Trastuzumab Resistance: Can Genetics Lead Us to New Options?

Maurie Markman, MD


January 23, 2013

Frequent Mutational Activation of the P13K-AKT Pathway in Trastuzumab-Resistant Breast Cancer

Chandarlapaty S, Sakr RA, Giri D, et al
Clin Cancer Res. 2012;18:6784-7791


In an effort to explain the development of resistance to trastuzumab in the tumors of patients with HER2-overexpressing breast cancer, investigators conducted a detailed analysis for the presence of several potential molecular abnormalities in samples obtained through biopsy after disease progression while the patients were receiving trastuzumab.

Of the 60 evaluable tumors, 53 showed persistent overexpression of the HER2 receptor. Of the 7 tumors that did not overexpress the receptor on posttreatment biopsy, 5 were found not to overexpress HER2 on re-review of the original specimen. Thus, only 2 of 55 specimens that overexpressed HER2 were found to have lost this biological characteristic after development of trastuzumab resistance.

In contrast, reduced or absent expression of PTEN, an important molecular regulator in the "pro-growth" PI3K pathway, or the presence of a mutation in PIK3CA, which activates the PI3K pathways, was far more common: Overall, 71% had PTEN loss and/or PIK3CA mutations. Of note, in an unrelated group of 73 HER2-positive cases of breast cancer, only 44% showed these particular molecular abnormalities.


The administration of trastuzumab to breast cancer patients whose tumors overexpress the HER2 receptor has been shown to improve survival when delivered in both the metastatic and adjuvant settings. Unfortunately, clinical resistance to this agent is not infrequent, particularly in the metastatic setting.

A critical initial step in defining strategies to overcome resistance is to establish a firm understanding of the molecular basis for its development. The current report strongly suggests that loss of HER2 overexpression as a mechanism for trastuzumab resistance in breast cancer is uncommon (fewer than 5% of cases). Indeed, given that 5 of 7 tumors that "lost" HER2 overexpression turned out to be misclassified as HER2-positive on reexamination of the original specimen, it may be prudent to consider reexamination if overexpression is not seen on posttreatment biopsy.

Conversely, abnormalities in the PIK3CA pathway (PIK3CA mutations or loss of PTEN activity) in patients with trastuzumab resistance are very common and are seen considerably more frequently than in those who were not previously treated with trastuzumab.

It remains uncertain whether the current observation reveals the -- or even "a" -- major mechanism for trastuzumab resistance and subsequent cancer cell survival, but the data suggest a clear path forward in the development of strategies to overcome resistance.

For patients with newly diagnosed HER2-overexpressing breast cancer, an appropriate strategy might include analyzing the tumor for evidence of PI3K pathway abnormalities and, if these molecular abnormalities are present, treating with trastuzumab or other inhibitors of HER2 plus a PIK3CA inhibitor, many of which are in active clinical development.

Alternatively, if PI3K-associated mutation status is not known prior to initiating treatment, patients with HER2-positive breast cancer whose cancer progresses despite trastuzumab could have the tumor analyzed at progression and then be started on a PIK3CA inhibitor if an abnormality in this pathway is detected.

This paper is one more excellent example of the increasing clinical relevance of molecular analysis of individual tumor specimens in critically defining optimal care for each patient.



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