ABSTRACT Alterations in the PI3K signaling pathway are common in hormone receptor‐positive (HR+)/HER2‐negative metastatic breast cancer (MBC) and are associated with response to PI3K and AKT inhibitor‐targeted therapies. When metastasis biopsy is unavailable for genetic testing, circulating tumor DNA (ctDNA) analysis is an alternative strategy for tumor genotyping, but it is less sensitive for gain and loss analysis. Here, we assess molecular alterations of the genes of this axis—PIK3CA, AKT1, and PTEN—in circulating tumor cells (CTCs) from patients with HR+/HER2− MBC. CTCs from blood were isolated as single cells with DEPArrayNxT. Libraries were prepared for copy number analysis (CNA) and investigation of PIK3CA, AKT1, and PTEN mutational status. A subset of viable CTCs underwent 3′ RNA sequencing for transcriptomic profiling. CTCs of 4/5 MBC patients (80%) exhibited single nucleotide variants (SNVs), and heterogeneity was observed at inter‐ and intra‐patient levels. CNA profiling of CTCs from 8 patients revealed amplifications and gains of chromosomal regions hosting PIK3CA, AKT1, and PTEN. Notably, one patient presented both 10q32.31 loss and a nonsense mutation of the remaining PTEN allele, suggesting PTEN loss of function, an event potentially missed by ctDNA analysis. Integrated transcriptomic analysis highlighted patient‐specific enrichment of pathways related to metabolism and RNA processing. Conclusively, single‐CTC analysis enables comprehensive characterization of the PI3K/AKT/PTEN pathway, revealing molecular heterogeneity and capturing events not detectable by tumor tissue or ctDNA. This approach may enhance molecular stratification and guide the use of targeted therapies in MBC, supporting its integration into future precision oncology frameworks.
T. Rossi, M. Palleschi, C. Gianni et al.· Cancer Science· 0 citations
Despite significant advances in early detection and therapeutic strategies, breast cancer (BC) continues to pose a major public health challenge.
The treatment of HER2-positive (HER2 +) BC has evolved substantially over recent years with the advent of monoclonal antibodies (mAbs), small-molecule tyrosine kinase inhibitors (TKIs), and antibody–drug conjugates (ADCs). Clinical progress has been significantly accelerated by a deeper understanding of the immune-regulatory properties of this subtype and its interactions with the tumor microenvironment.
Despite the availability of effective HER2-targeted therapies, approximately one-third of patients develops resistance, highlighting the need for novel and more durable treatment strategies. Indeed, while current treatments have shown promising efficacy by promoting a “passive immune response,” they are associated with the emergence of resistant clones.
Conversely, vaccine-based therapies are designed to elicit a durable “active immune response” by presenting tumor-associated antigens that stimulate the host immune system to recognize and eliminate malignant cells. This approach has the potential to generate long-lasting immunological memory, preventing recurrence, disease progression, and the emergence of immune-evasive tumor variants.
This review provides a comprehensive overview of cancer vaccines strategies for HER2 + BC with emphasis on their mechanisms, advantages, limitations, and their current developmental status. We explore diverse delivery platforms, including peptide/protein-based, nucleic acid, and cell-based vaccines. The clinical utility of these strategies is assessed across different disease settings: from prevention and interception in pre-invasive lesions, to the (neo)adjuvant treatment of early-stage BC and the management of advanced metastatic disease. While advanced-stage BC often presents an immunosuppressive tumor microenvironment that hinders vaccine efficacy, early-stage disease offers a more favorable immunological milieu for inducing robust and durable T-cell responses. Furthermore, we discuss emerging innovations such as neoantigen discovery, next-generation adjuvants (e.g., TLR and STING agonists), and novel combinatorial approaches with checkpoint inhibitors to overcome immune evasion.
Although most BC vaccines remain under clinical investigation, they represent a promising frontier for achieving disease control and the coming decade is expected to yield pivotal insights into their clinical utility and therapeutic potential.
A. Caltavituro, C. Martinelli, M. Palleschi et al.· Journal of Experimental &...· 0 citations
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