Predicting for activity of second-line trastuzumab-based therapy in her2-positive advanced breast cancer

<p>Abstract</p> <p>Background</p> <p>In Her2-positive advanced breast cancer, the upfront use of trastuzumab is well established. Upon progression on first-line therapy, patients may be switched to lapatinib. Others however remain candidates for continued antibody treatment (treatment beyond progression). Here, we aimed to identify factors predicting for activity of second-line trastuzumab-based therapy.</p> <p>Methods</p> <p>Ninety-seven patients treated with > 1 line of trastuzumab-containing therapy were available for this analysis. Her2-status was determined by immunohistochemistry and re-analyzed by FISH if a score of 2+ was gained. Time to progression (TTP) on second-line therapy was defined as primary study endpoint. TTP and overall survival (OS) were estimated using the Kaplan-Meier product limit method. Multivariate analyses (Cox proportional hazards model, multinomial logistic regression) were applied in order to identify factors associated with TTP, response, OS, and incidence of brain metastases. <it>p </it>values < 0.05 were considered to indicate statistical significance.</p> <p>Results</p> <p>Median TTP on second-line trastuzumab-based therapy was 7 months (95% CI 5.74-8.26), and 8 months (95% CI 6.25-9.74) on first-line, respectively (n.s.). In the multivariate models, none of the clinical or histopthological features could reliably predict for activity of second-line trastuzumab-based treatment. OS was 43 months suggesting improved survival in patients treated with trastuzumab in multiple-lines. A significant deterioration of cardiac function was observed in three patients; 40.2% developed brain metastases while on second-line trastuzumab or thereafter.</p> <p>Conclusion</p> <p>Trastuzumab beyond progression showed considerable activity. None of the variables investigated correlated with activity of second-line therapy. In order to predict for activity of second-line trastuzumab, it appears necessary to evaluate factors known to confer trastuzumab-resistance.</p

Cross-priming of cyclin B1, MUC-1 and survivin-specific CD8(+ )T cells by dendritic cells loaded with killed allogeneic breast cancer cells

INTRODUCTION: The ability of dendritic cells (DCs) to take up whole tumor cells and process their antigens for presentation to T cells ('cross-priming') is an important mechanism for induction of tumor specific immunity. METHODS: In vitro generated DCs were loaded with killed allogeneic breast cancer cells and offered to autologous naïve CD8(+ )T cells in 2-week and/or 3-week cultures. CD8(+ )T cell differentiation was measured by their capacity to secrete effector cytokines (interferon-γ) and kill breast cancer cells. Specificity was measured using peptides derived from defined breast cancer antigens. RESULTS: We found that DCs loaded with killed breast cancer cells can prime naïve CD8(+ )T cells to differentiate into effector cytotoxic T lymphocytes (CTLs). Importantly, these CTLs primed by DCs loaded with killed HLA-A*0201(- )breast cancer cells can kill HLA-A*0201(+ )breast cancer cells. Among the tumor specific CTLs, we found that CTLs specific for HLA-A2 restricted peptides derived from three well known shared breast tumor antigens, namely cyclin B1, MUC-1 and survivin. CONCLUSION: This ability of DCs loaded with killed allogeneic breast cancer cells to elicit multiantigen specific immunity supports their use as vaccines in patients with breast cancer

Uncertainties and controversies in axillary management of patients with breast cancer

The aims of this Oncoplastic Breast Consortium and European Breast Cancer Research Association of Surgical Trialists initiative were to identify uncertainties and controversies in axillary management of early breast cancer and to recommend appropriate strategies to address them. By use of Delphi methods, 15 questions were prioritized by more than 250 breast surgeons, patient advocates and radiation oncologists from 60 countries. Subsequently, a global virtual consensus panel considered available data, ongoing studies and resource utilization. It agreed that research should no longer be prioritized for standardization of axillary imaging, de-escalation of axillary surgery in node-positive cancer and risk evaluation of modern surgery and radiotherapy. Instead, expert consensus recommendations for clinical practice should be based on current evidence and updated once results from ongoing studies become available. Research on de-escalation of radiotherapy and identification of the most relevant endpoints in axillary management should encompass a meta-analysis to identify knowledge gaps, followed by a Delphi process to prioritize and a consensus conference to refine recommendations for specific trial designs. Finally, treatment of residual nodal disease after surgery was recommended to be assessed in a prospective register

Oncoplastic Breast Consortium consensus conference on nipple-sparing mastectomy

Purpose Indications for nipple-sparing mastectomy (NSM) have broadened to include the risk reducing setting and locally advanced tumors, which resulted in a dramatic increase in the use of NSM. The Oncoplastic Breast Consortium consensus conference on NSM and immediate reconstruction was held to address a variety of questions in clinical practice and research based on published evidence and expert panel opinion. Methods The panel consisted of 44 breast surgeons from 14 countries across four continents with a background in gynecology, general or reconstructive surgery and a practice dedicated to breast cancer, as well as a patient advocate. Panelists presented evidence summaries relating to each topic for debate during the in-person consensus conference. The iterative process in question development, voting, and wording of the recommendations followed the modified Delphi methodology. Results Consensus recommendations were reached in 35, majority recommendations in 24, and no recommendations in the remaining 12 questions. The panel acknowledged the need for standardization of various aspects of NSM and immediate reconstruction. It endorsed several oncological contraindications to the preservation of the skin and nipple. Furthermore, it recommended inclusion of patients in prospective registries and routine assessment of patient-reported outcomes. Considerable heterogeneity in breast reconstruction practice became obvious during the conference. Conclusions In case of conflicting or missing evidence to guide treatment, the consensus conference revealed substantial disagreement in expert panel opinion, which, among others, supports the need for a randomized trial to evaluate the safest and most efficacious reconstruction techniques

Oncoplastic Breast Consortium consensus conference on nipple-sparing mastectomy.

Purpose Indications for nipple-sparing mastectomy (NSM) have broadened to include the risk reducing setting and locally advanced tumors, which resulted in a dramatic increase in the use of NSM. The Oncoplastic Breast Consortium consensus conference on NSM and immediate reconstruction was held to address a variety of questions in clinical practice and research based on published evidence and expert panel opinion. Methods The panel consisted of 44 breast surgeons from 14 countries across four continents with a background in gynecology, general or reconstructive surgery and a practice dedicated to breast cancer, as well as a patient advocate. Panelists presented evidence summaries relating to each topic for debate during the in-person consensus conference. The iterative process in question development, voting, and wording of the recommendations followed the modified Delphi methodology. Results Consensus recommendations were reached in 35, majority recommendations in 24, and no recommendations in the remaining 12 questions. The panel acknowledged the need for standardization of various aspects of NSM and immediate reconstruction. It endorsed several oncological contraindications to the preservation of the skin and nipple. Furthermore, it recommended inclusion of patients in prospective registries and routine assessment of patient-reported outcomes. Considerable heterogeneity in breast reconstruction practice became obvious during the conference. Conclusions In case of conflicting or missing evidence to guide treatment, the consensus conference revealed substantial disagreement in expert panel opinion, which, among others, supports the need for a randomized trial to evaluate the safest and most efficacious reconstruction techniques

Cost-effectiveness analysis of prognostic gene expression signature-based stratification of early breast cancer patients

BACKGROUND: The individual risk of recurrence in hormone receptor-positive primary breast cancer patients determines whether adjuvant endocrine therapy should be combined with chemotherapy. Clinicopathological parameters and molecular tests such as EndoPredict(®) (EPclin) can support decision making in patients with estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative cancer. OBJECTIVE: Using a life-long Markov state transition model, we determined the health economic impact and incremental cost effectiveness of EPclin-based risk stratification in combination with clinical guidelines [German-S3, National Comprehensive Cancer Center Network (NCCN), and St. Gallen] to decide on chemotherapy use. METHODS: Information on overall and metastasis-free survival came from Austrian Breast & Colorectal Cancer Study Group clinical trials 6/8 (n = 1,619) and published literature. Effectiveness was assessed as quality-adjusted life-years (QALYs). Costs (2010) were assessed from a German third-party payer perspective. RESULTS: Lifetime costs per patient ranged from 28,268 (St.Gallen and EPclin) to 33,756 (NCCN). Due to an imperfect prognostic value and differences in chemotherapy use, strategies achieved between 13.165 QALYs (NCCN) and 13.173 QALYs (EPclin alone) per patient. Using German-S3 as reference, three strategies showed dominant results (St. Gallen and EPclin, German-S3 and EPclin, EPclin alone). Compared to German-S3, the addition of EPclin saved 3,388 and gained 0.002 QALYs per patient. Combining guidelines with EPclin remained preferable in sensitivity analysis. CONCLUSION: Our study suggests that molecular markers can be sensibly combined with clinical guidelines to determine the risk profile of adjuvant breast cancer patients. Compared with the current German best practice (German-S3), combinations of EPclin with the St. Gallen, German-S3 or NCCN guideline and EPclin alone were dominant from the perspective of the German healthcare system

Optimising translational oncology in clinical practice: Strategies to accelerate progress in drug development.

Despite intense efforts, the socioeconomic burden of cancer remains unacceptably high and treatment advances for many common cancers have been limited, suggesting a need for a new approach to drug development. One issue central to this lack of progress is the heterogeneity and genetic complexity of many tumours. This results in considerable variability in therapeutic response and requires knowledge of the molecular profile of the tumour to guide appropriate treatment selection for individual patients. While recent advances in the molecular characterisation of different cancer types have the potential to transform cancer treatment through precision medicine, such an approach presents a major economic challenge for drug development, since novel targeted agents may only be suitable for a small cohort of patients. Identifying the patients who would benefit from individual therapies and recruiting sufficient numbers of patients with particular cancer subtypes into clinical trials is challenging, and will require collaborative efforts from research groups and industry in order to accelerate progress. A number of molecular screening platforms have already been initiated across Europe, and it is hoped that these networks, along with future collaborations, will benefit not only patients but also society through cost reductions as a result of more efficient use of resources. This review discusses how current developments in translational oncology may be applied in clinical practice in the future, assesses current programmes for the molecular characterisation of cancer and describes possible collaborative approaches designed to maximise the benefits of translational science for patients with cancer.SCOPUS: re.jinfo:eu-repo/semantics/publishe