Advanced search
Start date

Evaluation of acquired resistance mechanisms to hormone therapy in metastatic breast cancer patients

Grant number: 16/05375-0
Support Opportunities:Regular Research Grants
Duration: August 01, 2017 - July 31, 2019
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Fabiana Bettoni
Grantee:Fabiana Bettoni
Host Institution: Hospital Sírio-Libanês. Sociedade Beneficente de Senhoras (SBSHSL). São Paulo , SP, Brazil
Associated researchers:Anamaria Aranha Camargo ; Franciele Hinterholz Knebel ; Pedro Alexandre Favoretto Galante


Approximately 70% of breast cancers express estrogen receptor ± (ER) and most of these are sensitive to endocrine therapies with drugs that suppress estrogen production (aromatase inhibitors) or direct inhibit the receptor (selective ER modulators (SERMs) or selective ER degraders (SERDs)). However, a significant fraction of patients with ER-positive breast cancer that benefit from adjuvant endocrine treatment recur with metastatic disease after prolonged exposure to these drugs. Even patients with ER positive metastatic breast cancer who respond to endocrine treatment will eventually progress with antiestrogen-resistant, hormone independent disease. Activating mutations in the estrogen receptor gene ESR-1 have been recently described in advanced RE-positive breast cancer resistant to hormonal therapy, particularly in metastatic patients exposed to therapy with aromatase inhibitors. ESR-1 mutations frequently occur in a hotspot region within the ligand binding domain of ER constitutively activating the receptor in a ligand independent manner and thus explaining the acquired resistance to hormonal therapy. Recent studies have reported the detection of ESR-1 mutations in circulating tumor DNA of metastatic breast cancer patients ensuring the establishment of a causal relationship among ESR-1 mutations and acquired resistance to therapy with aromatase inhibitors. Moreover it has been demonstrated that liquid biopsies can be used to detect ESR-1 mutations before clinical evidence of recurrence during hormonal therapy and that these mutations remain readly detectable in ctDNA many months and years after stopping therapy with aromatase inhibitors. It is noteworthy that these studies investigated the presence of ESR-1 recurrent mutations in codons 536, 537 e 538 and that it was detected in 20% of ctDNA from metastatic breast cancer patients that exhibited disease progression after treatment with aromatase inhibitors. Based on these remarks, we questioned the presence of other ESR-1 mutations that could be associated to acquired endocrine resistance in the remaining 80% patients. Furthermore, among patients with no mutations in ESR-1, we interrogated if exists a relationship of acquired resistance to hormonal therapy with mutations in any other gene. To answer these questions we intend to investigate the presence o ESR-1 mutations in the ctDNA of ER positive metastatic breast cancer patients after acquired resistance to therapy with aromatase inhibitors. For those patients that were not detected ESR-1 mutations, ctDNA will be analyzed by exome sequencing enabling the detection of unknown genomic alterations. This study will enable a better description of the association among ESR-1 mutations and acquired resistance to endocrine therapy as well as a better understanding of novel mechanisms of acquired resistance to these treatments. (AU)

Articles published in Agência FAPESP Newsletter about the research grant:
Articles published in other media outlets (0 total):
More itemsLess items

Please report errors in scientific publications list by writing to: