Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 166-181 http://medscipublisher.com/index.php/cge 172 HER2 protein. These tumors often exhibit alterations in the PI3K/Akt/mTOR pathway, which can predict responsiveness to targeted therapies such as PI3K and mTOR inhibitors (Schettini and Prat, 2021). Clinically, HER2-E tumors are associated with higher rates of pathological complete response (pCR) following neoadjuvant anti-HER2 therapies, such as trastuzumab and lapatinib, especially when used in combination with chemotherapy. This subtype is also linked to a higher likelihood of achieving pCR in hormone receptor-negative (HR-) cases compared to hormone receptor-positive (HR+) cases (Llombart-Cussac et al., 2017; Schettini et al., 2020). The presence of tumor-infiltrating lymphocytes (TILs) in HER2-E tumors further predicts a favorable response to neoadjuvant anti-HER2 treatments and may have prognostic significance (Schettini and Prat, 2021) (Figure 3). Figure 3 HER2-dependent pathway for proliferation and survival in HER2+ breast cancer (Adopted from Schettini and Prat, 2021) Image caption: Legend. cHER2+: clinically HER2-positive; HER2-E: HER2-Enriched. The red cone visually suggests a higher activation of the HER2-related pathway in cHER2+/HER2-E tumors, compared to cHER2+/non-HER2-E (Adopted from Schettini and Prat, 2021) The clinical implications of HER2-E tumors extend to the potential for de-escalation or escalation of systemic therapies based on the genomic profile. For instance, patients with HER2-E tumors may benefit from dual HER2 blockade without chemotherapy, as demonstrated in the PAMELA trial, where HER2-E status predicted a higher pCR rate with trastuzumab and lapatinib alone (Llombart-Cussac et al., 2017). Additionally, novel HER2-targeted therapies, such as antibody-drug conjugates, show promise in treating HER2-E tumors, even those with low HER2 expression (Schettini and Prat, 2021). 5.3 Triple-Negative breast cancer (TNBC) Triple-negative breast cancer (TNBC) is a highly heterogeneous and aggressive subtype of breast cancer, characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression. This subtype is associated with a poor prognosis and limited treatment options, primarily relying on chemotherapy (Lehmann and Pietenpol, 2015; Prat et al., 2015). Genomic and transcriptomic analyses have revealed distinct subtypes within TNBC, each with unique genetic and molecular features. These subtypes include luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed, and mesenchymal-like. The LAR subtype, for example, is characterized by the presence of ERBB2 somatic mutations and frequent CDKN2A loss, which may serve as potential therapeutic targets (Jiang et al., 2019). The basal-like subtype, which predominates in TNBC, is associated with high expression of cell cycle and DNA damage response genes, making it more responsive to DNA-damaging agents like cisplatin (Lehmann et al., 2011). The aggressive nature of TNBC is partly due to its high genomic instability and the presence of multiple genetic alterations, including mutations in the TP53 gene and copy number variations. These genetic features contribute to the rapid progression and poor clinical outcomes associated with TNBC (Lehmann and Pietenpol, 2015; Jiang et
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