Frequent Mutational Activation of the PI3K-AKT Pathway in Trastuzumab-Resistant BC

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Clin Cancer Res. 2012 Oct 23;[Epub Ahead of Print], S Chandarlapaty, RA Sakr, D Giri, et al

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In a prospective study, a high percentage of trastuzumab-resistant HER2+ breast tumors had PTEN loss and activating mutations of the PI3K/AKT pathway, while loss of HER2 overexpression was rare.

SUMMARY

OncologySTAT Editorial Team


Despite the efficacy of trastuzumab therapy in metastatic HER2-positive breast cancer, almost all patients eventually have disease progression. Determining the molecular basis for trastuzumab resistance has been hampered in part because of the difficulty in acquiring tumor samples from patients who progress while on trastuzumab.

Possible explanations for trastuzumab resistance, based on retrospective studies and laboratory models, include activation of the PI3K/AKT pathway, in response to either PIK3CA mutation or loss of the PTEN tumor suppressor; loss of HER2 expression; and certain activating mutations in HER2. To explore these findings, researchers from Memorial Sloan-Kettering Cancer Center analyzed prospectively acquired tissue samples.

From 2007 to 2011, tissue was collected from metastatic sites in 63 patients with HER2-positive breast cancer and either disease recurrence after receiving adjuvant trastuzumab or progression of metastatic disease while on a trastuzumab-containing regimen. A comparison cohort was comprised of 73 patients who had surgery for a HER2-positive primary tumor and did not receive trastuzumab.

The study showed that loss of HER2 expression was very rare in these cases with documented trastuzumab resistance. Of the 60 patients with sufficient material for analysis of HER2 expression, 53 (88%) maintained HER2 overexpression or amplification after exposure to trastuzumab. Among the 7 cases in which HER2 overexpression was lost, original FISH scores were positive in 5 cases, but all 5 had scores near the standard cut-off of 2.0. Further, in 3 cases with sufficient material for repeat analysis of the pretreatment tumor, HER2 overexpression was not confirmed.

Of the 45 patients with successful analysis for PIK3CA mutations, 13 (29%) had activating PIK3CA mutations in their metastatic lesions. In contrast, only 13 (18%) of the 73 controls not exposed to trastuzumab had an activating PIK3CA mutation.

Of 44 cases analyzed for known activating mutations in HER2 associated with resistance, only one case showed a mutation, and this case also had diminished PTEN expression.

In 56 trastuzumab-refractory metastatic tumors evaluable for PTEN, 33 (59%) had absent or significantly reduced PTEN, compared with 34% in the control cohort (P = .007). Among the 41 patients with both PIK3CA and PTEN evaluation, 29 had lesions with PIK3CA mutations, PTEN loss, or both, for a combined rate of 71%, compared with 44% (P = .007) in the comparison cohort.

The study results show that in tumors progressing on trastuzumab therapy, there is evidence for changes that activate PI3K/AKT signaling but little evidence for loss of HER2 overexpression. Thus, trastuzumab-refractory metastatic tumors that become resistant to trastuzumab are likely still dependent on HER2 as the oncogenic driver. This appears to be the case since agents that target HER2 by other means are often effective in trastuzumab-refractory tumors.

The study data support the possibility that combining PI3K/AKT inhibitors with HER2 inhibitors may be more effective than either used alone in patients with resistant metastatic disease.

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