- Breast cancer is the most prevalent cancer in women in the developed world and is the second most common cause of cancer-related death for women in the United States.
- It was estimated that in 2015, approximately 231,840 women in the United States would be diagnosed with the disease, and almost 40,000 would die as a result of it.
- Currently, a majority of patients presenting with localized disease will experience long-term disease-free survival, whereas those presenting with or who develop metastatic disease have a 5-year relative survival of only 24%, and almost none are cured.
- Hormone receptor-positive (HR+) breast cancer represents the most common subset in both the early- and late-stage settings, with >70% of tumors expressing these receptors.
- A greater understanding of the biologic pathways that contribute to hormone resistance has led to approval of targeted agents administered in combination with hormone therapy, including trastuzumab, everolimus, and palbociclib.
- Treatment should take into account the biology of the tumor and the menopausal status of the patient, with careful attention paid to ovarian production of estrogen (Figure 2) (Moderate Recommendation; EB/CB-B-I).
- Hormone therapy should be offered to patients whose tumors express any level of estrogen receptor (ER) and/or progesterone receptor (PR) ( Strong Recommendation; EB/CB-B-H).
- Endocrine therapy should be recommended as initial treatment for patients with HR metastatic breast cancer (MBC), except for patients with immediately life-threatening disease or for those who experience rapid visceral recurrence during adjuvant endocrine therapy (Strong Recommendation; EB-B-I).
- The use of combined endocrine therapy and chemotherapy is NOT recommended (Strong Recommendation; EB-B-H).
- Treatment should be administered until there is unequivocal evidence of disease progression as documented by imaging, clinical examination, or disease-related symptoms (Strong Recommendation; EB-B-H).
- Tumor markers or circulating tumor cells should not be used as the sole criteria for determining progression.
- Fulvestrant should be administered using the 500 mg dose and with a loading schedule (Strong Recommendation; EB-B-H).
- Treatment recommendations in the metastatic or advanced setting should be offered on the basis of type of adjuvant treatment, disease-free interval, and extent of disease at the time of recurrence (Figures 1 and 2). A specific hormonal agent may be used again if recurrence occurs >12 months from the last treatment (Strong Recommendation; EB/CB-B-H).
- Use of additional biomarkers is experimental and should be reserved for selection of treatment in clinical trials. There is no routine clinical role for genomic or expression profiling in the selection of treatment for HR MBC (Moderate Recommendation; CB-B-L).
- Patients should be encouraged to consider enrolling in clinical trials, including those receiving treatment in the first-line setting (Moderate Recommendation; EB/CB-B-I).
- Multiple clinical trials are ongoing or planned, with a focus on improving response to hormone therapy in metastatic disease.
- Postmenopausal women with HR MBC should be offered aromatase inhibitors (AIs) as first-line endocrine therapy (Figure 1) (Strong Recommendation; EB-B-H).
- Combination hormone therapy with fulvestrant, with a loading dose followed by 500 mg every 28 days, plus a nonsteroidal AI may be offered to patients with MBC without prior exposure to adjuvant endocrine therapy (Figure 1) (Moderate Recommendation; EB-B-I).
- Premenopausal women with HR MBC should be offered ovarian suppression or ablation in combination with hormone therapy (Strong Recommendation; EB-B-H).
- Ovarian suppression with either gonadotropin-releasing hormone (GnRH) agonists or ablation with oophorectomy seems to achieve similar results in MBC.
- For most patients, clinicians should use guidelines for postmenopausal women to guide the choice of hormone treatment, although sequential therapy can also be considered.
- Patients without exposure to prior hormone therapy can also be treated with tamoxifen or ovarian suppression or ablation alone, although combination therapy is preferred (Figure 2).
- Treatment should be on the basis of the biology of the tumor and the menopausal status of the patient, with careful attention paid to production of ovarian estrogen.
- The choice of second-line hormone therapy should take into account prior treatment exposure and response to previous endocrine therapy ( Strong Recommendation; EB-B-H).
- Sequential hormone therapy should be offered to patients with endocrine-responsive disease (Options are shown in Figure 1.) (Strong Recommendation; EB-B-H).
- Exemestane and everolimus may be offered to postmenopausal women with HR MBC who experience progression during treatment with nonsteroidal AIs, either before or after treatment with fulvestrant, because PFS but not overall survival was improved compared with exemestane alone. (Other options are shown in Figures 1 and 2.)
(Strong Recommendation; EB-B-H).
- This combination should NOT be offered as first-line therapy for patients who experience relapse >12 months from prior nonsteroidal AI therapy or for those who are naïve to hormone therapy.
- A nonsteroidal AI and palbociclib may be offered to postmenopausal women with treatment-naïve HR MBC. PFS but not overall survival was improved compared with the nonsteroidal AI letrozole alone (Other options are shown in Figures 1 and 2.) (Moderate Recommendation; EB-B-I).
- Palbociclib may also be offered in combination with fulvestrant in patients exposed to prior hormone therapy and up to one line of chemotherapy, on the basis of data from the phase III PALOMA-3 trial. Progression-free survival (PFS) was improved compared with fulvestrant alone; overall survival data are immature.
- Genomic or expression profiling should NOT be used to select treatment for HR MBC (Moderate Recommendation; CB-B-L).
- The addition of HER2-targeted therapy to first-line AIs should be offered to patients with HR , HER2 MBC in whom chemotherapy is not immediately indicated (Strong Recommendation; EB/CB-B-H).
- The addition of HER2-targeted therapy to first-line AIs improved PFS, without a demonstrated improvement in overall survival. HER2-targeted therapy combined with chemotherapy resulted in improvements in overall survival and is the preferred first-line approach in most cases.
- Fulvestrant and palbociclib may be offered to patients who experienced progression during prior treatment with AIs with or without one line of prior chemotherapy, because PFS was improved compared with fulvestrant alone.
- Treatment should be limited to those without prior exposure to cyclin-dependent kinase 4/6 inhibitors.
- Tumor markers or circulating tumor cells should NOT be used as the sole criteria for determining disease progression.
- Providers should recognize and acknowledge special issues faced by premenopausal women with MBC, including loss of fertility.
- Treatment should take into account the biology of the tumor and the menopausal status of the patient, with careful attention paid to ovarian production of estrogen.
- There is more toxicity associated with the combination of exemestane and everolimus compared with other single-agent endocrine options.
- There is more toxicity associated with the combination of palbociclib and endocrine therapy compared with other single-agent endocrine options.
- Palbociclib should be administered once per day for 21 days every
- The primary toxicity is neutropenia. Blood counts should be monitored every 14 days for the first two 28-day cycles, then at the start of each subsequent cycle, with neutropenia managed by dose delays and reductions.
- Although no data exist at present, any AI could be substituted depending on individual tolerance.
- On the basis of the data from PALOMA-3, palbociclib can also be combined with fulvestrant in the second-line setting or greater, including after one line of chemotherapy.
- Chemotherapy in combination with HER2-targeted therapy is indicated in de novo and visceral dominant disease, because this treatment offers a survival benefit compared with chemotherapy alone.
- There is no routine clinical role for genomic or expression profiling in the selection of treatment for HR MBC.
Table 1. Recommended Pharmaceuticals for HR+ Breast Cancer
|Tamoxifen||20–40 mg||Boxed Warning:|
|Anastrozole||1 mg PO qd||Contraindications:|
|Exemestane||25 mg PO qd after|
|Letrozole||2.5 mg PO qd||Contraindications:|
|CDK 4/6 kinase inhibitor|
|Palbociclib||125 mg PO qd taken with food for 21 days followed by 7 days off treatment||Should be reserved for patients without prior exposure to cyclin-dependent kinase 4/6 inhibitors Warnings:|
|Estrogen receptor antagonist|
|Fulvestrant||500 mg IM every|
2 weeks for three cycles
|Estradiol||2 mg PO tid||Boxed Warning:|
|Fluoxymesterone||Not FDA-approved for breast cancer Contraindications:|
|Megestrol acetate||160 mg PO qd||Contraindications:|
|Macrolide immunosuppressant – rapamycin (mTOR) inhibitor|
|Everolimus||Not FDA-approved for breast cancer Boxed Warning:|