Part XII · HER2-positive disease · Chapter 68

Deciding whether to treat before surgery

One question decides the order of treatment and surgery in this subtype, and it is asked before any drug is given.

1 · Stage and risk-adapted treatment selection

Early disease · HER2+ · adjuvant

Matching adjuvant HER2 treatment to baseline risk

What decides whether a HER2-positive tumour goes to treatment first or to surgery first?

Rationale: Every other question in this part assumes the setting has already been chosen. The choice itself is the first decision a clinic takes, and it determines what can be learned and what can be offered afterwards. Treating first makes the response measurable and opens post-neoadjuvant escalation. Operating first closes both and allows a lighter regimen.
Experiment: No trial randomises the order. What exists instead are two separate bodies of evidence built in populations defined by the choice. Single-group and randomised de-escalation studies in small node-negative tumours taken to surgery first, and randomised escalation on residual disease in tumours treated first.
Finding: Both strategies work in the populations they were tested in. A small node-negative tumour does well on a markedly reduced adjuvant regimen. A tumour with residual disease after preoperative treatment does better when treatment is escalated on that finding.
Limitation: The comparison a clinic wants has never been randomised, and the two bodies of evidence enrolled different disease. Reading them together makes the choice look settled at the extremes and leaves it unevidenced in the middle, which is where most patients are. The eligibility criteria, not the results, are what separate the two literatures.
Next question: If preoperative treatment is what makes escalation possible, is a tumour small enough for de-escalation also small enough that nothing would have been found to escalate on?

APT ATEMPT KATHERINE CompassHER2 RD TRAIN-2

Selection in this subtype turns on one question asked before any drug is given. Would knowing whether the tumour was eradicated change what happens next?

If the answer is yes, treat first and operate second. The post-neoadjuvant evidence in Post-neoadjuvant intensification for residual disease converts residual disease into a different regimen, and that option exists only if response was observed. If the answer is no, because the tumour is small and node-negative and the plan would be the same either way, then the neoadjuvant phase buys information nobody will act on.

That produces three bands in practice.

Small node-negative tumours, broadly stage I disease with clinically negative nodes, are treated with surgery first and a de-escalated adjuvant regimen De-escalated adjuvant therapy for small node-negative tumours.

Tumours of stage II or III, and any clinically node-positive disease, are treated with neoadjuvant systemic therapy. The backbone is in Chemotherapy backbones with trastuzumab and the response-adapted consequences in Dual blockade and what the pathological complete response gains bought.

Between those bands sits genuine uncertainty, and the commonest error is to resolve it with imaging alone. Clinical nodal staging is imperfect, so a tumour called node-negative before surgery may not be. Where that uncertainty is material, treating first preserves the option that surgery-first destroys. The general form of this reasoning is in Principles of multidisciplinary treatment and the staging limitations in Diagnostic evaluation and staging.

The decision is only worth making if the answer will be acted on. A neoadjuvant plan that routes residual disease to a conjugate commits the clinic to giving that conjugate, and a patient who would decline it gains nothing from being treated first. The same applies at the other end. A complete response opens the de-escalation questions in Response-adapted strategies and imaging-guided escalation, and those are decisions a service either offers or does not.

Two things this chapter does not carry. It does not choose the regimen, because that choice is made against trial evidence rather than against a rule, and it belongs next door. Nor does it apply to hormone receptor-positive HER2-positive disease without adjustment, because response is less frequent there and the band boundaries move with it Lower pathological complete response rates and what that does to the post-neoadjuvant decision.

Neoadjuvant regimens are in Neoadjuvant therapy, adjuvant and post-neoadjuvant regimens in Adjuvant and post-neoadjuvant therapy, and the triple-positive algorithm in Early triple-positive disease. What stays here is the question that decides which of those chapters a patient enters.