Current Status of Neoadjuvant Endocrine Therapy in Early Stage Breast Cancer (original) (raw)
Related papers
Breast Cancer Research and Treatment, 2008
Approximately 30% of patients with estrogen receptor (ER) positive breast cancers exhibit de novo or intrinsic resistance to endocrine therapies. The purpose of this study was to define genes that distinguish ER+ resistant from ER+ responsive tumors, prior to the start of hormone therapies. Previously untreated post-menopausal patients with ER+ breast cancers were treated for 4 months in a neoadjuvant setting with the aromatase inhibitor exemestane alone, or in combination with the antiestrogen tamoxifen. Matched pre-and post-treatment tumor samples from the same patient, were analyzed by gene expression profiling and were correlated with response to treatment. Genes associated with tumor shrinkage achieved by estrogen blockade therapy were identified, as were genes associated with resistance to treatment. Prediction Analysis of Microarrays (PAM) identified 50 genes that can predict response or intrinsic resistance to neoadjuvant endocrine therapy of ER+ tumors, 8 of which have been previously implicated as useful biomarkers in breast cancer. In summary, we identify genes associated with response to endocrine therapy that may distinguish ER+, hormone responsive breast cancers, from ER+ tumors that exhibit intrinsic or de novo resistance. We suggest that the estrogen signaling pathway is aberrant in ER+ tumors with intrinsic resistance. Lastly, the studies show upregulation of a ''lipogenic pathway'' in non-responsive ER+ tumors that may serve as a marker of intrinsic resistance. This pathway may represent an alternative target for therapeutic intervention.
Approximately 70% of patients have breast cancers that are oestrogen receptor alpha positive (ER+) and are therefore candidates for endocrine treatment. Many of these patients relapse in the years during or following completion of adjuvant endocrine therapy. Thus, many ER+ cancers have primary resistance or develop resistance to endocrine therapy during treatment. Recent improvements in our understanding of how tumours evolve during treatment with endocrine agents have identified both changes in gene expression and mutational profiles, in the primary cancer as well as in circulating tumour cells. Analysing these changes has the potential to improve the prediction of which specific patients will respond to endocrine treatment. Serially profiled biopsies during treatment in the neoadjuvant setting offer promise for accurate and early prediction of response to both current and novel drugs and allow investigation of mechanisms of resistance. In addition, recent advances in monitoring tumour evolution through non-invasive (liquid) sampling of circulating tumour cells and cell-free tumour DNA may provide a method to detect resistant clones and allow implementation of personalized treatments for metastatic breast cancer patients. This review summarises current and future biomarkers and signatures for predicting response to endocrine treatment, and discusses the potential for using approved drugs and novel agents to improve outcomes. Increased prediction accuracy is likely to require sequential sampling, utilising preoperative or neoadjuvant treatment and/or liquid biopsies and an improved understanding of both the dynamics and heterogeneity of breast cancer.
The Breast, 2007
Neoadjuvant endocrine therapy (NAET) can expand the number of breast cancer patients who can be treated with breast-conserving surgery and can predict benefit from adjuvant endocrine therapy. Because no validated surrogate markers for long-term outcome have been established, we conducted prospective trials to evaluate pathological response and Ki-67 index following treatment with tamoxifen or anastrozole. The study population included postmenopausal women with operable breast tumors that were both estrogen and progesterone receptor-positive and larger than 3 cm. Response was classified as pathological response (minimal response or better) and non-response. Non-responding (25.5%, vs. response 85.9%, p ¼ 0.002), axillary node-positive (58.4% vs. node negative 100%, p ¼ 0.045), and high pretreatment Ki-67 index (41.4% vs. low Ki-67 87.1%, p ¼ 0.03) patients were significantly associated with poor 5-year relapse-free survival. Multivariate analysis of relapse-free survival indicated that pathological response was independent. Therefore, pathological response may be a favorable prognostic factor after NAET.
Molecular Cancer Therapeutics, 2019
Endocrine therapy is important for management of patients with estrogen receptor (ER)–positive breast cancer; however, positive ER staining does not reliably predict therapy response. We assessed the potential to improve prediction of response to endocrine treatment of a novel test that quantifies functional ER pathway activity from mRNA levels of ER pathway–specific target genes. ER pathway activity was assessed on datasets from three neoadjuvant-treated ER-positive breast cancer patient cohorts: Edinburgh: 3-month letrozole, 55 pre-/2-week/posttreatment matched samples; TEAM IIa: 3- to 6-month exemestane, 49 pre-/28 posttreatment paired samples; and NEWEST: 16-week fulvestrant, 39 pretreatment samples. ER target gene mRNA levels were measured in fresh-frozen tissue (Edinburgh, NEWEST) with Affymetrix microarrays, and in formalin-fixed paraffin-embedded samples (TEAM IIa) with qRT-PCR. Approximately one third of ER-positive patients had a functionally inactive ER pathway activity s...
Multidisciplinary Approach to Neoadjuvant Endocrine Therapy in Breast Cancer: A Comprehensive Review
Revista brasileira de ginecologia e obstetricia : revista da Federacao Brasileira das Sociedades de Ginecologia e Obstetricia, 2016
Breast cancer is the most common type of cancer and the leading cause of cancer-related death among women worldwide. Hormone receptor-positive (HR+) tumors represent the most common form of this disease, with more than 70% of breast cancers expressing these receptors. Response and benefit to neoadjuvant chemotherapy (NCT) varies according to HR expression, with lower responses in luminal tumors as compared with hormone receptor-negative (HR-) and human epidermal growth factor receptor 2-positive (HER2+) tumors. Neoadjuvant endocrine therapy (NET) is an option for selected patients with HR+ locally advanced breast cancer. Neoadjuvant endocrine therapy has a favorable toxicity profile, and is associated with benefits such as having low cost and being more easily available even for cancer care professionals outside major urban areas or tertiary centers. These factors are particularly relevant, as 70% of breast cancer deaths occur in women from low-income and middle-income countries. Ad...
Predictive markers of endocrine response in breast cancer
World Journal of Experimental Medicine
Ongoing clinical and research efforts seek to optimise the use of endocrine therapy in the treatment of breast cancer. Accurate biomarkers are needed that predict response for individual patients. The presence of the estrogen receptor (ER) as the direct (for tamoxifen and fulvestrant) or indirect (for aromatase inhibitors) target molecule for endocrine therapy remains the foremost biomarker and determinant of response. However, ER expression only poorly predicts outcome and further indicators of response or resistance are required. The development and application of molecular signature assays such as Oncotype Dx, Prosigna, Mammaprint and Endopredict have provided valuable information on prognosis and these are being used to support clinical decision making on whether endocrine therapy alone alongside surgery is sufficient for ER-positive early stage breast cancers or whether combination of endocrine with chemotherapy are also warranted. Ki67, the proliferation marker, has been widely used in the neo-adjuvant (pre-operative) setting to help predict response and long term outcome. Gene expression studies within the same setting have allowed monitoring of changes of potential predictive markers. These have identified frequent changes in estrogenregulated and proliferation genes. Specific molecules such as mutant ER may also prove helpful biomarkers in predicting outcome and monitoring response to treatment.
Purpose The recent publication of the ACOSOG Z1031 trial results demonstrated that Ki-67 proliferation marker-based neoadjuvant endocrine therapy response monitoring could be used for tailoring the use of adjuvant chemotherapy in ER?HER2-negative breast cancer patients. In this paper, we describe the development of the Ki-67 clinical trial assay used for this study. Methods Ki-67 assay assessment focused on reproducing a 2.7% Ki-67 cut-point (CP) required for calculating the Preoperative Endocrine Prognostic Index and a 10% CP for poor endocrine therapy response identification within the first month of neoadjuvant endocrine treatment. Image analysis was assessed to increase the efficiency of the scoring process. Clinical outcome concordance for two independent Ki-67 scores was the primary performance metric. Results Discordant scores led to a triage approach where cases with complex histological features that software algorithms could not resolve were flagged for visual point counting (17%). The final Ki-67 scoring approach was run on T1/2 N0 cases from the P024 and POL trials (N = 58). The percent positive agreement for the 2.7% CP was 87.5% (95% CI 61.7–98.5%); percent negative agreement 88.9% (95% CI: 65.3–98.6%). Minor discordance did not affect the ability to predict similar relapse-free outcomes (Log-Rank P = 0.044 and P = 0.055). The data for the 10% early triage CP in the POL trial were similar (N = 66), the percentage positive agreement was 100%, and percent negative agreement 93.55% (95% CI: 78.58–99.21%). The independent survival predictions were concordant (Log-rank P = 0.0001 and P = 0.01). Conclusions We have developed an efficient and reproducible Ki-67 scoring system that was approved by the Clinical Trials Evaluation Program for NCI-supported neoadjuvant endocrine therapy trials. Using the methodology described here, investigators are able to identify a subgroup of patients with ER?HER2-negative breast
Breast Cancer, 2011
Aromatase inhibitors (AIs) were more effective than tamoxifen as a neoadjuvant endocrine therapy (NAE) for postmenopausal women with estrogen receptor (ER)positive breast cancer. Neoadjuvant AIs were shown to reduce tumor volume and to allow the performance of breast-conserving surgery (BCS) in cases that would normally require mastectomy. Predictive markers of neoadjuvant AIs may be ER-rich, progesterone receptor (PgR)rich and human epidermal growth factor receptor 2 (HER2)-negative tumors. However, the ability of HER2 expression to predict a response to neoadjuvant AIs is controversial. Pathological tumor size, nodal status, Ki67 level, and ER score are predictive for the survival of postmenopausal women with breast cancer who have been treated with NAE. These factors could be useful in order to select patients who do not require chemotherapy. Indeed, neoadjuvant AIs are a potential treatment option for postmenopausal women with ER-rich breast cancer who prefer BCS despite having large tumors suitable for mastectomy.
Development of new predictive markers for endocrine therapy and resistance in breast cancer
Acta Oncologica, 2008
Today, the decision to treat breast cancer patients with endocrine therapy relies solely on tumor expression of two predictive factors, the estrogen receptor and the progesterone receptor. Expression of these hormone receptors are, however, not a guarantee for a response to treatment and patients who experience response at first may become resistant after prolonged treatment. This paper describes the use of preclinical models to identify mechanisms and new markers for endocrine sensitivity and resistance and the translation of these data to clinical utility.
Use of neoadjuvant data to design adjuvant endocrine therapy trials for breast cancer
| Mature outcomes from adjuvant endocrine therapy trials in estrogen receptor-positive breast cancer have enabled comparisons with neoadjuvant clinical trials that have parallel randomizations of treatment in terms of the response of disseminated disease versus the local response within the breast. Imprecise end points, such as 'clinical response', have produced inconsistent results regarding the relationship between neoadjuvant and adjuvant endocrine therapy outcomes. However, the proliferation marker Ki-67, measured during neoadjuvant treatment, has predicted accurately and consistently the results of much larger studies in the adjuvant setting. In this Review, we summarize these trials and discuss the implications for the design of future adjuvant endocrine therapy trials. We conclude that there is sufficient evidence supporting the view that the degree of Ki-67 suppression is a reliable short-term surrogate for the adjuvant potential of endocrine drugs, at least in postmenopausal women. We propose that adjuvant endocrine therapy trials should only be conducted once adequately-powered neoadjuvant studies have indicated superior Ki-67 suppression in patients receiving experimental endocrine treatment versus the standard treatment.