Introduction Lymphocyte infiltration (LI) is often seen in breast cancer but its importance remains controversial. A positive correlation of human epidermal growth factor receptor 2 (HER2) amplification and LI has been described, which was associated with a more favorable outcome. However, specific lymphocytes might also promote tumor progression by shifting the cytokine milieu in the tumor.

The use of neoadjuvant systemic therapy (NST) for the treatment of primary breast cancer has constantly increased, especially in trials of new therapeutic regimens. In the 1980 s, NST was shown to substantially improve breast-conserving surgery rates and was first typically used for patients with inoperable locally advanced or inflammatory breast cancer. Investigators have since also used NST as an in vivo test for chemosensitivity by assessing pathologic complete response. Today, by using pathologic response and other biomarkers as intermediate end points, results from trials of new regimens and therapies that use NST are aimed to precede and anticipate the results from larger adjuvant trials. In 2003, a panel of representatives from various breast cancer clinical research groups was first convened in Biedenkopf to formulate recommendations on the use of NST. The obtained consensus was updated in two subsequent meetings in 2004 and 2006. The most recent conference on recommendations on the use of NST took place in 2010 and forms the basis of this report.

IntroductionCurrent prognostic gene expression profiles for breast cancer mainly reflect proliferation status and are most useful in ER-positive cancers. Triple negative breast cancers (TNBC) are clinically heterogeneous and prognostic markers and biology-based therapies are needed to better treat this disease.MethodsWe assembled Affymetrix gene expression data for 579 TNBC and performed unsupervised analysis to define metagenes that distinguish molecular subsets within TNBC. We used n = 394 cases for discovery and n = 185 cases for validation. Sixteen metagenes emerged that identified basal-like, apocrine and claudin-low molecular subtypes, or reflected various non-neoplastic cell populations, including immune cells, blood, adipocytes, stroma, angiogenesis and inflammation within the cancer. The expressions of these metagenes were correlated with survival and multivariate analysis was performed, including routine clinical and pathological variables.ResultsSeventy-three percent of TNBC displayed basal-like molecular subtype that correlated with high histological grade and younger age. Survival of basal-like TNBC was not different from non basal-like TNBC. High expression of immune cell metagenes was associated with good and high expression of inflammation and angiogenesis-related metagenes were associated with poor prognosis. A ratio of high B-cell and low IL-8 metagenes identified 32% of TNBC with good prognosis (hazard ratio (HR) 0.37, 95% CI 0.22 to 0.61; P < 0.001) and was the only significant predictor in multivariate analysis including routine clinicopathological variables.ConclusionsWe describe a ratio of high B-cell presence and low IL-8 activity as a powerful new prognostic marker for TNBC. Inhibition of the IL-8 pathway also represents an attractive novel therapeutic target for this disease.

The frequency of CAM use we found is in line with international data from CCCs in the USA. To our knowledge, this is the first study publishing data on the frequency of potential interactions. Thus, an initiative to protect women from the dangers of uncontrolled CAM use is urgently needed. In the discussion, we propose a concept of how to achieve this aim.

Evaluation and characterization of circulating tumor cells (CTCs) have become a major focus of translational cancer research. Presence of CTCs predicts worse clinical outcome in early and metastatic breast cancer. Whether all cells from the primary tumor have potential to disseminate and form subsequent metastasis remains unclear. As part of the metastatic cascade, tumor cells lose their cell-to-cell adhesion and undergo epithelial-mesenchymal transition (EMT) in order to enter blood circulation. During EMT epithelial antigens are downregulated; thus, such tumor cells might elude classical epithelial marker-based detection. Several researchers postulated that some CTCs express stem cell-like phenotype; this might lead to chemoresistance and enhanced metastatic potential of such cells. In the present review, we discuss current data on EMT and stem cell markers in CTCs of breast cancer and their clinical significance.

Radiation therapy is an integral part of the multidisciplinary management of breast cancer. Regional lymph node irradiation in younger trials seems to provide superior target coverage as well as a reduction in long-term toxicity resulting in a small benefit in the overall survival rate. For partial breast irradiation there are now two large trials available which support the role of partial breast irradiation in low risk breast cancer patients. Multiple randomized trials have established that a sequentially applied dose to the tumor bed improves local control with the cost of worse cosmetic results.

INTRODUCTION Circulating tumor cells (CTCs) may be used to improve cancer diagnosis, prognosis, and treatment. However, because knowledge regarding CTC biology is limited and the numbers of CTCs and CTC-positive cancer patients are low, progress in this field is slow. We addressed this limitation by combining diagnostic leukapheresis (DLA) and microfluidic enrichment to obtain large numbers of viable CTCs from metastasized breast cancer patients. METHODS DLA was applied to 9 patients, and 7.5 mL of peripheral blood was drawn. CTCs were enriched with the Parsortix™ system. The quality of CTCs from fresh and cryopreserved DLA products was tested, and CTCs were cultured in vitro. Single uncultured and cultured CTCs were isolated by micromanipulation to determine different parameters, such as genomic aberrations and mutation profiles of selected tumor-associated genes. Expression levels of estrogen receptor and HER2/neu were monitored during in vitro culture. RESULTS Viable CTCs from peripheral blood and fresh or frozen DLA products could be enriched. DLA increased the likelihood of successful CTC culture. Cryopreserved DLA products could be stored with minimal CTC loss and no overt reduction in the tumor cell quality and viability during an observation period of up to 3 years. The analyzed parameters did not change during in vitro culture. DLA samples with high CTC numbers and lower ratios of apoptotic CTCs were more likely to grow in culture. CONCLUSIONS The increased CTC numbers from fresh or cryopreserved DLA products facilitate multiple functional and molecular analyses and, thus, could improve our knowledge of their biology.

Background: It is well-known that tumor biology may change during the course of the disease due to clonal evolution, and such changes might have important implications for response to targeted treatments. Circulating tumor cells (CTCs) could serve as a real-time liquid biopsy to detect changes in tumor biology. It has been demonstrated that patients with HER2-negative metastatic breast cancer (MBC) may have discordant, HER2-positive CTCs in the peripheral blood. However, up to now there is no randomized clinical trial investigating whether treatment decisions based on CTC phenotype provide benefits in terms of improved outcome. The aim of the DETECT III study is to investigate whether patients with initially HER2-negative MBC and HER2-positive CTCs benefit from HER2-targeted therapy with the tyrosine kinase inhibitor lapatinib. In addition, the significance of CTCs as an early predictive marker for response to therapy will be analyzed. Methods: The randomized phase III DETECT III trial (NCT01619111) compares lapatinib in combination with standard therapy versus standard therapy alone in patients with initially HER2-negative MBC and HER2-positive CTCs. Efficacy of lapatinib treatment is evaluated by CTC clearance rate, progression-free survival (PFS) and overall survival (OS). In addition, we investigate the association between CTC results and both PFS and OS to assess the utility of CTCs as an early predictive marker for treatment response. CTC enumeration and phenotyping was performed using the CellSearch® technology (Menarini Silicon Biosystems; Bologna, Italy). Survival data are analyzed using log rank tests, univariable and adjusted multivariable cox regressions. Results: First results on CTC clearance rates, PFS and OS of 105 prospectively randomized patients will be presented. Conclusion: This first randomized clinical trial in breast cancer patients with treatment decisions being based on the phenotype of CTCs will show whether patients with HER2 negative MBC and HER2 positive CTCs benefit from additional HER2-targeted therapy with lapatinib. This finding might be increasingly important as novel HER2-targeted drugs become available. Citation Format: Tanja Fehm, Volkmar Mueller, Maggie Banys-Paluchowski, Peter A Fasching, Thomas WP Friedl, Andreas Hartkopf, Jens Huober, Christian Loehberg, Brigitte Rack, Sabine Riethdorf, Andreas Schneeweiss, Diethelm Wallwiener, Franziska Meier-Stiegen, Oliver Hoffmann, Lothar Müller, Pauline Wimberger, Eugen Ruckhaeberle, Jens Blohmer, Wolfgang Janni. Efficacy of the tyrosine kinase inhibitor lapatinib in the treatment of patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells - results from the randomized phase III DETECT III trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-12.