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Individualizing EBC Treatment
Improving Outcomes in HER2-Negative Early Breast Cancer With Individualized Targeted Approaches

Released: June 21, 2023

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Key Takeaways
  • Recent phase III clinical trials have led to new drug approvals/indications that allow more tailored treatment options and result in reduced recurrence rates in HER2-negative early breast cancer.
  • It is critical to integrate molecular features and clinical factors for risk assessment as treatment paradigms shift and treatment options are expanded. 

Never in breast oncology has it been more imperative to individualize treatment for early-stage HER2-negative breast cancer. Recent studies have led to exciting drug approvals in this space that are resulting in decreased rates of breast cancer recurrence. 

PARP-1 Inhibition With BRCA Germline Mutations
For patients with triple-negative breast cancer (TNBC) or hormone receptor (HR)‒positive/HER2-negative early breast cancer with BRCA1 or BRCA2 germline mutations, there is now consideration of using 1 year of adjuvant olaparib, an oral PARP-1 inhibitor, for those with high-risk clinicopathologic factors. Through this approach, the OlympiA trial demonstrated a significant improvement in invasive disease–free survival (iDFS) vs placebo (hazard ratio at median follow-up of 2.5 years: 0.58; 99.5% CI: 0.41-0.82; P <.001). 

CDK4/6 Inhibition for HR-Positive Disease
For patients with node-positive, high-risk HR-positive/HER2-negative early breast cancer, there is also now an FDA approval for the CDK4/6 inhibitor abemaciclib based on results from the monarchE trial, which demonstrated a significant improvement in iDFS with the addition of abemaciclib to endocrine therapy (ET) (hazard ratio: 0.75; 95% CI: 0.60-0.93; P = .01). The study compared standard ET (5-10 years) vs ET plus continuous abemaciclib (for 2 years) starting after a maximum of 16 months from surgery to randomization with or without prior (neo)adjuvant chemotherapy and radiotherapy. To apply these findings appropriately to clinical practice, it is critical to understand how “high risk” was defined, with the trial defining it either based on clinicopathologic risk factors (≥4 positive axillary lymph nodes [ALNs] or 1-3 positive ALNs and histologic grade ≥3 or tumor size ≥5 cm) or Ki-67 criteria (1-3 positive ALNs and centrally tested Ki-67 ≥20%, not grade 3, and tumor size <5 cm). 

Although the investigators found that a high Ki-67 index was prognostic of lower iDFS, the benefit of abemaciclib was consistent regardless of the Ki-67 index, demonstrating that Ki-67 expression level is not predictive of abemaciclib benefit. Initially, there were concerns that perhaps adjuvant CDK4/6 inhibitor treatment may just delay ultimate recurrence, but subsequent reports from the monarchE trial have continued to show a significant improvement in iDFS. At 4 years, the absolute difference in iDFS between the groups was 6.4% (85.8% with abemaciclib plus ET vs 79.4% with ET alone). At ASCO 2023, investigators also reported the results of a subgroup analysis from monarchE assessing efficacy and safety among 2 age group subsets: individuals younger than 65 years of age and those 65 years of age and older. The findings indicated that the addition of abemaciclib to ET was beneficial for both age groups, with hazard ratios for iDFS of 0.646 (95% CI: 0.554-0.753) among the younger group and 0.767 (95% CI: 0.556-1.059) among the older group. Abemaciclib dose adjustments were more frequent in the older group.

Also at ASCO 2023, investigators reported positive interim results from the randomized phase III NATALEE trial evaluating adjuvant therapy with the CDK4/6 inhibitor ribociclib in patients with HR-positive/HER2-negative early breast cancer. Ribociclib is currently approved by the FDA for the treatment of HR-positive/HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial ET-based treatment or following disease progression while receiving ET in postmenopausal women or in men. In the NATALEE trial, more than 5000 pre/postmenopausal women and men with HR-positive/HER2-negative, stage IIA (either N0 with grade 2 and Ki-67 ≥20%, Oncotype DX recurrence score ≥26, or high risk via genomic risk profiling, N0 with grade 3, or N1), stage IIB, or stage III breast cancer were randomized to receive a nonsteroidal aromatase inhibitor for ≥5 years with vs without 3 years of ribociclib treatment. At the second interim efficacy analysis, the trial met its primary endpoint, with the addition of ribociclib significantly improving iDFS vs nonsteroidal aromatase inhibitor treatment alone (3-year rate: 90.4% vs 87.1%, respectively; hazard ratio: 0.748; 95% CI: 0.618-0.906; P = .0014). The P value of .0014 met the protocol-defined stopping boundary for superior efficacy (1-sided P <.0128). Based on these findings, it is possible that a near-future FDA indication for ribociclib could include use as an adjuvant therapy option for patients with stage II-III HR-positive/HER2-negative early breast cancer at elevated risk of recurrence, including those with node-negative disease. This change would expand treatment options for patients, especially as the NATALEE trial included patients who were intermediate risk. 

Immunotherapy and Adjuvant Capecitabine in TNBC
For patients with TNBC, immunotherapy with pembrolizumab has been approved for patients with stage II/III disease beginning with the neoadjuvant component of treatment based on results of the KEYNOTE-522 trial, which demonstrated improved event-free survival with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab vs neoadjuvant chemotherapy alone (hazard ratio: 0.63; 95% CI: 0.48-0.82; P = .001). It was previously established by the CREATE-X trial that, for patients with TNBC who have residual disease following neoadjuvant chemotherapy, there are improved long-term outcomes if therapy is escalated in the adjuvant setting through the use of 6 months of oral chemotherapy with capecitabine (hazard ratio for recurrence, second cancer, or death: 0.70; 95% CI: 0.53-0.92; P = .01). 

Gene Expression Assays
Recent advances also have enabled individualizing treatment in terms of chemotherapy utility. The results of phase III trials using gene expression assays, such as TAILORx and RxPONDER, have helped establish which patients with HR-positive/HER2-negative early breast cancer do and do not benefit from chemotherapy. In the coming years, we continue to hope for strategies to further individualize treatment, including risk-adapted approaches, to reduce toxicity for those who need less treatment and improve outcomes for those who need more treatment. Overall, it is critical to integrate clinical and molecular factors for risk assessment as treatment paradigms shift and treatment options are expanded.

Your Thoughts?
What challenges have you experienced in your practice when it comes to incorporating newer treatment strategies for HER2-negative early breast cancer? Answer the polling question and join the conversation in the discussion section.

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Which of the following do you find to be the most challenging aspect of incorporating newer targeted therapies into early breast cancer management in your clinical practice?

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