HER-targeted tyrosine kinase inhibitors (TKIs) have demonstrated pro-apoptotic and antiproliferative effects in vitro and in vivo. The exact pathways through which TKIs exert their antineoplastic effects are, however, still not completely understood. Using Milliplex assays, we have investigated the effects of the three panHER-TKIs lapatinib, canertinib and afatinib on signal transduction cascade activation in SKBR3, T47D and Jurkat neoplastic cell lines. The growth-inhibitory effect of blockade of HER and of JNK and STAT5 signaling was measured by proliferation- and apoptosis-assays using formazan dye labeling of viable cells, Western blotting for cleaved PARP-1 and immunolabeling for active caspase 3, respectively. All three HER-TKIs clearly inhibited proliferation and increased apoptosis in HER2 overexpressing SKBR3 cells, while their effect was less pronounced on HER2 moderately expressing T47D cells where they exerted only a weak antiproliferative and essentially no pro-apoptotic effect. Remarkably, phosphorylation/activation of JNK and STAT5A/B were inhibited by HER-TKIs only in the sensitive, but not in the resistant cells. In contrast, phosphorylation/activation of ERK/MAPK, STAT3, CREB, p70 S6 kinase, IkBa, and p38 were equally affected by HER-TKIs in both cell lines. Moreover, we demonstrated that direct pharmacological blockade of JNK and STAT5 abrogates cell growth in both HER-TKI-sensitive as well as -resistant breast cancer cells, respectively. We have shown that HER-TKIs exert a HER2 expression-dependent anti-cancer effect in breast cancer cell lines. This involves blockade of JNK and STAT5A/B signaling, which have been found to be required for in vitro growth of these cell lines.

Even though trastuzumab is an effective therapy in early stage Her-2+ breast cancer, 40–50% of advanced Her-2+ breast cancer patients develop trastuzumab resistance. A potential resistance mechanism is aberrant downstream signal transmission due to loss of phosphatase and tensin homologue (PTEN). This study investigated the relationship between the expression of PTEN and trastuzumab response in Her-2 overexpressing metastatic breast cancer patients. Between 2000 and 2007, 164 patients with Her-2+ metastatic breast cancer received trastuzumab-based therapy in our institution. We analyzed PTEN status by immunohistochemistry of 115 available tumor tissues and analyzed associations with other histopathological parameters, response rate, progression free survival (PFS) and overall survival (OS) with a median follow-up of 60 months. Eighty patients were PTEN positive (69.6%) and 35 patients PTEN negative (30.4%). We found a significant association of the expression of PTEN and p53 (p = 0.041), while there was no association with grading, hormone receptor status, IGFR or MIB. We found significantly more cases with progressive disease under trastuzumab-based therapy in patients with PTEN positive breast cancers (p = 0.018), while there was no significant correlation with PFS or OS. In Her-2-positive metastatic breast cancers, PTEN positivity was significantly associated with progressive disease, but not with PFS or OS.

Summary: Background: This study investigated the impact of curative breast cancer surgery on patient satisfaction concerning cosmetic results and quality of life (QoL).Methods: In this study 61 participants completed questionnaires to evaluate their QoL and patient satisfaction with cosmetic results following breast cancer surgery. Cosmetic outcomes were evaluated by the breast surgeon and an independent breast specialist using the Harris scale and the breast analyzing tool (BAT).Results: Of the participants 71% completed all 4 follow-up visits, 38 (62%) patients received breast-conserving therapy (BCT) and 23 (38%) received a mastectomy. Surgery-associated complications arose in 2.6% of the patients who received BCT and 17.4% of patients who received a mastectomy. No significant differences in QoL between BCT patients and mastectomy patients were observed immediately after surgery, or after 6 and 12 months. Breast asymmetry, measured using the BAT score, and QoL scores were worst immediately after surgery. The surgeon rated the cosmetic results as better compared to the independent breast expert (p = 0.001). Furthermore, patients aged over 60 years old were less satisfied with the cosmetic outcome compared to younger patients at the time of discharge (p = 0.024). Patients who received a mastectomy were less satisfied when the resected volume was higher.Conclusion: Patient satisfaction was lowest immediately after surgery but improved during the following months, despite continued breast asymmetry. For mastectomy patients, a lower resected volume led to a higher satisfaction with cosmetic results. Satisfaction is subjective and cannot be determined from the esthetic satisfaction of the surgeon or using an objective tool measuring breast asymmetry.