Molecular In Vitro and In Vivo Diagnostics as the Impartible Basis of Multimodal Therapy Approaches in Precision Oncology

Abstract

AbstractIn 2000, more than two decades ago, genome-wide gene expression profiling became available and thereafter led to the dissection of cancer biology across almost all entities [1–3]. First, the molecular portraits based on RNA expression profiling (termed “heat maps”) were used in breast cancer to identify luminal, ERBB2-positive, and basal tumors. Interestingly, these subtypes not only elucidated the underlying biology but also directly suggested targeted treatment intervention with luminal tumors being hormone-dependent, ERBB2-positive tumors exposing the transmembrane receptor Her-2/neu and basal tumors lacking homogenous expression of typical targeted treatment options, with the latter being termed “triple negative” later on. Interestingly, genome-wide mutation analysis later on revealed that the luminal subtype, while bearing most mutations (such as PIK3CA) exhibited lowest immunogenicity and frequently absence of tumor-infiltrating lymphocytes. In contrast, the basal subtype turned out to have lowest rate of classical oncogens, but was dominated by loss-of-function mutation of p53 [4], while almost half of basal tumors being infiltrated by large amounts of immune cells. This led to the assumption that hormone regulation affects immune cell recognition and three biological axes (hormone, immune, and proliferation axis) were built up for breast cancer as being the coordinates of the biological universe of breast cancer [5, 6]. The therapeutic implication of these fundamental insights were further explored and validated the distinct sensitivity towards antihormonal treatment, ERBB2 targeting, and chemotherapy. Interestingly, the hormone-insensitive, highly proliferating basal and ERBB2-positive tumors with higher amounts of immune cell infiltrates did respond best to neoadjuvant treatment with superior outcome [7]. As one consequence, the concept arose to develop RNA-based vaccination concepts in the post-neoadjuvant situation of triple negative breast cancer not responding to neoadjuvant chemotherapy by targeting individual neo-epitope patterns [8], which has been investigated in the subsequent “Merit” trial with positive proof of concept [9]. In line with this, the first approval of checkpoint therapy treatment in breast cancer happened in the triple negative breast cancer subtype [10].