Kefah Mokbel: One-Size-Fits-All NACT in HR+/HER2 − Breast Cancer is No Longer Justified

Moving Beyond One-Size-Fits-All: The Shift Toward Precision Neoadjuvant Therapy

For years, the approach to treating HR+/HER2− breast cancer often followed a standardized path. However, emerging real-world data is challenging the status quo, suggesting that the traditional “one-size-fits-all” application of neoadjuvant chemotherapy (NACT) may be outdated. The goal is shifting from treating every patient with a specific receptor profile to a risk-adapted strategy that matches the intensity of the treatment to the biology of the tumor.

“One-size-fits-all NACT in HR+/HER2− breast cancer is no longer justified” Kefah Mokbel, Chair of Breast Cancer Surgery at London Breast Institute

Recent evidence from a cohort of 990 patients underscores this necessity. Even as NACT generally showed a survival advantage over upfront surgery—with an overall survival hazard ratio (HR) of 0.60, representing a 40% reduction in mortality—this benefit was far from universal. The data reveals a stark divide: while some patients thrive with chemotherapy before surgery, others derive no survival benefit at all.

The Luminal B Distinction: Identifying High-Risk Biology

The future of breast cancer treatment lies in the ability to distinguish between different “Luminal” subtypes. The most significant survival gains are now being linked to the Luminal B subgroup. In these patients, the overall survival HR dropped to 0.47, which equates to a 53% reduction in mortality.

Precision oncology is now focusing on specific biomarkers to identify who truly needs aggressive intervention. For high-risk Luminal B patients—defined by T3/N2 disease or a Ki-67 index of ≥30%—the impact is measurable. Data shows a 5-year overall survival rate of 91.5% for those receiving NACT, compared to 80.9% for those who did not, marking an absolute improvement of +10.6%.

The Role of Ki-67 in Clinical Decision Making

The Ki-67 protein, a marker of cell proliferation, is becoming a cornerstone of risk stratification. When Ki-67 is 30% or higher, it signals a more aggressive tumor biology that is more likely to respond to chemotherapy. By prioritizing NACT for these patients, clinicians can maximize survival while sparing lower-risk patients from the toxicity of unnecessary chemotherapy.

Future Trends: De-escalation and Risk-Adapted Care

The trajectory of oncology is moving toward de-escalation—the practice of reducing treatment intensity for patients who are unlikely to benefit from it. This trend is driven by the realization that overtreatment can lead to significant side effects without improving long-term outcomes.

Future clinical pathways are expected to integrate more robust real-world evidence (RWE) to supplement randomized controlled trials. The study conducted by Wei Wang and colleagues in a Chinese population highlights how regional and population-specific data can refine global treatment standards.

Integrating Real-World Evidence (RWE)

While prospective validation is still required to change definitive practice, the use of retrospective real-world analysis is accelerating. These studies allow researchers to analyze larger, more diverse cohorts—such as the 990 patients in the recent Frontiers in Oncology study—to see how treatments perform outside the strict confines of a clinical trial.

FAQ: Neoadjuvant Chemotherapy in HR+/HER2- Breast Cancer

What is NACT?
Neoadjuvant chemotherapy (NACT) is chemotherapy administered after a diagnosis but before the primary surgery to shrink a tumor and improve surgical outcomes.

Who benefits most from NACT in HR+/HER2- cases?
According to recent data, the most significant benefits are seen in high-risk Luminal B patients, particularly those with T3/N2 disease or a Ki-67 level of 30% or higher.

Why is “one-size-fits-all” treatment being discouraged?
Because lower-risk patients may derive no survival benefit from NACT, meaning they are exposed to the side effects of chemotherapy without a corresponding increase in their chance of survival.

What are the limitations of current real-world data?
Retrospective studies can be subject to selection bias and confounding factors. Prospective trials are necessary to officially update clinical guidelines.

To stay updated on the latest breakthroughs in breast oncology and surgical precision, explore our other coverage on Kefah Mokbel’s research and clinical insights.