J. Clin. Invest. 118(1): 51-63 (2007)
Breast cancer research offers a clinically important venue for exploring resistance to targeted therapy. Antagonists of estrogen receptor–dependent (ER-dependent) and human epidermal growth factor receptor 2 (HER2-dependent) signaling are mainstays of modern breast cancer treatment that enhance cure rates when applied against early-stage disease and contribute to disease remissions when applied against late-stage disease (1, 2).
J. Clin. Invest. 118(1): 51-63 (2007)
In principle, tumors can escape growth constraints imposed by targeted therapy either by reactivating the targeted signaling pathway or by perturbing untargeted compensatory pathways. Both mechanisms appear capable of promoting tumor escape in breast cancer patients. Resistance to first-line ER antagonists often involves reactivation of ER-dependent signaling, since cancers that become refractory to one agent frequently remain sensitive to a second agent that targets the ER via a distinct molecular interaction (1, 6). Similarly, some cancers acquire resistance to the HER2 antagonist trastuzumab but remain sensitive to lapatinib, a structurally distinct inhibitor (7). In contrast, other breast cancers that overexpress ER or HER2 seemingly acquire resistance to diverse pathway inhibitors in a single step or show a marked insensitivity to targeted therapy from the outset (5, 8). In the case of ER antagonists, de novo resistance has been linked to compensation mediated by activation of growth factor receptor pathways (1, 8). For HER2 antagonists, resistance has been associated with compensation mediated by the PI3K pathway, through either inactivation of the PTEN tumor suppressor or changes in HER3 activity (9, 10).
Women with confirmed invasive or preinvasive breast cancer, planned for immediate IBBR with skin‐ or nipple‐sparing mastectomy, were eligible for inclusion. Exclusion criteria were: previous radiotherapy, neoadjuvant chemotherapy, smoking, BMI of 30 kg/m2or above, predicted implant size smaller than 200 ml or greater than 600 ml, pregnant or lactating women, insulin‐dependent diabetes or any immunosuppressive disorder, allergy to porcine material or refusal to receive porcine material, or unable or unwilling to provide written informed consent. Written informed consent was obtained from all participants before any study‐related procedure was performed. The trial design has been described previously17.
