Targeted adjuvant therapy in breast cancer Zardavas, Dimitrios; Tryfonidis, Konstantinos; Goulioti, Theodora ...
Expert review of anticancer therapy
16, Issue:
12
Journal Article
Peer reviewed
The potential of molecular targeted therapy to improve the clinical outcomes of patients with early-stage breast cancer (BC) as adjuvant therapy has been first demonstrated through endocrine ...treatment. The introduction of HER2 blockade, through the successful clinical development of trastuzumab, changed the natural history of HER2-positive BC subtype. Areas covered: There are ongoing efforts to augment further the use of targeted agents as adjuvant treatment in BC, hoping that early introduction of targeted therapy blocking key oncogenic drivers of micro-residual disease, will significantly improve clinical outcomes. In the present Review, we present data through extensive search of PubMed about the following targeted adjuvant therapeutic strategies in BC: i) HER2 blockade and ongoing efforts to further augment its efficacy for patients with HER2-positive disease, ii) angiogenesis inhibition, iii) PI3K-mTOR- AKT pathway inhibition, iv) CDK4/6 inhibition, v) PARP inhibition. Expert commentary: we provide insights about challenges and potential ways to overcome them, in terms of successful clinical development of targeted agents as adjuvant therapy for patients with BC. In particular, we emphasize the need to systematically assess minimal residual cancer burden as a way to increase the rates of successful clinical development of targeted agents in the adjuvant setting.
Abstract Several breast cancer therapies can lead to cardiovascular toxicity: drugs such anthracyclines can cause permanent damage, anti-HER2 agents may cause transitory and reversible cardiac ...dysfunction and others, such as those used in endocrine therapy, primarily disturb lipid metabolism. Considering the seriousness of these complications, trials are now being conducted to address cardiotoxicity associated with new drugs; however, to fully understand their toxicity profiles, longer follow-up is needed. In this review, we compile the information available about cardiac toxicity related to well-established systemic breast cancer treatments, as well as newer drugs, including antiangiogenics, mTOR inhibitors and novel anti-HER2 agents. We also describe current and next generation cardiac biomarkers and functional tests that can optimize treatment and reduce and prevent the incidence of treatment-related cardiotoxicity
High-throughput technologies of molecular profiling in cancer, such as gene-expression profiling and next-generation sequencing, are expanding our knowledge of the molecular landscapes of several ...cancer types. This increasing knowledge coupled with the development of several molecularly targeted agents hold the promise for personalized cancer medicine to be fully realized. Moreover, an expanding armamentarium of targeted agents has been approved for the treatment of specific molecular cancer subgroups in different diagnoses. According to this paradigm, treatment selection should be dictated by the specific molecular aberrations found in each patient's tumor. The classical clinical trials paradigm of patients' eligibility being based on clinicopathologic parameters is being abandoned, with current clinical trials enrolling patients on the basis of specific molecular aberrations. New, innovative trial designs have been generated to better tackle the multiple challenges induced by the increasing molecular fragmentation of cancer, namely: (1) longitudinal cohort studies with or without downstream trials, (2) studies assessing the clinical utility of molecular profiling, (3) master or umbrella trials, (4) basket trials, (5) N-of-1 trials, and (6) adaptive design trials. This article provides an overview of the challenges for clinical trials in the era of molecular profiling of cancer. Subsequently, innovative trial designs with respective examples and their potential to expedite efficient clinical development of targeted anticancer agents is discussed.
Background
Biomarkers of cardiac damages, such as troponin T (TnT) and the amino-terminal fragment of brain natriuretic peptide (NT-proBNP), may be useful as early predictors of cardiac dysfunction. ...The role of these biomarkers in patients receiving lapatinib and/or trastuzumab before anthracyclines is unknown. This study explores TnT and NT-proBNP as predictors of early cardiac toxicity in neoadjuvant breast cancer patients.
Methods
This sub-study of the NEOALTTO trial tested if changes in the levels of TnT and NT-proBNP occurred after 2 weeks of anti-HER2 therapy (lapatinib, trastuzumab or their combination) alone and/or after 18 weeks of anti-HER2 therapy plus weekly paclitaxel.
Results
173 and 172 were tested at all three timepoints for NT-proBNP and TnT, respectively. The incidence of biomarker elevation was overall low at all timepoints for all the three treatment arms. A total of 13 CEs in 11 patients occurred. Biomarker elevations in patients with CEs were very rare; only one patient with subsequent CE had a NT-proBNP elevation at baseline and at week 2.
Conclusion
These results suggest that TnT and proBNP may not be useful as early predictors of cardiac toxicity in anthracycline-naïve patients receiving trastuzumab and/or lapatinib.
Abstract Background The European Union (EU) has adopted a common procedure for granting marketing authorisation for cancer drugs. Nevertheless, pricing and reimbursement decisions are a competency of ...EU national governments, and their policies are diverse. We aimed to evaluate the time for trastuzumab reimbursement approval and its association to health expenditure, to health policy performance, to the availability of cost-effectiveness studies and to breast cancer outcome. Methods Breast cancer outcome was estimated by the mortality/incidence (M/I) ratio. Trastuzumab reimbursement approval dates were provided by Roche. Spearman’s rank correlation and Wilcoxon rank-sum test were used to evaluate associations and/or differences between the variables studied. Additional analyses were made by grouping countries according to compliance to the 180 day timeframe stipulated in the EU 89/105/EEC Directive for drug pricing and reimbursement. Results A statistically significant inverse and strong correlation between breast cancer M/I ratio and health expenditure ( rs = –0.730, p < 0.001) and health policy performance ( rs = –0.711, p < 0.001) was found, meaning the better the score and the higher the expenditure, the fewer patients died after a breast cancer diagnosis. Factors associated with trastuzumab faster reimbursement and compliance to the 89/105/EEC Directive were better health policy score, higher health expenditure and availability of cost-effectiveness studies. Conclusion Higher health policy scores and health expenditure are associated with faster reimbursement of trastuzumab and better breast cancer outcome. Although the study design does not allow inference of causal associations, a marked difference is observed between Eastern and Western Europe, with long delays and increased breast cancer mortality identified in Eastern European countries.
Breast cancer oncology represents one of the disciplines where personalized cancer medicine has been most actively pursued. The class-discovery studies conceptually advanced the field, underlining ...the molecular heterogeneity governing this common disease. The advent of high-throughput molecular profiling technologies holds great promise for the advance of all aspects of personalized cancer medicine, namely accurate prognostication, prediction of response to common systemic therapies and individualized monitoring of the disease. Moreover, an ever-expanding arsenal of targeted therapeutic compounds under clinical development, coupled with emerging powerful tools for comprehensive molecular and functional characterization, pose significant promise for improved clinical outcomes for breast cancer patients. Interrogation of the germline genetic variation offers further promise towards tailoring of breast cancer management. Well-conducted prospective validation studies are needed if breast cancer personalized therapy is to transform from a dream into a reality.
Trastuzumab, a humanized anti-HER2 monoclonal antibody targeting the extracellular domain of this oncoprotein, represents the archetype of HER2 blocking agents. Its unprecedented efficacy for ...HER2-positive metastatic breast cancer (BC) led to its clinical development in the adjuvant setting. The HERceptin Adjuvant (HERA) is one of the pivotal adjuvant trastuzumab trials which proved that this compound can change the natural course of early stage HER2-positive BC. The HERA study led to the registration of trastuzumab for the adjuvant treatment of early HER2-positive BC. This trial randomized more than 5000 patients between 1 and 2 years of trastuzumab and observation after the completion of locoregional therapy and (neo)-adjuvant chemotherapy. Additionally, an abundance of subsequent substudies were conducted, addressing important clinical issues for this patient population. The present review article presents a comprehensive overview of the HERA study and its major contributions to the adjuvant treatment of HER2-positive BC patients. Emphasis is given on the lessons learned from this international collaborative experience and how this can be used as a stepping stone for further improvements in the field.
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