly required. In this article, we describe the long natural history of HR+ breast cancer and review current research and clinical strategies to address this clinical challenge.
Heterogeneity of Luminal Breast Cancer and Determinants of Prognosis and Biological Behavior
Classic clinicopathological factors such as tumor size, nodal status, histological grade, and human epidermal growth factor receptor 2 (HER2) co-expression are important predictors of patient outcome and are commonly factored into treatment algorithms for HR+ tumors, but their relationship to relapse patterns is less clear. A retrospective analysis of 3,000 patients with early-stage breast cancer demonstrated that larger tumor size predicted for both early recurrences (0 to 5 years after diagnosis) and late recurrences (5 to 12 years after diagnosis), but did not predict for late recurrences when controlled for nodal status. In contrast, nodal involvement was a good predictor of both early and late recurrences. Although tumor burden is incorporated in prognostic tools such as Adjuvant! Online (https://www.adjuvantonline.com), current clinical and molecular tools generally select for relapse primarily in the first 5 years and not for late relapse. Another retrospective analysis of 400 patients found no association between histological grade and time of relapse. In a meta-analysis of 10,000 patients, HER2 and HR coexpression was associated with poorer outcomes than HR+, HER2–non-amplified (HER2−) tumors.
Invasive lobular carcinoma (ILC) represents the second most common breast cancer histological subtype, accounting for 10% to 15% of breast cancers, and the vast majority express HR. ILC differs from invasive ductal carcinomas (IDCs) with respect to epidemiology, clinicopathological features, and natural history. In early-stage breast cancer, patients with ILC have a better overall survival (OS) in the first 10 years after diagnosis compared with those who have IDC, but the opposite was observed with longer follow-up. It is unclear whether these observed differences in the natural history can be explained solely by differences in histology, or whether they are influenced by the different distribution of molecular subtypes.
Molecular subtyping of breast cancer represents a major advance and includes at least two luminal subtypes (luminal A and B), each with distinct pathological characteristics and disease outcomes. Luminal A tumors are characterized by ER-regulated genes and better outcomes, while luminal B tumors have higher genomic grade values and are associated with poorer outcomes. Several multigene expression signatures and PAM50, a multi-gene expression signature using reverse transcriptase polymerase chain reaction (RT-PCR) to classify breast tumors into their major “intrinsic” subtypes, have been shown to provide prognostic value in early-stage breast cancer beyond traditional clinicopathological risk assessment.[16,17] These include Oncotype DX (Genomic Health), MammaPrint (Agendia), and Genomic Grade Index (Ipsogen), which also provide additional information on the benefit of chemotherapy in early-stage breast cancer. The common denominator in these multigene signatures is the inclusion of proliferation genes in their indices,[8,16] and they tend to identify patients at higher risk of early relapse. The combination of Ki67, HR, and HER2 expression have been used by some groups as an immunohistochemistry (IHC)-based surrogate for the molecular subtypes, with variable cut-off points for Ki67 proposed to differentiate between the low-proliferation luminal A and the high-proliferation luminal B tumors. A retrospective analysis of 2,000 patients with node-negative breast cancer from two phase III trials at a median follow-up of 13 years found that while patients with both IHC-defined luminal A and B tumors had a persistently elevated risk of late recurrence over time, patients with luminal B tumors had higher distant recurrence rates and significantly worse survival outcomes compared with those who had luminal A tumors. Therefore, both luminal A and B subtypes contribute to early and late recurrences, and there are few data to support the common assumption that luminal B tumors relapse early and luminal A tumors relapse late.
Relapse Patterns in Relation to Anti-Estrogen Resistance and Tumor Dormancy
Patients with HR+ tumors are at continued risk of relapse for many years after their initial breast cancer diagnosis. This clinical behavior is not unique to HR+ tumors; it is also seen in B-cell lymphoma, melanoma, prostate cancer, and renal cell cancer. Among women treated with tamoxifen for 5 years, more than half of all recurrences occur between 6 and 15 years after diagnosis. In a meta-analysis of 10,000 patients, HR-negative (HR−) tumors were found to have a poorer prognosis in the first few years after diagnosis, but after 5 to 10 years, HR+ tumors were associated with relatively poorer outcomes. Similarly, a combined analysis of 9,000 patients with node-negative disease found that patients who did not receive adjuvant therapy had a higher risk of recurrence 48 months after diagnosis if they had HR+ tumors rather than HR– tumors. In patients with HR+ breast cancer treated with tamoxifen, the risk of relapse exceeded that of HR− breast cancer after 5 years, and chemotherapy benefit was primarily in the earlier period. These findings are concordant with the overview data from the Early Breast Cancer Trialists Collaborative Group (EBCTCG).[1,2]
In thinking about the relapse patterns of HR+ breast cancer, it is important to consider its relation to anti-estrogen resistance and tumor dormancy, as the mechanisms underlying these two processes may be quite different (Figure). Resistance to anti-estrogen therapies can occur de novo (primary resistance) or be acquired (secondary resistance), and is likely a major cause of early relapse during adjuvant anti-estrogen therapy, and during progressive disease in metastatic breast cancer. Anti-estrogen resistance occurs despite continued expression of the ER, and the signaling pathways regulating this are thought to involve a complex signaling network that is poorly understood.
Tumor dormancy is a term used to describe subclinical residual disease, which typically either remains undetected or relapses after a long interval period (Figure). The regulation of the switch from quiescent dormancy to active regrowth in metastatic sites is poorly understood and likely includes interactions with host immunity and the metastatic niche. The bone marrow is a common homing organ for breast cancer metastases and dormant breast tumor cells. In a large pooled analysis of 4,700 patients with clinical stage I-III breast cancer who had screening bone marrow aspirates, a surprisingly large proportion (approximately 30%) of patients with HR+ tumors had micrometastatic bone marrow tumor involvement. The primary tumors were larger and associated with a higher histological grade and nodal involvement. Bone marrow micrometastases were a predictor of poor outcome on multivariate analysis, and correlated with subsequent bone metastases and overt metastasis to viscera and brain. The incidence of bone marrow micrometastases was significantly lower in another study of patients with early-stage breast cancer by the American College of Surgeons Oncology Group (3% positive in 3,413 bone marrow specimens analyzed), but as in the above study, the presence of bone marrow micro-metastases was associated with decreased survival.
The quantification of circulating tumor cells (CTCs) represents an area of active research as a marker of prognosis and treatment response. In a study of 36 patients with no clinical evidence of breast cancer for 7 to 22 years following mastectomy, IHC-detected CTCs were found in a third of patients. As CTCs have a limited lifespan in circulation, these findings suggest the presence of a metastatic niche that gives rise to these cells. As these patients may remain clinically disease-free for long periods, there is likely a homeostatic mechanism maintaining the balance between tumor replication and cell death that replenishes the CTCs at a subclinical level. In some patients, this balance keeps the dormant tumor cells in check for their entire life.
1. Davies C, Godwin J, Gray R, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378:771-84.
2. EBCTCG. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687-717.
3. Lupien M, Eeckhoute J, Meyer CA, et al. FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell. 2008;132:958-70.
4. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747-52.
5. Esserman LJ, Moore DH, Tsing PJ, et al. Biologic markers determine both the risk and the timing of recurrence in breast cancer. Breast Cancer Res Treat. 2011;129:607-16.
6. Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol. 1996;14:2738-46.
7. Goss PE, Ingle JN, Pater JL, et al. Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen. J Clin Oncol. 2008; 26:1948-55.
8. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:3726-34.
9. Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol. 2010; 28:509-18.
10. Lin NU, Winer EP. Optimizing endocrine therapy for estrogen receptor-positive breast cancer: treating the right patients for the right length of time. J Clin Oncol. 2008;26:1919-21.
11. Blows FM, Driver KE, Schmidt MK, et al. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med. 2010;7:
12. Rakha EA, Ellis IO. Lobular breast carcinoma and its variants. Semin Diagn Pathol. 2010;27:49-61.
13. Pestalozzi BC, Zahrieh D, Mallon E, et al. Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast: combined results of 15 International Breast Cancer Study Group clinical trials. J Clin Oncol. 2008;26:3006-14.
14. Loi S, Haibe-Kains B, Desmedt C, et al. Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. J Clin Oncol. 2007;25:1239-46.
15. Parker JS, Mullins M, Cheang MC, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27:1160-7.
16. Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med. 2009;360:790-800.
17. Nielsen TO, Parker JS, Leung S, et al. A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer. Clin Cancer Res. 2010;16:5222-32.
18. van 't Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530-6.
19. Filho OM, Ignatiadis M, Sotiriou C. Genomic Grade Index: an important tool for assessing breast cancer tumor grade and prognosis. Crit Rev Oncol Hematol. 2011;77:20-9.
20. Cheang MC, Chia SK, Voduc D, et al. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 2009;101:736-50.
21. Metzger O, Sun Z, Viale G, et al. Patterns of breast cancer relapse according to breast cancer subtypes in lymph node-negative breast cancer—results from International Breast Cancer Study Group Trials VIII and IX. Cancer Res. 70(24s): abstr P5-13-01.
22. Uhr JW, Pantel K. Controversies in clinical cancer dormancy. Proc Natl Acad Sci U S A. 2011;108:12396-400.
23. Dignam JJ, Dukic V, Anderson SJ, et al. Hazard of recurrence and adjuvant treatment effects over time in lymph node-negative breast cancer. Breast Cancer Res Treat. 2009;116:595-602.
24. Pantel K, Brakenhoff RH, Brandt B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer. 2008;8:329-40.
25. Braun S, Vogl FD, Naume B, et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med. 2005;353:793-802.
26. Giuliano AE, Hawes D, Ballman KV, et al. Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer. JAMA. 2011;306:385-93.
27. Meng S, Tripathy D, Frenkel EP, et al. Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res. 2004;10:8152-62.
28. Goldhirsch A, Ingle JN, Gelber RD, et al. Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol. 2009;20:1319-29.
29. Burstein HJ, Griggs JJ, Prestrud AA, Temin S. American Society of Clinical Oncology clinical practice guideline update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Oncol Pract. 2010;6:243-6.
30. Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 1999;17:1474-81.
31. Kim C, Tang G, Pogue-Geile KL, et al. Estrogen receptor (ESR1) mRNA expression and benefit from tamoxifen in the treatment and prevention of estrogen receptor-positive breast cancer. J Clin Oncol. 2011;29:4160-7.
32. Cuzick J, Sestak I, Baum M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010;11:1135-41.
33. Piccart-Gebhart MJ. New developments in hormone receptor-positive disease. Oncologist. 2011;
34. Goldhirsch A, Wood WC, Coates AS, et al. Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011;22:1736-47.
35. Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 2010;11:55-65.
36. Cardoso F, van 't Veer L, Rutgers E, et al. Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol. 2008;26:729-35.
37. Sparano JA, Paik S. Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol. 2008;26:721-8.
38. Jakesz R, Samonigg H, Greil R. Extended adjuvant treatment with anastrozole: results from the Austrian Breast and Colorectal Cancer Study Group Trial 6a (ABCSG-6a). J Clin Oncol. 2005;23(16S): abstr 527.
39. Mamounas EP, Jeong JH, Wickerham DL, et al. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 trial. J Clin Oncol. 2008;
40. De Laurentiis M, Arpino G, Massarelli E, et al. A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clin Cancer Res. 2005;11: 4741-8.
41. Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol. 2011;29:4452-61.
42. Bachelot T, Bourgier C, Cropet C, et al. TAMRAD: a GINECO randomized phase II trial of everolimus in combination with tamoxifen versus tamoxifen alone in patients with hormone-receptor positive, HER2 negative metastatic breast cancer with prior exposure to aromatase inhibitors. Cancer Res. 2010;70:77s.
43. Baselga J, Semiglazov V, van Dam P, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2009;27:2630-7.
44. Bogina G, Bortesi L, Marconi M, et al. Comparison of hormonal receptor and HER-2 status between breast primary tumours and relapsing tumours: clinical implications of progesterone receptor loss. Virchows Arch. 2011;459:1-10.
45. Broom RJ, Tang PA, Simmons C, et al. Changes in estrogen receptor, progesterone receptor and HER-2/neu status with time: discordance rates between primary and metastatic breast cancer. Anticancer Res. 2009;29:1557-62.
46. Liu MC, Dixon JM, Xuan JJ, et al. Molecular signaling distinguishes early ER positive breast cancer recurrences despite adjuvant tamoxifen. Cancer Res. 2011;71:98s-9s.
47. Saghatchian M, Mittempergher L, Michiels S, et al. Characterization of breast cancer distant metastasis based on outcome over time using a gene expression profiling approach and identification of pathway activities of late relapse. Cancer Res. 2011;71:97s.
48. Ross-Innes CS, Stark R, Teschendorff AE, et al. Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature. 2012;481:389-93.
49. Miller TW, Balko JM, Ghazoui Z, et al. A gene expression signature from human breast cancer cells with acquired hormone independence identifies MYC as a mediator of antiestrogen resistance. Clin Cancer Res. 2011;17:2024-34.
50. Millour J, Constantinidou D, Stavropoulou AV, et al. FOXM1 is a transcriptional target of ER alpha and has a critical role in breast cancer endocrine sensitivity and resistance. Oncogene. 2010;29:2983-95.
51. Zhu Y, Wang A, Liu MC, et al. Estrogen receptor alpha positive breast tumors and breast cancer cell lines share similarities in their transcriptome data structures. Int J Oncol. 2006;29:1581-9.