Endocrine Treatment and Targeted Therapy for HR-Positive, HER2-Negative Metastatic Breast Cancer

Publication Date: May 17, 2023
Last Updated: May 23, 2023

Summary of Recommendations

Recommendations from 2023 Rapid Recommendation Update

To aid in treatment selection, the Expert Panel recommends routine testing for emergence of ESR1 mutations at recurrence or progression on ET (with or without CDK4/6 inhibitor) in patients with ER-positive, HER2-negative MBC. Testing with a CLIA-certified assay should be performed on blood or tissue obtained at the time of progression, as ESR1 mutations develop in response to selection pressure during treatment and are typically undetectable in the primary tumor; blood-based ctDNA is preferred owing to greater sensitivity. If not performed earlier, testing for PIK3CA mutations should also be performed to guide further therapy. Patients whose tumor or ctDNA tests remain ESR1 wildtype may warrant retesting at subsequent progression(s) to determine if an ESR1 mutation has arisen. ( EB , H , B , S )
Patients previously treated with ET and a CDK4/6 inhibitor for advanced breast cancer have several therapeutic options if choosing to continue endocrine-based approaches. For patients with prior CDK4/6 inhibitor treatment and ESR1 wildtype tumors, appropriate subsequent ET options include fulvestrant, aromatase inhibitor, or tamoxifen monotherapy, or ET in combination with targeted agents such as alpelisib (for PIK3CA mutated tumors), or everolimus. For patients with prior CDK4/6 inhibitor treatment and a detectable ESR1 mutation, options include elacestrant or other ET either alone or in combination with targeted agents such as alpelisib (for PIK3CA-mutated tumors) or everolimus. Elacestrant has comparable or greater activity than SOC ET monotherapy. Currently, there are no data on safety or clinical efficacy to support the use of elacestrant in combination with targeted agents. ( EB , H , B , S )


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 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

Recommendation Grading


The information in this patient summary should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.



Endocrine Treatment and Targeted Therapy for HR-Positive, HER2-Negative Metastatic Breast Cancer

Authoring Organization

Publication Month/Year

May 17, 2023

Last Updated Month/Year

July 14, 2023

Document Type


Country of Publication


Target Patient Population

Women and men with HR-positive, HER2-negative MBC

Target Provider Population

Oncology specialists, other health care providers (including primary care physicians, specialists, nurses, social workers, and any other relevant member of a comprehensive multidisciplinary cancer care team

Inclusion Criteria

Male, Female, Adult, Older adult

Health Care Settings

Ambulatory, Hospital, Outpatient

Intended Users

Nurse, nurse practitioner, physician, physician assistant


Treatment, Management

Diseases/Conditions (MeSH)

D001943 - Breast Neoplasms


breast cancer, Metastatic Breast Cancer, HER2, HER2 Negative

Source Citation

Burstein HJ, et al. Testing for ESR1 Mutations to Guide Therapy for HR-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update. J Clin Oncol. 2023 May 17 doi: 10.1200/JCO.23.00638.

Burstein HJ et al. Endocrine Treatment and Targeted Therapy for HR-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Update. J Clin Oncol. 2021 July 29 doi: 10.1200/JCO.21.01392.

Supplemental Methodology Resources

Data Supplement, Evidence Tables


Number of Source Documents
Literature Search Start Date
January 1, 2016
Literature Search End Date
December 1, 2020