Genomic Profiling in Luminal Breast Cancer

The developments in gene expression analysis have made it possible tosub-classify hormone receptor-positive (luminal) breast cancer indifferent prognostic subgroups. This sub-classification is currentlyused in clinical routine as prognostic signature (e. g. 21-gene OnoctypeDX (R), 70-gene Mammaprint (R)). As yet, the optimal method forsub-classification has not been defined. Moreover, there is no evidencefrom prospective trials. This review explores widely used genomicsignatures in luminal breast cancer, making a critical appraisal ofevidence from retrospective/prospective trials. It is based onsystematic literature search performed using Medline (accessed September2013) and abstracts presented at the Annual Meeting of American Societyof Clinical Oncology and San Antonio Breast Cancer Symposium

WSG ADAPT - adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early breast cancer: study protocol for a prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III trial

Background: Adjuvant treatment decision-making based on conventional clinical/pathological and prognostic single molecular markers or genomic signatures is a therapeutic area in which over-/under-treatment are still key clinical problems even though substantial and continuous improvement of outcome has been achieved over the past decades. Response to therapy is currently not considered in the decision-making procedure. ADAPT is one of the first new generation (neo) adjuvant trials dealing with individualization of (neo) adjuvant decision-making in early breast cancer and aims to establish early predictive surrogate markers, e. g., Ki-67, for therapy response under a short induction treatment in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment. Methods/design: The prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III ADAPT trial has an innovative ``umbrella{''} protocol design. The ``umbrella{''} is common for all patients, consisting of dynamic testing of early therapy response. ADAPT will recruit 4,936 patients according to their respective breast cancer subtype in four distinct sub-trials at 80 trial sites in Germany; 4,000 patients with hormone receptor positive (HR+) and HER2 negative disease will be included in the ADAPT HR+/HER2-sub-trial, where treatment decision is based on risk assessment and therapy response to induction therapy, and 380 patients will be included in ADAPT HER2+/HR+. A further 220 patients will be included in ADAPT HER2+/HR- and 336 patients will be recruited for ADAPT Triple Negative. These three sub-trials focus on identification of early surrogate markers for therapy success in the neoadjuvant setting. Patients will be allocated to the respective sub-trial according to the result of their diagnostic core biopsy, as reported by local/central pathology for HR and HER2 status. Discussion: Recent trials, such as the GeparTrio, have shown that response-guided therapy using clinical response may improve outcome. For chemotherapy or HER2-targeted treatment, pathologic complete response in a neoadjuvant setting is an excellent predictor of outcome. For endocrine therapy, response to short induction treatment - as defined by decrease in tumor cell proliferation - strongly correlates with outcome. ADAPT now aims to combine static prognostic and dynamic predictive markers, focusing not just on single therapeutic targets, but also on general markers of proliferation and cell death. Biomarker analysis will help to optimize selection of subtype-specific treatment. Trial registration: ClinicalTrials.gov: ADAPT Umbrella: NCT01781338; ADAPT HR+/HER2-: NCT01779206; ADAPT HER2+/HR+: NCT01745965; ADAPT HER2+/HR-: NCT01817452; ADAPT TN: NCT01815242

Adding epoetin alfa to intense dose-dense adjuvant chemotherapy for breast cancer : randomized clinical trial

BACKGROUND: The AGO-ETC trial compared 5-year relapse-free survival of intense dose-dense (IDD) sequential chemotherapy with epirubicin (E), paclitaxel (T), and cyclophosphamide (C) (IDD-ETC) every 2 weeks vs conventional scheduled epirubicin/cyclophosphamide followed by paclitaxel (EC→T) (every 3 weeks) as adjuvant treatment in high-risk breast cancer patients. The objective of this study was to evaluate the safety and efficacy of epoetin alfa in a second randomization of the intense dose-dense arm. METHODS: One thousand two hundred eighty-four patients were enrolled; 658 patients were randomly assigned to the IDD-ETC treatment group. Within the IDD-ETC group, 324 patients were further randomly assigned to the epoetin alfa group, and 319 were randomly assigned to the non-erythropoiesis-stimulating agent (ESA) control group. Primary efficacy endpoints included change in hemoglobin level from baseline to Cycle 9 and the percentage of subjects requiring red blood cell transfusion. Relapse-free survival, overall survival, and intramammary relapse were secondary endpoints estimated with Kaplan-Meier and Cox regression methods. Except for the primary hypothesis, all statistical tests were two-sided. RESULTS: Epoetin alfa avoided the decrease in hemoglobin level (no decrease in the epoetin alfa group vs -2.20g/dL change for the control group; P < .001) and statistically significantly reduced the percentage of subjects requiring red blood cell transfusion (12.8% vs 28.1%; P < .0001). The incidence of thrombotic events was 7% in the epoetin alfa arm vs 3% in the control arm. After a median follow-up of 62 months, epoetin alfa treatment did not affect overall survival, relapse-free survival, or intramammary relapse. CONCLUSIONS: Epoetin alfa resulted in improved hemoglobin levels and decreased transfusions without an impact on relapse-free or overall survival. However, epoetin alfa had an adverse effect, resulting in increased thrombosis

Genomic Profiling in Luminal Breast Cancer

The developments in gene expression analysis have made it possible tosub-classify hormone receptor-positive (luminal) breast cancer indifferent prognostic subgroups. This sub-classification is currentlyused in clinical routine as prognostic signature (e. g. 21-gene OnoctypeDX (R), 70-gene Mammaprint (R)). As yet, the optimal method forsub-classification has not been defined. Moreover, there is no evidencefrom prospective trials. This review explores widely used genomicsignatures in luminal breast cancer, making a critical appraisal ofevidence from retrospective/prospective trials. It is based onsystematic literature search performed using Medline (accessed September2013) and abstracts presented at the Annual Meeting of American Societyof Clinical Oncology and San Antonio Breast Cancer Symposium

Zurich Consensus: German Expert Opinion on the St. Gallen Votes on 15 March 2009 (11th International Conference at St. Gallen: Primary Therapy of Early Breast Cancer)

A German working group of 23 breast cancer experts discussed the results from the vote at this year's St. Gallen Consensus Conference on Primary Therapy for Early Breast Cancer ( March 11-14, 2009) and came up with some concrete recommendations for day-to-day therapeutic decisions in Germany. Due the fact that the concept of the St. Gallen Consensus Conference merely allows for a minimal consensus, the objective of the working group was to provide practice-related recommendations for day-to-day clinical decisions in Germany. One area of emphasis at St. Gallen was tumor biology as a starting point for reaching individual therapeutic decisions. Intensive discussion was necessary with respect to the clinical relevance of predictive and prognostic factors. A new addition to the area of systemic therapy was a first-ever discussion of the adjuvant administration of bisphosponates and the fact that therapy with trastuzumab in HER2 overexpressing breast cancer has been defined as the standard for neoadjuvant therapy. The value of taxanes as a component of (neo) adjuvant chemotherapy as well as the value of aromatase inhibitors for the endocrine adjuvant treatment of postmenopausal patients were affirmed

Zurich Consensus: Statement of German Experts on St. Gallen Conference 2011 on Primary Breast Cancer (Zurich 2011)

Every 2 years, the International Consensus Conference on the Treatment of Primary Breast Cancer takes place in St. Gallen. Given that the concept of the St. Gallen Consensus Conference mainly reflects an international opinion, it appears useful to adapt the results of the vote for everyday therapy in Germany. A German working group comprising 28 breast cancer experts, amongst whom there are 3 members of the international St. Gallen panel, has therefore commented on this year's St. Gallen Consensus Conference (2011) from the German viewpoint. The focus of interest of this year's St. Gallen Conference was tumour biology as the starting point for decisions regarding individual therapy. There was an intensive discussion in relation to the clinical relevance of predictive and prognostic factors and possible consequences for decisions regarding therapy. Therefore, questions concerning the indication for adjuvant chemotherapy focused especially on the significance of the molecular phenotype of the tumour. In addition, important points for discussion were also the value of complete axillary dissection and the use of accelerated complete breast irradiation

Evidence-based guidelines for managing patients with primary ER+ HER2− breast cancer deferred from surgery due to the COVID-19 pandemic

Many patients with ER+ HER2- primary breast cancer are being deferred from surgery to neoadjuvant endocrine therapy (NeoET) during the COVID-19 pandemic. We have collated data from multiple international trials of presurgical endocrine therapy in order to provide guidance on the identification of patients who may have insufficiently endocrine-sensitive tumors and should be prioritised for early surgery or neoadjuvant chemotherapy rather than NeoET during or in the aftermath of the COVID-19 pandemic for safety or when surgical activity needs to be prioritized. For postmenopausal patients, our data provide strong support for the use of ER and PgR status at diagnosis for triaging of patients into three groups in which (taking into account clinical factors): (i) NeoET is likely to be inappropriate (Allred ER 10%) indicates a higher priority for early surgery. Too few data were available for premenopausal patients to provide a similar treatment algorithm. These guidelines should be helpful for managing patients with early ER+ HER2- breast cancer during and in the aftermath of the COVID-19 crisis

Patient’s Anastrozole Compliance to Therapy (PACT) Program: Baseline Data and Patient Characteristics from a Population-Based, Randomized Study Evaluating Compliance to Aromatase Inhibitor Therapy in Postmenopausal Women with Hormone-Sensitive Early Breast Cancer

BACKGROUND: The Patient's Anastrozole Compliance to Therapy (PACT) program is a large randomized study designed to assess whether the provision of educational materials (EM) could improve compliance with aromatase inhibitor therapy in postmenopausal women with early, hormone receptor-positive breast cancer. PATIENTS AND METHODS: The PACT study presented a large, homogeneous dataset. The baseline analysis included patient demographics and initial treatments and patient perceptions about treatment and quality of life. RESULTS: Overall, 4,923 patients were enrolled at 109 German breast cancer centers/clinics in cooperation with 1,361 office-based gynecologists/oncologists. 4,844 women were randomized 1:1 to standard therapy (n = 2,402) or standard therapy plus EM (n = 2,442). Prior breast-conserving surgery and mastectomy had been received by 76% and 24% of the patients, respectively. Radiotherapy was scheduled for 85% of the patients, adjuvant chemotherapy for 38%. Reflecting the postmenopausal, hormone-sensitive nature of this population, only 285 patients (7%) had received neoadjuvant chemotherapy. CONCLUSIONS: A comparison with epidemiological data from the West German Breast Center suggests that the patients in the PACT study are representative of a general postmenopausal early breast cancer population and that the findings may be applicable to ‘real-world’ Germany and beyond. Compliance data from PACT are eagerly anticipated

70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer.

The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy. In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher. A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease. Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. (Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31.)