Impact of Neoadjuvant Chemotherapy on Surgical Outcomes and Conversion to Node-Negativity in Invasive Lobular Breast Cancer: Analysis of Molecularly High-Risk Tumors by Histologic Subtype on the I-SPY2 Clinical Trial

Background: Invasive lobular carcinoma (ILC) has lower response rates to neoadjuvant chemotherapy (NAC) than invasive ductal carcinoma. While ILC often has low-risk biology, there is a high-risk subset within this heterogeneous tumor type. We compared surgical treatment and response rates by histology in I-SPY2, a multicenter NAC trial. Methods: We evaluated 1329 patients with stage II–III breast cancer and high-risk 70-gene assay. Patients with classic, pleomorphic, or mixed lobular/ductal histology were included in the lobular cohort. We evaluated rates of mastectomy, positive margins, axillary dissection, and conversion from clinical node-positive (cN+) to pathologic node-negative (ypN−) status after NAC. Results: Overall, 124 patients (9.3%) had lobular histology, with 69% being hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−). There was no difference in mastectomy rate (57.2% for lobular vs. 55.8% for non-lobular). The ILC cohort had more positive margins after lumpectomy than the non-ILC cohort (21.2% vs. 7.9%; p = 0.023). Within cN0 cases, axillary dissection was significantly more common among the lobular cases (24.1% vs. 14.0%; p = 0.039). Conversion from cN+ to ypN0 did not differ statistically between lobular and non-lobular cases (40.9% vs. 51.2%; p = 0.11). The nodal conversion rate among cN+lobular tumors was 30.6% in HR+/HER2−, 72.7% in HER2+, and 66.7% in triple-negative cases. Conclusions: These data demonstrate the challenges of surgical management for ILC but hold promise that molecular classification can improve treatment selection. While high genomic risk is generally less common among ILC, our findings suggest that gene expression assays in cN+ILC patients can identify a subset who may benefit from NAC.