Abstract P6-04-10: Clinicopathological and molecular characteristics of pleomorphic invasive lobular carcinoma of breast
Authors: Segar J , Baker AF , MacKerricher W , Nagle R , Livingston R , Clarke K , Ley M , Viscusi R , Gonzalez V , LeBeau L , Chalasani P 
Published: May 2016

Abstract
Background: Pleomorphic invasive lobular carcinoma (PILC) is described as a distinct morphological variant of invasive lobular carcinoma (ILC) but its clinical behavior is not well characterized. PILCs have loss of E-cadherin similar to ILCs but have distinct morphological features like nuclear contour irregularity, a single prominent nucleolus, increased hyperchromasia and more frequent mitoses. In addition, some studies have reported that PILCs have acquired further molecular alterations such as gain of HER2/neu, amplification of c-myc and loss of p53. To the best of our knowledge there have been no studies evaluating Phosphoinositide 3 kinase/Akt/mammalian (or mechanistic) target of rapamycin (PI3K/Akt/mTOR) pathway in PILC. We hypothesize that there is increased activation of PI3K/Akt/mTOR pathway in PILC compared to ILC. Activation of the PI3k/Akt/mTOR pathway was evaluated by quantifying protein expression of phosphatase and tensin homolog (PTEN) and phosphorylated-S6 kinase1 (p-S6K1). PTEN is a negative regulator of the PI3K pathway and its loss/decreased expression (by mutation or allelic imbalance) activates downstream signaling. Loss (or decrease) of PTEN expression has been reported to be associated with PI3K pathway activation in more than 50% of ER+ breast tumors. Since PI3K pathway can be activated by other mechanisms in addition to PTEN loss, we hypothesized that evaluation of pS6K1 may predict activation of this pathway more than PTEN protein expression alone.
Methods: We conducted a retrospective translational study at the University of Arizona Cancer Center. Our Pathology database was searched to identify PILCs from 2012-2014. Two investigators reviewed the pathology reports independently and abstracted clinocopathological data. Formalin-fixed paraffin embedded (FFPE) primary PILCs were stained for PTEN and pS6K1 expression. Expression of PTEN and pS6K1 was quantified by long score methodology as low (≤ 10), moderate (11-50) or high (≥ 50) expression.
Results: We identified 19 patients with PILC. All tumors were either moderately (n=10) or poorly differentiated (n=9). Estrogen receptor (ER) was positive in all, progesterone receptor (PR) was positive in 11(52%) and HER2 was negative in all tumors. Proliferation index (Ki67) was elevated in all tumors (median 32%, range 20-70%). Lymph nodes were involved with metastatic carcinoma in 7 patients (negative in 9 and unknown in 3). The 21-gene recurrence score assay (Oncotype Dx) was performed in 10 patients and demonstrated higher scores (median 23, range 6-36) with the majority being in the intermediate or high range (8/10). Expression of PTEN and p-S6K1 was quantified on 10 FFPE tumor tissues. PTEN expression was high in all while pS6K1 was high in 8 and low in 2 tumors.
Conclusion: PILCs are a biologically distinct group of ILC. Clinicopathological characteristics suggest they would have a more clinically aggressive behavior (higher grade, high proliferative index and 21 gene recurrence score). In addition, our results indicate that PI3k/Akt/mTOR pathway in activated in majority of these tumors and that PTEN is not the key regulator of this pathway. Genomic profiling is currently underway to further analyze other causes of pathway activation.
Citation Format: Segar J, Baker AF, MacKerricher W, Nagle R, Livingston R, Clarke K, Ley M, Viscusi R, Gonzalez V, LeBeau L, Chalasani P. Clinicopathological and molecular characteristics of pleomorphic invasive lobular carcinoma of breast. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-04-10.