Abstract PS4-12: Potential value of FOXA1 expression as genomic predictor of response to docetaxel and carboplatin neoadjuvant (NA) chemotherapy in patients with triple negative breast cancer (TNBC)
Authors: López-Tarruella Sara , del Monte-Millán María , Alvarez Enrique , Jerez Yolanda , Saenz José Ángel García , Echavarria Isabel , Moreno Fernando , Márquez-Rodas Ivan , Bueno-Muiño Coralia , Herrero Blanca , Cebollero Maria , Ramos-Medina Rocío , Lobato Nerea , González del Val Ricardo , Palomero Maria Isabel , Lizarraga Santiago , Bohn Uriel , Ballesteros Ana Isabel , Rincón Patricia , Massarrah Tatiana , Ocaña Inmaculada , Villarejo Lucía , Perou Charles M , Martin Miguel 
Published: February 2021

Abstract
Background: TNBC is a particularly aggressive subtype with high recurrence rates and poor long-term survival. Anthracycline-free regimens based on docetaxel plus carboplatin (TCb) achieve around 50-55% pathologic complete responses (pCR) which correlates with better survival outcomes. Identification of genomic predictors of response is key to individualize therapies for this heterogeneous breast cancer (BC) subgroup. FOXA1 is a pioneer factor for androgen (AR) and estrogen receptors (ER). Its under-expression has been linked to cancer stemness in TNBC and better prognosis in ER-positive BC. The differential expression of AR, FOXA1 and BRCA1 is associated with sensitivity to chemotherapy in TNBC patients. Data support the plasticity role of FOXA1 driving basal to luminal BC cells by inducing luminal genes but also by repressing the basal phenotype and thus, tumor aggressiveness, although its role as a biomarker in TNBC is still controversial. We have analyzed RNAseq data of FOXA1 and AR in a series of TNBC tumors homogenously treated with neoadjuvant TCb to study their correlation with survival and response. Methodology: 300 TNBC patients have been included in a multicenter, prospective, non-randomized trial aimed to identify predictors of response to TCb in the neoadjuvant setting (NCT01560663). 278/300 patients were evaluable. PAM50 subtypes (NanoString nCounter) and RNAseq (HiSeq2500) were analyzed for those patients with both available samples and evaluable pathological response (n=208). Correlations were studied by the Kendall method. Linear or logistic regressions were adjusted for univariant analysis depending on numerical or categorical response variables, respectively. Results: FOXA1 and AR were differentially expressed between basal and non-basal tumor subtypes (PAM50), being overexpressed in non-basal (p&lt;0.001 for both FOXA1 and AR). FOXA1 and AR were significantly overexpressed in non-basal subtypes from the Vanderbilt TNBC-type classification (36/208) as well. Both genes expression showed a significant correlation with several luminal marker genes. AR was significantly associated with ANXA9 (p=0,008), GATA3 (p=0,00002) and XBP1 (p&lt;0.001), while FOXA1 expression was positively associated with ANXA9 (p=0,03), ESR1 (p&lt;0.001),GATA3 (p&lt;0.001) and XBP1 (p&lt;0.001). In terms of response, significant differences in FOXA1 expression levels were found between responders and non-responders by Residual Disease Burden (RCB) classification taking response as binary variable of PCR vs RCB-I/II/III (p=0.003) as well as pCR/RCB-I vs RCB-II/III (p=0.008) with responders showing a lower FOXA1 expression level. The same analysis for AR expression did not show statistically significant differences. Within the PAM50 basal subgroup, neither AR nor FOXA1 individual gene expression (172/208) showed association with response. For survival, with a median follow-up of 36 months, neither FOXA1 nor AR showed significant impact on EFS or OS per univariate Cox regression analysis (EFS: HRFOXA1 1.076; p=0.307; HRAR 1.156, p=0.084 and OS: HRFOXA11.120, p=0.140; HRAR 1.152, p=0.121). Conclusions: Within our cohort, FOXA1 expression is a better predictor of response to NA chemotherapy than AR. FOXA1 is overexpressed in TNBC tumors who do not achieve pCR with neoadjuvant TCb chemotherapy, correlating with non-basal tumor subtypes. This suggests that measuring FOXA1 expression levels in patients with TNBC could be useful to predict response to TCb regimen enabling physicians to select more effective alternative NA schemes in this population.
Citation Format: Sara López-Tarruella, María del Monte-Millán, Enrique Alvarez, Yolanda Jerez, José Ángel García Saenz, Isabel Echavarria, Fernando Moreno, Ivan Márquez-Rodas, Coralia Bueno-Muiño, Blanca Herrero, Maria Cebollero, Rocío Ramos-Medina, Nerea Lobato, Ricardo González del Val, Maria Isabel Palomero, Santiago Lizarraga, Uriel Bohn, Ana Isabel Ballesteros, Patricia Rincón, Tatiana Massarrah, Inmaculada Ocaña, Lucía Villarejo, Charles M Perou, Miguel Martin. Potential value of FOXA1 expression as genomic predictor of response to docetaxel and carboplatin neoadjuvant (NA) chemotherapy in patients with triple negative breast cancer (TNBC) [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 PS4-12.