Treatment Of Invasive Lobular Carcinoma Research Articles

Abstract PO3-18-08: Rational therapeutic combination of Bromodomain and Extra-Terminal domain (BET) inhibitor and Fibroblast Growth Factor Receptor (FGFR) inhibitor for treatment of invasive lobular carcinoma

Abstract Background: Invasive lobular carcinoma (ILC) is the second most pervasive subtype after invasive ductal carcinoma (IDC), accounting for approximately 10-15% of all breast cancers. It is characterized by loss of E-cadherin expression and non-adherent tumor cells that invade the stroma in a “single-file” pattern. Women with ILC are typically diagnosed at an older age and later stage with ER-positive disease. ILC is more likely to exhibit late recurrence and metastasize to the gastrointestinal tract and urogenital tract compared with IDC. It is routinely treated with anti-endocrine therapy and chemotherapy, however, while not entirely chemo-refractory, displays a poor response to chemotherapy compared with IDC. As such, options for recurrent disease are limited and there is an urgent need to develop tailored therapy for ILC, especially for those patients that recur. The family of bromodomain and extra-terminal domain (BET) proteins, comprising BRD2/3/4/T, are epigenetic readers that bind to acetylated lysine residues on histones and recruit transcription factors to drive the expression of oncogenes. Previously. we discovered that BRD3 is a marker of poor prognosis in ILC and there is emerging evidence that BET inhibitors (iBET) are effective in diverse types of breast cancer. Here, we investigated the therapeutic potential of iBET in ILC, alone and in combination with FGFR inhibitors. Methods: IC50s for a panel of iBET using two typical ILC cell lines MDA-MB-134VI (MM134) and SUM44PE (SUM44) were determined. RNA-sequencing and Genexplain analysis was applied to reveal transcriptional networks, master regulators and potential resistance mechanisms. BRD3 and FGFR3 were knocked down using siRNA to evaluate their function in ILC cell lines. Furthermore, we utilized ILC cell-derived xenograft (CDX) models in SCID-beige mice established by mammary intraductal (MIND) implantation to evaluate the therapeutic potency of iBET alone or in combination with fibroblast growth factor receptor (FGFR) inhibitor in vivo. Results: We demonstrated that iBET significantly inhibited ILC cell growth in both 2D and 3D culture, with the greatest potency demonstrated by JQ1 and Mivebresib (ABBV-075). RNA-sequencing revealed dysregulated pathways in cell cycle division, DNA damage, apoptosis and MAPK signaling following iBET treatment. Reverse engineering of transcriptional profiles using Genexplain revealed that FGFR3 is a significantly upregulated master regulator (MTR) among 142 MTRs across both cell lines and both iBETs. Upregulation of FGFR3 after iBET treatment was verified at the protein level by Western blotting. We also show that BRD3 and FGFR3 knockdown significantly inhibited cell growth, which supports the key role both play in ILC progression. Further, we analyzed the iBET therapeutic effect when combined with the FGFR inhibitor, erdafitinib, as a strategy to overcome potential resistance due to FGFR upregulation post iBET treatment. This revealed that the combination of iBET and erdafitinib could inhibit ILC cell growth more effectively compared to using either agent alone. Furthermore, our in vivo study showed that JQ1 could inhibit tumor growth in a SUM44-MIND model and alleviate metastasis to peritoneum, bone and ovary compared with the vehicle group. Moreover, we also assessed the combination of mivebresib and erdafitinib in vivo. This revealed that iBET and an FGFR inhibitor work synergistically to decrease tumour burden and metastatic potential in both MM134-MIND and SUM44-MIND models. Conclusion: Our results provide evidence that iBET, either alone or in combination with erdafitinib, is remarkably effective at inhibiting ILC growth, both in vitro and in vivo and represents a rational therapeutic strategy for recurrent ILC patients in the future. Citation Format: Binbin Gao, Elspeth Ward, Anna Blümel, Emer Conroy, Rachel Moore, Grainne Cremin, Rachel Bleach, Kathryn Haley, Tríona Ní Chonghaíle, Andreas Lindner, Jochen Prehn, Yi Zhang, Idalia Cruz, Leena Hilakivi-Clarke, Georgios Sflomos, Cathrin Brisken, William Gallagher, Darran O'Connor. Rational therapeutic combination of Bromodomain and Extra-Terminal domain (BET) inhibitor and Fibroblast Growth Factor Receptor (FGFR) inhibitor for treatment of invasive lobular carcinoma [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-08.

Abstract ED02-03: Innovative approaches at the diagnosis and treatment of invasive lobular carcinoma

Abstract Invasive Lobular Carcinoma (ILC) represents a unique subtype of breast cancer characterized by distinctive clinical and molecular features. This presentation aims to delve into innovative approaches in the diagnosis and treatment of ILC, focusing on novel techniques in imaging, unique molecular findings, signaling pathway alterations, targetable biomarkers, and microenvironment profiling that can pave the way for the development of novel therapies. Imaging Techniques in ILC: Accurate diagnosis is the foundation for effective treatment. ILC often presents diagnostic challenges due to the fact that lobular cells tends to infiltrate the affected organs in a diffuse manner instead of forming a discrete tumor mass making diagnostic imaging such as screening mammograms and CT scans less precise. This presentation will explore cutting-edge imaging techniques such as contrast-enhanced mammography, novel radioisotopes for positron emission tomography (PET) such as Fluoroestradiol F18 (FES), Fluciclovine and prostate-specific membrane antigen (PSMA) for improved detection and characterization of ILC lesions. Furthermore, we will discuss emerging modalities like radiomics and artificial intelligence, which hold promise in enhancing early diagnosis and risk assessment. Molecular Insights into ILC: ILC is distinguished by its unique molecular profile, notably the loss of E-cadherin expression. We will delve into recent advancements in understanding the molecular landscape of ILC, including genomic alterations, epigenetic changes, and the role of signaling pathways providing insights into potential therapeutic vulnerabilities. Targetable Biomarkers and Pathways: Identification of targetable biomarkers is essential for the development of precision therapies in ILC. This presentation will highlight promising targets, including ERBB2 (HER2), ROS1, TROP2, AKT1 along with other novel biomarkers. Microenvironment Profiling: The tumor microenvironment plays a pivotal role in cancer progression and therapy response. We will discuss recent advancements in characterizing the ILC microenvironment, including the immune cell infiltrate and stromal components. Understanding the dynamic interplay between the tumor and its microenvironment can inform the development of immunotherapies and combination strategies tailored to ILC. In conclusion, this presentation will provide a comprehensive overview of the latest innovations in ILC diagnosis and treatment. Our exploration of advanced imaging techniques, molecular findings, targetable pathways, biomarkers, and microenvironment profiling will shed light on the exciting potential for personalized therapeutic approaches in the management of ILC. By staying at the forefront of these developments, we can pave the way for improved outcomes and enhanced quality of life for patients with ILC. Citation Format: J. Mouabbi. Innovative approaches at the diagnosis and treatment of invasive lobular carcinoma [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr ED02-03.

The Role of Magnetic Resonance Imaging in the Preoperative Staging and Treatment of Invasive Lobular Carcinoma

IntroductionInvasive lobular carcinoma (ILC) is known for its diffuse growth pattern and its associated challenges in diagnosing. Magnetic resonance imaging (MRI) is the most accurate imaging modality and might aid in improving preoperative staging compared to full field digital mammography (FFDM) and ultrasound (US), however current literature is inconsistent. The aim of this paper is to evaluate the accuracy of MRI staging compared to FFDM/US and pathology results. MethodsIn this single-centre retrospective study, all patients diagnosed with ILC between 2014 and 2019 who underwent preoperative MRI were included. Specific parameters studied were: (1) the need for second-look targeted biopsies, (2) detection of new tumors (ie, contralateral or multifocal), (3) changes in cTNM-classification, and (4) impact on final treatment plan. Bland-Altman plots were used to compare the tumor sizes measured on MRI and FFDM/US with actual pathological tumor sizes. ResultsNinety-nine patients were included. After performing preoperative MRI, 9 (9.1%) multifocal tumors were diagnosed after additional biopsies. Contralateral tumors were detected twice (2.0%) and cN classification was upgraded in 7 cases (7.1%). Surgical treatment or neoadjuvant treatment plans were changed in 16 patients (16.1%). Compared to histopathological results, FFDM/US underestimated tumor size with a mean of 0.4 cm (Limit of agreement (LoA): -2.8 cm to 2.0 cm) whereas MRI overestimated tumor size with a mean of 0.6 cm (LoA: -1.9 cm to 3.0 cm). ConclusionsIn our study, mean differences in tumor size measurements using FFDM/US and MRI were comparable, with similar random errors. MRI correctly diagnosed multifocal and contralateral tumors more often and provided a better cN staging.

Timing evolution of lobular breast cancer through phylogenetic analysis.

SummaryBackgroundLate distant recurrence is a challenge for the treatment of invasive lobular carcinoma (ILC) of the breast. Despite in-depth characterisation of primary ILC, the molecular landscape of metastatic ILC is still only partially understood.MethodsWe retrospectively identified 38 ILC patients from the tissue banks of six European institutions. DNA extracted from patient matched primary and metastatic FFPE tissue blocks was whole genome sequenced to compute somatic copy number aberrations. This, in turn, was used to infer the evolutionary history of these patients.FindingsThe data show different metastatic seeding patterns, with both an early and late divergence of the metastatic lineage observed in ILC. Additionally, cascading dissemination from a metastatic precursor was a dominant rule. Alterations in key cancer driver genes, such as TP53 or CCND1, were acquired early while additional aberrations were present only in the metastatic branch. In about 30% of the patients, the metastatic lineage harboured less aberrations than the primary tumour suggesting a period of tumour dormancy or prolonged adaptation at the distant site. This phenomenon was mostly observed in tumours from de novo metastatic patients.InterpretationOur results provide insights into ILC evolution and offer potential paths for optimised ILC care.FundingThis work has received financial support from Les Amis de l'Institut Bordet, MEDIC, the Breast Cancer Research Foundation (BCRF) and the Belgian Fonds National de la Recherche Scientifique (F.R.S-FNRS).

Abstract PD14-07: Bromodomain and Extra-Terminal motif (BET) inhibitors are a rational therapeutic choice for treatment of invasive lobular carcinoma

Abstract Invasive lobular carcinoma (ILC) is the second most common type of breast cancer accounting for approximately 10-15% of all breast tumours. ILC is characterized by inactivation of E-Cadherin and cancer cells that invade the stroma in a "single-file" pattern. Women with ILC are more likely to have hormone receptor-positive disease. ILCs are three times more likely to metastasize to the peritoneum, gastrointestinal tract, and ovaries. ILC are currently treated in the same manner as all other ER+ breast cancers. Like invasive ductal carcinoma (IDC), anti-estrogen resistance has emerged as a significant problem in the management of ILC. Approximately half of the recurrences of ER+ breast tumors respond to anti-endocrine treatment, while the other half are resistant. Additionally, anti-estrogen-resistant breast tumor cells appear to have/acquire a more aggressive, invasive phenotype compared to their anti-estrogen-responsive counterparts. ILC is considered to be chemo-resistant and ILC patients receive no additional benefit from adjuvant chemotherapy. As such, there is a pressing need to develop tailored therapeutic options for endocrine-resistant ILC patients. The bromodomain and extra-terminal (BET) motif family are epigenetic readers that bind to acetylated histones, recruiting co-factors to regulate transcription. As part of the FP7 RATHER project aimed at identifying rational treatment options for ILC, we discovered that BRD3 (uniquely among the BET family members) is a marker of poor prognosis in ILC but not in ER+ breast cancers as a whole. We subsequently validated this in an independent cohort from the METABRIC study. These data suggest that Brd3 may play a significant role in tumour progression in ILC and may be a rational therapeutic target for lobular tumours. Using the two ILC cell lines SUM44PE (SUM44) and MDA MB 134 VI (MM134) previously shown to be anti-endocrine resistant we assessed the therapeutic potential of BET inhibition. We found that ILC cell lines that do not respond to anti-endocrine therapy are sensitive to a panel of BET inhibitors in both 2D and 3D assays. In particular the BET inhibitors JQ1 and Mivebresib had the highest potency, these BET inhibitors were selected for further research. Next, a multi-omics approach merging RNA-sequencing with mass spectrometry was utilised to dissect the transcriptional networks employed by BET inhibitors in this ILC setting. RNA-sequencing revealed dysregulated pathways in cell cycle division, DNA damage, apoptosis and MAPK signalling following treatment. Further, rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) was carried out to find the binding partners of the BRD proteins. Integrated pathway analysis through Genome Enhancer was used to assess the master regulators (MTRs) which drive BET inhibitor function. There was 142 MTRs found across the two cell lines treated with both inhibitors. Of note the MTR, FGFR3, was shown to regulate the downstream targets of both BET inhibitors. Further analysis of BET inhibition combined with erdafitinib, an FGFR inhibitor, drives increased cell inhibition compared to either agent alone. Finally, the efficacy of JQ1 in targeting ILC was assessed in vivo. We utilised the ILC cell-derived xenograft (CDX) models established by mammary intraductal implantation. The efficacy of BET inhibition alone and in combination with anti-endocrine therapies, tamoxifen and fulvestrant were assessed in the MM134 cell line. We found that JQ1 works synergistically with tamoxifen to significantly decrease tumour burden and metastatic potential in this tamoxifen resistant ILC model. Taken together this data highlights the need for tailored therapeutics in ILC research and highlights the use of BET inhibition in the anti-endocrine resistant ILC setting. Citation Format: Elspeth Ward, Anna Blümel, Emer Conroy, Grainne Cremin, Binbin Gao, William Gallagher, Idalia Cruz, Leena Hilakivi-Clarke, George Sflomos, Cathrin Brisken, Darran O'Connor. Bromodomain and Extra-Terminal motif (BET) inhibitors are a rational therapeutic choice for treatment of invasive lobular carcinoma [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD14-07.

Abstract P3-01-25: Assessing the impact of preoperative breast MRI on time to treatment for invasive lobular carcinoma

Abstract Background: Invasive lobular carcinoma (ILC) has increased rates of multifocal, multicentric, and bilateral disease. Despite high sensitivity in detection of ILC, preoperative breast MRI is not routinely done. Additional findings requiring biopsy may be necessary, which would possibly delay time to treatment (TTT). Increased TTT is associated with increased risk of mortality in early stage breast cancer. This study investigates the effect of preoperative MRI on TTT in ILC. Methods: A retrospective study utilizing an institutional database identified patients with ILC treated from 2004-2017. Patient and disease characteristics were recorded, including preoperative breast imaging modalities, new findings on preoperative breast MRI, and dates of treatment. Patients who had surgery were studied and separated into four groups: no MRI (No-MRI), MRI without new lesion (MRI-NNL), MRI with new lesion not biopsied (MRI-NL-NB), and MRI with new lesion that was biopsied (MRI-NL-B). TTT was defined as days from diagnosis to surgical management. Results: Of the total 691 patients, 452 (65.4%) received a preoperative MRI. Preoperative MRI was more likely among younger patients (mean age 58.5 vs. 67.4 years old, p<0.001), those with a lower BMI (mean 27.8 vs. 30.1 kg/m2, p<0.001), more advanced clinical tumor stage (II-IV: 55.1% vs. 24.4%, p<0.001), and less clinical node involvement (83.1% vs. 89.9%, p=0.016). Among the 452 patients who had an MRI, 39.4% had an additional lesion identified (MRI-NL-NB 14.4%, MRI-NL-B 25.0%). Bilateral mastectomy occurred more frequently among those in MRI-NL-NB and MRI-NL-B (p<0.001). Overall median (IQR) TTT was 40 (26, 64) days, with median TTT 34 (20, 57) days for patients without MRI and 41 (28, 65) days for patients who received MRI (p=0.0001). Among those who received MRI, the median TTT was 42 days for MRI-NNL, 36 days for MRI-NL-NB, and 42 days for MRI-NL-B (p=0.0005). Median follow up was 6 years. Recurrence free survival (RFS) was similar between patients with and without preoperative MRI. RFS was also similar among No-MRI, MRI-NNL, MRI-NL-NB, and MRI-NL-B (5-year RFS: 91.1%, 89.0%, 93.6%, 90.1%, respectively, p=0.41). Conclusions: This analysis demonstrates an increase in median TTT by up to 8 days for patients receiving preoperative MRI compared to those who did not have a preoperative MRI. Interestingly, patients with new findings on MRI which were not biopsied had TTT more similar to those who did not have a preoperative MRI. Although TTT was different between these four groups, RFS was not decreased in the MRI group despite a delay in TTT, suggesting that the delay does not meaningfully impact clinical outcomes. Optimal management of ILC requires a balance between expedited TTT and a thorough investigation to determine the scope of disease. Citation Format: Matthew D. Wright, Marcus S. Dempster, Ayat ElSherif, Daniela Cocco, Stephanie A. Valente, Hong Li, Megan L. Kruse. Assessing the impact of preoperative breast MRI on time to treatment for invasive lobular carcinoma [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-01-25.

Positive margins after mastectomy in patients with invasive lobular carcinoma of the breast: Incidence and management strategies

BackgroundSurgical treatment of invasive lobular carcinoma (ILC) is challenging due to its diffuse growth pattern, and the positive margin rate after mastectomy is poorly described. MethodsWe retrospectively determined the positive margin rate in those with stage I-III ILC undergoing mastectomy. We evaluated the relationship between management strategy and recurrence free survival (RFS). ResultsIn 357 patients, the positive margin rate was 10.6% overall and 18.7% in those with T3 tumors. Having a positive margin was associated with significantly shorter RFS on multivariate analysis (p = 0.01). Undergoing additional local treatment (radiation or re-excision) for a positive margin was significantly associated with improved RFS (p = 0.004). Older women with positive margins were significantly less likely to undergo additional local therapy. ConclusionsEven mastectomy fails to clear margins in a high proportion of patients with large ILC tumors, a finding which may warrant testing neoadjuvant strategies even prior to planned mastectomy.

Lobular Breast Cancer: A Review.

Invasive lobular carcinoma accounts for 5%–15% of all invasive breast cancers, with a marked increase in incidence rates over the past two decades. Distinctive biological hallmarks of invasive lobular carcinoma include the loss of cell adhesion molecule E-cadherin leading to cells with a discohesive morphology, proliferating into single-file strands and estrogen receptor positivity. These key molecular features can make diagnosis difficult, as invasive lobular carcinoma is challenging to detect both physically and with current standard imaging. Treatment of invasive lobular carcinoma strongly favors endocrine therapy due to low chemosensitivity and lower rates of pathological response as a result. This review will summarize the distinct biological and molecular features of invasive lobular carcinoma, focusing on the diagnostic challenges faced and the subsequent surgical and medical management strategies. Prospective therapeutic options will also be explored, highlighting how furthering our understanding of the unique biology of lobular breast carcinoma is essential in guiding and informing the treatment of patients in the future.

Response of metastatic mouse invasive lobular carcinoma to mTOR inhibition is partly mediated by the adaptive immune system

ABSTRACT Effective treatment of invasive lobular carcinoma (ILC) of the breast is hampered by late detection, invasive growth, distant metastasis, and poor response to chemotherapy. Phosphoinositide 3-kinase (PI3K) signaling, one of the major druggable oncogenic signaling networks, is frequently activated in ILC. We investigated treatment response and resistance to AZD8055, an inhibitor of mammalian target of rapamycin (mTOR), in the K14-cre;Cdh1Flox/Flox;Trp53Flox/Flox (KEP) mouse model of metastatic ILC. Inhibition of mTOR signaling blocked the growth of primary KEP tumors as well as the progression of metastatic disease. However, primary tumors and distant metastases eventually acquired resistance after long-term AZD8055 treatment, despite continued effective suppression of mTOR signaling in cancer cells. Interestingly, therapeutic responses were associated with increased expression of genes related to antigen presentation. Consistent with this observation, increased numbers of tumor-infiltrating major histocompatibility complex class II-positive (MHCII+) immune cells were observed in treatment-responsive KEP tumors. Acquisition of treatment resistance was associated with loss of MHCII+ cells and reduced expression of genes related to the adaptive immune system. The therapeutic efficacy of mTOR inhibition was reduced in Rag1−/- mice lacking mature T and B lymphocytes, compared to immunocompetent mice. Furthermore, therapy responsiveness could be partially rescued by transplanting AZD8055-resistant KEP tumors into treatment-naïve immunocompetent hosts. Collectively, these data indicate that the PI3K signaling pathway is an attractive therapeutic target in invasive lobular carcinoma, and that part of the therapeutic effect of mTOR inhibition is mediated by the adaptive immune system.

Abstract 5791: Bromodomain inhibitors for the treatment of invasive lobular carcinoma

Abstract 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<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.

Abstract P1-09-02: Bromodomain inhibitors for the treatment of invasive lobular carcinoma

Abstract 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<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. These results should now be investigated in vivo before a prospective clinical trial. This material is based upon works supported by the Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT Grant CCRC13GAL" and the SFi CDA Award 15/CDA/3438 Citation Format: O'Connor DP, Walsh L, Fan Y, Tarrant F, Chin S-F, Schouten P, Caldas C, Bernards R, Ni Chonghaile T, Gallagher WM. Bromodomain inhibitors for the treatment of invasive lobular carcinoma [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-09-02.

Analysis of stage and clinical pathological characteristics of invasive lobular carcinoma with the 8th AJCC Cancer Staging system

Objective To study the meaning of breast cancer staging system by AJCC eighth edition to invasive lobular carcinoma and analysis the clinical pathological characteristics. Methods According to the eighth edition of the AJCC staging to evaluate the TNM stage and prognosis evaluation of invasive lobular carcinoma cancer patient in Peking University Shenzhen Hospital from 2011 to 2016, and compared with others in clinical pathological data. Results There were 21 cases of invasive lobular carcinoma, accounting for 2.7% of all invasive breast cancer. We found that invasive lobular carcinoma shows no significant difference (P>0.05) in ages, menstrual status, molecular features and anatomic staging and prognosis staging with others; histological grade were significantly different (P< 0.05). There were significant differences in the prognosis and staging of invasive lobular carcinoma. Conclusions Eighth AJCC staging system provides a new reference for the clinical treatment of breast cancer, should be evaluated with anatomic stage. Histological grade is relatively good in invasive lobular carcinoma and the prognosis is good, needs more research to the individualized treatment of invasive lobular carcinoma. Key words: Breast neoplasms; 8th AJCC cancer Staging system; Invasive lobular carcinoma; Anatomy; Prognosis

Abstract P6-11-06: Bromodomain inhibitors represent a rational therapeutic option for the treatment of invasive lobular carcinoma

Abstract 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 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 was associated with poor recurrence-free survival (p&amp;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. These results should now be investigated in vivo before a prospective clinical trial. "This material is based upon works supported by the Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT Grant CCRC13GAL". Citation Format: O'Connor DP, Walsh L, Tarrant F, Chin S-F, Schouten P, Linn S, Bernards R, Caldas C, Gallagher WM, ni Chonghaile T. Bromodomain inhibitors represent a rational therapeutic option for the treatment of invasive lobular carcinoma [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-06.

Recurrent invasive lobular carcinoma presenting as a ruptured breast implant

BackgroundFor years, the treatment for invasive lobular carcinoma (ILC) has been mastectomy secondary to the lack of studies investigating the efficacy of breast conservation therapy on patients afflicted with ILC and due to the lack of long-term follow up investigating locoregional recurrence in this patient population. In this article we report the clinical course of a patient diagnosed with ILC.Case reportWe describe the case of a 50-year-old woman with stage IIB (T2N1M0) ER/PR positive right breast ILC who underwent a right modified radical mastectomy, postoperative chemotherapy, a prophylactic left simple mastectomy with bilateral breast reconstruction and tamoxifen. Approximately 12 years later, she presented with a deflated breast implant and recurrent breast cancer with metastatic spread. She received palliative radiotherapy then palliative chemotherapy. Unfortunately, she succumbed to the cancer less than a year after being diagnosed with metastatic disease.ConclusionsThis may be the first case report of a ruptured breast implant presenting at the same time as the diagnosis of recurrent breast cancer.

Cost effectiveness and impact of pre-operative MR imaging in assessment and surgical treatment of invasive lobular carcinoma of the breast

Cost effectiveness and impact of pre-operative MR imaging in assessment and surgical treatment of invasive lobular carcinoma of the breast

215 Special aspects of local treatment for invasive lobular carcinoma

215 Special aspects of local treatment for invasive lobular carcinoma

Is Surgical Training Excellent in the United Kingdom? – Preliminary Results of an Ongoing Prospective Survey

Is Surgical Training Excellent in the United Kingdom? – Preliminary Results of an Ongoing Prospective Survey

Treatment of invasive lobular carcinoma with breast conserving therapy

11046 Background: Invasive lobular carcinoma (ILC) is the second most common histological type of breast carcinoma .There is still a persisting concern regarding the use of breast-conserving therapy(BCT) in patients with ILC.Difficulty to identify the exact size , location of ILC and multifocality and/or multicentricity are the reasons to suggest that patients with ILC might be poor candidates for BCT. The aim of our current study was to evaluate the possibilty of risk adapted BCT for patients with ILC with or without breast irradiation. Methods: 277 patients with ILC pure or mixed type between 1994 and 2006 were accrued for pospective risk adapted therapy. Contraindications for BCT are multicentricity , inability to obtain negative margins or poor cosmesis. Palpation, mammograpy,ultrasound were routinely done and preoperative MRI in cases with no sharp tumor image. Breast conserving surgery was standardised by performing a radial segmental resection. Inking margins,histological semiserial step sections and specimen radiography was done. Sharp dileneated ILC with a free margins of &gt;/= 1cm and no lymphvesel invasion(LVI) were treated by BCT without breast irradiation(Rx). Patients with ER + were treated with endocrine therapy.Mean follow-up time was 74 months. Results: Of the 277 ILC cases , 55(19,8%) were treated by mastectomy and five patients palliatively because of distant metastases. 217 ILC (79%) were treated with BCT (T1:108/48%;T2:45(21%);T3:67/31% ; NO:135/62%; ER+: 295/94%). 6 patients(2,8%) had local recurrence(LR). 161 ILC (T1 38%; T2 22%; T3 39%; N0 55%) were treated with BCT with Rx. Patients mean age was 57 years. 6(3,7%) of the patients had local recurrence (4 LR only, 2 LR and distant metastases). 56 ILC (T1 69%; T2 15% T3 22% ; NO 81%) were treated with BCT without Rx. Mean age 66 years. There were no LR , 2 patients had distant metastases. Conclusions: Using strict selecting criteria with a standardized breast conserving surgical procedure, thorough histological examination and using all breast imaging possibilities risk adapted BCT for ILC are not more likely to fail than BCT of other types of breast cancer. These results support the use of BCT for ILC patients. No significant financial relationships to disclose.

Surgical treatment for invasive lobular carcinoma of the breast

The management and outcome of 131 women with infiltrating lobular carcinoma treated in the Belfast City Hospital between October 1987 and February 1999 were reviewed. Two patients had primary hormonal treatment and were excluded from the statistical analysis, and 129 patients were followed up. Fifty-four patients (41%) had initial breast conservation surgery, which was followed by re-excision of margins in eight patients (14.8%) and completion total mastectomy in 26 patients (48.1%). The breast conservation surgery group, 28 patients (21.7%), was compared with the total mastectomy group, 101 patients (78.2%), after a median follow-up period of 90 months (range 24–160 months). The overall survival was 68.7%. Survival analysis was performed using Kaplan–Meier and Cox regression which showed that lymph node involvement and tumour grade were the only variables affecting survival ( P<0.0001, and 0.01, respectively). The type of surgery performed did not affect survival ( P=0.42). The total number of patients who developed local recurrence was 17 patients (13.1%, 12 patients in the breast conservation surgery group and five patients in the total mastectomy group, P<0.0001). Kaplan–Meier analysis of local recurrence showed that the type of surgery ( P<0.0001), patient age ( P=0.02), tumour grade ( P=0.002), adjuvant radiotherapy ( P=0.013), chemotherapy ( P=0.031) and hormonal treatment ( P=0.003) significantly affected local recurrence. Cox regression analysis showed that the only factor significantly affecting local recurrence was the type of surgery performed ( P=0.02). Patients who underwent mastectomy had less local recurrence than those who had breast conservation surgery. Local recurrence after breast conservation surgery is high, even with clear surgical margins and post-operative radiotherapy. The authors believe that total mastectomy for infiltrating lobular carcinoma is a safer option to control local disease, especially in younger patients and those with high-grade tumours. Overall survival is not affected by the type of surgical treatment. Local recurrence can be a late event and a long-term follow-up is recommended.

Optimal surgical treatment of invasive lobular carcinoma of the breast.

The roles of breast conservation and surgical evaluation of the contralateral breast in the treatment of lobular carcinoma of the breast remain unclear. The aim of this study was to compare local recurrence, 5-year survival, and incidence of contralateral breast cancer in women with lobular carcinoma to that in women with infiltrating ductal carcinoma. Women with infiltrating ductal carcinoma (IDC) and invasive lobular breast carcinoma (ILC) diagnosed during the years 1984 to 1994 were identified through a statewide tumor registry. The women were divided into groups based on their histology and treatment (breast conservation or modified radical mastectomy). The incidences of contralateral breast cancer, local recurrence, and 5-year survival were compared within each histologic group and treatment category. During the period 1984 to 1994, 4886 women were diagnosed with invasive lobular or ductal breast carcinoma. Of these, 316 (6.5%) had infiltrating lobular cancer. The 5-year survival rates were 68% and 71% for ILC and IDC, respectively (p = 0.5). The local recurrence rates were 2.8% and 4.3% for ILC treated with lumpectomy and axillary nodal dissection (LAND) and modified radical mastectomy (MRM), respectively, which were not significantly different from that obtained with IDC (LAND = 2.5%, MRM = 2.1%). The incidence of contralateral breast cancer during the period was 6.6% and 6.5% for ILC and IDC, respectively. Invasive lobular carcinoma can be safely treated with breast conservation with no difference in local recurrence or survival. In the absence of a suspicious finding on clinical or radiologic examination, routine contralateral breast intervention is not recommended.