To escalate or de-escalate? The question in HER2-positive breast cancer (2)

Offering the trastuzumab–chemotherapy combination to all those with HER2-positive early-stage breast cancer has benefitted many but has led to the overtreatment of an increasing proportion of patients. Adding unnecessary treatments to an effective regimen increases toxicity without necessarily improving outcomes. We need to de-escalate treatment in suitable patients, which may also help to reduce the healthcare financial burden.In patients with small (≤2 cm), node-negative tumours, outcomes with adjuvant paclitaxel–trastuzumab—without anthracycline—remains an excellent treatment with a low recurrence risk, suggesting that escalated treatment is not required in these patients. De-escalation by shortening trastuzumab therapy failed to demonstrate non-inferiority to the 1-year regimen in three studies, while in the PERSEPHONE study, 6-month trastuzumab was non-inferior to a 12-month regimen, with less cardiotoxicity and fewer severe toxicities. While 1-year trastuzumab remains the standard-of-care for HER2-positive early-stage breast cancer, a less intensive regimen could be an option for patients with lower recurrence risk. Additionally, shortening therapy allows patients to resume their normal lives as early as possible.Another chemotherapy-free, de-escalation approach is to co-target HER2 and oestrogen (ER) receptors in patients with tumours positive for these receptors who have a lower likelihood of achieving pCR with neoadjuvant treatment compared with their ER-negative counterparts. The NA-PHER2 trial of an exploratory trastuzumab–pertuzumab–fulvestrant–palbociclib regimen in these patients showed a significant reduction of Ki67 expression, a marker of cell proliferation.Currently, treatment decisions are guided by tumour size, nodal status and ER status. However, lack of prognostic factors to determine recurrence risk or predictive factors to identify patients likely to benefit from a given treatment limit the ability of clinicians to offer de-escalated treatment to patients.I strongly believe that in the future, tumour genomic factors or biological features, such as tumour infiltrating lymphocytes, will help us to understand when to escalate or de-escalate therapy.

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