Abstract
Next generation sequencing (NGS) together with protein expression analysis is back bone of molecularly targeted therapy in precision medicine. Our retrospective study shows our experience with NGS of 324 genes in combination with protein expression in patients with advanced breast cancer (aBC). The primary purpose was to analyze the prevalence of individual genetic alterations combined with protein expression to define potential targets for an individualized therapy. Between April 2018 and September 2019, 41 patients with aBC were offered a NGS test. The test was used to detect clinically relevant genomic alterations and to support further targeted therapy decisions. Hormone receptors, ERBB2 of tumors and PD-L1 was stained by immunohistochemistry. The data was recorded up to September 2019. After prior consent 41 results were available for further analysis. The most common BC subtypes were triple-negative (n = 16), HR+/ERBB2− (n = 15), and ERBB2+ (n = 9), with one missing data of the primary tumor. 27 patients had more than one genetic alteration. The most common alterations were PIK3CA (n = 14) and ERBB2 alterations (n = 11). Followed by ESR1 (n = 10), FGFR1 (n = 7) and PTEN (n = 7). 68% of the alterations were clinically relevant (tier I and II of ESCAT classification). The most common treatment recommendation was ERBB2-directed therapy (single or double blockade, trastuzumab emtansine and lapatinib) followed by alpelisib in combination with fulvestrant. Comprehensive genomic profiling combined with protein expression analysis in aBC allowed a guided personalized therapy for half of our patients. So far there are no well-defined tools allowing interpretations of genomic alterations detected by NGS in combination with protein expression and other factors.
Highlights
Generation sequencing (NGS) together with protein expression analysis is back bone of molecularly targeted therapy in precision medicine
The traditional risk and treatment assessment of primary breast cancer was traditionally based on tumor size, lymph node involvement, grading and proliferation index according to the Ki67, and hormone receptor and ERBB2 amplification status[1]
Alpelisib and Olaparib are two targeted therapies recently approved by the FDA to the mutational status of tumor. Alpelisib[3,4] is indicated in HR+/ERBB2− metastatic breast cancer with PIC3CA mutation and Olaparib[5] is approved for treatment of germline BRCAmutated advanced disease
Summary
Generation sequencing (NGS) together with protein expression analysis is back bone of molecularly targeted therapy in precision medicine. Comprehensive genomic profiling combined with protein expression analysis in aBC allowed a guided personalized therapy for half of our patients. There are no well-defined tools allowing interpretations of genomic alterations detected by NGS in combination with protein expression and other factors. The recommendation for treatment strategies in the (neo-)adjuvant setting of breast cancer therapy was improved due to the implementation of multi gene expression tests such as Oncotype DX and EndoPredict tests in selective patients’ cohorts Spite of these advances in molecular analysis of primary tumor genotypes, in the setting of advanced disease, molecular genetic-based biomarkers are not used routinely. There are no well-defined tools that allow interpretations of genomic alterations detected by NGS in combination with protein expression of tumor[7]. There are different frameworks that assign individual gene alterations and corresponding treatments, classified into tiers by the evidence strength from clinical studies; the most established so far is the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT)
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