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

Rita A Mukhtar ¹, Katrina Dimitroff ², Christina Yau ²

¹UC San Francisco, 1825 4th st, San Francisco, CA, 94158, USA. Rita.Mukhtar@ucsf.edu.
²UC San Francisco, 1825 4th st, San Francisco, CA, 94158, USA.
³Columbia University, New York, USA.
⁴Wake Forest, Winston-Salem, USA.
⁵Yale, New Haven, USA.
⁶University of California, Davis, Davis, USA.
⁷H. Lee Moffitt Cancer Center, Tampa, USA.
⁸University of Alabama Birmingham, Birmingham, USA.
⁹Montefiore Medical Center, Bronx, USA.
¹⁰University of Pennsylvania, Philadelphia, USA.
¹¹Emory, Atlanta, USA.
¹²Loyola University, Chicago, USA.
¹³MD Anderson Cancer Center, Houston, USA.
¹⁴University of Minnesota, Minneapolis, USA.
¹⁵Gemini Group, Ann Arbor, MI, USA.
¹⁶UC San Diego, San Diego, USA.
¹⁷Georgetown University, Washington, USA.
¹⁸Mayo Clinic, Rochester, USA.

⁰UC San Francisco, 1825 4th st, San Francisco, CA, 94158, USA. Rita.Mukhtar@ucsf.edu.

Annals of Surgical Oncology +

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July 24, 2025

View abstract on PubMed

Summary

Invasive lobular carcinoma (ILC) presents surgical challenges, with higher positive margin rates than other breast cancers. However, gene expression assays may help identify ILC patients who benefit from neoadjuvant chemotherapy (NAC).

Area Of Science

Oncology
Surgical Oncology
Genomics

Background

Invasive lobular carcinoma (ILC) exhibits lower response rates to neoadjuvant chemotherapy (NAC) compared to invasive ductal carcinoma.
While often characterized by low-risk biology, a high-risk subset exists within the heterogeneous ILC tumor type.
This study compares surgical outcomes and treatment response based on histology within the I-SPY2 multicenter NAC trial.

Purpose Of The Study

To compare surgical treatment and response rates between invasive lobular carcinoma (ILC) and other breast cancer histologies following neoadjuvant chemotherapy (NAC).
To evaluate the impact of histology on surgical outcomes, including mastectomy rates, margin positivity, and axillary staging.
To assess the efficacy of NAC in converting node-positive to node-negative status in ILC versus non-ILC patients.

Main Methods

Analysis of 1329 patients with stage II-III breast cancer and high-risk 70-gene assay results from the I-SPY2 trial.
Inclusion of patients with classic, pleomorphic, or mixed lobular/ductal histology in the lobular cohort.
Evaluation of mastectomy rates, positive margins, axillary dissection, and clinical node-positive (cN+) to pathologic node-negative (ypN-) conversion post-NAC.

Main Results

124 patients (9.3%) had lobular histology, predominantly hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-).
No significant difference in mastectomy rates was observed between lobular and non-lobular cohorts.
The ILC cohort showed higher rates of positive margins after lumpectomy (21.2% vs. 7.9%) and more frequent axillary dissection in node-negative cases (24.1% vs. 14.0%).
Conversion from cN+ to ypN0 did not differ statistically (40.9% vs. 51.2%), but nodal conversion rates varied by subtype in ILC (30.6% in HR+/HER2-, 72.7% in HER2+, 66.7% in triple-negative).

Conclusions

Surgical management of ILC presents distinct challenges, but molecular classification holds promise for optimizing treatment selection.
Gene expression assays can identify a subset of cN+ ILC patients who may benefit from NAC, despite ILC generally having lower genomic risk.
These findings underscore the need for tailored surgical and systemic treatment strategies for ILC based on its heterogeneity.

Keywords:

Breast cancer Lobular carcinoma Neoadjuvant chemotherapy Nodal response