BackgroundMonoclonal antibodies (mAb), such as trastuzumab are a valuable addition to breast cancer therapy. Data obtained from neoadjuvant settings revealed that antibody-dependent cell-mediated cytotoxicity (ADCC) is a major mechanism of action for the mAb trastuzumab. Conflicting results still call into question whether disease progression, prolonged treatment or concomitant chemotherapy influences ADCC and related immunological phenomena.MethodsWe analyzed the activity of ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) of peripheral blood mononuclear cells (PBMCs) from human epidermal growth factor receptor 2 (HER2/neu) positive breast cancer patients receiving trastuzumab therapy either in an adjuvant (n = 13) or metastatic (n = 15) setting as well as from trastuzumab treatment-naive (t-naive) HER2/neu negative patients (n = 15). PBMCs from healthy volunteers (n = 24) were used as controls. ADCC and ADCP activity was correlated with the expression of antibody binding Fc-gamma receptor (FcγR)I (CD64), FcγRII (CD32) and FcγRIII (CD16) on CD14+ (monocytes) and CD56+ (NK) cells, as well as the expression of CD107a+ (LAMP-1) on CD56+ cells and the total amount of CD4+CD25+FOXP3+ (Treg) cells. In metastatic patients, markers were correlated with progression-free survival (PFS).ResultsADCC activity was significantly down regulated in metastatic, adjuvant and t-naive patient cohorts as compared to healthy controls. Reduced ADCC activity was inversely correlated with the expression of CD107a on CD56+ cells in adjuvant patients. ADCC and ADCP activity of the patient cohorts were similar, regardless of treatment duration or additional chemotherapy. PFS in metastatic patients inversely correlated with the number of peripheral Treg cells.ConclusionThe reduction of ADCC in patients as compared to healthy controls calls for adjuvant strategies, such as immune-enhancing agents, to improve the activity of trastuzumab. However, efficacy of trastuzumab-specific ADCC and ADCP appears not to be affected by treatment duration, disease progression or concomitant chemotherapy. This finding supports the application of trastuzumab at any stage of the disease.

These results suggest that polymorphisms in tested TLR genes are not likely to be associated with increased risk for developing breast cancer.

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We analysed the association of a single nucleotide polymorphism (SNP) in the gene encoding the IL‐12 subunit p40 (IL12B, rs3212227, A>C) with breast cancer. The SNPs allelic and genotypic frequencies were compared between patients (n = 191) and healthy (n = 194) women in a case–control study from Croatia. The major allele (A) was associated with susceptibility to breast cancer (P = 0.003; OR = 1.67; 95% CI: 1.17–2.38). Likewise, the minor allele (C) was significantly correlated with protection (P = 0.003; OR = 0.60; 95% CI: 0.42–0.86). At the genotype level, AA homozygosity was significantly associated with predisposition to disease (P = 0.013; OR = 1.68, 95% CI: 1.09–2.59), whereas the minor allele homozygosity (CC) was correlated with protection to disease (P = 0.020, OR = 0.28, 95% CI: 0.09–0.91). The heterozygous genotype showed no significant correlation with disease. The product of the IL12B gene (IL‐12 p40) can either form a homodimeric cytokine or be part of two pro‐inflammatory (IL‐12 and IL‐23) cytokines. It is presently unclear whether the major allele is associated with higher or lower protein levels of IL‐12 p40 and IL‐12 p70, which are critical in inflammation and adaptive immune responses. However, as the A allele is high producer of IL12B (p40) mRNA, these results might imply that higher levels of IL‐12 p40 (either as homodimers or joined with one or both of the other two subunits) predispose to breast cancer.

Toll-like receptor (TLR) 4 signaling pathway has been shown to support tumor cell growth in vitro and in vivo. Its stimulation on breast cancer cell lines induces β1 integrin and promotes tumor invasiveness. However, its role in predicting clinical behavior of tumor is not yet clarified. Therefore, we investigated TLR4 and β1 integrin expression on 133 primary breast cancer samples by immunohistochemistry and correlated it with overall survival and disease-free survival of patients as well as with clinicopathological characteristics of the tumor. We found higher β1 integrin expression in invasive lobular cancer in comparison with other tumor types. No significant association of TLR4 and β1 integrin expression with overall survival or disease-free survival was seen. Therefore, we conclude that expression of these markers is of biological interest but appears to be of little additional use as predictive clinical marker.

Prolonged or repeated stimulation of Toll-like receptor (TLR) 4 leads to hyporesponsiveness of monocyte-derived macrophages, which seems to be a hallmark of immunosuppression related to sepsis and cancer. Two negative regulators of TLR-4 signaling are IL-1 receptor-associated kinase M and B-cell leukemia 3. Here, we demonstrate that the expression of both proteins is inhibited when the TLR-7/TLR-8 agonist CL097 is added to monocyte cultures despite costimulation with the TLR-4 agonist LPS or hyaluronic acid. Reduction of IL-1 receptor-associated kinase M and B-cell leukemia 3 was paralleled by a significant increased cytokine induction of TNF-alpha, IL-10, and IL-12 observed after intracellular and extracellular TLR stimulation. In ex vivo stimulated whole blood of patients who have prolonged sepsis or metastatic cancer, TLR-7/TLR-8 agonists retained their ability of increased stimulation of TNF-alpha. These data might add to the understanding of sepsis and cancer-associated immune suppression in men.

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Epidermal growth factor receptor (EGFR) mutations are a rare occurrence in small cell lung cancer (SCLC), existing either de novo or in cases of transformedEGFR-mutant (mt) adenocarcinoma. In thede novosetting, treatment outcomes and response to EGFR-tyrosine kinase inhibitors is unclear. We report a rare case of a female patient, who had never smoked, withde novo EGFR-mt SCLC and describe treatment outcomes to both platinum-based chemotherapy and erlotinib. Considering the rarity ofEGFRmutations reported in SCLC and the unclear role of EGFR-tyrosine kinase inhibitors in this setting, a review of the literature will also be presented.