Optimizing the Use of Aromatase Inhibitors

EXPERT’S CORNER-Nearly three quarters of breast cancer patients have tumors that express estrogen receptors (ERs) or progesterone receptors (PRs); approximately half of these patients are postmenopausal. We look to endocrine therapy, therefore, to prevent recurrences and save lives in the majority of early breast cancer patients and to prolong survival in the advanced disease setting. We are fortunate to have several means of targeting the estrogen signaling pathway. The third-generation aromatase inhibitors (AIs)-anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin)-are increasingly being found to improve upon the efficacy we observed for decades with tamoxifen.

But we still have important questions to resolve in order to make the best use of endocrine therapies. What is the best sequence, timing, and duration of AI use? How can we minimize side effects? These and other issues were addressed in studies reported at the 2008 San Antonio Breast Cancer Symposium (SABCS).

First, a meta-analysis presented at SABCS (abstract 12) confirmed the relative value of AIs vs tamoxifen. As initial monotherapy, AIs reduced the risk of recurrence by 23% vs tamoxifen; for patients who switched to AIs aft er 2 to 3 years of tamoxifen, AIs reduced the risk by 29%, a finding that was echoed in the findings of ABCSG trial 8 (abstract 14).

According to these findings, AIs, given by either approach, outperform tamoxifen, as previous studies have also shown. The ATAC trial provides the longest followup of AI treatment, with 100-mo data showing a statistically significant 24% reduction in risk of all recurrences, 15% improvement in disease-free survival, 16% reduction in risk of distant metastases, and 40% reduction in incidence of contralateral breast cancer (Forbes JF et al: Lancet Oncol 9:45-53, 2008). These data strongly support the use of an AI as initial adjuvant therapy in postmenopausal women with hormone receptor–positive early-stage breast cancer. The long-term ATAC data, the meta-analysis, and ABCSG trial 8 provide confirmation for using these agents with confidence during the treatment course of essentially all hormone-sensitive breast cancer patients.

Of course, side effects with AIs concern us. The ATAC 100-mo data are reassuring regarding long-term safety; we will learn more from a further mature analysis. Early on we learned from ATAC that bone health would be the primary concern with AIs. Overall, anastrozole had a better tolerability profile than tamoxifen and was associated with greater compliance. Joint symptoms and fractures increased with the AI, but fracture rates fell compared with those for tamoxifen-treated patients once treatment was discontinued. Anastrozole was associated with more hot fl ushes but less vaginal bleeding and discharge, thromboembolic and ischemic cerebrovascular events, and endometrial cancers. We clinicians can anticipate and manage musculoskeletal problems. We can monitor bone mineral density and use bisphosphonates to preserve bone health, as in the ZO-FAST trial (abstract 44). Tamoxifen’s side effects may not be as predictable or avoidable, especially the slight but worrisome risk of endometrial cancer.

We should also be aware that when joint and vasomotor symptoms do occur with AIs, they can be perceived as signs of recurrence. Patients should be reassured that the drug is working as planned. In fact, their symptoms may be predictive of improved outcomes, according to a recent study by Cuzick et al: ATAC patients with new joint and vasomotor symptoms at the 3-mo visit had a statistically significant 16% reduced risk of recurrence; new joint symptoms alone were associated with a 40% reduced risk (Cuzick J et al: Lancet Oncol 9:1143- 1148, 2008). We can hypothesize that patients reporting new symptoms were more adherent to treatment, had more responsive genomic mechanisms, or metabolized AIs better. Either way, the suggestion that new symptoms are biomarkers of response can be useful in providing reassurance to patients and helping them stay on treatment.

Metastatic Disease

In metastatic disease, we have an additional new endocrine agent in the armamentarium: fulvestrant (Faslodex), an ER downregulator. Studies have shown fulvestrant to be comparable to tamoxifen in previously untreated ER+ patients, but fulvestrant has the advantage of lacking an agonistic effect on the endometrium.

We are still learning how to optimize use of this drug. While 250 mg monthly is the standard dose, it is likely that higher doses may be more effective, as shown in the SABCS presentation by Matthew Ellis (abstract 6126). Higher loading doses may be another means of more rapidly increasing the therapeutic level of the drug.

Currently ongoing trials will further define how to effectively utilize fulvestrant in metastatic disease, and will help determine its role in early-stage disease as well. In postmenopausal patients with advanced disease, studies are beginning to evaluate combining fulvestrant with AIs. The SWOG study S0226 is comparing anastrozole to anastrozole + fulvestrant as first-line therapy. In the UK, the SoFEA (Study of Faslodex, Exemestane, and Arimidex) trial is randomizing patients whose disease progressed while on an AI to fulvestrant alone, fulvestrant + anastrozole, or exemestane (Aromasin) alone. These studies of the fulvestrant/AI combination are based on the suggestion that estrogen-deprived cells become supersensitive to lower doses of estradiol and thus can be restimulated. The combination may more fully suppress estradiol and thus be more protective.

Improving Efficacy

Can we improve upon the efficacy of endocrine therapies by giving them in combination or combining them with other classes of agents? There is reason to think so. Angela Brodie’s group has shown in a preclinical model that using two agents- letrozole (Femara) and fulvestrant-was more effective in suppressing tumor growth than either agent alone, in sequence with tamoxifen, or in higher doses (Jelovac D et al: Cancer Res 65:5439-5444, 2005). More recently, as seen at SABCS, investigators capitalized on the crosstalk between the estrogen and HER2 signaling pathways by pairing letrozole with lapatinib (Tykerb), finding that the dual blockade enhanced disease control compared with the AI alone in postmenopausal women with HR+, HER2+ disease (abstract 46).

We hope that someday we can predict which patients may require more aggressive treatment. We seem to be a step closer to this: the ATAC Trialists’ Group reports that the Oncotype DX Recurrence Score is useful in assessing risk of distant recurrence in patients on AIs (abstract 53).

Future Directions

While we still grapple with the details of how best to use endocrine therapies, it is clear that the evolution of these agents has helped to change the natural history of early breast cancer and to prolong survival in metastatic disease. Our MD Anderson study (Giordano SH et al: Cancer 100:44-52, 2004), corroborated by others, established just this: in more recent years patients with recurrent breast cancer have had a greater chance of improved survival. For each year since 1974, patients experienced a 1% reduction in the risk of dying from their disease. We can mainly attribute this to having an ever-growing number of therapeutic agents to treat our patients with metastatic disease. As we learn how to optimize their use, these statistics will only improve.

Disclosures:

Financial Disclosure: Dr. Buzdar has received grants for clinical research from AstraZeneca, Genentech, Pfi zer, Lilly, Taiho, and Roche; he has received honoraria from AstraZeneca, Genentech, and Pfi zer.