If a breast cancer patient is estrogen receptor (ER) negative or human epidermal growth factor receptor (HER) negative, does that mean the cancer won't respond to treatment?

ER-Negative or HER2-Negative Breast Cancer: Treatment Response

No, ER-negative or HER2-negative status does NOT mean the cancer won't respond to treatment—it only means the cancer won't respond to specific targeted therapies directed at those receptors, but multiple other effective treatment options remain available. 1

Understanding Receptor Status and Treatment Implications

ER-Negative Tumors

• ER-negative breast cancers will not respond to endocrine therapy (tamoxifen, aromatase inhibitors) because these tumors lack the estrogen receptor target that these medications block 1
• However, ER-negative tumors remain highly responsive to chemotherapy, which works through mechanisms independent of hormone receptors 1
• Triple-negative breast cancer (ER-negative, PR-negative, HER2-negative) represents 10-20% of breast cancers and is routinely treated with chemotherapy as the primary systemic therapy 1

HER2-Negative Tumors

• HER2-negative status means the tumor will not respond to HER2-targeted therapies like trastuzumab or pertuzumab 1
• If the tumor is hormone receptor-positive (ER+ or PR+) and HER2-negative, endocrine therapy remains highly effective, with tamoxifen reducing recurrence risk by one-third and death by 31% 1, 2
• HER2-negative tumors that are also hormone receptor-positive represent 65-70% of all breast cancers and have excellent treatment options with endocrine therapy 3

Treatment Algorithm by Receptor Subtype

ER-Positive/HER2-Negative (Most Common: 65-70% of cases)

• Primary treatment: Endocrine therapy for 5-10 years (aromatase inhibitors for postmenopausal, tamoxifen for premenopausal) 1, 3
• Add chemotherapy for high-risk features based on tumor size, grade, nodal status, or genomic testing 1, 4
• Consider CDK4/6 inhibitors combined with endocrine therapy for high-risk early-stage or metastatic disease 3

ER-Negative/HER2-Positive

• Primary treatment: Chemotherapy plus HER2-targeted therapy (trastuzumab for 1 year) 1, 5
• Consider dual HER2 blockade (trastuzumab + pertuzumab) for tumors >1cm or node-positive disease 5
• No role for endocrine therapy in this subtype 1, 5

Triple-Negative (ER-Negative/PR-Negative/HER2-Negative)

• Primary treatment: Chemotherapy with anthracycline and taxane-based regimens 1
• Consider immunotherapy (pembrolizumab) for PD-L1 positive tumors 1
• Test for BRCA mutations—if positive, consider PARP inhibitors for metastatic disease 1
• Despite lack of targeted therapy options, many triple-negative tumors respond well to chemotherapy 1, 6

ER-Positive/HER2-Positive

• Dual pathway targeting: Endocrine therapy PLUS HER2-targeted therapy 1, 7
• Chemotherapy typically added due to bidirectional crosstalk between ER and HER2 pathways 7
• Both pathways must be blocked to prevent resistance 7

Critical Clinical Pitfalls

Low ER Expression (1-10% Positive)

• ER-low-positive tumors (1-10% staining) behave more like ER-negative cancers but may still derive some benefit from endocrine therapy 1
• The ASCO/CAP guidelines recommend reporting these as "ER Low Positive" with discussion of limited data 1
• Consider both chemotherapy AND endocrine therapy for these borderline cases, as the benefit from endocrine therapy alone is uncertain 1, 4

Retesting on Recurrence

• Receptor status can change between primary tumor and recurrence in 3.4-60% of cases for ER and up to 10% for HER2 1
• NCCN guidelines recommend biopsy and retesting of metastatic disease, especially if originally negative or unknown 1
• A change from negative to positive opens new treatment options 1

ER-Negative/PR-Positive Paradox

• This rare phenotype (ER-negative but PR-positive) is frequently due to technical artifact and should prompt repeat testing 1
• If confirmed, may still consider endocrine therapy despite limited efficacy data 1

Prognosis Considerations

• ER-negative status is associated with higher early recurrence risk (peak within 3 years) but does not mean untreatable 1
• HER2-positive status historically indicated poor prognosis, but with modern HER2-targeted therapy, outcomes have dramatically improved 1, 7
• Triple-negative breast cancer has higher mortality rates in the first 5 years but responds to chemotherapy 1, 6
• ER-positive/HER2-negative tumors have the best overall prognosis with appropriate endocrine therapy 1, 3