Patient Care

Advances in Targeted Therapy for Breast Cancer

Recent clinical trials have provided additional first-line therapeutic treatment options that improve overall survival and progression-free survival in women with breast cancer.

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It is estimated that there were more than 3.1 million women living in the U.S. with a history of invasive breast cancer as of January 1, 2014, and an additional 231,840 women will be newly diagnosed with invasive breast cancer in 2015. 1,2 The median age at the time of breast cancer diagnosis is 61 years. About 20% of breast cancers occur among women aged < 50 years, and 43% occur in women aged > 65 years.

The treatment and prognosis for breast cancer depend on the stage at diagnosis, the biologic characteristics of the tumor, and the age and health of the patient. The overall 5-year relative survival rate for female patients with breast cancer has improved from 75% to 90% from 1975 to 1977 and from 2003 to 2009, respectively, largely due to improvements in treatment (ie, chemotherapy, hormone therapy, and targeted drugs) and because of earlier diagnosis resulting from the widespread use of mammography and other screening tools. 2

Estrogen Receptor-Positive Therapies

Women with breast cancer who test positive for hormone receptors are candidates for treatment with hormone therapy to reduce the likelihood of recurrence or as a core component of treatment for advanced disease. Currently available endocrine strategies for the treatment of estrogen receptor- (ER) positive breast cancer include targeting the ER with the antiestrogen drug tamoxifen. Another option is suppressing the amount of available ligand (estrogen) for the receptor either with gonadal suppression in premenopausal oophorectomy, or luteinizing hormonereleasing hormone agonists, or with the aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole in postmenopausal women and by downregulating the receptor with fulvestrant. Given their proven efficacy and generally favorable adverse effect (AE) profile, these endocrine therapies are widely used in the treatment of both early-stage and recurrent and/or metastatic breast cancer.

Recent studies have offered new treatments for patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Innovative hormonal and targeted therapies for advanced disease as well as new data on adjuvant hormonal therapy for young high-risk patients are changing the available therapeutic options.

Advanced Metastatic Treatments

Treatment for metastatic hormone receptor-positive breast cancer has shifted from traditional cytotoxic chemotherapies to targeted therapeutic options. Most treatment guidelines, including the National Comprehensive Cancer Network guidelines, recommend targeted therapy with AIs or selective ER modulators rather than chemotherapy, except in the case of visceral crisis. 3

Until recently, there had been relatively little guidance to inform which hormonal therapy was most appropriate. Aromatase inhibitors were generally reserved for postmenopausal women, whereas tamoxifen was preferred in premenopausal women.

Fulvestrant

The FDA initially approved fulvestrant, a hormone receptor downregulator, in 2002 at a 250-mg dose, following progression on an anti-estrogen therapy, such as tamoxifen in postmenopausal women with stage IV breast cancer. The FDA approval was based on similar response rates for the already approved agent anastrozole. 4 However, pharmacokinetic findings from the phase 3 EFECT trial in 2008 prompted researchers to explore a 500-mg dose of fulvestrant. 5

The recently published FIRST study is a phase 2, randomized, open-label study comparing fulvestrant 500 mg with anastrozole 1 mg as first-line hormonal therapy for postmenopausal women with hormone receptorpositive advanced breast cancer. Fulvestrant was given 500 mg once monthly with an extra dose given on day 14 of month 1. The trial enrolled 233 patients. The median time to progression was 23.4 months for fulvestrant and 13.1 months for anastrozole. These results translate into a 34% reduction in the risk of progression. 6

These outcomes suggest that fulvestrant is as viable and perhaps even preferred first-line therapy for postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer. The impressive results from this trial are likely, because the study used the 500-mg dose of fulvestrant, which is twice the dose used in the original trials. However, the 500-mg dose has previously been studied, and long-term outcome data suggest both safety and efficiency. The large randomized, double-blinded phase 3 CONFIRM trial, published in 2013, compared the 250-mg dose with the 500-mg dose and found that the higher dose was associated with a 19% reduction in the risk of death and a 4.1 month increase in median overall survival (OS) without any new safety concerns. 5

Palbociclib

The FDA recently granted accelerated approval to palbociclib in combination with letrozole for the first-line therapy of advanced hormone receptor-positive, HER2-negative breast cancer in postmenopausal women. Palbociclib is an oral small-molecular inhibitor of cyclindependent kinases 4 and 6. Preclinical data suggested synergy with anti-estrogen therapies and inhibition of breast cancer cell growth.7

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