Early triple-negative breast cancer

Early triple-negative disease is basal-like in most cases, almost always TP53-mutant, carries a germline BRCA1 or BRCA2 mutation in roughly one in five patients and is the breast cancer with the most immune infiltration. Because there is no receptor to block, chemotherapy has carried the curative burden, and it is given before surgery whenever the tumour is over 2 cm or the nodes are involved, both to shrink it and because the response at surgery, measured as pathological complete response or residual cancer burden, is the strongest predictor of relapse. Platinum added to a taxane and anthracycline raised complete response rates in GeparSixto, CALGB 40603 and BrighTNess, and tumours under 1 cm without node involvement often need no chemotherapy at all, with high tumour-infiltrating lymphocytes marking a group whose outcome is excellent regardless.

KEYNOTE-522 rewrote the standard. It randomised 1,174 patients with stage II or III disease to pembrolizumab or placebo with carboplatin and paclitaxel then an anthracycline and cyclophosphamide before surgery, followed by pembrolizumab or placebo for nine cycles after. Pathological complete response rose from 51.2 to 64.8 percent, event-free survival improved (hazard ratio 0.63) and, unusually for a neoadjuvant trial, overall survival did too, with the seven-year update showing 85.1 against 77.2 percent alive; the FDA approved the regimen in July 2021 and it is given whatever the PD-L1 score. IMpassion031 showed atezolizumab raises complete response in the same setting (58 against 41 percent) but never became a standard.

What follows surgery depends on what the pathologist finds. Women with a complete response finish their year of pembrolizumab and whether they need it at all is being tested in OptimICE-pCR. Women with residual disease and a germline BRCA mutation take olaparib for a year: OlympiA randomised 1,836 such patients with HER2-negative disease, about four in five triple-negative, and improved invasive disease-free survival (hazard ratio 0.58) and overall survival (hazard ratio 0.72). Others are offered six to eight cycles of capecitabine on the strength of CREATE-X, a Japanese trial of 910 women with residual HER2-negative disease in which five-year disease-free survival rose from 67.6 to 74.1 percent with the largest survival gain in the triple-negative group. None of these post-surgery trials included pembrolizumab, so how the pieces combine is unknown, and ASCENT-05 is testing sacituzumab govitecan with pembrolizumab in residual disease while SCARLET asks whether the anthracycline can be dropped and circulating tumour DNA is being studied to find the women who still harbour disease.