Mutational Activation of PI3K-AKT Pathway and Change in HER2 Expression in Trastuzumab-resistant Breast Cancer

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Insensitivity of HER2-amplified breast cancer to trastuzumab (Herceptin) has been associated with both changes in HER2 expression and activation of the PI3K-AKT pathway in laboratory studies. Chandarlapaty and colleagues from Memorial- Sloan Kettering Cancer Center in New York and Fox Chase Cancer Center in Philadelphia recently reported that the predominant alterations found in prospectively collected trastuzumab-refractory breast tumors were loss of PTEN or PIK3CA mutation.

In 60 tumor samples from patients with recurrence after adjuvant trastuzumab or progression of metastatic disease during trastuzumab, HER2 expression persisted in 53 (88%) after trastuzumab exposure; in the 7 cases without HER2 overexpression, repeat analysis of pretreatment samples showed no HER2 overexpression in 5.

Absent or significantly diminished PTEN expression was found in 33 (59%) of 56 evaluable cases and activating mutations in PIK3CA were found in 13 (29%) of 45 evaluable cases. The combined rate of PTEN loss and PIK3CA mutation in these trastuzumab-refractory tumors was 71%, compared with 44% (P = .007) in a cohort of 73 HER2-amplified tumors in patients not exposed to trastuzumab.
As concluded by the investigators, “In this series of prospectively collected trastuzumab-refractory human breast cancers, loss of HER2 overexpression was rare while activation of the PI3K-AKT pathway through loss of PTEN or PIK3CA mutation was frequently observed.” ■

Chandarlapaty S, et al: Clin Cancer Res. October 23, 2012 (early release online).




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