Aggressive Breast Cancer by Regina H. DeFrina

By Regina H. DeFrina

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Increased Signaling from other Receptors Activating the MAPK and PI3K Pathways Overexpression of insulin-like growth factor-1 receptor (IGF1R) is also associated with trastuzumab resistance, as this receptor physically interacts with and phosphorylates HER2. Breast cancer cells with overexpression of both HER2 and IGF1R are resistant to trastuzumab [115]. In vitro, inhibition of IGF1R signaling has been shown to restore trastuzumab resistance, demonstrating the importance of this pathway as potential therapeutic target [115].

Rilke and colleagues examined the relationship of HER2 with a range of pathological, clinical, and biological factors suggested to have an impact on breast 12 Myra F. Barginear and Daniel R. Budman cancer prognosis [50]. Surgical specimens from 2,000 breast cancer patients were systematically evaluated for 18 clinico-pathologic parameters. As expected, the two most significant, individual, prognostic factors were lymph node status and tumor size. Other single factors with a significant impact on survival were mitotic index, tumor grade, menopausal status, HER2 status and age.

TGF-α is a ligand of the HER family that can lead to formation of heterodimers involving HER2. In vitro, trastuzumab was less efficient in inhibiting cell growth in presence of TGF-α [113]. In addition, increased levels of the HER family ligands heregulin and EGF blocked trastuzumab-mediated growth inhibition in HER2 overexpressing breast cancer cell lines [114]. Molecular profiling of tumor cells to detect the relative level of HER family members, their ligand and endogenous inhibitors might be useful for predicting trastuzumab sensitivity.

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