Estrogen Receptor-positive Early Breast Cancer Research Articles

Impact of 70-Gene Signature Use on Adjuvant Chemotherapy Decisions in Patients With Estrogen Receptor-Positive Early Breast Cancer: Results of a Prospective Cohort Study.

Purpose Gene-expression profiles increasingly are used in addition to conventional prognostic factors to guide adjuvant chemotherapy (CT) decisions. The Dutch guideline suggests use of validated gene-expression profiles in patients with estrogen receptor (ER) -positive, early-stage breast cancer without overt lymph node metastases. We aimed to assess the impact of a 70-gene signature (70-GS) test on CT decisions in patients with ER-positive, early-stage breast cancer. Patients and Methods In a prospective, observational, multicenter study in patients younger than 70 years old who had undergone surgery for ER-positive, early-stage breast cancer, physicians were asked whether they intended to administer adjuvant CT before deployment of the 70-GS test and after the test result was available. Results Between October 1, 2013, and December 31, 2015, 660 patients, treated in 33 hospitals, were enrolled. Fifty-one percent of patients had pT1cN0, BRII, HER2-Neu-negative breast cancer. On the basis of conventional clinicopathological characteristics, physicians recommended CT in 270 (41%) of the 660 patients and recommended withholding CT in 107 (16%) of the 660 patients. For the remaining 43% of patients, the physicians were unsure and unable to give advice before 70-GS testing. In patients for whom CT was initially recommended or not recommended, 56% and 59%, respectively, were assigned to a low-risk profile by the 70-GS (κ, 0.02; 95% CI, -0.08 to 0.11). After disclosure of the 70-GS test result, the preliminary advice was changed in 51% of patients who received a recommendation before testing; the definitive CT recommendation of the physician was in line with the 70-GS result in 96% of patients. Conclusion In this prospective, multicenter study in a selection of patients with ER-positive, early-stage breast cancer, 70-GS use changed the physician-intended recommendation to administer CT in half of the patients.

Identifying biomarkers to select patients with early breast cancer suitable for extended adjuvant endocrine therapy.

In this review, we summarize recent and current biomarkers and assays that are being considered in the selection of suitable patients with estrogen receptor-positive early breast cancer for extended (years 5-10) adjuvant endocrine therapy (AET). Women with estrogen receptor-positive early-stage breast cancer (65% of cases) continue to have late risk for distant recurrence extending beyond 5 years from surgery. Recent large trials have consistently demonstrated improvement for prolonging endocrine therapy. However, endocrine therapy can cause women bothersome side effects and can negatively impact quality of life. Determining which patients remain at risk for disease recurrence and predicting which of these patients would derive the most benefit from the addition of extended AET are key issues faced by patients and oncologists today. A number of predictive molecular assays have been developed and are being considered as tools to be used in guiding the implementation of adjuvant systemic therapy. The future holds much promise and as more information and understanding is acquired, treatment regimens will increasingly incorporate clinically validated biomarker assays in the decision-making process that will be of great benefit to these patients. Proving clinical utility, though, will ultimately decide their implementation.

Extended adjuvant endocrine therapy in hormone-receptor-positive early breast cancer.

The risk of relapse associated with oestrogen receptor-positive early breast cancer persists for at least 15 years after diagnosis. Several large clinical trials have examined extended adjuvant endocrine therapy. The MA.17 trial demonstrated improved disease-free survival (DFS) with use of letrozole for 5 years after some years of tamoxifen and an overall survival advantage for this approach in women with node-positive oestrogen receptor-positive cancer at diagnosis. The subsequent adjuvant tamoxifen - to offer more? and adjuvant tamoxifen: longer against shorter trials demonstrated a DFS advantage for 10 years of tamoxifen over 5 years. The recently reported MA.17R trial randomized women who had already completed 5 years of aromatase inhibitor therapy with or without previous tamoxifen to further 5 years of letrozole or placebo. DFS was significantly improved in the extended letrozole group, quality of life was similar but bone fracture rates were higher. The absolute benefit in terms of reduced distant recurrences in these studies is modest, and tolerability and compliance challenges remain. Physicians and patients now have multiple evidence-based treatment options for women who complete 5 years of adjuvant endocrine therapy. Extended therapy with either tamoxifen or letrozole should be considered for all and decision based on menopausal status, individual risk, tolerance and magnitude of potential benefit.

The Role of the 21-Gene Recurrence Score in Breast Cancer Treatment.

Several multi-gene assays have been developed to predict the risk of recurrence in patients with estrogen receptor-positive early breast cancer and in whom endocrine therapy is planned. The 21-gene assay is widely used and its prognostic value has been retrospectively validated, showing significant differences in the risk of distant recurrence for patients at high versus low risk. Its role in predicting chemotherapy benefit has also been established, showing a clear benefit for high-risk patients and minimal benefit in those at low risk. These findings have been prospectively investigated in TAILORx (Trial Assigning Individualized Options for Treatment), where available data from the low-risk cohort confirms the prognostic value of this diagnostic test. The prognostic utility of the 21-gene assay increases when combined with clinicopathologic variables, and data from integrated models suggest that its use should be limited to patients with tumor characteristics suggestive of potential chemotherapy benefit. Furthermore, the 21-gene assay has been shown to impact clinical decision making in a cost-effective manner, although direct evidence of benefit from modified treatment recommendations is yet to be proven. The prognostic value of this test has also been shown in populations with node-positive or locally advanced disease treated with neoadjuvant chemotherapy, and ongoing trials aim to prospectively validate these findings.

New insights on PI3K/AKT pathway alterations and clinical outcomes in breast cancer.

PI3K/AKT signaling pathway plays an important role in tumorigenesis and regulates critical cellular functions including survival, proliferation and metabolism. PIK3CA mutations and AKT activation by phosphorylation (pAKT) are often detected in many cancers and especially at high frequencies in breast cancer. Mounting data suggest that PIK3CA mutations or pAKT are mostly associated with better or insignificant outcomes in estrogen receptor-positive (ER+) early stage breast cancer and tend to be with worse prognosis in ER- disease. pAKT expression has been identified to predict paclitaxel chemotherapy benefit in node-positive breast cancer. Preclinical and neoadjuvant trial data suggest that PIK3CA alterations confer resistance to HER2-targeted therapy and are associated with lower pathological complete response (pCR) rate in HER2-positive breast cancer. However, recent results from randomized clinical trials of adjuvant and metastatic settings show that patients with mutant and wildtype PIK3CA tumors derived similar benefit from anti-HER2 therapy. This article, with our new insights, aims to decipher the mixed data and discusses the influence of the potential confounding factors in the assessments. We also share our views for validation of PI3K/AKT alterations in relation to clinical outcome in the context of specific breast cancer subtypes and treatment modalities towards further advance of the precision medicine for breast cancer treatment.

The impact of the 21-gene assay on adjuvant treatment decisions in oestrogen receptor-positive early breast cancer: a prospective study.

Background:International guidelines, including NICE, recommend using the 21-gene Recurrence Score assay for guiding adjuvant treatment decisions in ER+, HER2-negative early breast cancer (BC). We investigated the impact of adding this assay to standard pathological tests on clinicians'/patients' treatment decisions and on patients' decisional conflict in the United Kingdom.Methods:In this prospective multicentre study, eligibility criteria included: ER+ HER2-negative BC (N0/Nmic for patients ⩽50 years; ⩽3 positive lymph nodes for patients >50 years) and being fit for chemotherapy. Physicians'/patients' treatment choices and patients' decisional conflict were recorded pre- and post testing.Results:The analysis included 137 patients. Overall, adjuvant treatment recommendations changed in 40.7% of patients, with the direction of the change consistent with the Recurrence Score results (net decrease in chemotherapy recommendation rate in low Recurrence Score patients and net increase in high Recurrence Score patients). Patients' choices were generally consistent with physicians' recommendations. Post-testing, patients' decisional conflict decreased significantly (P<0.0001). In the 67 patients meeting the NICE criteria for testing, the recommendation change rate was 49.3%.Conclusions:Recurrence Score testing significantly influenced treatment recommendations overall and in the subgroup of patients meeting the NICE criteria, suggesting that this test could substantially alter treatment patterns in the United Kingdom.

Abstract P5-08-06: Comparison of risk prediction with the 21-gene recurrence score (oncotype DX) and the 70-gene signature (MammaPrint) in patients with estrogen receptor-positive early stage breast cancer

Abstract Background: Gene expression profiling assays estimate prognosis &amp; predict benefit from adjuvant chemotherapy in patients (pts) with estrogen receptor positive (ER+) early stage breast cancer (ESBC). The 21-gene recurrence score (RS) and 70-gene signature (MP) are widely used assays. Pts may have both tests performed to adjudicate discordant results. We compared RS and MP in pts with both tests and evaluated their impact on adjuvant treatment decisions. Methods: This was a retrospective clinical cohort study from 5 centers from 2007-2014. Eligibility included ER+ ESBC with RS and MP results from the same tissue sample; exclusions included carcinoma in situ, primary metastatic disease, &amp; bilateral breast cancer. Two definitions of RS risk were evaluated (Genomic Health [GH] or TAILORx [TRx]): low risk (GH:0-17) or (TRx:0-10); intermediate risk (GH:18-30) or (TRx:11-25); and high risk (GH:&amp;gt;31) or (TRx:&amp;gt;26). Demographic, clinicopathologic (CP) data, and treatment decisions were extracted from medical records. Agreement was assessed between RS and MP using weighted kappa scores. CP factors were assessed with the t-test and chi-square test. Results: 123 pts were identified from UCSF or 4 US Oncology Network practices. 60 pts had low risk RS (GH); 27 were low risk by MP (45% agreement). 15 cases had a low risk RS (TRx); 9 were low risk by MP (60%). 10 pts had high risk RS (GH); 8 were high risk by MP (80.0%). Similarly, 18 cases had high risk (TRx) RS;16 were high risk by MP (88%). Using the RS GH risk definition, there was poor agreement for low risk RS/MP and high risk RS/MP (kappa=0.169). However, using the TRx RS risk definition, there was good agreement for low risk RS/ MP and high risk RS/MP (kappa=0.509). 53 pts had intermediate risk RS by (GH); by MP 16 were low risk (30%), and 37 were high risk (70%). 90 pts had an intermediate risk RS by TRx; by MP 34 were low risk (37.8%), and 56 were high risk by MP (62.2%). Using TRx RS increased the number of pts classified as intermediate risk compared to GH RS (73.2 vs 43.1%). Complete adjuvant treatment data were available for 90 patients. Of 40 pts with low risk RS (GH), 25% received chemotherapy associated with node status but not tumor size, grade, or MP. Of 10 pts with high risk RS (GH), 70% received chemotherapy without association with CP features or MP. For the 45 pts with intermediate risk RS (GH), 53% received chemotherapy, without correlation with CP features. Receipt of chemotherapy was positively associated with MP high risk, but this was not significant (odds ratio 2.08, 95% CI 0.54-8.01); p-0.29. Conclusion: Concordance in risk prediction between RS and MP was greater using RS defined by TRx compared to GH, and RS using TRx increases those categorized as intermediate risk. There appeared to be no correlation between CP features and decisions to use chemotherapy across risk groups. Interestingly, in those with intermediate risk RS (GH or TRx), there was a non-significant trend toward use of chemotherapy in those with high risk by MP. Although gene expression tests are used frequently to aid in treatment decisions in ESBC, considerable variation exists in their application in clinical practice. Citation Format: Jiang H, Denduluri N, Majure M, Favret A, Rugo HS. Comparison of risk prediction with the 21-gene recurrence score (oncotype DX) and the 70-gene signature (MammaPrint) in patients with estrogen receptor-positive early stage breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-06.

Abstract 5290: Identification of novel prognostic genes associated with risk of recurrence in early breast cancer patients

Abstract Introduction : In order to determine the need for adjuvant chemotherapy in early estrogen receptor-positive breast cancer, especially luminal A, it is important to identify patients at high risk of recurrence. This study was performed to identify novel prognostic genes associated with the recurrence risk of patients with lymph node-negative luminal A (LN−/LumA) breast cancer. Methods : RNA was extracted from formalin-fixed, paraffin-embedded (FFPE) breast cancer tissues. The expression levels of 16 candidate genes identified from our previous study were measured using quantitative real-time reverse transcription-PCR in 926 FFPE samples. We used Cox proportional hazards models to assess the prognostic value of clinical and gene variables for recurrence. Results : Of the 796 patients with recurrence-free survival (RFS) and 826 patients with overall survival (OS), 24.4% (194/796) and 24.0% (198/826), respectively, had LN−/LumA breast cancer. Univariate analysis showed that clinical variables such as tumor size, involvement of lymph nodes, and tumor stage were not significantly associated with RFS and OS of patients with this subtype. In contrast, there was a significant association between gene expression and patient outcomes. Higher expression of 4 proliferation-related genes (F4, M4, R3, and U4) was significantly correlated with shorter OS and RFS. Importantly, in multivariate analyses, high expression of R3 and U4 remained significantly associated with RFS. While not significantly related to RFS in univariate analysis, immune response-related B5 expression had a significantly lower harzard ratio in the multivariate analysis (P = 0.004), indicating it was an independent positive prognostic factor. Higher expression of M4 (P = 0.014) and R3 (P = 0.01) was independently associated with shorter OS. When tested using gene variables, prognostic models for risk of recurrence included M4, R3, U4, and B5. Moreover, patients with low B5 and high U4 expressions had a significantly shorter RFS than those with high B5 and low U4 expressions. Conclusions : Novel prognostic genes identified in our study give more significant information on the risk of recurrence than clinical variables in patients with LN−/LumA breast cancer. Multigene expression signatures, including immune response-related genes, can be used to identify patients at high risk of recurrence in this subtype of breast cancer. Citation Format: Mi Jeong Kwon. Identification of novel prognostic genes associated with risk of recurrence in early breast cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5290. doi:10.1158/1538-7445.AM2015-5290

Clinical utility of the IHC4+C score in oestrogen receptor-positive early breast cancer: a prospective decision impact study.

Background:Most oestrogen receptor (ER)-positive early breast cancer diagnosed today is highly curable with multimodality treatment. Systemic adjuvant treatments including endocrine therapy and chemotherapy have made a significant contribution to the increasing cure rates over the past three decades. However not all women will require chemotherapy. The IHC4+C score is a prognostic tool that integrates four immunohistochemical measures with clinicopathological features to estimate the residual risk of distant recurrence at 10 years in post-menopausal women with ER-positive breast cancer who have received 5 years of endocrine therapy. Retrospective studies indicate that the test can identify a set of women that are at such low risk of recurrence that chemotherapy can be of little benefit.Methods:In this study, 124 patients were prospectively selected from the multidisciplinary team meeting between January 2013 and April 2014 for IHC4+C testing. Adjuvant systemic treatment recommendations by clinicians were recorded without and with the availability of the score in addition to the patient's decision.Results:There was concordance in the MDT's recommendation without and with the availability of the score in 73% of cases. Clinicians recommended chemotherapy or at least its discussion to 74 (59%) patients, which fell to 32 (34%) patients after the IHC4+C score was made available, sparing one in four tested patients a chemotherapy recommendation, along with its toxicity and expense.Conclusion:This decision impact study shows that when used by clinicians in the multidisciplinary team meeting for adjuvant decision-making, a significant proportion of patients are spared chemotherapy recommendations.

Prospective Clinical Utility Study of the Use of the 21-Gene Assay in Adjuvant Clinical Decision Making in Women With Estrogen Receptor-Positive Early Invasive Breast Cancer: Results From the SWITCH Study.

The 21-gene Oncotype DX Recurrence Score assay is a validated assay to help decide the appropriate treatment for estrogen receptor-positive (ER+), early-stage breast cancer (EBC) in the adjuvant setting. The choice of adjuvant treatments might vary considerably in different countries according to various treatment guidelines. This prospective multicenter study is the first to assess the impact of the Oncotype DX assay in the French clinical setting. A total of 100 patients with ER+, human epidermal growth factor receptor 2-negative EBC, and node-negative (pN0) disease or micrometastases in up to 3 lymph nodes (pN1mi) were enrolled. Treatment recommendations, physicians' confidence before and after knowing the Recurrence Score value, and physicians' perception of the assay were recorded. Of the 100 patients, 95 were evaluable (83 pN0, 12 pN1mi). Treatment recommendations changed in 37% of patients, predominantly from chemoendocrine to endocrine treatment alone. The proportion of patients recommended chemotherapy decreased from 52% pretest to 25% post-test. Of patients originally recommended chemotherapy, 61% were recommended endocrine treatment alone after receiving the Recurrence Score result. For both pN0 and pN1mi patients, post-test recommendations appeared to follow the Recurrence Score result for low and high values. Physicians' confidence improved significantly. These are the first prospective data on the impact of the Oncotype DX assay on adjuvant treatment decisions in France. Using the assay was associated with a significant change in treatment decisions and an overall reduction in chemotherapy use. These data are consistent with those presented from European and non-European studies.

The UZ Leuven Policy for Extended Adjuvant Anti-estrogen Therapy in Women With Early Estrogen Receptor-Positive Breast Cancer.

Opinion statement: Five years after adjuvant endocrine treatment for estrogen receptor (ER)-positive breast cancer, patients have a 2 to 20 % risk of metastatic relapse during the next 5 years. Extended adjuvant endocrine therapy seems to further lower this. In UZ Leuven, extended endocrine therapy is now discussed unless the tumor was a grade 1-2, pT1N0, ER-positive, progesterone receptor (PR)-positive, HER2-negative lesion. After 5 years of adjuvant tamoxifen treatment for ER-positive breast cancer, we encourage women to take another 5 years of tamoxifen. If the tumor was lymph node-positive at diagnosis and patients are menopausal after the first 5 years of tamoxifen, we advise to take prolonged treatment with an oral aromatase inhibitor (AI). For this particular group, available data for extending endocrine therapy with an AI after 5 years of tamoxifen are strongest and more convincing for letrozole than for anastrozole or exemestane. Under these conditions, letrozole is reimbursed for 3 years in Belgium. If women are postmenopausal at diagnosis and already used an oral AI at any time during the first 5 years, we discuss an extra 5 years of tamoxifen. Results from ongoing clinical trials will tell us whether in these cases prolonged AI use is better than tamoxifen so that therapy can be adapted. Benefit from extended adjuvant endocrine therapy is likely larger with better compliance and potential side effects of extended endocrine therapy need to be discussed. Therefore, when advising extended adjuvant endocrine treatment, a balance should always be made between relapse risk and treatment tolerance/compliance.

Economic evaluation of hormonal therapies for postmenopausal women with estrogen receptor-positive early breast cancer in Canada.

Aromatase inhibitor (ai) therapy has been subjected to numerous cost-effectiveness analyses. However, with most ais having reached the end of patent protection and with maturation of the clinical trials data, a re-analysis of ai cost-effectiveness and a consideration of ai use as part of sequential therapy is desirable. Our objective was to assess the cost-effectiveness of the 5-year upfront and sequential tamoxifen (tam) and ai hormonal strategies currently used for treating patients with estrogen receptor (er)-positive early breast cancer. The cost-effectiveness analysis used a Markov model that took a Canadian health system perspective with a lifetime time horizon. The base case involved 65-year-old women with er-positive early breast cancer. Probabilistic sensitivity analyses were used to incorporate parameter uncertainties. An expected-value-of-perfect-information test was performed to identify future research directions. Outcomes were quality-adjusted life-years (qalys) and costs. The sequential tam-ai strategy was less costly than the other strategies, but less effective than upfront ai and more effective than upfront tam. Upfront ai was more effective and less costly than upfront tam because of less breast cancer recurrence and differences in adverse events. In an exploratory analysis that included a sequential ai-tam strategy, ai-tam dominated based on small numerical differences unlikely to be clinically significant; that strategy was thus not used in the base-case analysis. In postmenopausal women with er-positive early breast cancer, strategies using ais appear to provide more benefit than strategies using tam alone. Among the ai-containing strategies, sequential strategies using tam and an ai appear to provide benefits similar to those provided by upfront ai, but at a lower cost.

The clinical impact of 21-gene recurrence score on treatment decisions for patients with hormone receptor-positive early breast cancer in Korea.

PurposeThe 21-gene (Oncotype DX) recurrence score (RS) assay is useful in predicting the benefits of adjuvant chemotherapy for early breast cancer patients and is widely used in Western countries. However, to date, it has not gained much popularity in East Asia. We analyzed the results from five institutions’ experience from using the 21-gene assay and examined the impact of assay results on decision making of chemotherapy in Korean breast cancer patients and the associations between RS and clinicopathologic characteristics.Materials and MethodsThe 21-gene assay was performed on 212 patients with estrogen receptor-positive early breast cancer in five institutions. Each center made systemic treatment decisions both before and after the knowledge of assay results.ResultsAmong the 212 patients, 132 (62.3%) had a low RS of < 18, 60 (28.3%) had an intermediate RS of 18-30, and 20 (9.4%) had a high RS of ≥ 31. Histologic grade, presence of micrometastases, Ki-67, and presence of lymphatic invasion were statistically associated with the RS results. Treatment decisions were changed in 115 of 212 patients (54.2%) in 109 of 212 (51.4%) from chemotherapy plus hormone therapy to hormone therapy, and in six of 212 (2.8%) from hormone therapy to chemotherapy plus hormone therapy.ConclusionThe 21-gene breast cancer assay proved to have a significant impact on treatment decision- making. The test reduces chemotherapy use in more than 50% of Korean estrogen receptor-positive, early breast cancer patients.

288P - Impact of the 21-Gene Breast Cancer Assay on Treatment Recommendations for Estrogen Receptor-Positive (Er+) Early Stage Breast Cancer (Esbc) in Hong Kong

ABSTRACT Aim: The 21-gene breast cancer assay has been validated to assess risk of distant recurrence and the likelihood of chemotherapy (CT) benefit in ER+ ESBC patients in a number of different populations. In Hong Kong >80% of breast cancers are ESBC and >60% of these women receive CT. The assay's impact on adjuvant treatment recommendations has not been reported in a Chinese population. This prospective decision impact study measured changes in physician treatment recommendations in this new population of patients. Methods: Eligible patients from 6 institutions had ER + , T1-3 N0-1mi M0 ESBC. After surgery, physicians discussed treatment options with patients, then ordered the assay. After receipt of the result the treatment recommendation was reassessed. Changes in treatment recommendation, CT utilization, and physician confidence were measured, as was physician rating of influence on their recommendation. Results: One hundred fifty consecutive patients were enrolled. Four were not evaluable. The remaining 146 eligible patients had treatment recommendations before and after testing. CT recommendations, which included changes in CT intensity, were changed for 34/146 patients, (23.3%, 95% CI 16.7%-31.0%). There were 27 changes in treatment recommendations of adding or removing CT altogether (18.5% change, 95% CI 12.6%-25.8%). CT recommendations decreased from 52.1% to 37.7%, a net reduction of 14.4% (p Conclusions: The primary outcome suggests that the 21-gene breast cancer assay influences adjuvant treatment recommendations by physicians in Hong Kong for their patients with ESBC. Disclosure: R. Leung, T. Yau and P. Cheung:: We received financial support from Genomic Health, Inc. for the conduct of this study. I have no other conflicts of interest to declare; C. Chao: I am an employee and hold stock shares in Genomic Health which develops and commercializes the Oncotype DX assay; C. Yoshizawa: I am an employee and hold stock shares in Genomic Health which develops and commercializes the Oncotype DX assay.

Antiestrogenic effects of the fetal estrogen estetrol in women with estrogen-receptor positive early breast cancer.

Estetrol (E4) is a fetal estrogen with estrogenic effects on reproductive organs and bone in preclinical models and in postmenopausal women. However, E4 exerts antiestrogenic effects on breast cancer (BC) cell growth in vitro and in vivo. We have investigated the effect of 14 days preoperative treatment with 20mg E4 per day on tumor proliferation markers, sex steroid receptor expression and endocrine parameters in a prospective, randomized, placebo-controlled, preoperative window trial in 30 pre- and post-menopausal women with estrogen-receptor positive early BC. E4 had a significant pro-apoptotic effect on tumor tissue, whereas Ki67 expression remained unchanged in both pre- and post-menopausal women. E4 increased sex-hormone-binding globulin significantly thereby reducing the concentrations of bioavailable estradiol. Follicle-stimulating hormone levels decreased in postmenopausal women only and luteinizing hormone levels remained unchanged. Systemic insulin growth factor-1 levels decreased significantly. Intratumoral epithelial ERα expression decreased significantly and a trend was found towards an increased expression of ERβ. This clinical data support the preclinical findings that E4 has antiestrogenic effects on BC cells, whereas earlier studies have shown that E4 has estrogenic effects on reproductive tissues and bone. Further clinical studies seem acceptable and are needed to confirm the safety and efficacy of E4 for the breast in hormone replacement therapy, including hormone replacement therapy in women who have or have had BC, especially in those BC patients treated with aromatase inhibitors and suffering from serious complaints due to estrogen deficiency.

Combination treatment of tamoxifen with risperidone in breast cancer.

Tamoxifen has long been used and still is the most commonly used endocrine therapy for treatment of both early and advanced estrogen receptor-positive breast cancer in pre- and post-menopause women. Tamoxifen exerts its cytotoxic effect primarily through cytostasis which is associated with the accumulation of cells in the G0/G1 phase of the cell cycle. Apoptotic activity can also be exerted by tamoxifen which involves cleavage of caspase 9, caspase 7, caspase 3, and poly-ADP-ribose polymerase (PARP). Down-regulation of anti-apoptotic proteins Bcl-2 and Bcl-xL and up-regulation of pro-apoptotic proteins Bax and Bak have also been observed. In addition, stress response protein of GRP 94 and GRP 78 have also been induced by tamoxifen in our study. However, side effects occur during tamoxifen treatment in breast cancer patients. Researching into combination regimen of tamoxifen and drug(s) that relieves tamoxifen-induced hot flushes is important, because drug interactions may decrease tamoxifen efficacy. Risperidone has been shown to be effective in reducing or eliminating hot flushes on women with hormonal variations. In this present study, we demonstrated that combination of tamoxifen with risperidone did not interfered tamoxifen-induced cytotoxic effects in both in vitro and in vivo models, while fluoxetine abrogated the effects of tamoxifen. This is the first paper suggesting the possibility of combination treatment of tamoxifen with risperidone in breast cancer patients, providing a conceivable resolution of tamoxifen-induced side effects without interfering the efficacy of tamoxifen against breast cancer.

Treatment decisions in estrogen receptor-positive early breast cancer patients with intermediate oncotype DX recurrence score results

This retrospective study evaluated the impact of intermediate Recurrence Score® results on adjuvant treatment decisions in estrogen receptor-positive (ER+) early invasive breast cancer, comparing treatment recommendations pre-testing with actual treatments received post-testing. Of the 111 patients included in the analysis, 78 (70.3%) had hormonal therapy (HT) and 33 (29.7%) had chemohormonal therapy (CHT) recommendations pre-testing. The Recurrence Score was significantly higher in those with a pre-testing CHT recommendation compared with those with a pre-testing HT recommendation (median of 24 vs. 22; P = 0.047; Mann–Whitney–Wilcoxon [MWW] test). Post-testing, treatment of 24 patients (21.6%) was different from their pre-testing recommendation. The difference between CHT recommendation rate pre-testing and the rate of CHT received post-testing was nonsignificant for the entire cohort and for patients’ subgroups (by age, tumor size, and grade) (P >0.17; McNemar’s test). Following classification of the cohort into two Recurrence Score subcategories (low-intermediate, [18-25]; high-intermediate, [26-30]), changes in treatment decisions (pre-testing recommendations vs. actual treatments received post testing) were reported for 16.5% of low-intermediate and 34.4% of high-intermediate patients. Post-testing, the rate of CHT decreased (by 58%) in the low-intermediate subcategory and increased (by 64%) in the high-intermediate subcategory (P <0.01, both subcategories). In logistic regression analyses, the Recurrence Score subcategory was the only significant predictor of changes in treatment decisions (pre-testing recommendations vs. actual treatments received post testing; P <0.01). The only significant difference between the two subsets of patients with such a change (HT to CHT, 11 patients; CHT to HT, 13 patients) was the Recurrence Score (median of 28 vs. 20, respectively; P = 0.0014; MWW test). These findings demonstrate that intermediate Recurrence Score results provide clinically relevant information and impact treatment decisions in ER + early breast cancer.

Locoregional Recurrence and Survival Rates after Breast-Conserving Surgery and Hormonal Therapy in 70-Year-Old or Older Patients with Stage I or IIA Breast Carcinoma

Background: Data for treatment of elderly women (≥ 70 years) with estrogen receptor-positive early stage breast cancer are available. We have compared different treatment options to determine whether lumpectomy (LU) plus adjuvant hormonal therapy (HT) is as effective as combined LU, HT, and radiotherapy (RT). Method: Medical records of elderly patients over 69 years of age who had been treated for T1N0M0 (stage I) and T2N0M0 (stage IIA) at 2 different medical centers between March 2004 and January 2011 were assessed, and 35 patients were included in this study. 21 of these patients underwent only breast-conserving surgery (BCS) and HT (Group 1: T1N0M0-Group 1a, n = 16; T2N0M0-Group 1b, n = 5) and the others either BCS, HT and RT (Group 2, n = 4) or BCS, chemotherapy (CT), HT and RT (Group 3, n = 10). Adjuvant HT for all the patients comprised aromatase inhibitors. Results: The mean follow-up period for Groups 1, 2 and 3 were 32.2, 31.3 and 20.4 months, respectively. No locoregional recurrence or cancer-specific mortality occurred in any of these patients; 1 patient from Group 1 died of a different cause. Discussion: The BCS+HT regimen seems to be an efficient treatment option for early stage breast cancer in selected 70-year-old and older patient groups.

Abstract P6-07-03: Risk classification of Early Stage Breast Cancer as Assessed by MammaPrint and Oncotype DX Genomic Assays

Abstract Background: The 21-gene Oncotype DX® Recurrence Score® assay has been validated for prediction of 10-year risk of distant recurrence and likelihood of benefit from chemotherapy (CT) in patients (Pts) with estrogen receptor-positive (ER+) early stage breast cancer (ESBC). MammaPrint® is a multi-gene assay that has been validated as a prognosticator in a heterogenous Pt population that includes ER+, ER−, triple negative and HER2+ Pts. While the development and validation cohorts for these genomic assays are significantly different, the tests are frequently believed to provide equivalent information. The aim of the present study was to assess how these tests classify patients when compared side by side in the same Pt specimen. Materials and methods: Pts with ER+, HER2−, ESBC in which the MammaPrint assay had been sent were identified at the Institut du Sein, Paris, France. Clinical and pathological characteristics and the MammaPrint results (failure, low or high risk) were collected. Oncotype DX quantitative RT-PCR analysis was performed at Genomic Health and was blinded to the clinical and MammaPrint data. Descriptive statistics were calculated for failure rates, cross classification, and tumor characteristics. Results: Informed consent and sufficient tumor material for analysis was available from 67 Pts who were predominantly low and intermediate risk by clinicopathologic features: Tumor grade- 24 low, 36 intermediate and 7 high; Histology- 49 ductal, 14 lobular and 4 other. MammaPrint analysis had failed to deliver result for 10 of the 67 Pts. Recurrence Score results were generated in all 67 Pts. The risk classification of the MammaPrint and Oncotype DX tests in the 57 patients where both results were available is presented in the Table below. Of note, there were only 2 high Recurrence Score results compared with 22 high risk MammaPrint results. Furthermore, 45% of the Pts with high risk MammaPrint result had a low Recurrence Score result; they also had high quantitative ER expression of more than 9.5 expression units by RT-PCR, which is associated with likely hormonal therapy benefit. There was no clear association between tumor characteristics and MammaPrint failure or differences in risk classification. Conclusions: This direct comparison demonstrates that the MammaPrint and Oncotype DX tests classify a large proportion of Pts differently. Of note, nearly half of the Pts with high risk MammaPrint result had a low Recurrence Score indicating minimal, if any, benefit from chemotherapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-03.

297 Efficacy and Safety of Fetal Human Estrogen Estetrol (E4) in Women with Estrogen-receptor Positive Early Breast Cancer

297 Efficacy and Safety of Fetal Human Estrogen Estetrol (E4) in Women with Estrogen-receptor Positive Early Breast Cancer