HR-Positive, HER2-Negative Metastatic Breast Cancer
Endocrine Treatment and Targeted Therapy
- The purpose of this guideline is to update recommendations of the American Society of Clinical Oncology (ASCO) systemic therapy for hormone receptor (HR)-positive metastatic breast cancer (MBC) guideline.a
- Specifically, it:
- provides a new recommendation for the use of alpelisib in the treatment of patients with hormone receptor-positive metastatic breast cancer
- addresses the role of biomarkers in treatment selection for this patient population and
- amends prior recommendations concerning the use of CDK4/6 inhibitors in the treatment of these patients.
- Note that this guideline provides recommendations for endocrine therapy and targeted therapy, including CDK 4/6 and PI3 kinase inhibition for hormone receptor-positive metastatic breast cancer patients. A companion guidelineb provides recommendations for use of chemo-and targeted therapy for patients with HER2-negative metastatic breast cancer that is either endocrine-pretreated or hormone receptor-negative
New Recommendations from 2021 Focused Guideline Update
- Alpelisib in combination with endocrine therapy should be offered to postmenopausal patients in combination with fulvestrant, and to male patients, with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer following prior endocrine therapy including an aromatase inhibitor, with or without a CDK4/6 inhibitor. Careful screening for and management of common toxicities are required.
- To guide the decision to use alpelisib in combination with fulvestrant in postmenopausal patients, and in male patients, with HR-positive metastatic breast cancer, clinicians should use next generation sequencing in tumor tissue or cell-free DNA in plasma to detect PIK3CA mutations. If no mutation is found in cell free DNA, testing in tumor tissue, if available, should be used as this will detect a small number of additional patients with PIK3CA mutations.
- There are insufficient data at present to recommend routine testing for ESR1 mutations to guide therapy for HR-positive, HER2-negative MBC. Existing data suggest reduced efficacy of aromatase inhibitors compared to the selective estrogen receptor degrader (SERD) fulvestrant in patients who have tumor or circulating tumor DNA with ESR1 mutations.
- Patients with metastatic HR-positive but HER2-negative breast cancer with germline BRCA1 or 2 mutations who are no longer benefiting from endocrine therapy may be offered an oral PARP inhibitor in the first- through to third-line setting rather than chemotherapy.
- A nonsteroidal AI and a CDK4/6 inhibitor should be offered to postmenopausal patients and to premenopausal patients combined with chemical ovarian function suppression, and to male patients (with a gonadotropin-releasing hormone analog), with treatment-naïve HR-positive MBC.
- Fulvestrant and a CDK4/6 inhibitor should be offered to patients with progressive disease during treatment with AIs (or who develop a recurrence within one year of adjuvant AI therapy) with or without one line of prior chemotherapy for metastatic disease, or as first-line therapy. Treatment should be limited to those without prior exposure to CDK4/6 inhibitors in the metastatic setting.
Recommendations Unchanged from 2016 Guideline
- Postmenopausal women with metastatic, HR-positive breast cancer should be offered AIs as first-line endocrine therapy.
- Combination hormone therapy with fulvestrant with a loading dose followed by 500 mg every 28 days combined with a nonsteroidal aromatase inhibitor may be offered for patients with metastatic breast cancer without prior exposure to adjuvant endocrine therapy
- Premenopausal women with metastatic hormone receptor positive breast cancer should be offered ovarian suppression/ablation in combination with hormonal therapy. Ovarian suppression with either gonadotropin releasing hormone (GnRH) agonists or ablation with oophorectomy appears to achieve similar results in metastatic breast cancer. 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/ablation alone although combination therapy is preferred. Treatment should be based on the biology of the tumor and the menopausal status of the patient with careful attention paid to production of ovarian estrogen.
- 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.
- The choice of second-line hormonal therapy should take into account prior treatment exposure and response to previous endocrine therapy.
- Sequential hormonal therapy should be offered to patients with endocrine responsive disease.
- Fulvestrant should be administered using the 500 mg dose and with a loading schedule.
- Exemestane and everolimus may be offered to postmenopausal women with hormone receptor positive metastatic breast cancer progressing on prior treatment with non-steroidal AIs, either before or after treatment with fulvestrant, as PFS but not OS is improved compared to exemestane alone. This combination should not be offered as first-line therapy for patients who relapse more than 12 months from prior nonsteroidal AI therapy or for those who are naïve to hormonal therapy.
- Hormonal therapy should be offered to patients whose tumors express any level of estrogen and/or progesterone receptors.
- Treatment recommendations should be offered based on the type of adjuvant treatment, disease free interval and extent of disease at the time of recurrence. A specific hormone agent may be used again if recurrence occurs >12 months from last treatment.
- Endocrine therapy should be recommended as initial treatment for patients with HR-positive, metastatic breast cancer except in patients with immediately life-threatening disease or in those with rapid visceral recurrence on adjuvant endocrine therapy.
- The use of combined endocrine therapy and chemotherapy is not recommended.
- Treatment should be given until there is unequivocal evidence of disease progression as documented by imaging, clinical examination or disease-related symptoms. Tumor markers or circulating tumor cells should not be used as the sole criteria for determining progression.
- The addition of HER2 targeted therapy to first-line AIs should be offered to patients with hormone receptor positive, HER2 positive metastatic breast cancer in whom chemotherapy is not immediately indicated.The addition of HER2 targeted therapy to first-line AIs improves PFS without a demonstrated improvement in OS. HER2 targeted therapy combined with chemotherapy has resulted in improvement in OS, and is the preferred first-line approach in most cases.
- Patients should be encouraged to consider enrolling in clinical trials, including those receiving treatment in the first-line setting. Multiple clinical trials are ongoing or planned, with a focus on improving response to hormonal therapy in metastatic disease
Figure 1. Algorithm for Endocrine Treatment and Targeted Therapy for HR positive, HER2 negative Metastatic Breast Cancer
|19100||Biopsy of breast; percutaneous|
|19101||Biopsy of breast; open|
|19120||Excision of cyst, fibroadenoma, or other benign or malignant tumor, aberrant breast tissue, duct lesion, nipple or areolar lesion (except 19300), open, male or female, 1 or more lesions|
|19125||Excision of breast lesion identified by preoperative placement of radiological marker, open; single lesion|
|19126||Excision of breast lesion identified by preoperative placement of radiological marker, open; ach additional lesion separately identified by a preoperative radiological marker (List separately in addition to code for primary procedure)|
|19281||Placement of breast localization device(s) (eg, clip, metallic pellet, wire/needle, radioactive seeds), percutaneous; first lesion, including mammographic guidance|
|19282||Placement of breast localization device(s) (eg, clip, metallic pellet, wire/needle, radioactive seeds), percutaneous; ach additional lesion, including mammographic guidance (List separately in addition to code for primary procedure)|
|19283||Placement of breast localization device(s) (eg, clip, metallic pellet, wire/needle, radioactive seeds), percutaneous; first lesion, including stereotactic guidance|
|19284||Placement of breast localization device(s) (eg, clip, metallic pellet, wire/needle, radioactive seeds), percutaneous; each additional lesion, including stereotactic guidance (List separately in addition to code for primary procedure)|
|19285||Placement of breast localization device(s) (eg, clip, metallic pellet, wire/needle, radioactive seeds), percutaneous; first lesion, including ultrasound guidance|
|19286||Placement of breast localization device(s) (eg, clip, metallic pellet, wire/needle, radioactive seeds), percutaneous; each additional lesion, including ultrasound guidance (List separately in addition to code for primary procedure)|
|19287||Placement of breast localization device(s) (eg clip, metallic pellet, wire/needle, radioactive seeds), percutaneous; first lesion, including magnetic resonance guidance|
|19288||Placement of breast localization device(s) (eg clip, metallic pellet, wire/needle, radioactive seeds), percutaneous; each additional lesion, including magnetic resonance guidance (List separately in addition to code for primary procedure)|
|19296||Placement of radiotherapy afterloading expandable catheter (single or multichannel) into the breast for interstitial radioelement application following partial mastectomy, includes imaging guidance; on date separate from partial mastectomy|
|19297||Placement of radiotherapy afterloading expandable catheter (single or multichannel) into the breast for interstitial radioelement application following partial mastectomy, includes imaging guidance; concurrent with partial mastectomy (List separately in addition to code for primary procedure)|
|19298||Placement of radiotherapy after loading brachytherapy catheters (multiple tube and button type) into the breast for interstitial radioelement application following (at the time of or subsequent to) partial mastectomy, includes imaging guidance|
|58661||Laparoscopy, surgical; with removal of adnexal structures (partial or total oophorectomy and/or salpingectomy)|
|58720||Salpingo-oophorectomy, complete or partial, unilateral or bilateral (separate procedure)|
|76641||Ultrasound, breast, unilateral, real time with image documentation, including axilla when performed; complete|
|76642||Ultrasound, breast, unilateral, real time with image documentation, including axilla when performed; limited|
|77061||Digital breast tomosynthesis; unilateral|
|77062||Digital breast tomosynthesis; bilateral|
|77065||Diagnostic mammography, including computer-aided detection (CAD) when performed; unilateral|
|77066||Diagnostic mammography, including computer-aided detection (CAD) when performed; bilateral|
|81432||Hereditary breast cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); genomic sequence analysis panel, must include sequencing of at least 10 genes, always including BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, PALB2, PTEN, STK11, and TP53|
|81433||Hereditary breast cancer-related disorders (eg|
|81519||Oncology (breast), mRNA, gene expression profiling by real-time RT-PCR of 21 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as recurrence score|
|84233||Receptor assay; estrogen|
|84234||Receptor assay; progesterone|
|88305||Level IV - Surgical pathology, gross and microscopic examination|
|88307||Level V - Surgical pathology, gross and microscopic examination|
|81307||PALB2 (partner and localizer of BRCA2) (eg, breast and pancreatic cancer) gene analysis; full gene sequence|
|81308||PALB2 (partner and localizer of BRCA2) (eg, breast and pancreatic cancer) gene analysis; known familial variant|
|Z17.0||Estrogen receptor positive status [ER+]|
|Z17.1||Estrogen receptor negative status [ER-]|
|Z78.0||Asymptomatic menopausal state||Type|
|N95||Menopausal and other perimenopausal disorders|