Background

Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer is notable for its aggressive behavior, however with the introduction of trastuzumab in the early 2000’s, prognosis has improved. This thesis investigates the efficacy of trastuzumab in real-world settings after its introduction and evaluates the prognostic value of molecular biomarkers, aiming to optimize treatment approaches and improve patient outcomes.

Material and Methods

HER2-positive patients treated in the advanced and early stages of breast cancer were retrospectively identified using Swedish patient registries and through the review of medical records.

Study I included 46 patients with advanced breast cancer treated with trastuzumab between 2000 and 2007. Immunohistochemical analysis of several proteins hypothesized to be involved in trastuzumab resistance were evaluated. Additionally, gene copy number variations were analyzed using droplet digital PCR.

Study II include 599 patients who received adjuvant trastuzumab between 2006 and 2014 in the Southeastern health care region, in order to evaluate the implementation of trastuzumab after its approval and to evaluate patient outcomes with regard to clinicopathological variables.

Study III conducted quantitative analyses of stromal tumor-infiltrating lymphocytes (sTILs) in patients with available tumor material from the same cohort identified in study II. Additionally, a case-control study of 21 cases with 21 matched controls treated with trastuzumab were analyzed with RNA-sequencing in order to identify important differentially expressed genes.

Results

Study I demonstrated that trastuzumab treatment in a real-world setting had similar survival as in pivotal clinical trials. Additionally, high amplification of HER2 correlated with improved progression-free survival (PFS) and overall survival (OS) in advanced breast cancer patients and PTPN2 gain was correlated with reduced PFS and OS.

Study II confirmed trastuzumab's efficacy in a large real-world cohort. Trastuzumab treatment, estrogen receptor (ER) status and number of metastatic lymph nodes were the most important prognostic factors for breast cancer-specific survival and distant recurrence-free survival.

Study III identified a significant association between high levels of sTILs and improved overall survival. Additionally, several G-protein coupled receptors (GPCRs) involved in EGFR and Wnt signaling were found to be upregulated in cases vs controls.

Conclusions

Trastuzumab maintains its efficacy in clinical practice, affirming its role in current treatment regimens for HER2-positive breast cancer. The findings support the prognostic significance of sTILs and suggest HER2-amplification levels as a relevant prognostic factor. We propose PTPN2 and several GPCRs as areas for future research.