Ki-67 Proliferation Score Above 45.8% Predicts Chemotherapy Response in Early Triple-Negative Breast Cancer

A large analysis of national registry data has identified a simple, widely available biomarker that may help determine which patients with the smallest category of triple-negative breast cancer should receive chemotherapy before surgery rather than after it. Researchers at Johns Hopkins University School of Medicine, publishing in Breast Cancer Research and Treatment, examined 8,831 women with T1cN0M0 triple-negative breast cancer and found that tumors with a Ki-67 proliferation index of 45.8 percent or higher achieved a pathologic complete response to neoadjuvant chemotherapy at more than twice the rate of tumors falling below that threshold. Because pathologic complete response is one of the strongest early predictors of long-term survival in this disease, the finding offers a potentially practical tool for a clinical decision that has long divided breast cancer specialists.

Triple-negative breast cancer is defined by the absence of the three molecular handles that anchor most modern breast cancer therapy: the estrogen receptor, the progesterone receptor, and HER2. Without those targets, endocrine agents and HER2-directed drugs are ineffective, leaving cytotoxic chemotherapy as the systemic backbone of treatment. Although triple-negative tumors account for only about 10 to 15 percent of breast cancers, they carry a disproportionate share of the disease’s mortality because they tend to grow quickly, are more likely to metastasize, and historically have fewer therapeutic options. For patients whose tumors are caught early, the central treatment question is not whether chemotherapy helps but when it should be given.

That question is most acute for T1c tumors, which measure between one and two centimeters and have not spread to regional lymph nodes or distant sites. The T1cN0M0 designation describes a small, node-negative cancer, yet even at this stage triple-negative biology demands systemic therapy to reduce recurrence risk. The debate concerns sequencing. Neoadjuvant chemotherapy, delivered before surgery, offers the chance to shrink the tumor, potentially enabling less extensive operations, and provides real-time information about how the cancer responds to treatment. Adjuvant chemotherapy, given after surgery, achieves the same cytotoxic goal but leaves the surgeon operating on a tumor that has never been exposed to drugs. National guidelines leave room for either approach in this small-tumor setting, and practice varies considerably across institutions.

The reason sequencing remains contested is that neither strategy has demonstrated superior overall survival. Multiple prior analyses, including studies of the same National Cancer Database, have found that patients with clinically node-negative T1 triple-negative tumors fare equally well whether chemotherapy comes first or last. If survival outcomes are equivalent, the choice between the two approaches hinges on secondary benefits: the possibility of breast-conserving surgery, the prognostic information embedded in treatment response, and patient preference. The Johns Hopkins team, led by breast surgical oncology researcher Andrew Venardi, set out to sharpen that calculus by asking a more granular question: within this seemingly uniform early-stage population, which patients are actually likely to benefit from going first with chemotherapy?

The answer, they hypothesized, might lie in Ki-67, a nuclear protein expressed by cells that are actively dividing. Pathologists measure Ki-67 by immunohistochemistry, staining tumor samples and counting the percentage of positive cells, which yields a proliferation index reflecting how fast the cancer is growing. The logic connecting Ki-67 to neoadjuvant strategy is mechanistically straightforward: chemotherapy agents such as anthracyclines and taxanes preferentially kill rapidly proliferating cells, so tumors with a high fraction of dividing cells should, in principle, be more sensitive to upfront drug treatment. Previous studies have associated high Ki-67 expression with better responses to neoadjuvant chemotherapy in triple-negative disease, but the specific threshold that separates responders from non-responders in the earliest tumor category had not been clearly defined using large-scale national data.

To conduct the analysis, the researchers queried the National Cancer Database for female patients aged 18 and older diagnosed with T1N0M0 triple-negative breast cancer between 2018 and 2022 who underwent both chemotherapy and surgery. The National Cancer Database, jointly maintained by the American College of Surgeons and the American Cancer Society, captures roughly 70 percent of newly diagnosed cancer cases in the United States, providing the statistical power that single-institution series cannot match. Patients were divided into a neoadjuvant chemotherapy cohort and an adjuvant chemotherapy cohort. Because the two groups differ systematically in tumor size, grade, and other characteristics—surgeons and oncologists tend to select patients for upfront chemotherapy based on perceived risk—the team applied inverse probability of treatment weighting, a statistical technique that re-weights the cohorts to mimic the balance of a randomized trial.

The survival analysis produced a finding consistent with the existing literature: overall survival did not differ significantly between the neoadjuvant and adjuvant groups. Multivariate Cox regression, which adjusts for competing variables simultaneously, instead identified three factors associated with worse survival. Lymphovascular invasion, the presence of tumor cells within small blood or lymphatic vessels, signaled a higher risk of microscopic spread. The invasive lobular subtype, which arises in the milk-producing lobules rather than the ducts, and mixed lobular-ductal tumors were also linked to poorer outcomes. Lobular triple-negative cancers are rare and biologically distinct, and recent registry-based studies have shown they can carry worse survival despite appearing indolent, so their emergence as an adverse marker in this dataset aligns with a growing body of evidence.

The most consequential result came from the response analysis. Among patients who received neoadjuvant chemotherapy, those who achieved a pathologic complete response—meaning no residual invasive cancer was found in the breast or lymph nodes at the time of surgery—had markedly better survival than those who did not. Non-responders faced a hazard ratio of 3.59 for worse overall survival compared with patients who achieved a complete response. This echoes the findings of a large meta-analysis showing that pathologic complete response in triple-negative breast cancer is strongly associated with improved long-term event-free and overall survival. In other words, while the timing of chemotherapy may not change survival on average, achieving eradication of the tumor before surgery identifies a subgroup whose prognosis is transformed.

That is where the Ki-67 threshold enters. Using a receiver operating characteristic curve, the researchers plotted the relationship between Ki-67 expression and pathologic complete response and applied the maximum Youden index, a standard method for finding the cutoff point that best balances sensitivity and specificity. The threshold that emerged was 45.8 percent. Patients whose tumors expressed Ki-67 at or above that level achieved a pathologic complete response rate of 45.3 percent, while those below it responded at a rate of only 21.8 percent. Expressed differently, a high proliferation index more than doubled the odds that upfront chemotherapy would completely eliminate the tumor. Logistic regression confirmed Ki-67 expression as an independent predictor of complete response, suggesting the association held after accounting for other tumor characteristics.

The clinical implications are tangible for a patient population that often faces an anxious choice. A woman with a 1.5-centimeter, node-negative triple-negative tumor whose biopsy shows a Ki-67 index of 50 percent now has registry-scale evidence that chemotherapy before surgery is likely to produce a complete response, with the dual benefits of maximal prognostic information and a survival outcome that appears markedly better than that of non-responders. Conversely, a patient with a low proliferation index may reasonably opt for surgery first, since her probability of achieving a complete response is lower and adjuvant chemotherapy delivers equivalent survival. The authors emphasize that the study is retrospective and that Ki-67 measurement itself has well-known variability between laboratories and staining protocols, so the 45.8 percent cutoff should be validated prospectively before it reshapes guidelines. Still, as the field moves from one-size-fits-all recommendations toward personalized sequencing in stage I triple-negative breast cancer, a routine pathology marker already on every diagnostic report may prove to be the deciding variable.

Subject of Research: Ki-67 expression as a predictor of pathologic complete response to neoadjuvant chemotherapy in early-stage triple-negative breast cancer

Article Title: Ki-67 expression and rates of pathologic complete response in T1cN0M0 triple-negative breast cancer: a national cancer database analysis

Article References: Venardi, A., Shojaeian, F., Diaz, S., Schuster, C. R., Rath, P., Shaid, I., Singh, A., Santa-Maria, C., & Sogunro, O. (2026). Ki-67 expression and rates of pathologic complete response in T1cN0M0 triple-negative breast cancer: a national cancer database analysis. Breast Cancer Research and Treatment, 219(3), Article 21. https://doi.org/10.1007/s10549-026-08086-1

Image Credits: AI Generated

DOI: 10.1007/s10549-026-08086-1

Keywords: triple-negative breast cancer, Ki-67, neoadjuvant chemotherapy, pathologic complete response, National Cancer Database, T1cN0M0, proliferation index, biomarker, breast surgical oncology, lymphovascular invasion, invasive lobular carcinoma, personalized treatment