Translational studies within the TAMRAD randomized GINECO trial: evidence for mTORC1 activation marker as a predictive factor for everolimus efficacy in advanced breast cancer

Ann Oncol. 2015 Jan;26(1):120-125. doi: 10.1093/annonc/mdu497. Epub 2014 Oct 31.

Abstract

Background: Everolimus is an agent frequently associated with specific toxicities. Predictive markers of efficacy are needed to help define which patients could benefit from it. The goal of this exploratory study was to identify potential predictive biomarkers in the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activation pathway using primary tumor samples collected during the phase II tamoxifen plus everolimus (TAMRAD) trial.

Patients and methods: Tumor tissues were collected retrospectively from the TAMRAD trial. Immunohistochemistry was carried out using specific antibodies directed toward proteins that result in mTORC1 activation [canonical phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mTOR or alternative pathways]. DNA was extracted from the tumor tissue; mutation screening in the PIK3CA gene (exons 9 and 20) and the KRAS gene (exons 2 and 3) was first carried out using Sanger direct sequencing, and then completed by next-generation sequencing for PIK3CA. An exploratory analysis of everolimus efficacy in terms of a time-to-progression (TTP) increase was carried out in each biomarker subgroup (high versus low expression referring to the median percentage of marked cells).

Results: A total of 55 primary tumor samples from the TAMRAD trial—25 from the tamoxifen-alone group and 30 from the tamoxifen/everolimus group—were evaluated for biomarkers. The subgroups most likely to have an improvement in TTP with tamoxifen/everolimus therapy, compared with tamoxifen alone, were patients with high p4EBP1, low 4EBP1, low liver kinase B1, low pAkt, and low PI3K. Among the 45 samples screened for mutation status, nine samples (20%; 95% CI 9.6-34.6) had a PIK3CA mutation. KRAS mutation was observed in one patient.

Conclusions: A positive correlation between late effectors of mTORC1 activation, a positive correlation between Akt-independent mTORC1 activation, and an inverse correlation between canonical PI3K/Akt/mTOR pathway and everolimus efficacy were observed in this exploratory analysis. However, these correlations need to be validated in larger studies before applying the findings to routine clinical practice.

Trial registration: ClinicalTrials.gov NCT01298713.

Keywords: biomarkers; breast cancer; everolimus; mTORC1; tamoxifen.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Base Sequence
  • Biomarkers, Tumor / genetics*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / mortality
  • Cell Cycle Proteins
  • Class I Phosphatidylinositol 3-Kinases
  • Everolimus
  • Female
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Middle Aged
  • Multiprotein Complexes / genetics*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins p21(ras)
  • Retrospective Studies
  • Sequence Analysis, DNA
  • Sirolimus / analogs & derivatives*
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / metabolism
  • Tamoxifen / therapeutic use
  • ras Proteins / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • KRAS protein, human
  • Multiprotein Complexes
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Tamoxifen
  • Everolimus
  • MTOR protein, human
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • Sirolimus

Associated data

  • ClinicalTrials.gov/NCT01298713