July 12, 2024

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Guidelines for Early HR+/HER2- Breast Cancer Treatment Strategies

Guidelines for Early HR+/HER2- Breast Cancer Treatment Strategies

Guidelines for Early HR+/HER2- Breast Cancer Treatment Strategies

Latest Guidelines Summarize Systemic Treatment Strategies for the Most Common HR+/HER2- Breast Cancer.

HR-positive/HER2-negative (HR+/HER2-) breast cancer represents the most prevalent type of early-stage breast cancer, accounting for over 70% of global cases.

Recently, the European Society for Medical Oncology (ESMO) released comprehensive clinical practice guidelines for early-stage breast cancer. “Medical Perspectives” highlights key updates in systemic treatment strategies for early-stage HR+/HER2- breast cancer.

Guidelines for Early HR+/HER2- Breast Cancer Treatment Strategies

Timing of Systemic Treatment for Early Breast Cancer:

Neoadjuvant systemic treatment for breast cancer refers to comprehensive systemic therapy administered before planned surgery for newly diagnosed breast cancer without distant metastasis. Adjuvant systemic treatment, on the other hand, involves systemic therapy after surgical removal of the breast lump to prevent or delay disease progression, reduce recurrence, and manage metastasis.

The guidelines emphasize that neoadjuvant systemic treatment should commence as soon as possible after the patient completes diagnosis and staging (ideally within 2-4 weeks). Adjuvant systemic treatment should start without undue delay (ideally within 4-6 weeks), as data suggests that delaying adjuvant systemic treatment beyond 12 weeks may compromise its effectiveness.

Additionally, if a patient qualifies for systemic adjuvant chemotherapy, the same drug regimen as adjuvant treatment may be considered for neoadjuvant therapy. Unless contraindicated, all hormone receptor-positive (HR+) breast cancer patients should undergo endocrine therapy (ET).

Selection Criteria for Neoadjuvant Systemic Treatment:

Individualized treatment for HR+/HER2- patients depends on tumor staging, biological characteristics (such as molecular subtype), and menopausal status. High-risk HR+/HER2- breast cancer patients typically benefit from treatment based on aromatase inhibitors (AIs). These patients may also consider chemotherapy, targeted therapy, and extended adjuvant ET. Pre-menopausal HR+/HER2- patients may require ovarian function suppression (OFS) and chemotherapy.

For most HR+/HER2- breast cancer patients discovered through screening, surgery is the initial treatment. However, for patients with larger tumors or clinical lymph node involvement, neoadjuvant systemic treatment is a preferred option. Neoadjuvant chemotherapy effectively achieves tumor downsizing in HR+/HER2- patients, but it’s important to note that achieving pathological complete response (pCR) is less common in this group.

Selection Criteria for Adjuvant Systemic Treatment:

Overall, adjuvant chemotherapy contributes to a 25-30% improvement in relative recurrence risk and survival rate for patients of any subtype. However, in postmenopausal patients with negative lymph nodes or 1-3 positive lymph nodes and low-risk genomic features, adjuvant chemotherapy may not further reduce recurrence compared to ET alone. In premenopausal patients with similar characteristics, adjuvant chemotherapy does decrease recurrence compared to ET alone.

Evaluation of ET effectiveness can be assessed based on Ki-67 levels after 4 weeks of preoperative ET. For HR+/HER2- patients with 0-3 positive lymph nodes (especially postmenopausal patients) who need chemotherapy, the standard regimen includes anthracyclines, taxanes, and alkylating agents. Non-anthracycline-based regimens may be suitable for stage I and II HR+/HER2- breast cancer with limited lymph node involvement.

Four Key Roles of Adjuvant Endocrine Therapy:

Adjuvant ET is almost universally applicable for invasive HR+/HER2- breast cancer patients at any stage and HER2 status. It reduces the risk of local and distant recurrence, contralateral breast cancer, and improves overall survival.

In high-risk premenopausal HR+/HER2- patients, combining ovarian function suppression (OFS) with AIs or tamoxifen lowers the risk of recurrence and improves overall survival compared to tamoxifen alone. In postmenopausal patients, using AIs before tamoxifen or sequentially after 2-3 years of tamoxifen reduces recurrence risk, especially in higher-stage breast cancer.

Standard adjuvant ET typically lasts for 5 years but can be extended to 7 or 10 years to further decrease recurrence risk and extend survival, especially in higher-stage patients.

Assistance in Reducing Recurrence Risk and Minimizing Side Effects:

In postmenopausal early breast cancer patients and premenopausal patients receiving OFS treatment, bisphosphonate adjuvant therapy reduces the risk of tumor recurrence and mitigates observed bone loss or osteoporosis side effects during AI treatment.

Meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group indicates the benefit of this treatment irrespective of HR status, type of bisphosphonate, or treatment plan.

Value of CDK4/6 Inhibitors and PARP Inhibitors:

Combining cyclin-dependent kinase 4/6 (CDK4/6) inhibitors with ET has been extensively studied for its impact on survival outcomes in early HR+/HER2- breast cancer patients. Current evidence suggests that adding abemaciclib to ET for 2 years can reduce the absolute recurrence risk by 6.4% over 4 years.

The NATALEE trial evaluated the efficacy and safety of adding ribociclib to adjuvant ET for 3 years in stage 2 or 3 HR+/HER2- breast cancer patients. The trial achieved its primary endpoint, with a 3.3% improvement in 3-year invasive disease-free survival (iDFS) (HR=0.748; 95% CI 0.618-0.906; P=0.0014). Ribociclib may become another treatment option for moderate to high-risk HR+/HER2- breast cancer patients.

In patients with germline BRCA1/2 mutations and high-risk HER2- breast cancer, regardless of HR status, adjuvant treatment with the PARP inhibitor olaparib for 1 year improves disease-free survival (DFS) (HR=0.63; 95% CI 0.5-0.78) and overall survival (OS) (HR=0.68; 95% CI 0.47-0.97; P=0.009). At 4 years, the absolute differences in iDFS and distant DFS were 7.3% (95% CI 3.0%-11.5%) and 7.4% (95% CI 3.6%-11.3%), respectively.

The guidelines emphasize that while supportive interventions can reduce many treatment-related side effects, patient preferences are crucial in making decisions about early systemic treatment, considering that many treatments for estrogen receptor (ER)-positive breast cancer moderately reduce recurrence risk or extend OS, especially for low-risk HR+/HER2- breast cancer patients.

Guidelines for Early HR+/HER2- Breast Cancer Treatment Strategies


[1] S. Loibl et al., Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Annals of oncology. Doi: 10.1016/j.annonc.2023.11.016

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