A brief upfront course of radiation might make immune checkpoint inhibitors more effective for some patients with HR-positive, HER2-negative breast cancer that has spread to regional lymph nodes. 

The finding comes from the phase 2 P-RAD trial, which found that a 3-day course of 24 Gy radiation, along with one concomitant dose of pembrolizumab, significantly increased T-cell infiltration of breast tumors ahead of neoadjuvant therapy. The approach also correlated with higher lymph node clearance at surgery vs no upfront radiation.

“Our study suggests that radiation could be used in a new way to prime the immune system and enhance the effects of immunotherapy,” said Gaorav Gupta, MD, PhD, a breast cancer radiologist at the University of North Carolina, Chapel Hill, who presented the study at the recent San Antonio Breast Cancer Symposium. 

“If we want to increase the number of patients who are responding to immunochemotherapy, we should do future trials that look at this,” Gupta told Medscape Medical News. 

Based on prior studies, patients with higher-risk HR-positive, HER2-negative breast cancer may benefit from having an immune checkpoint inhibitor (ICI) added to neoadjuvant chemotherapy — but only if their tumors already have high T-cell infiltration or high PD-L1 expression.

Radiation is known to turn some immunologically “cold” tumors into “hot” tumors that the immune system recognizes. In the P-RAD trial, Gupta and colleagues wanted to discover whether “boost radiotherapy,” given upfront along with an ICI, can prime the immune system and potentially enhance the effects of immunotherapy.

Carlos Arteaga, MD, of UT Southwestern Medical Center in Dallas, called the results “very interesting,” but stressed that additional randomized studies are needed to show whether boost radiation ultimately makes a difference in patient outcomes.

“It’s early days, and this is going to take some further work,” said Arteaga, who moderated a press briefing on the findings. 

The trial included 51 patients (median age, 49.5 years) at 10 cancer centers who were randomly assigned equally to either no radiation, a 9 Gy dose, or a 24 Gy dose delivered over 3 days with one pembrolizumab infusion. 

The women were at high risk for recurrence and all had positive lymph nodes, but only the primary tumors were radiated in the study; the lymph nodes were shielded. 

Breast tumors were biopsied at 2 weeks to assess T-cell infiltration, the study’s primary endpoint. The patients then went on to receive 12 weeks of paclitaxel plus pembrolizumab, followed by four cycles of adriamycin-cyclophosphamide plus pembrolizumab, with surgery at completion.

Among 49 evaluable patients, T-cell infiltration increased in tandem with radiation dose: 53% of women in the 24 Gy group hit the highest quartile of T-cell infiltration, versus 40% in the 9 Gy group, and 31% in the no-radiation arm. Because of the small sample size, only the difference between the 24 Gy and no-radiation groups was statistically significant (P = .027).

Overall, patients with high T-cell infiltration also had higher levels of PD-L1 expression.

The researchers looked at surgery outcomes as well, although the trial was not powered to detect clinically meaningful differences in those endpoints. There were “favorable trends,” Gupta said, with lymph node clearance at surgery being 33% in the 24 Gy arm, versus 29% in the 9 Gy arm and 24% in the no-radiation arm.

As for why lymph nodes showed increased clearance even though they weren’t directly radiated, Gupta noted that radiation activates antigen-presenting cells in tumors, which can then travel to the lymph nodes and stimulate T-cells and B-cells to attack the cancer there.

The boost radiation approach also induced favorable immunologic changes, including formation of tertiary lymphoid structures near the tumor that contained T cells, B cells, and dendritic cells. Those structures, Gupta said, have been associated with better immunotherapy responses in other cancer types. 

Finally, in an exploratory analysis, the researchers found that only patients with non-luminal A tumors had a good response to boost radiation. Of 15 such patients, 7 had lymph node clearance at surgery, compared with 1 of 16 patients with luminal A tumors who received boost radiation.

Moving forward, Gupta said he wants to conduct another phase 2 study focused on patients with non-luminal A tumors.

It’s not clear why those patients showed a better response in P-RAD. But Gupta noted there are some biological differences between luminal A and non-luminal A tumors in terms of immune recognition and immune suppression.

Importantly, Gupta said, upfront radiation did not seem to add to treatment toxicity, with no signs that it increased surgical wound complications or patient-reported side effects.

The work was funded by Merck (the manufacturer of pembrolizumab), Breast Cancer Research Foundation, Translational Breast Cancer Research Consortium, the Susan G. Komen Foundation, the US Department of Defense, and Natera. Gupta disclosed research funding from Merck. Arteaga disclosed research funding from Pfizer and Lilly.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com