Guidance for Canadian Breast Cancer Practice: National Consensus Recommendations for the Systemic Treatment of Patients with HER2+ Breast Cancer in Both the Early and Metastatic Settings (2025 Update).

Biopsy, Genomic Testing, and General Principles

• REC-01

  If feasible, biopsy of a recurrent lesion(s) should be considered at the time of diagnosis to evaluate biomarkers (ER/PR/HER2 status) and confirm a breast cancer diagnosis if the clinical course is not as expected. [1]

  Strong recommendationDiagnostic / Biomarker Assessment
• REC-02

  Testing for somatic pathway alterations (e.g., PIK3CA, PTEN, AKT, ESR1) and pathogenic germline variants (e.g., BRCA mutations) is standard of care when it may inform treatment decisions. Testing should be performed with appropriate methods and in a timely manner to guide treatment decisions. [2]

  Strong recommendationDiagnostic / Genomic Testing
• REC-03

  In the management of HR+/HER2− metastatic breast cancer, it is essential to balance disease control with quality of life, allowing patients to maintain daily activities and minimize treatment-related discomfort. [3]

  Strong recommendationGeneral Care Principles
• REC-04

  The treatment and management of breast cancer in men is the same as in pre/perimenopausal women (i.e., ET + CDK4/6i +/– LHRH agonist in the first-line metastatic setting). Given the rarity of breast cancer in men, participation in clinical trials should be encouraged whenever possible. [4]

  Strong recommendationTreatment Selection

First-line Treatment of Endocrine-Sensitive Disease

• REC-05

  For patients with HR+/HER2− metastatic breast cancer who have not received prior or recent ET, the standard of care ET backbone in the first-line metastatic setting is an AI. [5]

  Strong recommendationEndocrine Therapy
• REC-06

  For patients with de novo metastatic HR+/HER2− breast cancer, or those whose disease relapses >12 months after completing adjuvant AI, and regardless of adjuvant treatment with CDK4/6i, the standard of care first-line treatment is CDK4/6i + AI. The preferred CDK4/6i is either ribociclib or abemaciclib; however, in the case of contraindications or intolerance, palbociclib may be considered. [6]

  Strong recommendationCombination Therapy (CDK4/6i + ET)

First-line Treatment of Endocrine-Eligible Disease (Relapse on or <= 12m after adjuvant AI)

• REC-07

  For patients with HR+/HER2− breast cancer without a PIK3CA mutation and whose disease relapses on or ≤12 months after completion of adjuvant AI, SERD is the preferred ET backbone. [7]

  Strong recommendationEndocrine Therapy
• REC-08

  For patients with HR+/HER2− breast cancer without a PIK3CA mutation and whose disease relapses on or ≤12 months after completion of adjuvant AI, and without prior adjuvant CDK4/6i, the standard of care treatment is either ribociclib + fulvestrant or abemaciclib + fulvestrant. In the case of contraindications or intolerance, palbociclib + fulvestrant may be considered. [8]

  Strong recommendationCombination Therapy (CDK4/6i + ET)
• REC-09

  For patients with HR+/HER2− breast cancer without a PIK3CA mutation and whose disease relapses on or ≤12 months after completion of adjuvant AI, and with prior adjuvant CDK4/6i, rechallenge with ET + CDK4/6i should be considered, depending on the clinical situation and timing of relapse. [9]

  Moderate recommendationCombination Therapy Rechallenge
• REC-10

  For patients with HR+/HER2− breast cancer with a PIK3CA mutation and whose disease relapses on or ≤12 months after completion of adjuvant AI, inavolisib + palbociclib + fulvestrant is the standard of care. [11]

  Strong recommendationTargeted Triple Therapy (PI3Ki + CDK4/6i + ET)

Special Populations

• REC-11

  For patients with HR+/HER2− metastatic breast cancer and limited life expectancy or for those who, with shared decision-making, wish not to have intensive monitoring or toxicities, ET alone is a reasonable option. [12]

  Expert opinionEndocrine Monotherapy
• REC-12

  For eligible older patients (e.g., ≥75 years of age) with HR+/HER2− metastatic breast cancer, the standard of care at standard recommended doses remains the same as that for younger patients. [13]

  Strong recommendationTreatment Selection
• REC-13

  For patients with HR+/HER2− metastatic breast cancer and visceral disease and in the absence of true visceral crisis, ribociclib + ET or abemaciclib + ET is standard of care (instead of chemotherapy) with close monitoring for progression of disease or lack of response. Palbociclib + ET may be considered if neither ribociclib nor abemaciclib are suitable. [14]

  Strong recommendationCombination Therapy vs Chemotherapy
• REC-14

  For patients with HR+/HER2− metastatic breast cancer with bone metastases, the use of bone-modifying agents (e.g., bisphosphonates or denosumab) is standard of care to reduce and delay skeletal related adverse events. [15]

  Strong recommendationSupportive Care
• REC-15

  For patients with HR+/HER2− metastatic breast cancer with CNS involvement, a multidisciplinary team should be involved in providing recommendations for optimal local and systemic therapies. Currently, there is insufficient evidence to recommend any given systemic therapy alone (in the absence of local therapy) for the treatment of 'active' HR+/HER2− CNS metastases. [16]

  Moderate recommendationMultidisciplinary Care

Second-line Treatment

• REC-16

  For patients with HR+/HER2− metastatic breast cancer with no targetable mutations whose disease progresses on first-line therapy of ET + CDK4/6i, switching ET + another CDK4/6i could be considered. Everolimus + ET is another consideration. [17]

  Moderate recommendationTreatment Sequencing
• REC-17

  For patients with HR+/HER2− metastatic breast cancer with ESR1 mutations (without PIK3CA alterations) whose disease progresses on first-line therapy of AI + CDK4/6i, a SERD is standard of care ET, either as monotherapy or in combination with a targeted agent. [18]

  Strong recommendationTargeted Endocrine Therapy
• REC-18

  For patients with HR+/HER2− metastatic breast cancer whose disease progresses on first-line therapy and whose tumour has an PI3K/AKT/PTEN pathway alteration (with no prior PI3K/AKT/PTEN-directed therapy), standard of care in the second-line setting is capivasertib + fulvestrant. [Strong recommendation] Alpelisib + fulvestrant could be considered for patients with a confirmed PIK3CA mutation. [Moderate recommendation] [19]

  Strong recommendation / Moderate recommendationTargeted Therapy

Third-line Treatment

• REC-19

  For patients who have had two prior lines of ET (without CDK4/6i) in the metastatic setting and whose disease progresses, a trial of CDK4/6i + ET using a different ET agent should be considered. [20]

  Moderate recommendationCombination Therapy (CDK4/6i + ET)

Treatment of Endocrine-Ineligible Disease

• REC-20

  For patients with HR+/HER2− metastatic breast cancer that is ET ineligible and has progressed after prior ET + CDK4/6i in any setting, chemotherapy, including ADC, is the standard of care. [21]

  Strong recommendationChemotherapy / ADC Selection
• REC-21

  (a) For patients with HR+/HER2-low or ultralow metastatic breast cancer that has progressed on prior ET + CDK4/6i, T-DXd is an option as the next line of systemic therapy if no prior chemotherapy has been given, guided by shared decision-making. [Strong recommendation] (b) For patients with HER2-low disease who have not previously received T-DXd, but who have received at least one line of chemotherapy, T-DXd is standard of care. [Strong recommendation] [23]

  Strong recommendationAntibody-Drug Conjugate (ADC) Treatment
• REC-22

  For patients with HR+/HER2− metastatic breast cancer with germline BRCA1/2 mutations who are no longer benefiting from ET, an oral PARP inhibitor should be considered post-ET instead of chemotherapy. [24]

  Strong recommendationPARP Inhibitor Treatment
• REC-23

  For patients with HR+/HER2− metastatic breast cancer that has progressed and who have received ≥2 chemotherapy regimens and no prior ADC, sacituzumab govitecan is the standard of care. [25]

  Strong recommendationAntibody-Drug Conjugate (ADC) Treatment

Therapeutic Area

Guideline Scope

Inclusion Criteria

• Hormone receptor-positive (HR+) status [3]
• HER2-negative (HER2-) status [3]
• Metastatic breast cancer [3]

Exclusion Criteria

• Visceral crisis (for endocrine-based therapies) [5]

Special Populations

Related

• ESMO Clinical Practice Guideline for the Diagnosis, Staging and Treatment of Patients with Metastatic Breast Cancer [34]
• ASCO Guideline: Endocrine Treatment and Targeted Therapy for Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer [15]

Comparable guidelines from other societies

• European Society For Medical Oncology (ESMO) Clinical Practice Guidelines [26, 29]
• American Society of Clinical Oncology (ASCO) Guidelines [26, 30]
• National Comprehensive Cancer Network (NCCN) Guidelines [31]