The Natural History of Hormone Receptor–Positive Breast Cancer
By Elgene Lim, MD, PhD1, Otto Metzger-Filho, MD1, Eric P. Winer, MD1 |
August 10, 2012
1Division of Women’s Cancers, Dana-Farber Cancer Institute, Boston, Massachusetts
The challenge of late recurrences and a relatively low annual recurrence risk in breast cancer is unique to the luminal cancer subtypes. Large patient databases and long-term follow-up of patients are required to identify patients at greatest risk of recurrence, and pooled analyses of large clinical trials and nontrial data repositories are needed. There is also the added challenge of identifying tumor blocks to elucidate the molecular differences between tumors that relapse early, relapse late, or do not relapse at all. An improved understanding of these differences will enable better prediction of early treatment failure, and will guide the use of novel strategies specifically directed at preventing early and late relapse. Additionally, the study of paired primary and metastatic tumor tissue, through RNA and gene sequencing platforms, may provide valuable molecular insights by identifying genes and pathways involved in the development of anti-estrogen resistance, and those that predict relapse risk. The discrepancy rate in paired primary and metastatic cancers for ER expression ranges from 3% to 36%, and from 25% to 48% for PR expression.[44,45] The basis of HR discordance is not well understood, and possible hypotheses include the variability in testing procedures, particularly when paired tissues are not tested concurrently; deterioration of sample quality over time; heterogeneity in tumor samples and sampling variability; and phenotypic drift as a result of tumor progression and/or treatment. The latter is particularly relevant in the setting of effective anti-estrogen therapy, potentially resulting in the selection of a resistant clone that is not dependent on ER signaling. Most consensus statements recommend that metastatic tumors be biopsied to reassess tumor phenotype, and while it is not possible to perform a repeat biopsy on every patient, it should be considered. Additional research biopsies should also be considered at this time to facilitate future research.
Recent efforts at identifying predictors of late relapse include a study of women with early-stage HR+ breast cancer treated with tamoxifen(Drug information on tamoxifen) and followed up for a minimum of 10 years, in which transcriptomic differences in the primary tumor tissues of patients with distant relapses occurring at 3 or fewer years from diagnosis were compared to relapses that occurred after 7 years. There was an increased relative expression of ESR1, ESR2, EGFR, BCL2, and AR in the late recurrence group and increased expression of CALM1, CALM2, CALM3, SRC, CDK1, and MAPK1 in the early recurrence group. A similar retrospective study was performed on patients with HR+ HER2− tumors who did not receive adjuvant therapy, comparing tumors from patients who relapsed after ≥ 7 years to patients who had not relapsed after 10 years. This study identified a 241-prove gene signature in the late relapse group using the nearest centroid algorithm. While it did not have a high predictive value in a small validation dataset, the functional annotation of this signature showed activation of pathways related to inflammatory response and angiogenesis in the late-relapsing tumors. Another novel approach is the genome-wide mapping of ER binding sites using chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) techniques in HR+ primary breast cancers and metastases. Anti-estrogen–resistant cancers were found to continue to recruit ER to chromatin, but in tumors that were likely to relapse, unique ER-binding regions were acquired and the reprogramming of ER dynamics was mediated by the forkhead box protein A1 (FOXA1), an important pioneer factor for ER-chromatin binding. Gene signatures derived from the acquired ER regulatory regions associated with poor clinical outcome specifically predicted for clinical outcome in HR+ disease. These translational studies using new technologies provide us with a greater depth of insight into the underlying genomic differences between HR+ breast cancers that define differences in response to treatment and outcome; the challenge is to identify suitably large and appropriate cohorts to validate these hypotheses.
Finally, there are significant technical advances in assays to detect small numbers of nucleated blood or bone marrow cells at frequencies of 1 per 106–107 cells. Once extracted, these cells can be studied at a molecular or functional level through cell culture, and may provide a surrogate view of the metastatic tumor population, as well as important insights into the mechanisms and patterns of disease recurrence in breast cancer. Should CTCs accurately reflect the biological and molecular characteristics in metastatic and subclinical HR+ tumor populations, they would represent a valuable resource in the study of anti-estrogen sensitivity, resistance, and tumor dormancy.
Multiple preclinical models of anti-estrogen resistance have been developed in breast cancer cell lines, including long-term estrogen-deprived (LTED) or estrogen-independent cells as models for resistance to AIs, and tamoxifen- and fulvestrant-resistant models.[49,50] There are global similarities in gene expression between HR+ cell lines and patient tumor samples, thereby supporting the validity of this approach to studying underlying mechanisms of anti-estrogen resistance. These approaches have led to the identification of genetic and epigenetic factors that regulate ER signaling and endocrine signaling, such as the forkhead box protein FOXM1, which is activated through an estrogen-response element located in its proximal promoter region. Silencing of FOXM1 results in a reduction in estrogen-induced proliferation and overcomes acquired tamoxifen resistance in HR+ breast cancer cells. Another approach has been to obtain gene expression signatures using either anti-estrogen–resistant cell lines and/or patient data sets with disease outcome to predict for resistance to endocrine therapy. By comparing the profiles of LTED cells to their parental counterparts, gene signatures for estrogen-independent growth and MYC transcription factor activation (by gene set analysis) were found to predict for early recurrence following adjuvant tamoxifen therapy in a validation patient cohort. MYC may thus be a potential therapeutic target in anti-estrogen–resistant breast cancer. The same investigators also demonstrated evidence of hyperactivation of the PI3K pathway in preclinical LTED tumor models, and these cells were sensitive to both anti-estrogens and PI3K pathway inhibitions, thereby providing preclinical rationale for the simultaneous inhibition of these pathways. In spite of these insights, development of relevant preclinical models that accurately simulate patients’ tumor biology remains a challenge.
While much of the research and treatment focus has been on extending the duration of anti-estrogen therapy and adding chemotherapy to prevent relapse, these approaches are not without morbidity, and we need to focus on overtreatment at well as undertreatment. As with chemotherapy, efforts are required to identify additional bio-
markers besides HR expression, to better select subsets of patients who would or would not benefit from anti-estrogen therapy. It remains impossible to predict whether an individual patient will benefit from endocrine treatment, and what the magnitude or duration of any benefit will be; better predictors of each patient’s anti-estrogen responsiveness are clearly needed. Prolonged anti-estrogen therapy (or reinstitution of anti-estrogen therapy after a treatment-free interval) will almost certainly be beneficial for some patients, particularly those with highly endocrine-responsive disease. For other patients, however, extended therapy is insufficient, and it remains to be seen whether combining endocrine therapy with other targeted approaches would be beneficial. Such approaches will need to be informed by a more comprehensive understanding of the heterogeneity that underlies luminal breast cancer. Tumor dormancy remains an area of active investigation and may also shed light on approaches than can reduce the risk of late recurrence.
The path forward requires a comprehensive preclinical and translational approach, incorporating the elucidation of the biology of HR signaling, mechanisms of anti-estrogen resistance and tumor dormancy. Long-term clinically annotated patient cohorts and access to tumor samples are required to make headway into the understanding of late relapse. Finally, in collaboration with our patients, we need to develop a strategy of increasing rates of obtaining metastatic biopsies at critical time points, such as at tumor progression, and to incorporate novel technologies, such as the molecular and functional study of disseminated tumor cells, into our research armamentarium.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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