What is the optimal treatment for a patient with metastatic breast cancer that is estrogen receptor (ER) positive and progesterone receptor (PR) positive, with human epidermal growth factor receptor 2 (HER2) equivocal status, who has progressed after treatment with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor?

Optimal Treatment for Metastatic ER/PR+ HER2 Equivocal Breast Cancer After CDK4/6 Inhibitor Progression

First, clarify HER2 status through reflex testing on the metastatic lesion using an alternative FDA-approved method, as equivocal results require additional testing to definitively determine whether HER2-targeted therapy should be added to your treatment plan. 1

Critical First Step: Resolve HER2 Equivocal Status

• Perform reflex HER2 testing using an alternative method or on a different portion of the same specimen, as equivocal results are insufficient to guide treatment decisions and must be resolved before proceeding 1
• If reflex testing confirms HER2-negative status, proceed with the ER/PR+ HER2-negative treatment algorithm below 1
• If reflex testing confirms HER2-positive status, switch to HER2-targeted therapy (trastuzumab + pertuzumab + chemotherapy or endocrine therapy), as this fundamentally changes the treatment paradigm 1

Molecular Testing Before Second-Line Treatment Selection

Order comprehensive molecular profiling immediately upon progression, as specific mutations directly determine optimal therapy selection and significantly impact outcomes. 1

Required Testing:

• Somatic PIK3CA mutation testing (tissue or liquid biopsy) - determines eligibility for alpelisib 1
• Somatic ESR1 mutation testing (optional but recommended if considering further aromatase inhibitor) - predicts resistance to aromatase inhibitors 1
• Germline BRCA1/2 and PALB2 mutation testing (optional) - determines eligibility for PARP inhibitors 1

Treatment Algorithm Based on Disease Burden and Molecular Profile

If NO Imminent Organ Failure (Preferred Scenario):

For PIK3CA-Mutated Tumors:

Fulvestrant + alpelisib is the preferred option [Level I, Grade B evidence; ESMO-MCBS score: 2; ESCAT score: I-A], as the SOLAR-1 trial demonstrated median PFS of 11.0 months versus 5.7 months with fulvestrant alone (HR 0.65, p<0.001) 1

• Critical toxicity management: Implement weekly laboratory and symptom monitoring for the first 4 weeks of alpelisib therapy, as median time to grade 3 hyperglycemia is 15 days and grade 3 rash is 13 days 1
• Preventive measures: Start nonsedating antihistamines or steroids prophylactically to reduce rash incidence, and have metformin available for hyperglycemia management 1

For Germline BRCA1/2 or PALB2 Mutations:

PARP inhibitor monotherapy (olaparib or talazoparib) is strongly recommended [Level I, Grade B evidence; ESMO-MCBS score: 4; ESCAT score: I-A] 1

For PIK3CA Wild-Type or Unknown Status:

Exemestane + everolimus is the evidence-based option [Level I, Grade B evidence; ESMO-MCBS score: 2] 1

• Alternative options include fulvestrant + everolimus [Level II, Grade B; off-label] or tamoxifen + everolimus [Level II, Grade B; off-label] 1
• Note: Everolimus efficacy is diminished after prior CDK4/6 inhibitor exposure, with treatment duration of only 4-5 months compared to CDK4/6-naïve patients 1
• If PIK3CA status cannot be determined and tolerability profile favors everolimus over alpelisib, everolimus may be offered as a clinical option 1

Alternative Endocrine Monotherapy Options:

Single-agent aromatase inhibitor, tamoxifen, or fulvestrant may be considered based on prior treatment history, duration of response to previous endocrine therapy (preferably >12 months), and disease burden 1

If Imminent Organ Failure Present:

Proceed directly to chemotherapy, as endocrine-based approaches are too slow to achieve disease control in visceral crisis 1

Common Pitfalls and Critical Caveats

Regarding CDK4/6 Inhibitor Continuation:

• Do NOT continue the same CDK4/6 inhibitor after progression, as there is no prospective evidence supporting this approach and retrospective data show poor outcomes 1, 2
• Switching to a different CDK4/6 inhibitor after severe toxicity (not progression) may be considered, but data supporting rechallenge after progression remain mixed 1, 3

Regarding Treatment Sequencing:

• The optimal sequence after CDK4/6 inhibitor progression remains uncertain and depends on prior agents used, duration of response to previous endocrine therapy, disease burden, and treatment availability 1
• Patients with short response to CDK4/6 inhibitors (<6 months) suggest endocrine-resistant disease and should be considered for chemotherapy earlier 4

Regarding HER2 Equivocal Status:

• Never treat HER2 equivocal disease as HER2-negative without confirmatory testing, as this may deny patients potentially life-prolonging HER2-targeted therapy 1
• If results remain indeterminate after reflex testing, final treatment decisions should involve consultation between pathologist and oncologist 1

Monitoring and Subsequent Lines

• Evaluate response after approximately 3 months through clinical assessment, imaging, and tumor markers 5
• Continue effective therapy until disease progression or unacceptable toxicity 5
• After progression on multiple lines of endocrine therapy ± targeted agents, transition to chemotherapy 1