Elsevier

Clinical Breast Cancer

Volume 15, Issue 1, February 2015, Pages 48-53
Clinical Breast Cancer

Original Study
Everolimus-Induced Hematologic Changes in Patients With Metastatic Breast Cancer

These data were presented in part at the 36th Annual San Antonio Breast Cancer Symposium in 2013.
https://doi.org/10.1016/j.clbc.2014.07.002Get rights and content

Abstract

Background

Everolimus, which inhibits the mammalian target of rapamycin (mTOR), is increasingly used in breast cancer and familiarity with its full range of toxicity is critical for practicing oncologists.

Patients and Methods

We studied hematologic changes in 31 patients with metastatic breast cancer treated in a phase II clinical trial using everolimus. Complete blood counts were collected at baseline, 2 weeks, 4 weeks, every 4 weeks during treatment, and 1 month after discontinuation. Adverse events were defined using Common Toxicity Criteria version 3. Linear mixed models with fixed effects of time and random intercepts and slopes were used to study trends and comparisons were conducted using paired t tests.

Results

Anemia was reported in 22 patients (71%), thrombocytopenia in 17 (55%), and leukopenia in 14 (45%). These were predominantly grade 1 or 2 and did not require dose modification. Red blood cell mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) both decreased significantly over time (P < .0001) starting at 2 weeks with no significant change in mean corpuscular hemoglobin concentration (MCHC) (P = .104). Both MCV and MCH increased 1 month after treatment discontinuation (P values < .0001 and .0003, respectively) indicating reversibility of this effect. Although total leukocyte counts remained largely stable, lymphocyte percentage progressively decreased over time with a trend for increased neutrophils.

Conclusion

In addition to anemia, leukopenia, and thrombocytopenia, everolimus consistently induces red cell microcytosis and reduced hemoglobin content. Lymphopenia may contribute to immune suppression and increased risk of infection. Familiarity with these hematologic changes is prudent as more patients are treated with this class of drugs.

Introduction

Increasingly, the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway has emerged as a critical survival pathway in cancer cell growth and survival over the last decade,1 and inhibitors of mTOR are now frequently used in the treatment of patients with a variety of cancers. In addition, mTOR is a phylogenetically conserved master regulator in a number of critical biologic processes through its largely conserved role in cell growth, nutrition, and energy metabolism.2, 3

Everolimus, which is an oral inhibitor of mTOR, is approved by the Food and Drug Administration for the treatment of several cancers including renal cell carcinoma,4 progressive neuroendocrine tumors of pancreatic origin,5 giant cell astrocytoma,6 and, most recently, metastatic hormone receptor-positive breast cancer that has become resistant to aromatase inhibitor therapy.7 Despite the established efficacy and value of using everolimus and other mTOR inhibitors in cancer patients, this class of drugs is associated with classic well described toxicities such as mucositis8 and pneumonitis,9 in addition to several unfavorable metabolic changes, including hyperglycemia and dyslipidemia.10 Myelosuppression, which is a well described toxicity of traditional chemotherapeutic agents, can also develop with mTOR inhibition, although it is typically less frequent and not as severe in magnitude. Recently, several articles reviewed the hematologic toxicities associated with mTOR inhibitor use11, 12 with a particular emphasis on describing reduction in cell counts (anemia, thrombocytopenia, or leukopenia). These toxicities are presumed to be related to the antiproliferative effects of mTOR inhibition, but the exact mechanisms are not yet fully characterized.13

In this report, we describe hematologic changes encountered during a phase II trial using everolimus for patients with metastatic breast cancer. This was prompted by our observation of a consistent decrease in mean corpuscular volume (MCV) during therapy, which led to further examination of hematologic changes during the trial. With increasing use of this class of drugs in cancer, awareness of these changes is important for the treating oncologist and might shed light on additional potential mechanisms for the anticancer effect of everolimus and similar rapalogs.

Section snippets

Patient Data

Complete blood counts (CBCs) including leukocyte differential and red blood cell indices were analyzed from patients enrolled in a phase II trial of combined everolimus with fulvestrant for metastatic breast cancer (clinicaltrials.gov identifier: NCT00570921).14 Patients were treated with everolimus 10 mg daily along with fulvestrant loading dose regimen: 500 mg on day 1, and 250 mg on day 14, day 28, and monthly thereafter. CBCs, and clinical and biochemical data, were collected at baseline,

Anemia, Thrombocytopenia, and Leukopenia

Hematologic toxicities were commonly observed on study treatment. These were recently highlighted in the clinical trial report14 and are summarized herein in more detail (Table 1). Of the total number of toxicities, 76% of toxicities were Grade 1% and 22% were Grade 2, with 1 Grade 3 toxicity (anemia), which was deemed unlikely related to study treatment. There were no Grade 4 toxicities. Everolimus dose was not adjusted based on blood count changes and the full dose of 10 mg daily was

Discussion

mTOR is a PI3K-like serine/threonine protein kinase that exists in the cytoplasmic compartment in 2 distinct complexes; mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).13, 16 mTORC1, which includes RAPTOR, is driven in part by growth factor signaling, surface receptors, and is sensitive to various nutrients. Activation of mTORC1 drives downstream signaling through S6 kinase (S6K) and 4E-binding protein 1 (4E-BP1), which are critical downstream effectors of cellular proliferation and growth,

Conclusion

Hematologic changes and toxicities are common in breast cancer patients treated with everolimus, including multiple cytopenias, reduced lymphocyte counts, and a noticeable early and progressive decrease in red blood cell size and hemoglobin content. It is important for practicing oncologists to be aware of the hematologic changes that occur during treatment with everolimus and, in particular, consider this association in the differential diagnosis of microcytic anemia in cancer patients. The

Acknowledgments

The clinical trial was funded by a grant from Novartis (S. Massarweh).

References (26)

  • D.M. Sabatini

    mTOR and cancer: insights into a complex relationship

    Nat Rev Cancer

    (2006)
  • R. Zoncu et al.

    mTOR: from growth signal integration to cancer, diabetes and ageing

    Nat Rev Mol Cell Biol

    (2011)
  • R.J. Motzer et al.

    Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors

    Cancer

    (2010)
  • Cited by (0)

    ClinicalTrials.gov NCT00570921.

    View full text