What is the role of adjuvant chemotherapy in patients with estrogen receptor positive (ER+), progesterone receptor positive (PR+), and human epidermal growth factor receptor 2 negative (HER2-) breast cancer?

Adjuvant Chemotherapy for ER+/PR+/HER2- Breast Cancer

Adjuvant endocrine therapy is mandatory for all ER+/PR+/HER2- breast cancer patients, while the decision to add chemotherapy depends primarily on genomic testing (21-gene recurrence score) combined with nodal status, tumor size, grade, and patient age. 1

Core Treatment Principle

All patients with ER+/PR+/HER2- invasive breast cancer should receive adjuvant endocrine therapy regardless of age, lymph node status, or whether chemotherapy is administered. 1 The critical question is whether to add chemotherapy to endocrine therapy, not whether to give endocrine therapy at all.

Decision Algorithm for Adding Chemotherapy

Node-Negative Disease

Use the 21-gene recurrence score (Oncotype DX) to guide chemotherapy decisions: 1

• Recurrence Score 0-10: No benefit from adding chemotherapy to endocrine therapy. Proceed with endocrine therapy alone. 1

• Recurrence Score 11-25:

  • Age ≤50 years AND RS 16-25: Add chemotherapy before endocrine therapy, as this subgroup showed lower distant recurrence rates with chemotherapy in TAILORx trial. 1
  • Age >50 years OR RS 11-15: Endocrine therapy alone is sufficient, as TAILORx showed similar disease-free survival at 9 years. 1

• Recurrence Score ≥31: Clear benefit from adjuvant chemotherapy. Administer chemotherapy first, followed by sequential endocrine therapy. 1

Node-Positive Disease (1-3 Positive Nodes)

The RxPONDER trial results guide treatment: 1

• Recurrence Score ≤25: The absolute benefit from chemotherapy is very small in patients with limited nodal disease (1-3 positive nodes) and low recurrence scores. 1

  • RS ≤11: 5-year disease-free survival of 94.4% with endocrine therapy alone per West German Plan B study. 1
  • RS <18: 5-year risk of distant recurrence only 2.7% with endocrine therapy alone. 1

• Recurrence Score ≥31: Clear benefit from adjuvant chemotherapy even with node-positive disease, as demonstrated in SWOG 8814 trial (10-year DFS: 55% vs 43%; 10-year OS: 73% vs 54%). 1

Node-Positive Disease (≥4 Positive Nodes)

Chemotherapy is generally recommended regardless of recurrence score, though genomic testing may still provide prognostic information. 1

Sequencing of Therapies

When both chemotherapy and endocrine therapy are indicated, chemotherapy must be given first, followed by sequential endocrine therapy—never concurrent. 1, 2 This sequencing is critical as tamoxifen decreases the annual odds of recurrence by 41% and death by 31% when given after chemotherapy. 1

Endocrine Therapy Selection

Postmenopausal Women

• Aromatase inhibitors (anastrozole, letrozole, or exemestane) are preferred over tamoxifen for 5-10 years, reducing annual odds of recurrence by approximately 5% in absolute terms compared to tamoxifen. 2, 3

Premenopausal Women

• Tamoxifen 20 mg daily for 5-10 years is the standard approach. 1, 2
• High-risk premenopausal patients: Consider ovarian function suppression plus aromatase inhibitor. 1, 3

Duration of Endocrine Therapy

• Standard duration: 5 years for both tamoxifen and aromatase inhibitors. 2, 3
• Extended therapy to 10 years total: Recommended for node-positive disease, as it reduces late recurrence risk but increases adverse events including bone fractures and cardiovascular events. 2, 3

Chemotherapy Regimens When Indicated

Preferred regimens include: 3

• Anthracycline-based followed by taxanes (AC→paclitaxel or docetaxel)
• Docetaxel-cyclophosphamide

Taxanes provide particular benefit in hormone receptor-positive disease by overcoming relative chemoresistance. 3

Critical Caveats

ER-Low-Positive Tumors (1-10% Staining)

This heterogeneous group behaves more like ER-negative cancers. Individualized risk-benefit assessment is mandatory for both endocrine therapy and chemotherapy, as these patients may derive limited benefit from endocrine therapy alone and should be considered for chemotherapy more liberally. 1, 3

Menopausal Status Assessment

Cannot be determined while receiving ovarian function suppression. Monitor estradiol and FSH/LH levels if under age 60 and amenorrheic for ≤12 months, particularly after chemotherapy, while on tamoxifen with or without ovarian suppression, after switching from tamoxifen to aromatase inhibitor, and prior to each GnRH agonist dose. 1, 2

Genomic Testing Limitations

The 21-gene assay (Oncotype DX) is the only multigene assay clinically validated for predicting chemotherapy benefit, not just prognosis. 1 Other assays like MammaPrint and EndoPredict should not be used to guide chemotherapy decisions in this population. 1

HER2 Status Consideration

Despite potential relative endocrine resistance in HER2-positive tumors, endocrine therapy should still be used in ER/PR-positive patients regardless of HER2 status given the favorable toxicity profile. 1, 2