Abstract Background: Aromatase inhibitors (AIs) have an established role in the treatment of estrogen receptor alpha positive (ER+) post-menopausal breast cancer. Response rates are 50-70% in the neoadjuvant setting and lower in advanced disease. There is a need to identify biomarkers to predict response that outperform those currently available, to be able to offer more stratified treatments and improved patient care. Methods: Pre- and on-treatment (at 14 days and 3-months) biopsies were obtained from 89 post-menopausal women with ER+ breast cancer receiving 3 months of neoadjuvant Letrozole. Illumina Beadarray gene expression data (n = 34) were combined with Affymetrix GeneChip data (n = 55) and cross-platform integration approaches developed as part of this study were implemented to combine data. Dynamic clinical response was assessed for each patient using periodic 3D ultrasound measurements performed during treatment. A gene classifier was developed from pre and 14 day gene array expression data to predict response. An independent series from the Royal Marsden was used to validate the classifier. Results: Response to endocrine therapy in the neoadjuvant setting based on the expression of 4 genes has been developed. The classifier comprises baseline expression of an immune signalling gene and an apoptosis related gene, together with 14 day expression of two proliferation genes. Early on-treatment gene changes in combination with pre-treatment gene expression significantly improve predictive power compared to pre-treatment gene expression alone. The classifier had a 96% accuracy in a training dataset (n = 73) and 91% accuracy in an independent validation dataset (n = 44) dataset. Table 1 AccuracySensitivitySpecificityPPVNPVAUC (ROC)Training0.960.890.980.890.960.96Validation0.910.80.970.920.9NASensitivity and specificity of model in training and validation datasets Expression of the pre-treatment immune signalling gene alone predicted for response with 85% and 82% accuracy in training and validation datasets respectively. Higher pre-treatment levels of this gene were associated with a significantly better 1 year progression free survival (PFS) (P = 0.0001). In a larger series of patients treated with neoadjuvant Letrozole (n = 129) higher expression of this gene alone was associated with a significantly improved 10 year RFS (p = 0.0359). In a separate tamoxifen treated cohort (n = 212) higher expression of this gene at diagnosis was associated with a significantly improved 5 year (p = 0.0015) and 10 year (p = 0.04) recurrence free survival (RFS). Conclusion: • A 4 gene classifier has been developed and validated to predict response to neoadjuvant Letrozole. • One of the genes identified is a significant predictor in independent data sets of long term RFS in endocrine treated patients. • This new classifier has the potential to predict accurately the benefit of endocrine therapy and has huge potential clinical value. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-2.
Pre-operative endocrine therapy can be used to down-stage large or locally advanced breast cancers in ER+ disease. In the last four decades, it has evolved from a treatment perceived as an alternative to surgery for those too unfit to undergo surgery or chemotherapy, to the present day where it is a valuable and valid option in the treatment of postmenopausal women with ER-rich (Allred score 7–8, or > 50% staining for ER) breast cancer. Emerging data from the metastatic setting is translating into neoadjuvant trials, utilising dual endocrine targeting or combinations of endocrine agents and other targeted drugs, including those acting against components of the PI3K pathway and the cell cycle. The routine use of peri-operative endocrine therapy in all ER+ tumours may help to yield important long-term prognostic information, and guide adjuvant endocrine therapy. Pre-operative endocrine therapy is an exciting and evolving area with emerging new approaches. In this review, established evidence and emerging data on its applications are discussed.
Abstract Background Recommendations for mastectomy by multidisciplinary teams (MDTs) may contribute to variation in mastectomy rates. The primary aim of this multicentre prospective observational study was to describe current practice in MDT decision-making for recommending mastectomy. A secondary aim was to determine factors contributing to variation in mastectomy rates. Methods Consecutive patients undergoing mastectomy between 1 June 2015 and 29 February 2016 at participating units across the UK were recruited. Details of neoadjuvant systemic treatment (NST), operative and oncological data, and rationale for recommending mastectomy by MDTs were collected. Results Overall, 1776 women with breast cancer underwent 1823 mastectomies at 68 units. Mastectomy was advised by MDTs for 1402 (76·9 per cent) of these lesions. The most common reasons for advising mastectomy were large tumour to breast size ratio (530 women, 29·1 per cent) and multicentric disease (372, 20·4 per cent). In total, 202 postmenopausal women with oestrogen receptor-positive (ER+) unifocal tumours were advised mastectomy and not offered NST, owing to large tumour to breast size ratio in 173 women (85·6 per cent). Seventy-five women aged less than 70 years with human epidermal growth factor receptor 2-positive (HER2+) tumours were advised mastectomy and not offered NST, owing to large tumour to breast size ratio in 45 women (60 per cent). Conclusion Most mastectomies are advised for large tumour to breast size ratio, but there is an inconsistency in the use of NST to downsize tumours in patients with large ER+ or HER2+ cancers. The application of standardized recommendations for NST could reduce the number of mastectomies advised by MDTs.
<p>Microsoft Excel workbook containing the following gene lists and information; A) 500 most variable genes from Figure 1D, B) differentially expressed genes between ILC and IDC at baseline and 3 months of treatment using Rank Products with a cut-off of 0.05 PFP figure 2, C) differentially expressed genes after 3 months of letrozole in ILC and IDCILC tumors using pairwise Rank Products with a cut-off of 0.05 PFP (percent false positive) from figure 3, D) genes from Sikora et al. 2014 [5] that were represented in the combined Affymetrix/Illumina dataset, E) Additional sample information including the NCBI GEO Accession numbers of the Affymetrix data.</p>
Abstract Background: ER+/HER2+ accounts for up to 10% of all breast cancers (BCs) and most are treated with endocrine therapy (ET) after surgery to reduce the recurrence risk. We developed and validated an immunohistochemistry (IHC) based test (EA2Clin) that incorporates baseline IL6ST, clinical variables and on-treatment measurement of MCM4. Responders (Rs) and non-responders (NRs) to ET are identified and it accurately estimates recurrence-free survival (RFS) and BC-specific overall survival (BCSS). The aim was to determine if EA2Clin could accurately predict ER+/HER2+ patients likely to benefit from ET and to determine if it can identify those for whom HER2-targeted therapies are required. Methods: 3 cohorts were studied: A: 32 post-menopausal women (PMW) with large ER+/HER2+ BC treated with neoadjuvant (3-6 months) then adjuvant letrozole. 5 also received adjuvant chemotherapy plus Herceptin. Neoadjuvant clinical response was assessed by changes in tumour volume. Tumour core biopsies were taken at 0, 14 days and 3 months. Gene expression analysis using Illumina HT12 whole-genome beadarrays was performed on a subset (n=17) where fresh tissue was available. B: 13 PMW with ER+/HER2+ BC who were treated by surgery without neoadjuvant therapy. RNA was extracted from excision tissues and analysed using whole-genome Affymetrix U133A microarrays. C: 15 PMW with ER+/HER2+ BC treated with 2-weeks of pre-operative letrozole (n=7) or anastrozole (n=8). All received adjuvant letrozole. Tissues were collected at pre-treatment and at surgery. None received Herceptin or chemotherapy. All patients were followed-up after surgery (median follow-up = 6.4 years). Results: In cohort A, half (16/32) of the patients responded to ET with tumour volume reductions of >70% with neoadjuvant treatment. Innate resistance was apparent in 3 patients with continued tumour growth on ET, whereas 13 patients developed resistance after a period of response. EAClin2 predicted neoadjuvant response with a 92% accuracy. There was increased expression of phospho-AKT and phospho-ERK in NRs, not seen in Rs. Half (8/16) of the NR cancers expressed phospho-ER; but was not seen in any responsive cancer. Gene expression analysis in 17 patients showed increased MAPK and PI3K pathway activity in the 9 NR compared with the 8 R tumours. These results were recapitulated in cohort B where MAPK and PI3K activity were associated with low levels of IL6ST. In the 16/32 patients who responded well to neoadjuvant ET the actuarial recurrence rate was 0% at 5 and 10 years. The rate of recurrence in the NR was 30% at both 5 and 10 years. Of the 5 patients who received chemotherapy plus Herceptin, none recurred despite a poor response to neoadjuvant letrozole (median length to last follow-up was 6.1 years). Initial data suggest that in cohort B EA2Clin identifies a group of ER+/HER2+ cancers that can be managed by ET alone. Conclusions: · The EA2Clin test identifies ER+/HER2+ BCs who respond well to ET alone and those with a poor clinical response who have higher risk of recurrence. · NR to ET have increased expression of PI3K and MAPK pathways, consistent with active HER2 signalling. · There is potential role for EA2Clin in selecting ER+/HER2+ patients that require and benefit from HER2-targeted therapies. Citation Format: Turnbull AK, Webber V, McStay D, Arthur L, Martinez-Perez C, Fernando A, Renshaw L, Keys J, Clarke R, Sims AH, Dixon JM. Predicting benefit from HER2-targeted therapies in patients with ER+/HER2+ breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-26.
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