Ki-67 Expression and Rates of Pathologic Complete Response in T1cN0M0 Triple-Negative Breast Cancer: A National Cancer Database Analysis

Breast cancer is not a single disease but a collection of different conditions, each behaving in its own way. One particularly aggressive form is known as triple-negative breast cancer. It earns this name because the cancer cells lack three specific receptors that doctors usually look for: estrogen, progesterone, and a protein called HER2. Without these receptors, the cancer cannot be treated with hormone therapies or targeted drugs that work for other types, leaving chemotherapy as the primary weapon. For patients with small, early-stage tumors that have not spread to the lymph nodes, doctors face a difficult choice about when to give this chemotherapy. They can administer it after surgery to clean up any remaining cells, or they can give it before surgery to shrink the tumor first. This second approach, called neoadjuvant chemotherapy, offers a unique advantage: if the treatment works perfectly, the surgeon may find no trace of cancer left in the tissue removed during the operation. This total disappearance of the tumor is a powerful sign that the patient is likely to do well in the long run. However, not every patient responds to the drugs in the same way, and finding a reliable way to predict who will benefit from receiving chemotherapy before surgery has remained a challenge.

A team of researchers at Johns Hopkins University and other institutions turned to a massive national database to solve this puzzle. They focused specifically on women with the smallest type of triple-negative breast cancer, known as T1cN0M0, which describes a tumor just under two centimeters that has not spread to nearby lymph nodes or distant parts of the body. The researchers examined records from nearly nine thousand women treated between 2018 and 2022. Their goal was to see if giving chemotherapy before surgery offered a survival advantage over giving it after, and more importantly, to find a biological clue that could tell doctors which patients were most likely to achieve that perfect, total response to the treatment. They looked closely at a protein called Ki-67, which acts as a marker for how fast a cell is dividing. In general, a higher level of this protein means the cancer cells are growing and multiplying rapidly, which often makes them more vulnerable to chemotherapy drugs that target fast-growing cells.

When the researchers compared the survival rates of women who received chemotherapy before surgery against those who received it after, they found no significant difference in how long the patients lived. This suggests that for this specific group of patients with small tumors, the timing of the chemotherapy does not change the ultimate outcome of survival. However, the story changed when they looked at who actually achieved a complete disappearance of the tumor. Among the women who received chemotherapy before surgery, those whose tumors vanished completely had significantly better survival rates than those whose tumors did not disappear. This confirmed that while the timing of the treatment might not matter for everyone, achieving a complete response is a critical milestone for those who receive the pre-surgery approach. The real breakthrough came when the team analyzed the Ki-67 levels. They discovered a clear tipping point in the data. Women whose tumors had a Ki-67 level of 45.8 percent or higher were much more likely to see their tumors disappear completely after chemotherapy. Specifically, about 45 percent of patients with high levels of this protein achieved a complete response, compared to only about 22 percent of those with lower levels.

The study also identified other factors that influenced survival. Patients whose cancer had invaded nearby blood or lymph vessels, or whose tumors had a specific cell structure known as lobular, tended to have worse survival outcomes. These findings help paint a clearer picture of the disease, showing that while the overall survival between the two treatment timings is similar, the biological makeup of the tumor dictates who will respond best to the pre-surgery strategy. The researchers noted that their data came from a large hospital registry, which is a strength, but also had limitations. For instance, the records did not always include details on whether patients received modern immunotherapy drugs, which are now becoming standard for some cases, and the data on the protein levels was not always complete. Despite these gaps, the analysis of nearly nine thousand patients provides a strong, real-world view of how this specific cancer behaves.

The ultimate value of this work lies in its potential to guide future decisions. By identifying that a Ki-67 level of 45.8 percent or higher predicts a much higher chance of a complete response, doctors may be able to select the right patients for chemotherapy before surgery with greater confidence. Instead of guessing, they can look at this specific biological marker to see if a patient is likely to benefit from shrinking the tumor before the operation. This does not mean that chemotherapy before surgery is the only option for everyone, but it offers a concrete tool to help personalize treatment. For patients with lower levels of the protein, the standard approach of surgery followed by chemotherapy might remain the best path, while those with high levels could be steered toward the pre-surgery route to maximize their chances of a complete cure. The study concludes that while the timing of treatment does not change survival for the group as a whole, matching the treatment strategy to the tumor's biology through this specific protein marker could help more patients achieve the best possible outcome.