Abstract P5-06-21: Prognostic and predictive value of PML in the ETNA study and the TCGA
Authors: Zambelli Stefania , Smart Chanel , Bianchini Giampaolo , Sassi Isabella , Mansutti Mauro , Anton Antonio , Calvo Lourdes , Bisagni Giancarlo , Bermejo Begona , Uggè Martina , Galbardi Barbara , Semiglazov Vladimir , Thill Marc , Chacon Jose Ignacio , Chan Arlene , Murillo Serafin Morales , Alvarez Isabel , Lahuerta Ainhara , Zucchinelli Patrizia , Doglioni Claudio , Valagussa Pinuccia , Tusquets Ignasi , Gianni Luca , Bernardi Rosa 
Published: March 2020

Abstract
Background. Although long considered a tumor suppressor gene, PML (promyelocytic leukemia) also plays tumor-promoting functions in specific contexts. In vitro and in vivo studies have demonstrated that PML is upregulated by HIF-1α transcriptional activation in triple-negative breast cancer (TNBC) cells and it is implicated in promoting metastasis downstream of HIF-1α. This pro-metastatic function of PML is inhibited by arsenic trioxide, a pharmacological compound currently in use in acute promyelocytic leukemia. However, the clinical relevance of PML expression in BC has not been extensively investigated. In this study, we evaluated the association of PML expression with clinic-pathological factors and outcome (pathological complete response -pCR- and risk of recurrence) in the ETNA trial, and risk of recurrence in the TCGA. Methods. In the ETNA study (NCT01822314) 695 patients with HER2-negative breast cancer (BC) were randomized to receive neoadjuvant paclitaxel or nab-paclitaxel followed by 4 cycles of an anthracycline regimen. In the ITT study population, the two treatments did not show significantly different rates of pCR nor different Event-Free Survival (EFS) (Gianni JAMA Oncol 2018, Gianni ASCO 2019). A central histologic assessment of ER, PgR, HER2 status and Ki67 was mandatory. We evaluated PML expression by immunohistochemistry using the continuous histoscore (H-score) on pre-treatment core biopsies. The H-score is generated from the estimation of the percentage of cells with no (0), light (1+), moderate (2+) and strong (3+) intensity staining, and the corresponding score is generated with the following algorithm: [1 × (% cells 1+) + 2 × (% cells 2+) + 3 × (% cells 3+)]. We evaluated the association of PML with clinic-pathological features and clinical outcomes (pCR and EFS) in triple negative (TN) and in LuminalB-like (ER+ and/or PgR+, Ki67≥14%) groups. We also investigated the association between PML mRNA expression (RNA-seq) and DFS in HER2-negative BC (TN, n=192; ER+/HER2-, n=702) in the TCGA dataset. Results. In the ETNA study, PML was successfully assessed and valuable in 491 pts (70.6%). The average PML expression was 126.3 (median 120, range 0-295). In the ETNA trial, TNBC showed the highest expression of PML (p&lt;1.0E-10). Within LumB-like tumors, the group with intermediate proliferation (Ki67 14-20%, LumB-int) had higher PML expression than the high proliferation group (Ki67&gt;20%, LumB-high) (p=0.0005). However, within the LumB-high group, higher proliferation (Ki67&gt;40%) showed a higher expression of PML (p=0.025), suggesting a non-linear relationship between PML and proliferation in luminal tumors. In LumB-high, PML was higher in PgR-negative tumors (p=1.0E-5). Finally, PML showed a positive association with higher stromal tumor-infiltrating lymphocytes (sTILs) both in LumB-like and TN group (p=0.019 and p=0.001, respectively). PML expression was not significantly associated with pCR and risk of recurrence in LumB-like nor in TN BC.In the TCGA dataset also PML expression was highest in the TN group (p&lt;1.0E-10). No association was found between PML expression and risk of recurrence in any molecular subgroup. Conclusions. PML expression assessed by IHC in the ETNA trial was not predictive of likelihood of pCR nor of risk of recurrence in LumB-like and TN breast cancer. PML mRNA expression was not prognostic in TN and LumB-like tumors also in the TCGA dataset. Some interesting associations with biological features emerged which warrants biological interpretation of the complex role of PML in breast cancer. Supported in part by an unrestricted grant from Celgene Sarl, Swizerland
Citation Format: Stefania Zambelli, Chanel Smart, Giampaolo Bianchini, Isabella Sassi, Mauro Mansutti, Antonio Anton, Lourdes Calvo, Giancarlo Bisagni, Begona Bermejo, Martina Uggè, Barbara Galbardi, Vladimir Semiglazov, Marc Thill, Jose Ignacio Chacon, Arlene Chan, Serafin Morales Murillo, Isabel Alvarez, Ainhara Lahuerta, Patrizia Zucchinelli, Claudio Doglioni, Pinuccia Valagussa, Ignasi Tusquets, Luca Gianni, Rosa Bernardi. Prognostic and predictive value of PML in the ETNA study and the TCGA [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-21.