Are We Hitting the Right Combination for Hormonally Sensitive Breast Cancer?
Authors: Debu Tripathy
Journal: Journal of Clinical Oncology (2009)

When it comes to opening a safe or playing the slot machines, the perfect combination yields dramatic results. In cancer therapy, the right combination has been particularly elusive. In addition to their direct effects on cell division, chemotherapeutic agents, like biologic drugs, modulate many pathways such as those involved in cell cycle control, cell death, and DNA repair. Combination chemotherapy has allowed the curability threshold to be crossed for lymphoma, but advanced-stage solid tumors that derive from heartier and topologically exterior epithelial cells remain for the most part incurable with combinations of cytotoxic agents. Biologic agents, defined as those that do not directly affect DNA synthesis, replication, or the cellular division machinery, have been an important part of cancer therapy ever since the role of sex steroid hormones were uncovered for prostate and breast cancers. The use of tamoxifen reduces recurrence by up to 50% and mortality by 30% in hormone receptor–positive earlystage breast cancer, but has much more modest effects on survival in advanced disease. However, some patients with advanced disease maintain sensitivity to hormonal therapy for years, whereas others exhibit initial intrinsic resistance; some develop resistance after some period of response or stability. The same principles hold for both cytotoxic and biologic therapies. There are multiple mechanisms of hormonal resistance, and strategies to reverse resistance are particularly attractive because of the low toxicity associated with hormonal therapy. Therefore, a clearly desirable combination would be that of a low-toxicity drug that modulates a resistance pathway in combination with hormonal therapy. Much attention has therefore been devoted to understanding how truly synergistic combinations can be identified and tested. Current preclinical models are not sufficiently robust to be very informative, and pilot clinical trials suffer from the fact that tumor heterogeneity might mask important benefits in difficult-to-identify, but biologically relevant, subsets. Therefore, new models of drug evaluation are sorely needed if combinatorial targeted therapeutic strategies are to accelerate improvements in cancer outcomes. These models must take into account the huge number of permutations that could potentially be tested and must address patient-specific tumor cellular circuitry. In the report by Baselga et al in this issue of Journal of Clinical Oncology, several contemporary tenets of pilot clinical and translation investigation were invoked. First, one of the more studied mechanisms of hormonal therapy, namely the activation of growth factor receptor–associated signaling, was used as the basis for the underlying hypothesis that modulation of signal transduction pathways might improve the efficacy of hormonal therapy. Second, a controlled (large, randomized, phase II) design was employed to generate a more valid comparator group as opposed to use of historical data. Third, a clinical model was chosen that allows real-time monitoring of the drug effect using validated clinical, imaging and tissue-based markers. Finally, exploratory biomarkers were incorporated into the trial, which include components of the targeted pathway that are known to be aberrant, to potentially yield patient selection strategies and to identify future targets. With these critical benchmarks met, do the results spell promise? This clinical trial serves as an excellent case study to examine the opportunities and pitfalls of this maturing model of translational research. First, one must examine the validity of the underlying hypothesis that supports mammalian targeted of rapamycin (mTOR) as a legitimate target to combine with hormonal therapy. Activation of growth factor receptor pathways mediated via the phosphatidylinositol 3-kinase (PI3K)/Akt axis can directly phosphorylate estrogen receptor and it coactivators, bypassing the antiproliferative effects of both tamoxifen and estrogen deprivation. Also, signaling via the ras-raf-MAP kinase arm can lead to epigenetic estrogen receptor gene silencing. Preclinical models have shown that growth factor receptor tyrosine kinase inhibitors like gefitinib can reverse hormonal resistance, and a small randomized neoadjuvant trial comparing gefitinib with or without anastrozole showed that clinical response was not significantly different, but that change in Ki-67 proliferative index was greater with combination therapy. In a recently reported phase III trial comparing anastrozole alone or with the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER-2) dual kinase inhibitor lapatinib, patients with advanced breast cancer showed a clear improvement in time to progression with combination therapy in the HER-2–positive subset as well as the overall population. Interestingly, there was a suggestion of greater activity with the combination in patients who progressed on or soon after tamoxifen, consistent with the notion that signal transduction is activated in hormonal resistance and can be manipulated to restore sensitivity. Inhibition of signaling further downstream along the PI3K/Akt arm could lead to more pronounced effects and might not be susceptible to bypass pathways. mTOR is a branch point component of the signal transduction pathway that promotes cell survival, leads to cell cycle entry via activation of S6 kinase, and activates the hypoxia-inducible transcriptional factor alpha (HIF1). The mTOR inhibitors temsirolimus and everolimus are effective in angiogenesis-driven renal cell carcinoma and are being increasingly explored in combinations with JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 16 JUNE 1 2009