Title: Neoadjuvant Chemotherapy for T3 tumors in the Era of Precision Medicine- Biology is Still King

Authors: Rakhshanda Rahman, Christin Collins*, Laura Lee, Alfredo Santillan, Mehran Habibi, Peter Blumencranz, Charlie Cox, James Pellicane, Peter Beitsch, Pat Whitworth, Harshini Ramaswamy, Nicole Stivers, Andrea Menicucci, William Audeh, Joyce O’Shaughnessy

*Presenting Author

Background: Clinical T3 (cT3) breast cancer is a vexing problem due to the challenge of cosmetically acceptable breast conservation leading NCCN and ASCO to recommend neoadjuvant chemotherapy (NCT). However, MammaPrint® risk of recurrence and BluePrint® molecular subtyping genomic signatures have demonstrated high accuracy in predicting chemotherapy response. Thus, genomic profiling can potentially enable Choosing Wisely® informed treatment choices and reduced toxicity for patients unlikely to benefit from NCT, despite larger size at presentation. In this study, we examined the utility of MammaPrint and BluePrint for identifying cT3 tumors that respond to NCT.

Methods: A pooled analysis from NBRST (NCT01479101), FLEX (NCT03053193) and MINT (NCT01501487) trials was conducted on all cT3 patients who received NCT, had MammaPrint and BluePrint results, and post-surgical pathological Complete Response (pCR) data. MammaPrint risk was characterized as Low or High Risk. BluePrint subtype classified tumors as Luminal-Type, HER2-Type, or Basal-Type. Luminal-Type tumors were further classified as Luminal A (Low Risk) or Luminal B (High Risk). tumor pCR rates were analyzed as an outcome measure. The association of genomic subtype and clinical features with likelihood of pCR was evaluated by multivariate logistic regression. Differences in pCR rates between genomic risk categories were evaluated by two-sided proportional z-test and stratified by nodal status.

Results: A total of 404 patients (MINT, n=67; NBRST, n=214; FLEX, n=123) with cT3 breast cancer underwent NCT followed by resection and 87 (21.5%) achieved pCR. The mean (SD) age was 52 (±12) years; 186 (51.7%) were premenopausal; 287 (71%) were node positive. Logistic regression revealed that MammaPrint/BluePrint subtyping showed significantly higher odds ratios for pCR in High Risk 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 the reference category (Luminal-Type), indicating strong positive associations. Only clinical subtype hormone receptor-positive (HR+), human epidermal growth factor-positive (HER2+) exhibited a higher likelihood of pCR (OR = 2.91, 95% CI: 0.97-8.23, p=0.048). Menopausal status, nodal status, and grade were not significantly associated with likelihood of pCR. Of the 209 (51.7%) patients with HR+, HER2- disease, 6.7% (14) achieved pCR. Among patients with HR+HER2-, cT3 MammaPrint/BluePrint Low Risk, Luminal A tumors (n=58), no (0%) pCR was achieved regardless of nodal involvement (n=37 node positive Low Risk). In contrast, MammaPrint High Risk (n=151) had significantly higher rates of pCR compared to Low Risk (p=0.036). By molecular subtype, pCR was achieved for 7 (5.8%) of the 120 Luminal B, and 7 (23.3%) of the 30 Basal Type, cT3 tumors.

Conclusion: These data suggest that patients with MammaPrint Low Risk, cT3 tumors are unlikely to respond to NCT. These data are in alignment with long-term follow-up, level 1A evidence from MINDACT showing that patients with MammaPrint Low Risk HR+HER2- tumors may safely omit chemotherapy, regardless of nodal involvement. Intuitively, testing newer agents or neoadjuvant endocrine therapy for downstaging or proceeding to definitive surgery should be considered for genomically low-risk, cT3 cancers.