Table 1.

Design elements of preoperative IO/RT clinical trials in breast cancer

Key elements	Pros	Cons
Inclusion of lymph node–positive disease only	Pathologic response in the nodes can serve as surrogate for abscopal effect when lymph nodes undergo pathologic evaluation after NAC	Reduced accrual by limiting eligible patients
Inclusion of TN and high-risk, HR+/HER2− breast cancer	Evaluation of the efficacy of IO/RT combinations across spectrum of breast cancer subtypes Addresses unmet clinical need for therapies that can potentially improve nodal response rates in high-risk HR+/HER2− disease	Inconsistencies in defining triple negative and “high-risk” HR+/HER2− based on clinical definitions and genomic assays
Testing multiple dose levels including a control (no RT)	Allows assessment of the independent contribution of RT in addition to IO	Uncertainty that any dose levels proposed are the “correct” doses to compare More complex than assuming a single, effective RT dose
Conducting trial within a cooperative group setting	Far-reaching impact, development of practices and tools more broadly applicable to multiple practice settings Often expedited accrual and shortened time to trial completion	Enhanced complexity and cost, relative to single-institutional experiences
Inclusion of SBRT and proton radiation therapy	Far-reaching impact, development of practices and tools more broadly applicable to multiple practice settings	Lack of widespread availability of protons across United States, increased complexities in treatment planning with unknown benefits Potential differences in immune system activation between protons and photons

Abbreviations: HR+/HER2− = hormone receptor positive/human estrogen receptor 2 negative; IO = immune oncology; NAC = neoadjuvant chemotherapy; RT = radiation therapy; SBRT = stereotactic body radiation therapy.