Targeting the insulin-like growth factor pathway in estrogen receptor-positive breast cancer: a bumpy start with an uncertain future.

During the last decade, we have made significant advances in the field of endocrine therapy for patients with hormone receptor (HR)positive early-stage breast cancer. The first report from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists in 2000 introduced the use of anastrozole in the adjuvant setting as an alternative to tamoxifen for women with HR-positive disease who were postmenopausal. Since that time, additional trials have demonstrated the benefit of all three aromatase inhibitors, either as initial endocrine therapy after surgery, as sequential therapy after 2 to 3 years of tamoxifen, or as extended adjuvant therapy after 5 years of tamoxifen. Despite these substantial gains, approximately one third of women with HRpositive early-stage disease will relapse, and the majority of these women will die from distant metastatic disease (MBC). Molecular cross talk between the estrogen receptor (ER) and growth factor receptor signaling pathways likely contributes to de novo or acquired resistance to endocrine therapy. In addition to classic ER activation by ligand binding (estrogen), a subset of the ER pool may initiate alternative cellular signaling by direct interaction with components of growth factor signaling pathways. As one example, upregulation of the human epidermal growth factor receptor 2 (HER2) pathway leads to ligand-independent phosphorylation of the ER and increased downstream signaling despite ongoing antiestrogen therapy. To counteract these resistance mechanisms, clinical trials that have combined endocrine therapy with anti-HER2 therapy (trastuzumab and lapatinib) have been performed in MBC and demonstrated increased clinical activity in patients with ER-positive, HER2-positive disease compared with endocrine therapy alone. However, definitive conclusions that support the beneficial effects of dual-targeted therapy are limited by the design of these trials, given that single-agent anti-HER2 therapy was not tested in these studies. In a similar fashion, other growth factor signaling pathways, such as the insulin-like growth factor (IGF) pathway, can activate ER signaling and contribute to resistance to endocrine therapy (Fig 1). The IGF system is composed of four related receptors (insulin receptor [IR], type 1 IGF receptor [IGF1R], and hybrid receptors between the IR and IGF1R), three ligands (IGF-1, IGF-2, and insulin), and six binding proteins (IGFBP-1 to IGFBP-6). There is a growing body of preclinical evidence that breast tumors express insulin and IGF-1 receptors, and that these receptors activate the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase signaling pathways. Inhibition of the IGF1R pathway in combination with letrozole synergistically inhibited proliferation and induced apoptosis in breast cancer cells. In addition, there is increasing evidence that women with early-stage breast cancer and hyperinsulinemia or elevated fasting C-peptide levels have a worse prognosis. Taken together, these findings support the hypothesis that dual targeting of the IGF1R and ER pathways is a rational strategy to prevent or delay the onset of endocrine resistance. In the article that accompanies this editorial, Pritchard et al report a randomized, open-label, phase III trial that compared 5 years of tamoxifen treatment with or without 2 years of long-acting–release octreotide as adjuvant therapy in 667 postmenopausal women with HR-positive early-stage breast cancer (NCIC Clinical Trials Group study MA.14, A Randomized Trial of Tamoxifen Therapy Versus Combined Tamoxifen and Octreotide LAR Therapy in the Adjuvant Treatment of Breast Cancer in Postmenopausal Women). Long-acting–release octreotide is a long-acting somatostatin analog that binds to somatostatin receptors, inhibiting secretion of pituitary and gastroenteropancreatic hormones including growth hormone, insulin, glucagon, cholecystokinin, and vasoactive intestinal peptide (Fig 1). Octreotide is commonly used in the clinic for a myriad of indications including the treatment of hormone-secreting tumors in the pituitary, the control of symptoms such as diarrhea and flushing in patients with metastatic carcinoid and vasoactive intestinal peptide–secreting tumors, and the treatment of diarrhea associated with AIDS, chemotherapy, and graft-versus-host disease. Octreotide was one of the first IGF-1 targeting agents available in the 1990s, and was chosen for this trial, which was initiated in 1996, on the basis of small MBC studies that showed antitumor activity and greater suppression of IGF-1 with octreotide plus tamoxifen compared with tamoxifen alone. In the MA.14 trial, the duration of octreotide was shortened from 5 to 2 years after a substantial rise was noted in the incidence of symptomatic gallbladder disease. As hypothesized by the study investigators, patients who were treated with octreotide plus tamoxifen had a greater reduction in IGF-1 levels compared with patients who were treated with tamoxifen alone. However, after a median follow-up of JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S