Exemestane in early breast cancer: a review

The adjuvant treatment of women with endocrine-sensitive early breast cancer has been dominated for the last 40 years by tamoxifen. However, the side-effects associated with this therapy have prompted a search for safer and biochemically more selective endocrine agents and led to the development of the third-generation aromatase inhibitors (AIs) anastrozole, letrozole and exemestane. Promising results in advanced disease have paved the way for treating early breast cancer, and AIs are increasingly replacing tamoxifen in the adjuvant setting. Several large, randomized trials with AIs have been completed or are ongoing in women with early-stage breast cancer, documenting the significant impact that these drugs are making on the risk for recurrence of breast cancer. As a result, there is increasing and widespread use of AI therapy for the treatment of early-stage endocrine-responsive breast cancer. This review summarizes the data for exemestane in the adjuvant setting, showing that a switch to exemestane after 2 to 3 years of tamoxifen therapy is associated with a statistically significant survival benefit and is regarded as being sensitive by international and national experts

Trastuzumab (Herceptin (R)): Monoclonal antibody in the treatment of HER2/neu-overexpressing breast cancer in the metastatic and (neo)adjuvant situation

Trastuzumab (Herceptin (R)) is a humanized monoclonal antibody that specifically targets HER2/neu (human epidermal growth factor receptor-2) breast cancer cells, which are overexpressed in about 25-30% of breast carcinomas. After phase I and II trials, several phase III studies of trastuzumab alone or in combination with various chemotherapies were conducted. Patients with HER2/neu overexpression levels of 3+ determined by immunohistochemical assay or gene amplification (fluorescence in situ hybridization) derive most clinical benefit from trastuzumab. Taking into consideration efficacy and side effect profile, the combination of trastuzumab and paclitaxel showed an improvement of all clinical parameters, including overall survival, for the first time in the history of palliative breast cancer therapy. The application of trastuzumab has meanwhile become an established part of systemic therapy of metastastic breast cancer, and excellent data of its application in the adjuvant setting now exist (NSABP-B31, NCCTG-N9831, HERA), with significantly better relapse-free survival in the treatment arms with trastuzumab. Ongoing trials investigate the role of trastuzumab in the neoadjuvant setting. Trastuzumab is generally well tolerated. Cardiotoxicity is the main concern, thus monitoring of cardiac function is recommended

Recent advances in systemic therapy. Advances in neoadjuvant (primary) systemic therapy with cytotoxic agents

Neoadjuvant therapy, also known as primary, induction, or preoperative therapy, is defined as the first systemic treatment a patient receives after cancer is diagnosed and indicates that subsequent therapies are intended. It was first used in the early 1970s for the treatment of inoperable locally advanced or inflammatory breast cancer. Based on a large body of clinical evidence and on the fact that primary breast cancer is today considered a systemic disease with a locoregional component, primary systemic therapy is now increasingly considered for women with operable disease for reducing mortality with lower toxicity, improving surgical options, and acquiring early information on response and biology of the disease

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

HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group

Pattern of S100-release in benign and malignant diseases beside malignant melanoma/Freisetzung von S100 bei benignen und malignen Erkrankungen jenseits des malignen Melanoms

Background: The usefulness of S100 as a prognostic marker and aid in follow-up care in patients with malignant melanoma as well as in individuals with various neurological pathologies is well known. The aim of this study was to investigate its release and clinical relevance in benign and malignant disorders beyond these indications to elucidate tumor and organ specificity of S100. Methods: S100 levels were studied in serum samples of 1856 untreated patients, among them 59 healthy individuals, 358 patients with benign disorders, and 1439 patients with malignant tumors. Results: Healthy individuals had low S100 levels reaching a median of 0.041 ng/mL and 95th and 100th percentiles of 0.096 ng/mL and 0.144 ng/mL, respectively. The medians of patient groups with benign diseases ranged from 0.030 to 0.057 ng/mL, patients with malignant diseases from 0.020 to 0.059 ng/mL, and thus were comparable to healthy individuals. Only 2% of patients with benign diseases, mainly suffering from infectious, autoimmune, or benign gastrointestinal diseases and 1% of patients with malignant diseases showed slightly higher values than healthy individuals, in most cases up to 0.5 ng/mL. Conclusions: In contrast to many other oncological biomarkers, S100 is only rarely released in elevated levels from most benign and malignant diseases apart from malignant melanoma and neurological diseases, resulting in superior organ and tumor specificity. As potentially influencing factors, severe infectious diseases have to be considered.Hintergrund: S100 ist als nützlicher Biomarker für die Prognoseaschätzung und die Verlaufsbeobachtung bei Patienten mit malignem Melanom und in Patienten mit verschiedenen neurologischen Erkrankungen anerkannt. Das Ziel dieser Studie war, die Freisetzung und klinische Relevanz von S100 bei anderen benignen and malignen Erkrankungen jenseits dieser Indikationen zu untersuchen, um die Tumor- und Organspezifität von S100 zu bewerten. Methoden: S100-Konzentrationen wurden in Serumproben von 1856 unbehandelten Patienten ermittelt, darunter 59 gesunde Personen, 358 Patienten mit benignen Erkrankungen und 1439 Patienten mit malignen Tumoren. Ergebnisse: Gesunde Personen hatten niedrige S100 Serumwerte, die einen Median von 0.041 ng/mL, eine 95. Perzentile von 0.096 ng/mL und ein Maximum von 0.144 ng/mL erreichten. Die Mediane der Patientengruppen lagen bei benignen Erkrankungen zwischen 0.030 und 0.057 ng/mL, bei Patienten mit malignen Tumoren zwischen 0.020 und 0.059 ng/mL – und waren somit vergleichbar zu gesunden Kontrollpersonen. Lediglich 2% der Patienten mit benignen Erkrankungen, v.a. infektiösen, autoimmunen oder benignen gastrointestinalen Erkrankungen, sowie 1% der Patienten mit malignen Tumoren wiesen im Vergleich zu gesunden Personen leicht erhöhte Werte auf – in den meisten Fällen bis 0.5 ng/mL. Schlussfolgerung: Im Gegensatz zu vielen anderen onkologischen Biomarkern wird S100 nur selten in höheren Konzentrationen von den meisten benignen und malignen Erkrankungen – mit Ausnahme des malignen Melanoms und neurologischer Erkrankungen – freigesetzt, was sich in einer sehr hohen Organ- und Tumorspezifität widerspiegelt. Als möglicher Einflussfaktor sind schwere infektiöse Erkrankungen zu berücksichtigen

Pattern of S100-release in benign and malignant diseases beside malignant melanoma/Freisetzung von S100 bei benignen und malignen Erkrankungen jenseits des malignen Melanoms

Background: The usefulness of S100 as a prognostic marker and aid in follow-up care in patients with malignant melanoma as well as in individuals with various neurological pathologies is well known. The aim of this study was to investigate its release and clinical relevance in benign and malignant disorders beyond these indications to elucidate tumor and organ specificity of S100. Methods: S100 levels were studied in serum samples of 1856 untreated patients, among them 59 healthy individuals, 358 patients with benign disorders, and 1439 patients with malignant tumors. Results: Healthy individuals had low S100 levels reaching a median of 0.041 ng/mL and 95th and 100th percentiles of 0.096 ng/mL and 0.144 ng/mL, respectively. The medians of patient groups with benign diseases ranged from 0.030 to 0.057 ng/mL, patients with malignant diseases from 0.020 to 0.059 ng/mL, and thus were comparable to healthy individuals. Only 2% of patients with benign diseases, mainly suffering from infectious, autoimmune, or benign gastrointestinal diseases and 1% of patients with malignant diseases showed slightly higher values than healthy individuals, in most cases up to 0.5 ng/mL. Conclusions: In contrast to many other oncological biomarkers, S100 is only rarely released in elevated levels from most benign and malignant diseases apart from malignant melanoma and neurological diseases, resulting in superior organ and tumor specificity. As potentially influencing factors, severe infectious diseases have to be considered.Hintergrund: S100 ist als nützlicher Biomarker für die Prognoseaschätzung und die Verlaufsbeobachtung bei Patienten mit malignem Melanom und in Patienten mit verschiedenen neurologischen Erkrankungen anerkannt. Das Ziel dieser Studie war, die Freisetzung und klinische Relevanz von S100 bei anderen benignen and malignen Erkrankungen jenseits dieser Indikationen zu untersuchen, um die Tumor- und Organspezifität von S100 zu bewerten. Methoden: S100-Konzentrationen wurden in Serumproben von 1856 unbehandelten Patienten ermittelt, darunter 59 gesunde Personen, 358 Patienten mit benignen Erkrankungen und 1439 Patienten mit malignen Tumoren. Ergebnisse: Gesunde Personen hatten niedrige S100 Serumwerte, die einen Median von 0.041 ng/mL, eine 95. Perzentile von 0.096 ng/mL und ein Maximum von 0.144 ng/mL erreichten. Die Mediane der Patientengruppen lagen bei benignen Erkrankungen zwischen 0.030 und 0.057 ng/mL, bei Patienten mit malignen Tumoren zwischen 0.020 und 0.059 ng/mL – und waren somit vergleichbar zu gesunden Kontrollpersonen. Lediglich 2% der Patienten mit benignen Erkrankungen, v.a. infektiösen, autoimmunen oder benignen gastrointestinalen Erkrankungen, sowie 1% der Patienten mit malignen Tumoren wiesen im Vergleich zu gesunden Personen leicht erhöhte Werte auf – in den meisten Fällen bis 0.5 ng/mL. Schlussfolgerung: Im Gegensatz zu vielen anderen onkologischen Biomarkern wird S100 nur selten in höheren Konzentrationen von den meisten benignen und malignen Erkrankungen – mit Ausnahme des malignen Melanoms und neurologischer Erkrankungen – freigesetzt, was sich in einer sehr hohen Organ- und Tumorspezifität widerspiegelt. Als möglicher Einflussfaktor sind schwere infektiöse Erkrankungen zu berücksichtigen

ABC6 Consensus: Assessment by a Group of German Experts

Background: The first International Consensus Conference for Advanced Breast Cancer (ABC1) took place 10 years ago in November 2011. The rationale was - and still is - to standardize treatment of advanced breast cancer (ABC) based on the available evidence and to ensure that worldwide all breast cancer patients receive adequate treatment and access to new therapies. Rationale for the Manuscript: The 6th International Consensus Conference for ABC (ABC6) took place from November 4 to 6, 2021 and was the first in a purely online format, due to the COVID-19 pandemic. In the present manuscript, a working group of German breast cancer experts comments on the voting results of the ABC6 panelists regarding their applicability for routine clinical practice in Germany. Method: The ABC6 votes mainly include modified or new statements. With regard to all statements not modified for the ABC6 consensus, the German experts refer to the published paper of the ABC5 consensus. The German experts base their comments on the current recommendations of the Breast Committee of the Gynecological Oncology Working Group (Arbeitsgemeinschaft Gynakologische Onkologie, AGO Mamma). Topics: ABC6 focused on new treatment options and their implications for clinical practice. Optimal therapy sequencing for example was one of the issues. To solve the challenge of a more individualized treatment, precision medicine is fundamental. Oligometastatic disease, brain metastases and adequate supportive and palliative care were also addressed. Of special interest was the treatment of inoperable locally advanced breast cancer, which was discussed as a separate topic. As in previous years, patient advocates from around the world were an integral part of the ABC6 conference and had a major input into the consensus

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