The stakes of the question are considerable. Multi-agent neoadjuvant therapy, meaning chemotherapy given before surgery, combined with the immune checkpoint inhibitor pembrolizumab, is the established standard for Stage II and III triple-negative breast cancer. That standard rests largely on the landmark KEYNOTE-522 trial, which showed that adding immunotherapy to neoadjuvant chemotherapy improved pathologic complete response rates, event-free survival, and overall survival. But the pivotal trials that cemented this approach either excluded patients with Stage I disease or failed to analyze them separately, leaving clinicians without direct evidence for the smallest tumors. Current National Comprehensive Cancer Network guidelines still recommend upfront surgery followed by adjuvant chemotherapy for node-negative tumors measuring one to two centimeters, reserving neoadjuvant strategies for higher-risk cases.

In practice, however, the lines are blurring. Neoadjuvant therapy offers real advantages: it tests a tumor’s chemosensitivity in the body, can shrink cancers enough to enable breast-conserving surgery, and provides a powerful prognostic signal. Patients who achieve a pathologic complete response, defined as no residual invasive disease at surgery, have excellent outcomes, while those with residual disease can be escalated to treatments such as adjuvant capecitabine, validated in the CREATE-X trial, or olaparib for patients with germline BRCA mutations, validated in the OlympiA trial. These residual-disease-directed strategies have given clinicians a practical reason to give therapy up front even when a tumor is small, since the response itself guides what happens next.

To map the contemporary landscape, the researchers assembled a cohort of 252 patients with T1-2N0M0 triple-negative breast cancer diagnosed between July 2021 and December 2024, then focused on a predefined small TNBC group of 215 patients: 154 with Stage I disease and 61 with node-negative Stage II tumors smaller than three centimeters. The cohort was demographically typical of triple-negative disease, with 82.5 percent grade 3 histology and 89.3 percent ductal histology. Overall, 70.6 percent of patients received neoadjuvant therapy, 98.8 percent underwent surgery, and 42.1 percent received adjuvant radiation. With a median follow-up of 2.6 years, recurrence occurred in 18 patients and death in 11, reflecting the generally favorable prognosis of small, node-negative tumors.

The most striking finding was the asymmetry between biology and treatment. Demographically, the Stage I and small Stage II groups were nearly indistinguishable, with similar ages, menopausal status, comorbidities, and BRCA mutation prevalence. Histopathologically they overlapped as well, although grade 3 histology was more common in the Stage II, under-three-centimeter group. Yet treatment diverged sharply. Neoadjuvant therapy was given to 85.2 percent of small Stage II patients versus 61.0 percent of Stage I patients. The KEYNOTE-522 regimen, combining chemotherapy with pembrolizumab, dominated both groups but was used far more often in Stage II disease, at 75.0 percent versus 45.7 percent. Adjuvant pembrolizumab followed the same pattern, given to 56.8 percent of small Stage II patients compared with 24.7 percent of Stage I patients.

Despite these markedly different treatment intensities, outcomes converged. Recurrence rates were 6.5 percent in the small Stage II group versus 3.3 percent in Stage I, and mortality rates were 1.9 percent versus 6.6 percent, neither difference statistically significant. Among the 146 patients treated with neoadjuvant therapy, the pathologic complete response rate was 51.3 percent overall, and it was essentially identical across the stage boundary: 51.1 percent for Stage I versus 51.9 percent for small Stage II tumors. No individual regimen separated itself from the pack. KEYNOTE-522 achieved a pCR rate of 52.4 percent in the combined small TNBC cohort, statistically indistinguishable from anthracycline-taxane regimens at 50.0 percent, carboplatin-taxane plus pembrolizumab at 45.8 percent, and other neoadjuvant approaches at 55.0 percent.

Survival analyses told a similar story of convergence. Event-free survival did not differ significantly between patients who received neoadjuvant therapy and those who did not within the small TNBC cohort, nor between Stage I and small Stage II patients treated with neoadjuvant therapy. Even within the KEYNOTE-522-treated subgroup, event-free survival did not significantly differ by stage. The authors caution that these survival findings are exploratory, limited by short follow-up, few events, and the selection biases inherent in any retrospective design. Treatment assignment was not randomized, and confounding by indication, in which sicker-appearing patients receive more intensive therapy, cannot be excluded. Subgroups were also small, precluding robust multivariable modeling.

Still, the pattern is clinically meaningful. The authors note that immune checkpoint inhibitors can produce durable endocrinopathies such as adrenal insufficiency or insulin-dependent diabetes, toxicities that weigh heavily in patients whose tumors already carry a favorable prognosis. Intensifying therapy for a two-centimeter node-negative tumor while withholding the same regimen from a 2.1-centimeter tumor, purely because it crosses an arbitrary size threshold, may not reflect underlying biology. The data suggest that node-negative tumors just below and above the two-centimeter T1c-T2a boundary may behave more alike than staging conventions assume, and that a size-based framework for small triple-negative breast cancer could better contextualize treatment decisions than the current stage-based one.

The study team is already moving toward prospective answers. Their center is conducting DETENTE-1, a phase 2 randomized pilot study in Stage I triple-negative breast cancer comparing three neoadjuvant strategies: carboplatin plus paclitaxel, carboplatin plus paclitaxel plus pembrolizumab, and pembrolizumab monotherapy. Such de-escalation trials could identify which small tumors truly need intensified chemoimmunotherapy and which can be spared its costs. The authors envision integrated risk-stratification models incorporating tumor size, genomic data, immune biomarkers, toxicity risk, and cost considerations to individualize neoadjuvant selection. For now, the message for patients and clinicians is nuanced: small node-negative triple-negative breast cancers respond to modern therapy at high rates and with low recurrence, but the evidence base for choosing among regimens remains thin, and the conventional stage boundary may be a poorer guide to biology than anyone assumed.

Subject of Research: Neoadjuvant therapy patterns and outcomes in small node-negative triple-negative breast cancer

Article Title: Contemporary therapy for small node-negative triple-negative breast cancer: a retrospective cohort study

Article References: Lee, B., Santos, B., McArthur, H., LeVee, A., Kordic, A., Zhang, S., & J. Gruber, J. (2026). Contemporary therapy for small node-negative triple-negative breast cancer: a retrospective cohort study. Breast Cancer Research and Treatment, 219(3), Article 15. https://doi.org/10.1007/s10549-026-08074-5

Image Credits: AI Generated

DOI: 10.1007/s10549-026-08074-5

Keywords: triple-negative breast cancer, neoadjuvant therapy, pembrolizumab, KEYNOTE-522, pathologic complete response, Stage I breast cancer, immunotherapy, cancer staging, treatment de-escalation, retrospective cohort study, event-free survival, breast-conserving surgery