Overcoming Resistance in Breast Cancer

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One validated mechanism of breast cancer resistance is HER2 gene amplification, which can now be treated with combined therapy, says Carlos L. Arteaga, MD. Although tumors often remain estrogen receptor (ER)-positive, breast cancers that are ER-positive lose ligand dependence and reactivate ER by a number of mechanisms, explains Arteaga, such as through gene amplification or ER mutations.

Research has supported that as many as 20% of tumors that have progressed after aromatase inhibitor or tamoxifen therapy express a reactivating mutation in the ligand binding domain of ER. This is important, says Arteaga, because these lesions may be sensitive to ER down regulators such as fulvestrant or other future down regulators currently in development.

The FERGI study assessed whether combining a PI3K inhibitor with endocrine therapy could help overcome resistance in ER-positive disease. In FERGI, progression-free survival was doubled with the addition of the PI3K inhibitor pictilisib to fulvestrant in patients with ER-positive and PR-positive metastatic breast cancer. In this group, the median PFS was 7.4 months with pictilisib compared with 3.7 months with fulvestrant alone (P = .002). However, a statistical difference was not seen in those with ER-positive disease alone.

Rebiopsies have shown that cells express more ER if PI3K is inhibited, so therapies should be combined with anti-ER agents in ER-positive disease, says Arteaga. However, at this time, PI3K inhibitors have not shown a response in the data, says Debu Tripathy, MD. There was a very low rate of hyperglycemia reported in the clinical studies evaluating PI3K inhibition, which Arteaga states may have been an indicator that the target was not inhibited. It is helpful to see target toxicity when interpreting results, comments Arteaga.

Another therapy within the PI3K pathway is the mTOR inhibitor everolimus, which has shown efficacy in resistant metastatic breast cancer. This therapy has shown classic "on target" adverse events, such as mucositis. Interestingly, in a study using German registry data, in patients with advanced hormone receptor positive disease who received everolimus with exemestane the primary reason for discontinuing therapy was mucositis, says Tripathy. In many second opinion cases he sees, everolimus is discontinued too soon. Duration of therapy may be extended with improved monitoring and management, such as prophylactic steroid mouthwashes or holding and re-starting therapy.