Abstract 5791: Bromodomain inhibitors for the treatment of invasive lobular carcinoma
Authors: O'connor Darran P. , Walsh Louise , Fan Yue , Tarrant Finbarr , Chin Suet-Feung , Schouten Philip , Caldas Carlos , Bernards Rene , Chonghaile Triona ni , Gallagher William 
Published: August 2018

Invasive lobular carcinoma (ILC) is the second most common type of breast cancer after invasive ductal carcinoma (IDC), accounting for approximately 10-15% of all breast tumors. ILC is characterized by inactivation of E-Cadherin and neoplastic cells that invade the stroma in a "single-file" pattern. Women with ILC are usually older, have used hormone replacement therapy and are more likely to have hormone receptor-positive disease. ILCs have similar survival to IDCs at both five and 10 years, but despite this, the clinical course is distinct: ILCs are three times more likely to metastasize to the peritoneum, gastrointestinal tract, and ovaries and are more frequently bilateral. Therefore, tailored therapeutic options for this distinct, hard-to-treat subtype of breast cancer are required.

As part of the RATHER FP7 HEALTH consortium (www.ratherproject.com), we carried out RNA-Seq analysis of 61 primary ILC samples and identified that high expression of the BET family protein Brd3 (uniquely among BRD family members) was associated with poor recurrence free survival (p=0.03, HR 8.63, CI 1.22-60.85). This observation was further validated in the independent METABRIC cohort (n=99), where again, high Brd3 expression (and not other BRD members) was associated with poor recurrence-free survival (p&lt;0.01, HR=3.16, CI 1.24-8.03). Using a two ILC cell lines (SUM44PE and MDA-MB134VI) we found that ILC cells were relatively resistant to the anti-estrogen therapies tamoxifen and fulvestrant compared to those derived from IDC. Next, we tested whether the ILC cell lines were sensitive to BET protein inhibition using the pan-BET family inhibitor JQ1. Interestingly, while JQ1 inhibited cell growth in both ILC cell lines tested, apoptosis was only induced in SUM44PE cells, while MDA-MB134VI cells exhibited G1 arrest. Dynamic BH3 profiling was used to dissect the underlying anti-apoptotic dependencies in each ILC cell type and showed that in the JQ1-resistant MDA-MB134VI cells, survival was predominantly Bcl2-dependent. Combination of JQ1 and the Bcl2-inhibitor venetoclax (ABT-199) synergistically killed MDA-MB134V1 cells compared to treatment with JQ1 alone, while combination with the Bcl2/Bcl-Xl/Bcl-W inhibitor navitoclax (ABT-263) added further synergy.

With a number of BET inhibitors now entering clinical trials, the data described here suggest that BET inhibition is a rational therapeutic option for some ILC cases, and for those that do not respond, combination with venetoclax may be a suitable therapeutic strategy. In our cell line models, baseline Bcl-2 expression was sufficient to predict induction of apoptosis in response to JQ1 and could be used to guide therapeutic choice.

Citation Format: Darran P. O'connor, Louise Walsh, Yue Fan, Finbarr Tarrant, Suet-Feung Chin, Philip Schouten, Carlos Caldas, Rene Bernards, Triona ni Chonghaile, William Gallagher. Bromodomain inhibitors for the treatment of invasive lobular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5791.