Real world data analysis of next generation sequencing and protein expression in metastatic breast cancer patients

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.

NGS-guided precision oncology in metastatic breast and gynecological cancer: first experiences at the CCC Munich LMU

“…As shown in the SAFIR01 trial, only a small number of patients benefit from personalized therapies mostly due to drug access problems. This problem could be solved by establishing a portfolio of early phase clinical basket trials or by early-access-programs [ 38 ]. Recent studies suggest that the implementation of a MTB improves access to targeted therapy [ 39 ].…”

PIK3CA Mutations as a Molecular Target for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer

“…Despite different platforms being commercially available, the NGS workflow follows the same four sequential phases (i.e., library generation, clonal amplification, massively parallel sequencing, and data analysis) (59). Hempel et al (13) adopted a broad NGS panel to analyze 41 MBC samples and detected PIK3CA mutations in 34% (n = 14) of them. In another study including patients with ET-resistant (n = 15) and ETsensitive (n = 9) breast cancer cases, the same authors were able FIGURE 2 | Type of mutations, frequency, and affected PIK3CA domains across breast cancers from The Cancer Genome Atlas (TCGA) Network and selected solid tumors from the Catalog Of Somatic Mutations In Cancer (COSMIC) datasets, including the mutations and exons covered by the FDA-approved the RT-PCR test.…”

“…Despite different platforms being commercially available, the NGS workflow follows the same four sequential phases (i.e., library generation, clonal amplification, massively parallel sequencing, and data analysis) ( 59 ). Hempel et al ( 13 ) adopted a broad NGS panel to analyze 41 MBC samples and detected PIK3CA mutations in 34% ( n = 14) of them. In another study including patients with ET-resistant ( n = 15) and ET-sensitive ( n = 9) breast cancer cases, the same authors were able to identify PIK3CA alterations in 55% ( n = 8) and 33% ( n = 3) of the cases, respectively ( 60 ).…”

“…A significant percentage of patients, however, eventually develop ET resistance due to several mechanisms, including the dysregulation of phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling ( 12 ). Approximately 40% of HR + /HER2 − MBC cases show hyperactivation of this pathway, which has now become a therapeutic target for the treatment of breast cancer ( 13 ).…”

Tubulin Tyrosine Ligase Like 4 (TTLL4) overexpression in breast cancer cells is associated with brain metastasis and alters exosome biogenesis

“…These cancer cells are highly aggressive and since most therapeutic compounds do not pass the blood-brain-barrier (BBB), they do not respond to hormone or chemotherapy. Clinical trials for new targeted therapies are in progress and the preliminary results are promising [1][2][3].…”