Prospective evaluation of pathologic response with neoadjuvant chemo-immunotherapy in metaplastic breast cancer.
Authors: Abuhadra Nour , Chen Yuan , Plitas George , Razavi Pedram , Pareja Fresia , Reis-Filho Jorge S. , Wen Hannah Yong , Khan Atif J. , Traina Tiffany A. , Downs-Canner Stephanie , Robson Mark E. , Norton Larry , Montagna Giacomo 
Published: June 2023

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Background: Metaplastic breast cancer (MpBC) is a rare aggressive histologic type of breast cancer that is often resistant to standard chemotherapy with pathologic complete response (pCR) rates ranging between 2-23%. PDL1 expression has been reported in up to 95% of primary MpBCs suggesting that response rates may be improved with addition of immune checkpoint blockade (ICB). Here we evaluate pCR rates (ypT0/is ypN0) in stage I-III MpBCs receiving neoadjuvant chemo-immunotherapy (NAT). Methods: The Memorial Sloan Kettering Cancer Center Rare Breast Cancer Program (CARE-4-RARE) is a new clinical and translational program dedicated to the study of rare breast cancers. Since the start of the program, 15 patients (pts) with early-stage MpBC have completed treatment with the neoadjuvant KEYNOTE-522 regimen. Wilcoxon rank-sum and Fisher’s exact tests were used to compare characteristics according to pCR status. All statistical tests used a significance level of 5%. Results: Median age at diagnosis was 50 (range, 43-60). All pts were female, 13% self-identified as Asians, 33% as Black and 53% as White. All tumors were poorly differentiated and of triple-negative phenotype, median tumor size was 3.2cm, 80% had stage II disease and 20% were clinically node positive. Metaplastic subtypes included 5 matrix-producing (33%), 3 spindle (20%), 4 squamous (27%), 3 mixed (20%). Of the 15 pts, 4 (27%) achieved a pCR, which suggest the possibility of a higher than expected pCR rate in MpBC with the addition of ICB to chemotherapy. We did not observe a significant difference in clinicopathological features between pCR vs. non-pCR groups. We observed numerical differences in pCR between MpBC subtypes though the p-value was not significant due to limited sample size. Of these 4 pts, 2 had matrix-producing and 2 had mixed subtypes. Two pts with pCR only received Cb+P+Pem. Three pts (20%) experienced PD (squamous n = 2, spindle n = 1) necessitating discontinuation of NAT and expediting surgery. Conclusions: This is the first prospective study to evaluate neoadjuvant ICB in MpBC. These data suggest the possibility of a higher than expected pCR rate in MpBC with the addition of ICB to chemotherapy (27%). This work suggests that neoadjuvant ICB should be considered in MpBC with close monitoring. Notably, 50% of reported pCR in this cohort were in pts who only received Cb+P+Pem. In spite of improved pCR rates, 20% of pts progressed during NAT highlighting the need for better treatment strategies in this treatment-refractory subset of MpBC and close monitoring to allow resection before progression to inoperability. The dichotomy in responses to ICB (super-responsive vs. super-refractory) may suggest the presence of unique biomarkers for immune response in MpBC. By the 2023 ASCO Annual Meeting a total of 26 pts will have completed NAT; we will report updated outcomes along with correlative immune biomarkers (sTIL, PDL1, TMB).