Christos Sotiriou, MD, PhD

Finding new treatments for patients with high-risk, early-stage estrogen receptor-positive/HER2-negative breast cancer.

Impact

High-risk, early-stage estrogen receptor (ER)-positive/HER2-negative breast cancers (also called luminal B) are often harder to treat because they do not respond as well to chemotherapy or immunotherapy compared to other breast cancer subtypes, and many patients face a risk of recurrence after standard treatment. This is largely because these tumors tend to be “immune-cold,” meaning the immune system does not naturally recognize or attack them strongly. Prior research has shown that combining radiotherapy with immunotherapy can modulate the immune system in complex ways. Understanding these effects in detail is crucial for tailoring treatments to be more effective. To that end, Dr. Sotiriou is conducting the Neo-CheckRay clinical trial (NCT03875573), an innovative phase II study testing whether combining three treatments—chemotherapy, targeted radiation, and immunotherapy—can improve outcomes for this patient population. The overarching goal is to improve understanding of how tumor and immune cells interact under different treatments, to identify potential biomarkers of response, and ultimately to better tailor effective treatment combinations and improve outcomes for patients with early-stage ER-positive/HER2-negative breast cancer.

Progress Thus Far

Neo-CheckRay tests whether adding immunotherapy to standard neoadjuvant chemotherapy plus a type of targeted radiation called stereotactic body radiotherapy (SBRT) can help the immune system fight cancer more effectively compared to chemotherapy and SBRT alone. Dr. Sotiriou and his team found that patients with PD-L1-negative tumors, typically those least likely to benefit from immunotherapy, showed a marked increase in complete tumor disappearance when immunotherapy was added after radiotherapy, supporting the idea that radiotherapy may help the immune system recognize the cancer. Building on this, the team completed a major single-cell analysis of tumor, lymph node, and normal breast tissue samples collected from participants before treatment, at six weeks, and at surgery. This analysis revealed that PD-L1-low and PD-L1-high tumors are not simply different degrees along the same immune spectrum, but distinct immune states. PD-L1-low tumors are dominated by cancer and supportive stromal cells with limited immune activation, while PD-L1-high tumors already contain more T cells, inflammatory signaling molecules, and other immune cells before treatment even begins. Using advanced methods that allow them to look at thousands of individual cells, the team found that tumors differ greatly in how ready they are to respond to immune treatment. Some tumors already showed signs that immune cells had entered the cancer area, while others were mainly made up of cancer and support cells, with fewer active immune cells. These findings help explain how treatments reshape the tumor environment and will guide the team’s next steps to uncover which patients are most likely to benefit from these therapies.

What’s next

In the upcoming year, Dr. Sotiriou and his team will complete integrated analyses of the full Neo-CheckRay single-cell dataset to define baseline and early on-treatment biomarkers of response to immunotherapy. The team will further characterize the tumor environment in patient samples from before and during treatment in patients who did and did not respond, examining how therapies reshape the tumor’s blood vessels, connective tissue, immune cells, and nearby lymph nodes. Ultimately, this work aims to help identify which patients are most likely to benefit from immunotherapy, which patients might safely avoid unnecessary treatment, and to guide future trials using radiotherapy as a practical strategy for stimulating anti-cancer immunity in breast cancer and potentially other immune-cold cancers.