Abstract PS18-04: Prospective evaluation of patients with metaplastic (Mp) triple negative breast cancer (TNBC): Molecular characteristics and outcomes with neoadjuvant therapy (NAT)
Authors: Abuhadra Nour , Yam Clinton , Sun Ryan , Huo Lei , White Jason , Ravenberg Elizabeth , Adrada Beatriz , Sahin Aysegul , Litton Jennifer , Lim Bora , Ueno Naoto T , Arun Banu , Tripathy Debu , Damodaran Senthil , Murthy Rashmi , Valero Vicente , Hortobagyi Gabriel , Ibrahim Nuhad , Thompson Alastair , Lucci Anthony , Mittendorf Elizabeth , Moulder Stacy , Chang Jeffrey 
Published: February 2021

Abstract
Background: MpBC is a rare breast cancer subtype that is commonly triple-negative and associated with a diminished response to NAT in published retrospective data sets, prompting some clinicians to recommend surgical resection followed by adjuvant therapy. Methods: The ARTEMIS trial (NCT02276443) uses imaging response and molecular profiling to personalize NAT in early stage TNBC. Patients with sensitive disease after 4 cycles of AC receive standard taxane-based NAT as the second phase of NAT, while those with resistant disease are offered biomarker-guided therapeutic trials. Pathologic response is assessed at surgical resection. Prospective data from 195 patients with early-stage TNBC (MpTNBC: N=37; Non-MpTNBC: N=158) enrolled on the ARTEMIS trial were evaluated. Due to short duration of follow-up, restricted mean survival time up to four years of follow-up was used to evaluate event-free survival (RM-EFS), metastasis-free survival (RM-MFS) and overall survival (RM-OS). RNAseq and whole exome sequencing (WES) were performed on pre-NAT core biopsies (155 and 158 non-MpTNBC respectively; 20 MpTNBC). Stromal tumor infiltrating lymphocytes (sTIL) and PD-L1 staining were also compared. Results: Pathologic complete response (pCR) rates were significantly lower in MpTNBC vs non-MpTNBC (18.9% vs. 41.4%, p=0.013). Among MpTNBC without pCR (n=30, 81%), 21 were detected early to have progression (PD) or suboptimal response to standard therapy with ultrasound and clinical exam and were offered the opportunity to participate in clinical trial. Notably, 6 patients (16.2%) had PD after 2 cycles of AC. There was a non-statistically significant trend of lower RM-EFS, RM-MFS, and RM-OS in MpTNBC; however, MpTNBCs with pCR had similar RM-OS compared to non-MpTNBCs with pCR. MpTNBCs had lower rates of high TIL (&gt;20%) compared to non-MpTNBCs (16% vs. 36%, p=0.02) but similar rates of PD-L1+ disease. Compared to non-MpTNBCs, using Vanderbilt classification methods, MpTNBCs were more frequently M/MSL subtype (50% vs 22%, p=0.011) and less frequently BL-1 subtype (p=0.028). By RNAseq, MpTNBC tumors had significantly lower gene expression of epithelial markers CDH1, EPCAM, ESRP1, and increased expression of EMT inducer TWIST1. WES identified PIK3CA missense mutations in 15% of MpTNBCs. Unsupervised clustering based on expression profiles revealed that 85% of MpTNBCs had a Mp-like expression signature. Interestingly, the Mp-like expression signature was identified in 12% of histologically defined non-MpTNBC. The pCR rate was lowest in the MpTNBC (18.9%) but similar between Mp-like TNBC (36.8%) and non-MpTNBC (42.2%). Conclusion: Early-stage MpTNBC has lower rates of pCR with NAT however those with pCR appear to have similar survival rates to non-MpTNBC with pCR. Notably, 16.2% of MpTNBC had PD after 2 cycles of AC NAT suggesting that a neoadjuvant approach with frequent imaging would reduce unnecessary exposure to inactive chemotherapy. 81% of MpTNBCs had either PD or suboptimal response to AC chemotherapy, thus novel treatment strategies need to be developed for this chemorefractory subtype of TNBC. PAM (PI3K/mTOR/AKT) pathway alterations were frequently detected in MpTNBCs and novel inhibitors should be further tested.
Citation Format: Nour Abuhadra, Clinton Yam, Ryan Sun, Lei Huo, Jason White, Elizabeth Ravenberg, Beatriz Adrada, Aysegul Sahin, Jennifer Litton, Bora Lim, Naoto T Ueno, Banu Arun, Debu Tripathy, Senthil Damodaran, Rashmi Murthy, Vicente Valero, Gabriel Hortobagyi, Nuhad Ibrahim, Alastair Thompson, Anthony Lucci, Elizabeth Mittendorf, Stacy Moulder, Jeffrey Chang. Prospective evaluation of patients with metaplastic (Mp) triple negative breast cancer (TNBC): Molecular characteristics and outcomes with neoadjuvant therapy (NAT) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-04.