CDK4/6 Inhibitors in Early-Stage Breast Cancer: A Response to Criticism and the Current Position

Major debates occasionally arise in oncology practice and can directly influence treatment standards. Recently, at the center of this discussion have been agents used in early-stage hormone receptor-positive (HR+) breast cancer: CDK4/6 inhibitors .

A critical article by Ian Tannock and colleagues created confusion about the adjuvant use of these agents, raising questions such as ‘Are we overusing them?’, ‘Is the toxicity worth it?’ and ‘Do they increase resistance?’

However, a paper in the Journal of Clinical Oncology by De Laurentiis and colleagues provides strong, clear answers to these criticisms on a scientific basis. This analysis clarifies why adjuvant CDK4/6 inhibitors should not be abandoned.

1) Criticism of Treatment Duration: Early-Stage and Metastatic Disease Are Not the Same

A central criticism was why these drugs, used for an average of 16–20 months in metastatic disease, are given for 2–3 years in early-stage disease.

If PFS durations in metastatic disease were used as a reference, today’s hormone therapy courses lasting 5–10 years would also have to be stopped at 15 months — which is clearly wrong.

2) The Debate over Toxicity and Financial Burden

The adverse effects of CDK4/6 inhibitors are generally manageable and can readily be controlled through dose adjustments.

The issue of ‘adverse effects’ must therefore be considered not solely as drug toxicity, but from the perspective of preventing recurrence .

3) A Clear, Technical Response to the Claim of ‘Statistical Bias’

Critics claimed that censoring in the studies could distort the results.

In some cases, these methodological factors were even shown to underestimate the drug’s benefit.

4) The Debate over Resistance Mechanisms: What Do the Clinical Data Say?

One claim was that CDK4/6 inhibitors might make tumors more resistant over the long term.

In other words, what is observed is the removal of the drug’s suppressive effect, not the tumor becoming more aggressive.

Is History Repeating Itself in Oncology: A ‘New Tamoxifen’?

The authors compare the absolute survival contribution of CDK4/6 inhibitors (abemaciclib and ribociclib) with major milestones in oncology history. Their analyses show that the effect of these agents in adjuvant treatment is more than a small improvement; like the introduction of Tamoxifen in the 1970s, it is a revolutionary step that fundamentally changes treatment standards and will endure for decades.

Conclusion: Adjuvant CDK4/6 Inhibitors Are a New Standard

The analysis by De Laurentiis and colleagues shows that the absolute benefit provided by CDK4/6 inhibitors may be more influential than many milestones in breast cancer history (such as the discovery of tamoxifen).

By clearly resolving the questions under discussion, this powerful article has renewed our confidence in practice.

References

• De Laurentiis M. et al. In Defense of Adjuvant CDK4/6 Inhibitors in Early Breast Cancer. J Clin Oncol 43, 3691–3697 (2025).
• Tannock IF, Khan QJ, Fojo T. Why we do not recommend adjuvant CDK4/6 inhibitors. J Clin Oncol 43:2456–2460 (2025).