Genomic Impact of Neoadjuvant Therapy on Breast Cancer: Incomplete Response is Associated with Altered Diagnostic Gene Signatures

Purpose: Neoadjuvant therapy (NAT) has been shown to clinically downstage locally advanced breast cancers. This study aimed to determine whether a meaningful change in gene signatures occurs between pre- and post-NAT breast cancers for patients who do not achieve a pathologic complete response.

Methods: The current analysis included women from the prospective Neoadjuvant Breast Registry Symphony Trial who had breast cancer and awaited NAT. MammaPrint and BluePrint (Agendia, Inc., Irvine, CA) assays were performed on pre- and post-NAT breast tumor samples.

Results: At the completion of NAT, 93 patients with residual disease had their remaining tumor analyzed for MammaPrint and BluePrint. Of 93 patients, 21 switched tumor classification: 16 from high risk (HR) to low risk (LR) and 1 from LR to HR (p < 0.001). Four additional patients switched molecular subtype but remained HR. Although only 17 patients switched in their MammaPrint risk classification, the underlying MPIndex was significantly altered after treatment across all patients (p < 0.001). Additionally, the three BluePrint indices for luminal, human epidermal growth factor receptor 2 (HER2), and basal type also were significantly altered after treatment, in a subtype-dependent manner.

Conclusion: This substudy showed that NAT significantly altered the genomic signature of the patient's breast cancer compared with the patient's pretreatment genomic profile. These alterations occurred in a subtype-dependent manner, suggesting that NAT may have either eliminated the most susceptible tumor subclone, leaving the treatment resistant clone with a different genetic signature, or altered molecular characteristics of the original cancer.