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Sensitivity to the aromatase inhibitor letrozole is prolonged after a "break" in treatment

Gauri Sabnis1, Olga Goloubeva, Rabia Gilani

  • 1Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

Molecular Cancer Therapeutics
|January 8, 2010
PubMed

Insights

A short break from letrozole treatment can restore its effectiveness in hormone-dependent cancers. This allows tumors to become sensitive to letrozole again, prolonging treatment response.

Area of Science:

  • Oncology
  • Endocrinology
  • Molecular Biology

Background:

  • Acquired resistance to letrozole in hormone-dependent cancers involves Her-2/MAPK pathway upregulation and ERalpha/aromatase downregulation.
  • Previous studies indicated that stopping letrozole or adding trastuzumab could reverse this resistance.

Purpose of the Study:

  • To compare intermittent letrozole treatment versus switching to trastuzumab for optimizing treatment in letrozole-resistant models.
  • To investigate the molecular mechanisms underlying resistance and resensitization to letrozole.

Main Methods:

  • Utilized a hormone-dependent xenograft model with letrozole-resistant tumors.
  • Compared three treatment arms: continuous letrozole, trastuzumab, and a treatment "off" period (supplement only).
  • Analyzed tumor protein expression and activity weekly to assess pathway modulation.

Main Results:

  • Letrozole withdrawal reversed resistance markers, decreasing Her-2/p-MAPK and increasing ERalpha/aromatase.
  • A 4-week "off" period followed by re-challenge with letrozole significantly prolonged response duration (P = 0.02).
  • Trastuzumab treatment did not inhibit tumor growth in this context.

Conclusions:

  • Discontinuous letrozole treatment, specifically a short "break", can re-sensitize tumors and prolong treatment efficacy.
  • Reversing cellular adaptation to low-estrogen environments is key to restoring letrozole responsiveness.
  • Intermittent therapy strategies warrant further investigation for managing acquired resistance in endocrine-resistant breast cancer.

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