What is the best treatment for a 36-year-old female with a 5 cm invasive breast cancer that is 15% Estrogen Receptor (ER) positive, Progesterone Receptor (PR) negative, Human Epidermal growth factor Receptor 2 (Her2) negative, and has a high Ki-67 index?

Treatment Approach for High-Risk ER-Low-Positive Breast Cancer

This 36-year-old premenopausal woman with a 5 cm, ER 15%/PR-negative/HER2-negative breast cancer with Ki-67 90% requires neoadjuvant chemotherapy followed by surgery, radiation, extended endocrine therapy with ovarian function suppression plus aromatase inhibitor, and adjuvant CDK4/6 inhibitor therapy. 1

Critical Context: ER-Low-Positive Disease

This case represents a particularly challenging scenario because the tumor is technically ER-positive (15% staining) but behaves more like triple-negative disease given the extremely high Ki-67 of 90%, PR negativity, and large size. ER-low-positive tumors (1-10% staining, though this extends to 15%) derive limited benefit from endocrine therapy alone and should be considered for chemotherapy more liberally. 2 The extremely high Ki-67 of 90% indicates an aggressive, highly proliferative tumor that warrants intensive multimodal therapy.

Neoadjuvant Chemotherapy (First-Line Treatment)

Neoadjuvant systemic therapy is strongly indicated for this large (5 cm) tumor to achieve surgical downstaging and potentially enable breast-conserving surgery. 1

Chemotherapy Regimen Selection

• Anthracycline, taxane, and alkylator-based chemotherapy regimens are standard for HR-positive, HER2-negative breast cancer warranting chemotherapy. 1
• Sequential administration of anthracyclines followed by taxanes (rather than concurrent) is recommended. 1
• Taxanes provide particular benefit in hormone receptor-positive disease by overcoming relative chemoresistance. 2
• The high Ki-67 (90%) and large tumor size (5 cm) make this patient an unequivocal candidate for intensive chemotherapy. 3, 4

Rationale for Neoadjuvant Approach

• The 5 cm tumor size makes neoadjuvant therapy preferable to potentially reduce the extent of surgery. 1
• While pathologic complete response (pCR) is uncommon in HR-positive disease, it occurs more frequently in young patients and those with high-grade tumors. 1
• The extremely high Ki-67 of 90% suggests this tumor may be more chemotherapy-sensitive than typical ER-positive cancers. 5, 3

Surgical Management

Following neoadjuvant chemotherapy, the patient requires either breast-conserving surgery with sentinel lymph node biopsy or mastectomy with sentinel lymph node biopsy, depending on tumor response, residual size, and patient preference. 6

• Breast-conserving surgery is now standard of care when feasible, achieving equivalent outcomes to mastectomy. 1
• Oncoplastic procedures should be considered to achieve better cosmetic outcomes given the large initial tumor size. 1
• Sentinel lymph node biopsy is the standard of care unless axillary node involvement is proven pre-operatively. 1

Radiation Therapy

Postoperative radiation therapy is strongly recommended after breast-conserving surgery. 1, 6

• Shorter fractionation schemes (15-16 fractions with 2.5-2.67 Gy single dose) are generally recommended. 1
• Post-mastectomy radiation should be considered if there are 1-3 positive axillary lymph nodes, especially with additional risk factors (which this patient has: large tumor size, high grade, high Ki-67). 1, 6

Adjuvant Endocrine Therapy (Following Chemotherapy)

Despite the low ER expression (15%), adjuvant endocrine therapy is indicated for all patients with any detectable ER expression (≥1%). 1

Specific Regimen for This High-Risk Premenopausal Patient

Ovarian function suppression (OFS) paired with an aromatase inhibitor is the optimal endocrine therapy for this high-risk premenopausal woman. 1

• Among premenopausal women with higher-risk HR-positive cancers, OFS paired with an AI or tamoxifen reduces the likelihood of recurrence and improves overall survival versus tamoxifen alone. 1
• OFS with an AI reduces recurrences compared with OFS with tamoxifen. 1
• Standard treatment duration is 5 years, but extended durations to 7 or 10 years further lower recurrence risk and increase survival, particularly in higher-stage cancers. 1

Bisphosphonate Therapy

Adjuvant bisphosphonate therapy should be added for premenopausal women receiving OFS, as it can lower the risk of tumor recurrence and mitigate osteopenia/osteoporosis seen with AIs. 1

• A meta-analysis indicates benefit irrespective of HR status and bisphosphonate type or regimen. 1
• Denosumab is not recommended based on mixed trial results. 1

Adjuvant CDK4/6 Inhibitor Therapy

This patient meets criteria for adjuvant CDK4/6 inhibitor therapy based on her high-risk features. 1

Abemaciclib Option

• Abemaciclib for 2 years reduced the absolute risk of recurrence at 4 years by 6.4% (HR 0.664, P < 0.0001) in women with HR-positive, HER2-negative breast cancer with either ≥4 involved lymph nodes, 1-3 positive nodes with either T3 (>5 cm) tumors or grade 3 histology or Ki-67 ≥20%. 1
• This patient's 5 cm tumor (T3) and Ki-67 of 90% make her eligible regardless of final nodal status.

Ribociclib Option

• Ribociclib 400 mg/day (days 1-21 of every 28-day cycle) for 3 years improved 3-year invasive disease-free survival by 3.3% (HR 0.748, P = 0.0014) in stage II or III HR-positive, HER2-negative breast cancer. 1
• This patient's stage II/III disease (based on 5 cm tumor) makes her eligible.

Sequencing of Therapies

The treatment sequence must be: neoadjuvant chemotherapy → surgery → radiation → endocrine therapy (OFS + AI) + CDK4/6 inhibitor. 1, 2

• Chemotherapy and endocrine therapy should not be given concurrently. 1
• Sequential rather than concurrent administration of cytotoxic and endocrine therapies is recommended. 1

Critical Caveats and Pitfalls

ER-Low-Positive Status

• The 15% ER positivity places this tumor in a gray zone where endocrine therapy benefit may be limited. 2
• The PR negativity, extremely high Ki-67 (90%), and large size suggest aggressive biology more similar to triple-negative disease. 7, 8
• Despite limited expected benefit from endocrine therapy, it should still be administered given any detectable ER expression, but chemotherapy is absolutely essential. 1, 2

Ki-67 Interpretation

• The Ki-67 of 90% is extraordinarily high and indicates an extremely aggressive, highly proliferative tumor. 5, 4
• Ki-67 >20% identifies patients who benefit most from chemotherapy in ER-positive disease. 1, 3
• This patient's Ki-67 of 90% far exceeds any threshold and mandates intensive chemotherapy. 5, 3, 4

Age Considerations

• At 36 years old, this premenopausal patient is at higher risk and requires more aggressive therapy. 1
• Young age increases the likelihood of chemotherapy benefit and pCR with neoadjuvant therapy. 1
• Fertility preservation discussions should occur before initiating chemotherapy if desired.

Monitoring During Treatment

• Menopausal status cannot be determined while receiving ovarian function suppression; monitoring estradiol and FSH/LH levels is recommended. 2
• Bone health monitoring with DEXA scans is essential for women on aromatase inhibitors. 1, 6