Treatment for Estrogen Receptor-Positive (ER+) Breast Cancer
For postmenopausal women with ER+ breast cancer, aromatase inhibitors (AIs) are the preferred first-line endocrine therapy, with or without the CDK 4/6 inhibitor palbociclib, while premenopausal women should receive tamoxifen with ovarian suppression or ablation. 1
Initial Treatment Decision: Endocrine Therapy vs. Chemotherapy
Endocrine therapy should be the initial treatment for ER+ breast cancer except in cases of immediately life-threatening disease or visceral crisis. 1 Sequential hormone therapy is the preferential treatment for most women with HR-positive disease, as historical data demonstrate that neither survival nor quality of life is improved by treating patients with chemotherapy when hormone therapy has a reasonable chance of providing disease control. 1
When to Consider Chemotherapy First:
- Immediately life-threatening disease where time to response is critical 1
- Extremely low levels of ER expression making endocrine treatment less likely to be effective 1
- ER+/HER2+ disease where combining chemotherapy and anti-HER2 treatments has a survival advantage 1
Important caveat: Concomitant chemo-endocrine therapy is not recommended—use sequential single-modality treatment instead. 1
Treatment by Menopausal Status
Postmenopausal Women
First-line therapy: Aromatase inhibitors (anastrozole, letrozole, or exemestane) are preferred over tamoxifen. 1 The combination of an AI with palbociclib can be considered as a first-line treatment option based on FDA approval. 1
Second-line therapy: Fulvestrant 500 mg with a loading schedule should be administered, and may be combined with palbociclib. 1 The combination of fulvestrant and palbociclib is reasonable in patients experiencing progression on AIs with no prior CDK inhibitor exposure, as PALOMA-3 demonstrated more than a doubling in progression-free survival. 1
Third-line therapy: Everolimus (an mTOR inhibitor) may be administered with exemestane to postmenopausal women whose disease progresses while receiving nonsteroidal AIs. 1
Monitoring requirement for palbociclib: Blood counts must be monitored before the start of each new cycle as well as on day 14 of the first two cycles, with dose delays and reductions to manage neutropenia. 1
Premenopausal Women
Standard approach: Tamoxifen with ovarian ablation or suppression using GnRH agonists (goserelin, leuprorelin, triptorelin, or buserelin). 1, 2 Assessment of menopausal status is critical for selecting the appropriate hormone therapy regimen. 3
Adjuvant duration: For premenopausal women who have received 5 years of adjuvant tamoxifen, they should be offered 10 years total duration of tamoxifen. 1 The two largest studies with longest follow-up show a breast cancer survival advantage with 10-year durations of tamoxifen use compared to 5 years. 1
Hormone Receptor Expression Thresholds
Hormone therapy should be offered to patients whose tumors express any level of ER and/or progesterone receptor (PR). 1 Although higher levels of ER and PR expression suggest greater likelihood of benefit, there are no specific thresholds beyond positivity for recommending treatment. 1
Critical testing recommendation: Testing for receptors should be performed on metastatic tumor tissue to confirm HR expression and HER2 status whenever feasible, because data demonstrate potential for change in receptor status from early- to late-stage tumors. 1 Caution should be used in interpreting receptor results obtained from bone biopsies because processing may affect results. 1
Impact of Prior Adjuvant Therapy
Treatment recommendations should be based on type of adjuvant treatment, disease-free interval, and extent of disease at recurrence. 1 A specific hormonal agent may be used again if recurrence occurs 12 months or more from last treatment. 1
Key principle: Recurrence on or within 12 months of last exposure to a specific hormonal agent is evidence for resistance to that agent; an alternate hormone therapy should be considered using the sequential treatment approach. 1
Specific Aromatase Inhibitor Considerations
There is evidence of incomplete cross-resistance between steroidal (exemestane) and non-steroidal aromatase inhibitors (anastrozole, letrozole). 1 Although there are no data supporting other AIs in combination with palbociclib beyond letrozole, it is reasonable to consider other nonsteroidal or steroidal AIs in the first-line setting based on individual tolerance. 1
FDA-approved dosing for exemestane: 25 mg once daily after a meal for both adjuvant and advanced breast cancer. 4 When used with strong CYP 3A4 inducers (rifampicin, phenytoin), increase to 50 mg once daily. 4
Bone Health Management
Reductions in bone mineral density occur with exemestane use. 4 Women with osteoporosis or at risk should have bone mineral density formally assessed by bone densitometry at treatment commencement, with monitoring and treatment as appropriate. 4
Vitamin D assessment: Routine assessment of 25-hydroxy vitamin D levels prior to starting aromatase inhibitor treatment should be performed due to high prevalence of vitamin D deficiency in women with early breast cancer. 4 Women with vitamin D deficiency should receive supplementation. 4
Critical Contraindications and Drug Interactions
Never coadminister exemestane with systemic estrogen-containing agents as these interfere with its pharmacologic action. 4 For women with an intact uterus requiring estrogen therapy for other indications, always combine estrogen with a progestin to reduce endometrial cancer risk. 3
Important drug interaction: Paroxetine and fluoxetine should not be offered to women taking tamoxifen as they inhibit conversion to active metabolites. 3 If hormone therapy is contraindicated for vasomotor symptoms, consider low-dose paroxetine (7.5 mg daily), venlafaxine, gabapentin, or clonidine as alternatives. 3
Response Evaluation
Response evaluation is recommended after 3 months of endocrine therapy by clinical evaluation, subjective symptom evaluation, blood tests, and repeating initially abnormal radiologic examinations. 1 Tumor markers should not be the sole criteria for determining tumor progression; serum tumor markers (CA 15.3) may be helpful in monitoring response of not easily measurable disease but should not be used as the only determinant for treatment decisions. 1