Title: Neoadjuvant Chemotherapy for T3 Tumors in the Era of Precision Medicine—Biology Is Still King

Authors: Rakhshanda Layeequr Rahman, Alfredo Santillan, Mehran Habibi, Peter Beitsch, Pat Whitworth, Harshini Ramaswamy, Nicole Chmielewski-Stivers, Andrea Menicucci, William Audeh, and Joyce O’Shaughnessy

Abtract: Clinical T3 (cT3) breast cancer (BC) presents a challenge for achieving cosmetically acceptable breast conservation, and neoadjuvant chemotherapy (NAC) is commonly used for cytoreduction in these high-risk cancers. MammaPrint® risk-of-recurrence and BluePrint® molecular subtyping genomic signatures have demonstrated high accuracy in predicting chemotherapy benefits. Here, we examined the utility of MammaPrint/BluePrint for predicting pathological Complete Response (pCR) rates to NAC among 404 patients diagnosed with cT3 early-stage BC. The association of genomic subtype and clinical features with the likelihood of pCR was evaluated by multivariate logistic regression. Differences in pCR rates between genomic risk categories were evaluated by a two-sided proportional z-test and stratified by nodal status. MammaPrint/BluePrint subtyping was associated with significantly higher odds ratios (ORs) for pCR in MammaPrint High-Risk/BluePrint Basal- Type (OR = 3.06, 95% CI: 1.15–8.19, p = 0.025) and HER2-Type (OR = 6.27, 95% CI: 2.19–19.38, p = 0.001) compared to BluePrint Luminal-Type. Of the 209 patients with hormone receptorpositive, HER2-negative disease, 6.7% achieved pCR, and MammaPrint High-Risk was associated with a significantly higher pCR rate (9.3%) compared to MammaPrint Low-Risk cancers (0%), regardless of nodal involvement (p = 0.036). These data show that for patients with MammaPrint Low-Risk, cT3 tumors are less likely to have clinically impactful cytoreduction from NAC, regardless of nodal involvement.