Early HER2-positive breast cancer

A year of trastuzumab is the foundation. HERA, NSABP B-31 and NCCTG N9831, reported together in 2005, showed that adding trastuzumab to adjuvant chemotherapy cut deaths by about a third, with ten-year overall survival of 84 percent against 75.2 percent in the joint American analysis. PERSEPHONE found six months almost as good as twelve (four-year disease-free survival 89.4 against 89.8 percent) with half the cardiac toxicity, but twelve months remains the standard. For tumours of 3 cm or less without node involvement, the single-arm APT study of twelve weeks of paclitaxel with a year of trastuzumab gave 93 percent seven-year disease-free survival and became the standard for stage I disease without a randomised trial.

For stage II and III disease treatment moved before surgery, where pathological complete response predicts cure and guides what follows. NeoSphere showed that pertuzumab added to trastuzumab and docetaxel raises the complete response rate, and TRAIN-2 (438 patients) showed that carboplatin and paclitaxel with both antibodies matched an anthracycline regimen (complete response 67 against 68 percent) with less cardiac damage, so anthracycline-free regimens became usual. KRISTINE (444 patients) tested replacing chemotherapy with trastuzumab emtansine plus pertuzumab and found fewer complete responses (44.4 against 55.7 percent) and more progression before surgery, a warning against de-escalating on antibody-drug conjugates alone. KATHERINE (1,486 women with residual invasive disease) showed that fourteen cycles of trastuzumab emtansine instead of trastuzumab halved recurrence (three-year invasive disease-free survival 88.3 against 77.0 percent) and improved seven-year overall survival (89.1 against 84.4 percent), and APHINITY (4,805 women) showed adjuvant pertuzumab adds a few points of invasive disease-free survival in node-positive disease and nothing in node-negative disease.

Trastuzumab deruxtecan is now reshaping both ends. DESTINY-Breast05 (1,635 women with residual disease) showed it beats trastuzumab emtansine, with three-year invasive disease-free survival of 92.4 against 83.7 percent (hazard ratio 0.47), and DESTINY-Breast11 (927 women) showed trastuzumab deruxtecan followed by taxane, trastuzumab and pertuzumab before surgery gives more complete responses than dose-dense anthracycline chemotherapy (67.3 against 56.3 percent); the FDA approved both indications in 2026. In the other direction, PHERGain used an early PET scan to identify women who could be cured with antibodies and no chemotherapy at all, with 95.4 percent three-year invasive disease-free survival in the adapted arm and about a third spared chemotherapy. Who can safely skip chemotherapy, whether interstitial lung disease is acceptable in a curative setting, and how hormone receptor-positive HER2-positive tumours should be treated differently are the open questions.