HR-Positive, HER2-Negative Metastatic Breast Cancer

Last updated January 17, 2022



  • 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
a Rugo HS, et al. J Clin Oncol 34:3069-103, 2016.b Moy B et al. J Clin Oncol doi:10.1200/JCO.21.01374.



New Recommendations from 2021 Focused Guideline Update

Recommendation 1.1

  • 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.
( EB , H , B , M )

Recommendation 2.1

  • 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.
( EB , H , B , S )

Recommendation 2.2

  • 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.
( IC , Ins , NB, M )

Recommendation 2.3

  • 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. 
( EB , I , B , S )
Qualifying Statements: Small single-arm studies show that oral PARP inhibitor therapy demonstrates high response rates in metastatic breast cancer encoding DNA repair defects, such as germline PALB2 mutation carriers and somatic BRCA mutations. It should also be noted that the randomized PARP inhibitor trials made no direct comparison with taxanes, anthracyclines, or platinums; comparative efficacy against these compounds is unknown.

Recommendation 3.1

  • 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.
( EB , H , B , S )

Recommendation 3.2

  • 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.
( EB , H , B , S )

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 OSHER2 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

Recommendation Grading

Source Citation

Burstein HJ, Somerfield MR, Barton DL, Dorris A, Fallowfield LJ, Jain D, Johnston SRD, Korde LA, Litton JK, Macrae ER, Peterson LL, Vikas P, Yung RL, Rugo HS. Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Update. J Clin Oncol. 2021 Dec 10;39(35):3959-3977. doi: 10.1200/JCO.21.01392. Epub 2021 Jul 29. PMID: 34324367; PMCID: PMC8659999.


This pocket guide attempts to define principles of practice that should produce high-quality patient care. It is applicable to specialists, primary care, and providers at all levels. This pocket guide should not be considered exclusive of other methods of care reasonably directed at obtaining the same results. The ultimate judgment concerning the propriety of any course of conduct must be made by the clinician after consideration of each individual patient situation. Neither IGC, the medical associations, nor the authors endorse any product or service associated with the distributor of this clinical reference tool.