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Clinical Trial
. 2011 Aug 10;29(23):3126-32.
doi: 10.1200/JCO.2010.32.2321. Epub 2011 Jul 5.

Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy

Phuong K Morrow  1 , Gerburg M Wulf, Joe Ensor, Daniel J Booser, Julia A Moore, Peter R Flores, Yan Xiong, Siyuan Zhang, Ian E Krop, Eric P Winer, David W Kindelberger, Jeanna Coviello, Aysegul A Sahin, Rodolfo Nuñez, Gabriel N Hortobagyi, Dihua Yu, Francisco J Esteva
Affiliations
Clinical Trial

Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy

Phuong K Morrow et al. J Clin Oncol. .

Abstract

Purpose: Trastuzumab resistance has been linked to activation of the phosphoinositol 3-kinase (PI3K) pathway. Phosphatase and tensin homolog (PTEN) is a dual phosphatase that counteracts the PI3K function; PTEN loss leads to activation of the Akt cascade and the downstream mammalian target of rapamycin (mTOR). Preclinical studies demonstrated that mTOR inhibition sensitized the response to trastuzumab in mice with HER2 overexpressing and PTEN-deficient breast xenografts. Our trial evaluated the safety and efficacy of the combination of everolimus and trastuzumab in women with HER2-overexpressing metastatic breast cancer (MBC) that progressed on trastuzumab-based therapy.

Patients and methods: This represents a pooled analysis (n = 47), stemming from two trials that occurred concurrently in The University of Texas MD Anderson Cancer Center, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute. Patients with HER2-overexpressing MBC who had progressed on trastuzumab-based therapy received trastuzumab every 3 weeks in combination with daily everolimus.

Results: Among 47 patients, the combination of everolimus and trastuzumab provided partial responses in seven patients (15%) and persistent stable disease (lasting 6 months or longer) in nine patients (19%), resulting in a clinical benefit rate of 34%. The median progression-free survival (PFS) was 4.1 month. Fatigue, infection, and mucositis were the predominant nonhematologic toxicities. Trastuzumab did not have significant influence on the pharmacokinetic profile of everolimus. Patients with PTEN loss demonstrated decreased overall survival (P = .048). However, PFS was not affected by PTEN loss.

Conclusion: Inhibition of mTOR results in clinical benefit and disease response in patients with trastuzumab-resistant HER2-overexpressing MBC.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
Patterns of (A) phosphatase and tensin homolog, (B) P-Src, (C) P-Akt, and (D) P-P70S6 expression in breast tumors.
Fig 2.
Fig 2.
Effect of phosphatase and tensin homolog (PTEN) loss on (A) overall survival and (B) progression-free survival.
Fig 3.
Fig 3.
Effect of the presence of phosphatase and tensin homolog (PTEN) loss or PIK3CA mutation (A) on overall survival and (B) progression-free survival.
See this image and copyright information in PMC

Comment in

References

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