Contemporary Therapy for Small Node-Negative Triple-Negative Breast Cancer: A Retrospective Cohort Study

Breast cancer remains the most common cancer diagnosis among women in the United States, and among its many forms, triple-negative breast cancer is often the most aggressive. This specific type of tumor lacks the three receptors that drive the growth of most other breast cancers, meaning it cannot be treated with the hormonal therapies that work for many patients. Instead, doctors rely on surgery and chemotherapy to remove or shrink the disease. For larger tumors or those that have spread to nearby lymph nodes, the standard approach has shifted in recent years. Rather than removing the tumor first, doctors now often administer chemotherapy and immunotherapy drugs before surgery. This pre-surgery treatment, known as neoadjuvant therapy, allows physicians to see how well the tumor responds to the drugs while it is still inside the body. If the drugs successfully eliminate all visible cancer cells before the operation, a result called a pathologic complete response, patients tend to have better long-term outcomes. However, for smaller tumors that have not spread to lymph nodes, the best path forward is less clear. These early-stage cancers generally have a good prognosis, raising the question of whether the intense, multi-drug regimens used for larger tumors are necessary or if they might expose patients to unnecessary side effects.

A team of researchers from The University of Texas Southwestern Medical Center and City of Hope National Medical Center set out to examine this question by looking at real-world data from patients treated between 2021 and 2024. They focused on a group they called "small triple-negative breast cancer," defined as tumors smaller than three centimeters that had not spread to lymph nodes. This group included patients with Stage I disease, where tumors are very small, and patients with early Stage II disease, where tumors are slightly larger but still under the three-centimeter mark. The researchers reviewed the medical records of 215 patients to see how they were treated and what happened to them afterward. They wanted to know if the standard practice of using aggressive pre-surgery therapy for the slightly larger tumors within this group was actually needed, or if the smaller tumors could be managed differently without compromising survival.

The study revealed a striking contrast between how these two groups of patients were treated and how similar their outcomes were. Although the tumors were biologically very similar, with most being high-grade and fast-growing, the treatment patterns diverged significantly based on the tumor size. Patients with the slightly larger tumors, those between two and three centimeters, were much more likely to receive the intensive pre-surgery therapy that includes immunotherapy. In fact, about 85 percent of these patients received this approach, compared to only 61 percent of the patients with the smallest tumors. Furthermore, the larger tumors were more frequently treated with a specific, widely used drug combination known as KEYNOTE-522, which pairs chemotherapy with an immunotherapy agent. Patients with the smallest tumors were more often treated with surgery first, followed by chemotherapy or other drugs afterward.

Despite these differences in strategy, the results for the patients were remarkably alike. The researchers found that the rate at which tumors completely disappeared before surgery was nearly identical for both groups, hovering around 51 percent. This means that the slightly larger tumors did not respond significantly better to the pre-surgery drugs than the smallest tumors did. More importantly, when the researchers looked at who survived without the cancer returning, they found no significant difference between the groups. Whether a patient received the intensive pre-surgery treatment or a different approach, the rates of recurrence and death were low and statistically similar. The data suggests that the extra intensity of the pre-surgery regimen for the slightly larger tumors did not translate into a measurable survival advantage over the other approaches used for the smallest tumors in this specific population.

These findings challenge the idea that tumor size alone should dictate the intensity of treatment for small, node-negative triple-negative breast cancer. The study indicates that the boundary between Stage I and early Stage II disease, which often triggers a shift to more aggressive therapy, may not reflect a true difference in how the cancer behaves or how it responds to treatment. While the current guidelines recommend upfront surgery for the smallest tumors and pre-surgery therapy for slightly larger ones, this real-world analysis shows that patients in both categories fared similarly. The researchers note that their study was retrospective, meaning it looked back at past data, and they did not have long-term follow-up for all patients. Therefore, they cannot definitively say that one approach is better than the other. However, the data strongly suggests that the current treatment framework might be over-treating some patients with small tumors who could potentially do just as well with a less intensive strategy.

The authors conclude that the medical community needs to rethink how it selects patients for these intensive therapies. They propose that future research should focus on developing better ways to predict which specific small tumors will benefit from pre-surgery immunotherapy and which will not. Rather than relying solely on the size of the tumor, doctors may need to consider a combination of factors, including the tumor's genetic makeup and the patient's overall health, to avoid unnecessary toxicity and cost. The study highlights that while immunotherapy has revolutionized the treatment of larger triple-negative breast cancers, its role in the smallest, early-stage cases remains an open question that requires more careful, prospective investigation to ensure patients receive the right level of care.