What is the recommended dosage and treatment protocol for Exemestane (Aromatase Inhibitor) in postmenopausal women with breast cancer?

Exemestane Dosing and Treatment Protocol for Postmenopausal Women with Breast Cancer

The recommended dose of exemestane is 25 mg orally once daily after a meal, administered for 5 years in the adjuvant setting or until disease progression in metastatic disease. 1

Standard Dosing Regimen

• Standard dose: 25 mg tablet once daily taken after a meal 1
• Duration in adjuvant setting: Complete a total of 5 consecutive years of adjuvant hormonal therapy (typically 2-3 years after initial tamoxifen therapy) 1
• Duration in advanced disease: Continue until disease progression 1

Dose Modifications

When exemestane is co-administered with strong CYP3A4 inducers (such as rifampicin or phenytoin), the dose must be increased to 50 mg once daily after a meal. 1 This is critical because strong CYP3A4 inducers significantly decrease exemestane exposure, potentially compromising efficacy.

Clinical Indications and Treatment Settings

Adjuvant Treatment (Early Breast Cancer)

Exemestane is indicated for adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received 2-3 years of tamoxifen and are switched to exemestane for completion of a total of 5 consecutive years of adjuvant hormonal therapy. 1

• The Intergroup Exemestane Study (IES) demonstrated superior disease-free survival when switching to exemestane after 2-3 years of tamoxifen compared to continuing tamoxifen for 5 years (HR 0.76,95% CI 0.66-0.88, P=0.0001) 2
• Overall survival benefit was significant only in patients with ER-positive tumors (HR 0.83,95% CI 0.69-1.00) 2

Advanced/Metastatic Breast Cancer

Exemestane is indicated for treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy. 1

First-Line Endocrine Therapy for Metastatic Disease

• Third-generation aromatase inhibitors (anastrozole, letrozole, exemestane) are recommended as first-line treatment for postmenopausal patients with hormone receptor-positive metastatic breast cancer based on more favorable toxicity profiles. 2
• Exemestane demonstrated superiority to tamoxifen in terms of objective response rate and time to progression in randomized phase III trials 2

Second-Line Endocrine Therapy

• Following tamoxifen failure, exemestane is recommended for second-line treatment based on superior side-effect profile compared to older agents like progestins. 2
• Exemestane showed superior efficacy to megestrol acetate in tamoxifen-refractory disease, with significantly prolonged duration of overall success, time to disease progression, and improved survival 3, 4

Treatment After Aromatase Inhibitor Failure

• Exemestane plus everolimus may be offered to postmenopausal women with HR-positive metastatic breast cancer progressing on prior nonsteroidal aromatase inhibitors, as progression-free survival (but not overall survival) is improved compared with exemestane alone. 2
• This combination should not be offered as first-line therapy for patients who relapse more than 12 months from prior nonsteroidal AI therapy 2

Risk Reduction Setting

Exemestane (25 mg per day orally for 5 years) should be discussed as an alternative to tamoxifen or raloxifene to reduce the risk of invasive breast cancer in postmenopausal women age ≥35 years at increased risk of breast cancer or with lobular carcinoma in situ (LCIS) or atypical hyperplasia. 2

• Exemestane should not be used for breast cancer risk reduction in premenopausal women 2
• The most favorable risk-benefit profile is seen in women at greatest risk of developing breast cancer 2

Critical Contraindications and Precautions

Absolute Contraindications

• Premenopausal women: Exemestane must not be used in premenopausal women outside clinical trials, as aromatase inhibitors do not adequately suppress ovarian estrogen synthesis 2
• Known hypersensitivity to exemestane or excipients 1
• Do not coadminister with estrogen-containing agents, as these interfere with pharmacologic action 1

Monitoring Requirements

Bone mineral density monitoring is essential, as exemestane causes significant reductions in BMD. 1

• At 24 months, exemestane caused -3.1% change in lumbar spine BMD and -4.2% change in femoral neck BMD compared to tamoxifen 1
• Women with osteoporosis or at risk should have formal bone densitometry assessment at treatment commencement 1
• Routine assessment of 25-hydroxy vitamin D levels should be performed prior to starting exemestane due to high prevalence of vitamin D deficiency in early breast cancer patients. 1
• Women with vitamin D deficiency should receive supplementation with vitamin D and calcium 2, 1

Laboratory Monitoring

• Approximately 20% of patients receiving exemestane experienced CTC grade 3 or 4 lymphocytopenia, though 89% had pre-existing lower grade lymphopenia 1
• Forty percent of patients either recovered or improved while on treatment 1

Comparative Efficacy Among Aromatase Inhibitors

The NCCN panel finds no meaningful differences in terms of efficacy or toxicity between the available aromatase inhibitors: anastrozole, letrozole, and exemestane. 2 All three have shown similar antitumor efficacy and toxicity profiles in randomized studies in the adjuvant setting 2.

Tolerability Profile

Exemestane is generally well tolerated at the recommended 25 mg daily dosage. 3, 4

• Most common adverse events: nausea, hot flushes, fatigue, increased sweating, and dizziness 3
• Hot flushes occur in approximately 14% of patients 5
• Compared with tamoxifen, exemestane has reduced incidence of endometrial changes, thromboembolic events, and hot flashes. 6
• Myalgias and arthralgias are associated with exemestane use 6
• Bone mineral density reductions and increased fracture risk occur during treatment but appear to return to pretreatment values after discontinuation 6

Treatment Duration and Discontinuation

• In the adjuvant setting, treatment should continue for the planned duration (typically 2-3 years after initial tamoxifen) to complete 5 total years of endocrine therapy. 1
• In metastatic disease, treatment should be given until unequivocal evidence of disease progression as documented by imaging, clinical examination, or disease-related symptoms. 2
• Tumor markers or circulating tumor cells should not be used as the sole criteria for determining progression 2