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Phase II trial of temsirolimus in patients with metastatic breast cancer

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Abstract

Preclinical models suggested that activating mutations of the PIK3CA gene are associated with sensitivity to inhibitors of the mammalian target of rapamycin (mTOR). In breast cancers, PIK3CA mutations are associated with estrogen receptor (ER) positivity. We therefore performed an open-label single arm phase II study of the rapamycin analog, temsirolimus, at a dose of 25 mg weekly, in women with pretreated breast cancers that were positive for ER, PR, or HER2. Archived formalin-fixed paraffin embedded tumor was collected for immunohistochemical evaluation of components of the PI3K/Akt/mTOR pathway and PIK3CA mutation analysis. Thirty-one patients were enrolled. There were no major objective responses; however, three patients had stable disease for over 24 weeks. Twenty-three tumor samples were available for mutational analysis. There were five tumors with PIK3CA mutations; no association was found between prolonged stable disease and PIK3CA mutation or any immunohistochemical marker. There was a trend toward improved progression free survival (PFS) for patients with positive nuclear staining for phospho-Akt308. One patient remains on study four and a half years after starting therapy; her tumor did not have a PIK3CA mutation. We conclude that single agent temsirolimus has minimal activity in a population of women with heavily pretreated breast cancer. We found no evidence that either absence of immunohistochemical staining for PTEN or mutations in the hotspot domains of PIK3CA in the primary tumor were associated with clinical benefit.

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Abbreviations

PIK3CA :

Gene encoding phosphoinositide-3-kinase, catalytic subunit

mTOR:

Mammalian target of rapamycin

mTORC1:

Mammalian target of rapamycin complex 1

mTORC2:

Mammalian target of rapamycin complex 2

ER:

Estrogen receptor

PR:

Progesterone receptor

HER2:

Human epidermal growth factor receptor 2

ECOG:

Eastern Cooperative Oncology Group

ANC:

Absolute neutrophil count

CYP3A4:

Cytochrome P450 3A4

RECIST:

Response evaluation criteria in solid tumors

FFPE:

Formalin-fixed paraffin embedded

PTEN:

Phosphatase and tensin homolog

SGK:

Serum and glucocorticoid-induced protein kinase

PDK:

Pyruvate dehydrogenase kinase

TBS:

Tris-buffered saline

H&E:

Hematoxylin and eosin

PCR:

Polymerase chain reaction

CR:

Complete response

PR:

Partial response

IHC:

Immunohistochemistry

PFS:

Progression free survival

IGF-1R:

Insulin-like growth factor receptor

FISH:

Fluorescent in situ hybridization

Ig:

Immunoglobulin

NA:

Not available

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Acknowledgments

This research was supported by the National Cancer Institute (P30CA1459931 S1 and P30CA91842 S2) and the Avon Foundation, as well as the University of Chicago Breast Cancer SPORE (P50 CA125183).

Conflict of interest

The authors declare that they have no relevant conflicts of interest except for Dr Fleming, who in the past received partial support (including drug) for costs of an unrelated investigator-initiated trial using Temsirolimus from Wyeth. The Temsirolimus for the trial reported in this manuscript was supplied by the NCI, and there was no financial support from Wyeth.

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Authors and Affiliations

  1. The University of Chicago Medical Center, 5841 South Maryland Ave., MC 2115, Chicago, IL, 60637, USA

    Gini F. Fleming, Dezheng Huo, Husain Sattar, Maria Tretiakova, Olwen M. Hahn, F. O. Olopade, R. Nanda, Philip C. Hoffman & Suzanne D. Conzen

  2. Washington University, St Louis, MO, USA

    Cynthia X. Ma, L. Lin, M. J. Naughton, Timothy Pluard & Matthew J. Ellis

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  1. Gini F. Fleming
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  2. Cynthia X. Ma
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Correspondence to Gini F. Fleming.

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Fleming, G.F., Ma, C.X., Huo, D. et al. Phase II trial of temsirolimus in patients with metastatic breast cancer. Breast Cancer Res Treat 136, 355–363 (2012). https://doi.org/10.1007/s10549-011-1910-7

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  • DOI: https://doi.org/10.1007/s10549-011-1910-7

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