The KEYNOTE-522 trial is a significant study that investigated the use of pembrolizumab, an immune checkpoint inhibitor targeting the PD-1/PD-L1 pathway, in combination with chemotherapy for patients with high-risk, early-stage triple-negative breast cancer (TNBC). The results of this trial have been influential in demonstrating the benefits of adding immunotherapy to standard neoadjuvant chemotherapy in the treatment of TN breast cancer. The KEYNOTE-522 trial is a well-designed, randomized controlled trial, the gold standard for clinical research, making its findings highly reliable.

Pembrolizumab works by inhibiting the PD-1/PD-L1 pathway, which tumors exploit to evade the immune system. By blocking this pathway, pembrolizumab helps the immune system recognize and attack cancer cells more effectively.

Neoadjuvant therapy refers to treatment given before the main treatment (usually surgery) to shrink tumors and potentially allow for less extensive surgery. To measure the impact, the pathological complete response (pCR) measures the absence of residual invasive cancer in the breast and lymph nodes after neoadjuvant treatment, and it strongly predicts long-term outcomes such as survival.

The KEYNOTE-522 trial revealed that adding pembrolizumab to neoadjuvant chemotherapy significantly improved the pCR rates compared to chemotherapy alone. This is a strong indicator of the treatment’s effectiveness. High pCR rates are linked to better long-term outcomes, indicating that more patients had no evidence of invasive cancer in their surgical specimens after receiving the combined treatment. Additionally, the trial showed an improvement in event-free survival (EFS) when pembrolizumab was given both before surgery (neoadjuvant phase) and continued after surgery (adjuvant phase), compared to chemotherapy alone.

The Residual Cancer Burden (RCB) index is another tool to assess the response to neoadjuvant chemotherapy. It quantifies the amount of residual disease in the breast and lymph nodes after treatment, taking into account factors such as the size of the residual tumor, the number of cancer cells present, and the degree of lymph node involvement. A lower RCB index indicates a better response to treatment and is associated with a more favorable prognosis.

The findings from KEYNOTE-522 suggest that pembrolizumab has a meaningful impact on both pCR rates and EFS in patients with high-risk, early-stage TNBC. This has implications for clinical practice, as it provides evidence supporting the use of pembrolizumab in combination with chemotherapy as a new standard of care for this aggressive subtype of breast cancer. The RCB index continues to be valuable in providing a more nuanced understanding of the extent of residual disease and can help inform prognosis and potentially guide further treatment decisions after neoadjuvant therapy.

While pembrolizumab improves pCR and EFS, it is essential to consider the potential for increased toxicity and side effects associated with immunotherapy, which can impact patients’ quality of life. Additionally, adding pembrolizumab to chemotherapy may significantly increase treatment costs, potentially limiting accessibility for some patients due to financial constraints or lack of insurance coverage. While the trial shows promising short-term results, long-term follow-up is necessary to confirm the sustained benefits and identify any late-onset side effects or complications. The trial’s findings may not apply uniformly to all high-risk, early-stage TNBC population subgroups. Further research is needed to identify which subgroups benefit the most from adding pembrolizumab. Future studies could refine criteria for selecting patients who are most likely to benefit from pembrolizumab, potentially using biomarkers to predict the response, and comparative studies with other immunotherapies or combination regimens could further elucidate the optimal treatment strategies for TNBC. The quality of life of patients undergoing this combined treatment is essential to balance efficacy with the patient experience.

Nonetheless, the KEYNOTE-522 trial represents a significant advancement in the treatment of high-risk, early-stage TNBC, highlighting the potential of pembrolizumab to improve outcomes in this challenging patient population.

Pic by freepik, Source: https://www.annalsofoncology.org/article/S0923-7534(24)00046-2/fulltext?rss=yes