Advances in the management of metastatic lobular breast cancer: Current evidence and emerging treatments.

Background: Young women in the US are experiencing rising rates of breast cancer, necessitating effective treatment strategies. Neoadjuvant chemotherapy (NACT) is widely used in clinical practice, yet research on post-NACT outcomes among young women is limited, especially for those with less common histology, e.g., invasive lobular carcinoma (ILC) or invasive ductal and lobular carcinoma (IDLC). In this study, we examined differential pathologic complete response (pCR) and overall survival (OS) between invasive ductal carcinoma (IDC), ILC, or IDLC among female patients (pts) aged ≤40 years with stage I-III disease who received NACT, stratified by molecular subtype. Methods: This hospital-based, retrospective study analyzed data from the 2010-2020 National Cancer Database. We assessed 4 molecular subtypes: HR+/HER2–, HR+/HER2+, HR–/HER2+, and TNBC. pCR, defined as ypT0/Tis ypN0, was modeled using logistic regression, and adjusted odds ratios (aOR) were calculated. OS was event or censored at the time of death from any cause or last known contact, with 5-/10-year OS rates estimated using the Kaplan-Meier method and compared using log-rank tests. We performed Cox regression to generate adjusted hazard ratios (aHR). All models were stratified by molecular subtype, adjusting for clinical T/N stage, tumor grade, PR status (HR+ only), race/ethnicity, year of diagnosis, and comorbidity score. Results: Of 26,480 young women (median follow-up 52.9 [IQR 32.9, 79.2] months), 95.8% had IDC, 2.1% ILC, and 2.1% IDLC. In the HR+/HER2– cohort, 14.9% of IDC pts achieved pCR compared to 3.3% of ILC and 4.1% of IDLC pts (p<.001). After covariate adjustment, pts with ILC (aOR 0.45, 95% CI: 0.23-0.86) or IDLC (aOR 0.49, 95% CI: 0.27-0.89) had lower odds of pCR than IDC pts. In the HR+/HER2+ cohort, a higher pCR rate was observed among IDC pts (33.8%) than ILC (24.3%) or IDLC (27.5%) pts (p=.033). However, the odds of pCR were not significantly different between IDC and ILC (aOR 0.90, 95% CI: 0.56-1.43) or IDLC (aOR 0.77, 95% CI: 0.52-1.13). In the HR–/HER2+ cohort, pCR rates were similar across histologic types (IDLC: 70.6%; ILC: 58.8%; IDC: 49.9%; p=.180). On multivariable regression, pts with ILC (aOR 1.68, 95% CI: 0.60-4.70) or IDLC (aOR 1.96, 95% CI: 0.67-5.73) had similar odds of pCR as those with IDC. In the TNBC cohort, IDC pts achieved a higher rate of pCR than ILC or IDLC pts (36.0%, 21.3% vs. 18.0%; p=.003). Compared to IDC pts, IDLC pts had lower odds of pCR (aOR 0.40, 95% CI: 0.18-0.9) while ILC pts had similar odds of pCR (aOR 0.70, 95% CI: 0.34-1.42). IDC was associated with significantly longer 5-/10-year OS rates (compared to ILC or IDLC) among pts with HR+/HER2– (p=.012) or TNBC (p<.001). In the adjusted models, pts with HR+/HER2– ILC (aHR 1.55, 95% CI: 1.15-2.10) or IDLC (aHR 1.52, 95% CI: 1.15-2.03) had a greater mortality risk than IDC pts. HR–/HER2+ ILC pts also had a higher risk of death than IDC pts (aHR 3.51, 95% CI: 1.10-11.15). In the TNBC cohort, ILC was associated with an increased mortality risk compared to IDC (aHR 2.28, 95% CI: 1.41-3.69). Conclusions: In this US national registry of young women with early-stage breast cancer who received NACT, pts with ILC or IDLC consistently exhibited lower pCR rates and poorer OS than those with IDC across molecular subtypes. These disparities underscore the need for tailored treatment interventions that account for histologic type, particularly for ILC, among young women. Our findings not only highlight the importance of informed NACT counseling, but also underscore the necessity for oncology programs to optimize therapeutic approaches and continue multidisciplinary efforts to reduce disparities specifically for young women with ILC. Citation Format: Jincong Freeman, Jared H. Hara, Olasubomi J. Omoleye, Ted O. Akhiwu, Shreyas Kalantri, Heather J. Hoffman. Early Invasive Lobular or Ductal Carcinoma with Differential Clinical Outcomes Across Molecular Subtypes among Young Women Who Received Neoadjuvant Chemotherapy [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-10-14.

Background: Invasive lobular carcinoma (ILC) has distinctive clinical and genomic features compared to invasive ductal carcinoma (IDC); however, for patients (pts) with ILC treatment is selected according to the same guidelines as IDC. Better characterization of ILC and development of specific approaches for ILC pts is an unmet need. Liquid biopsy (LB) is a useful tool to achieve this goal. Our group showed that, compared to IDC, ILC has specific circulating tumor DNA (ctDNA) alterations and higher CTC count. Another study reported higher detection of CTC clusters (CTC-CL), considered the main seed of metastasis, in ILC. This finding is paradoxical since cell-cell adhesion (a key feature of CTC-CL) is impaired in ILC. Interestingly, an association between CTC-CL counts and ctDNA CDH1 alterations (a hallmark of ILC) was reported, regardless of histology. To investigate whether different mechanisms are responsible for CTC clustering in ILC and IDC, in this study we characterized CTC-CL according to the breast cancer (BC) histotype. Methods: Blood samples were collected from 351 pts with stage IV BC before starting a new line of therapy at Northwestern University (Chicago, IL) between 2016 and 2021 (NU16B06 trial). Blood samples were processed with the CellSearch system for CTC and CTC-CL enumeration by a single expert operator. CTC-CL were defined as groups of ≥2 CTCs , or ≥1 CTC clustered with ≥2 white blood cells (WBCs). The number and size of CTC-CL, and the presence of WBCs in CTC-CL (heterotypic) were compared between ILC and IDC. Also, the association between CTC-CL and overall survival (OS) was tested. To further explore mechanisms of CTC-CL formations, we assessed potential differences in the association between CTC-CL presence and ctDNA alterations in ILC vs IDC. For ctDNA analysis, matched plasma samples were analyzed using Guardant360 and tested for the 10 most altered genes and CDH1. Results: Of the 351 pts included, 255 (73%) had IDC while 45 (13%) had ILC. Overall, CTC-CL were identified in 45 (13%) pts and only in those with ≥ 5 CTCs. The presence of CTC-CL was significantly higher among ILC pts (27% vs 11% in IDC, p=0.004) but the total number of clustered CTCs was significantly lower in ILC than IDC (median 4.5 vs 9.5, p=0.039), suggesting a smaller size of CTC-CL in ILC. Indeed, the median and maximum number of CTCs per CTC-CL was numerically lower in ILC than IDC. Heterotypic CTC-CL were identified in 6 (50%) and 10 (36%) of ILC and IDC pts, respectively. Among these pts, there was a trend for a higher median (0 vs 2, p=0.37) and maximum number of WBCs (2.5 vs 3.5, p=0.26) in CTC-CL in ILC than IDC. Overall, the presence of >3 CTC-CL was associated with shorter OS (6 vs 21 months, p=0.001). A matched plasma sample for ctDNA analysis was available for 129 IDC and 19 ILC pts. CDH1 alterations were detected in 2 IDC and 1 ILC pts and associated with CTC-CL (p=0.015) only in IDC. No significant association between ctDNA alterations and CTC-CL was observed in ILC possibly due to the small sample size; further analysis is ongoing. Conclusion: ILC is characterized by a higher number of CTC-CL than IDC. CTC-CL in ILC appear to be different from IDC, being smaller but more frequently associated with WBCs. This suggests a possible different biology for CTC-CL formation in ILC related to the impaired cell-cell adhesion and a specific role played by the CTC-CL microenvironment. Indeed, the interaction with immune cells in ILC may promote the survival in the bloodstream of smaller CTC-CL thus enhancing metastatic efficacy. Further studies including a larger number of pts are needed to validate and better elucidate these findings. The study of CTC-CL could shed light on the distinct pattern of metastatic spread of ILC, potentially offering therapeutic opportunities, and serving as a useful prognostic factor. Citation Format: Eleonora Nicolò, Elisabetta Molteni, Lorenzo Foffano, Lorenzo Gerratana, Mara S. Serafini, Letizia Pontolillo, Caterina Gianni, Laura Munoz-Arcos, Nadia Bayou, Kaylan Strickland, Hunter Gaudio, Brenno Pastò, Maroua Manai, Youbin Zhang, Paolo D’Amico, Andrew A. Davis, Jeannine Donahue, Huiping Liu, William J. Gradishar, Giuseppe Curigliano, Carolina Reduzzi, Massimo Cristofanilli. Investigating differences in the composition of circulating tumor cells (CTCs) clusters in invasive lobular and ductal carcinoma to decipher lobular breast cancer metastasis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-09-23.

Background:Invasive lobular carcinoma (ILC) is the second most common histology of breast cancer, accounting for approximately 10-15% of cases. Prior studies have demonstrated that loss of E-cadherin, as well as alterations in tissue including CDH1, FOXA1, TBX3 and PTEN loss, that were more commonly observed in Luminal A ILC, while GATA3 was more commonly observed in invasive ductal carcinoma (IDC) (Ciriello et al., Cell 2015). However, data regarding the characterization of circulating tumor DNA (ctDNA) in patients (pts) with metastatic ILC are limited. We hypothesized that there would be distinct mutational profiles between pts with metastatic ILC and IDC that could be characterized using ctDNA. Methods:This retrospective cohort study included de-identified clinical, pathological, and ctDNA data from pts with metastatic breast cancer (MBC) combined under a data use agreement and approved by the institutional review boards of three sites: Washington University in St. Louis (MO), Northwestern University (Chicago, IL), and Massachusetts General Hospital (Boston, MA). All pts included in the study had ctDNA testing per standard of care with plasma-based genotyping performed by Guardant360 (Redwood City, CA) between 2015-2020. Histological classification (ILC vs. IDC) was defined based on review of pathology reports from the primary tumor or from breast biopsies of de novo MBC, and additional clinical and pathological variables were obtained via electronic medical record review. Single nucleotide variants (SNVs) were annotated using OncoKB and ClinVar and only pathogenic variants were included. Mutational profiles were compared across histologic subtypes using Fisher’s exact test to assess differences in alteration frequency across subtypes. Multivariable analysis was performed. Results:A total of 994 pts with MBC underwent ctDNA testing and were included in the analysis. 10.7% of pts had ILC (N=106) and 89.3% had IDC (N=888). 89.4% of ILC cases were categorized as hormone-receptor positive (HR+) compared with 67.1% of IDC cases. Pts with ILC had a lower frequency of triple-negative (6.7% vs. 17.7%) and HER2 positive (3.9% vs. 15.2%) breast cancer compared with IDC. Pts with ILC had a significantly higher number of pathogenic SNVs compared with IDC (mean 4.45 vs. 2.77; P=0.0037). In contrast, pts with ILC had a significantly lower number of copy number alterations as compared to pts with IDC (mean 0.40 vs. 1.03; P=0.0017). No differences were observed in mutant allele frequency between pts with ILC and IDC. The 5 most common alterations observed in pts with ILC were the following: PIK3CA, TP53, ESR1, ERBB2, and ARID1A. Alterations in AR, BRAF, CDH1, ERBB2, FGFR2, IDH2, KRAS, NF1, PIK3CA, SMAD4, and TERT were significantly higher in ILC than IDC (all P<0.05). In contrast, mutations in GATA3, and amplifications in ERBB2 and MYC were significantly more common in pts with IDC (all P<0.05). In multivariable analysis, mutations in BRAF, CDH1, ERBB2, IDH2, TERT remained significantly higher in ILC, while amplification of MYC was significantly higher in IDC (all P<0.05). After restricting the analysis to pts with HR+ HER2 negative MBC, the following genes were significant in multivariate analysis: CDH1 and ERBB2 for pts with ILC and MYC amplification for pts with IDC (all P<0.05). Discussion:In this large, multi-institutional dataset, pts with metastatic ILC were characterized by a significantly higher number of SNVs in ctDNA compared to pts with IDC, suggesting higher mutational burden. We report several alterations that were significantly different in ILC vs. IDC. These results demonstrate the ctDNA profile of pts with ILC, and future studies should explore serial plasma-based genotyping to track ILC evolution to develop targeted precision medicine based therapeutic approaches for this unique subset of pts with MBC. Citation Format: Andrew A Davis, Lorenzo Gerratana, Katherine Clifton, Marko Velimirovic, Whitney L Hensing, Ami N Shah, Paolo D’Amico, Carolina Reduzzi, Qiang Zhang, Charles S Dai, Elyssa N Denault, Nusayba A Bagegni, Mateusz Opyrchal, Foluso O Ademuyiwa, Ron Bose, William J Gradishar, Amir Behdad, Cynthia X Ma, Aditya Bardia, Massimo Cristofanilli. Circulating tumor DNA characterization of invasive lobular carcinoma in patients with metastatic breast cancer [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 PD14-04.

Invasive lobular carcinoma (ILC) has a greater tendency to metastasize to the peritoneum, retroperitoneum, and gastrointestinal (GI) tract as compared to invasive carcinoma of no special type (NST). Like primary ILC in the breast, ILC metastases are frequently infiltrative and hypometabolic, rather than mass forming and hypermetabolic in nature. This renders them difficult to detect on conventional and metabolic imaging studies. As a result, intra-abdominal ILC metastases are often detected late, with patients presenting with clinical complications such as liver failure, hydronephrosis, or bowel obstruction. In patients with known history of ILC, certain imaging features are very suggestive of infiltrative metastatic ILC. These include retroperitoneal or peritoneal nodularity and linitis plastica appearance of the bowel. Recognition of linitis plastica on imaging should prompt deep or repeat biopsies. In this pictorial review, the authors aim to familiarize readers with imaging features and pitfalls for evaluation of intra-abdominal metastatic ILC. Awareness of these will allow the radiologist to assess these patients with a high index of suspicion and aid detection of metastatic disease. Also, this can direct histopathology and immunohistochemical staining to obtain the correct diagnosis in suspected metastatic disease.

Background: Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the two most common histologic subtypes of breast cancer (BC), with IDC accounting for approximately 70-80% of cases and ILC comprising 10-15%. Improved screening and advances in breast cancer treatment have increased survivorship but also heightened the risk of second primary malignancies (SPMs) among long-term survivors. Our study presents a comparative analysis of the types of SPMs among ILC and IDC survivors. Methods: Using the National Cancer Institute’s Surveillance, Epidemiology, and End Results(SEER) 8 database registry, we identified a cohort of female patients diagnosed with ILC and IDC between 1975 and 2022. We analyzed the incidence of SPM using the SEER*Stat MultiplePrimary-Standardized Incidence Ratio (MP-SIR) session for the overall cohort of females with ILC and IDC. The cohort was further stratified by age (< 40 years and >/= 40 years). Standardized incidence ratios (SIRs) were calculated to compare the observed rates with the expected rates between ILC/IDC and the general population. Results: Both ILC and IDC had an increased risk of all types of SPMs, with SIRs of 1.09 (95%CI: 1.06-1.11) for ILC and 1.14 (95% CI: 1.14-1.15) for IDC. Some sites emerged as commonsites of SPMs for both ILC and IDC, and those with highest SIRs include soft tissue (ILC: SIR =1.72; IDC: SIR = 1.55, p < 0.05), thyroid (ILC: SIR = 1.42; IDC: SIR = 1.22, p < 0.05), skinexcluding basal and squamous (ILC: SIR = 1.19; IDC: SIR = 1.06, p < 0.05), and acute myeloidleukemia (ILC: SIR = 1.90; IDC: SIR = 1.78, p < 0.05). Sites for SPM unique to ILC include mainly the stomach (SIR = 1.58, CI 1.33 - 1.86) and melanoma of the skin (SIR = 1.18, CI 1.05 -1.32). Sites for SPM unique to IDC with p < 0.05 include salivary gland, esophagus, pleura, lung, bones and joints, corpus uteri, and acute lymphocytic leukemia (Table). Greater incidence of SPMs was observed for patients age< 40 for both ILC and IDC (ILC: age < 40 SIR = 1.84 vs age >/= 40 SIR = 1.08; IDC: age < 40SIR = 1.98 vs age >/= 40 SIR = 1.11). For ILC, SPM with involvement of the stomach is seen in the cohort of both age categories, but did not reach statistical significance for age < 40 (age < 40:SIR = 4.22, CI 0.87-12.33; age >/= 40: SIR = 1.56, CI 1.31-1.84). Conclusion: Our study provides a detailed understanding of the variation in the pattern of SPMs for both ILC and IDC. Patients with ILC exhibited a higher propensity to develop SPM at specific sites, such as the stomach and skin melanoma, highlighting the need for further investigation into the underlying biological mechanisms. Conversely, IDC has a broader distribution of unique SPMs involving the lung, pleura, salivary gland, esophagus, uterus, and bones. Younger patients exhibited a higher risk of SPMs in both ILC and IDC cohorts. These findings underscore the importance of a tailored surveillance strategy based on histological subtype. Citation Format: S. Singh, S. Sangam, B. Zengin, S. Modi, H. Jain, A. MariamRoy. Comparative analysis of second primary malignancies in invasive lobular versus ductal breast carcinoma: A SEER-based study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-04-10.

Background: ILC is the second most common histologic subtype of breast cancer (BC) comprising about 15% of invasive BCs. Despite differences in clinical behavior compared to NST, patients (pts) with these histologies are treated the same. Genomic analyses may provide insights into treatment strategies for this subset of BCs. The genomic landscape of early-stage ILC has been previously described. In this analysis we describe the genomic alterations of pts with metastatic ILC and clinical outcomes in the metastatic setting compared to pts with NST histology. Methods: Pts with metastatic, ER+/HER2- BC seen at least once at Dana-Farber Cancer Institute between 7/1/2001 and 8/2/2022 who had targeted tumor only DNA sequencing (OncoPanel) of ≥1 archival tissue sample collected within 3 months (mo) of diagnosis of distant recurrence/de novo metastatic disease were included. Clinical annotation for these pts was available and median time to next treatment (mTTNT) for pts receiving endocrine therapy (ET) + CDK4/6 inhibitor as first-line treatment and median overall survival (mOS) were compared between ILC and NST cohorts. Genes with oncogenic single nucleotide variants (SNV) and copy number variants (CNV) occurring at a frequency above 0.03 were tested via Fisher enrichment, with a Benjamini-Hochberg correction, for differences across clinicopathological characteristics. Kaplan-Meier analysis and Cox proportional hazards models were used to assess significant predictors of survival across and within ILC and NST cohorts. Results: 533 pts met criteria for inclusion in the final analytic cohort (ILC n=125; NST n=408, mixed histology excluded). In the ILC cohort, at the time of initial diagnosis 8.0% of pts had stage I disease, 22.4% stage II, 27.2% stage III, and 40.8% de novo metastatic disease. The median disease-free interval was 5.4 years (yr) (range 1.0-30.9). Genomic analyses of ILC samples revealed 16 genes mutated and 2 genes with high amplifications (amp) or deep deletions in ≥3% of ILC tumors. The most commonly altered genes with SNVs or INDELS were CDH1 (76%), PIK3CA (58%), TP53 (14%), ESR1 (10%), PTEN (6%), NF1 (6%), MAP3K1 (6%), ERBB2 (6%), and AKT1 (5%). The genes with most frequent CNVs were CCND1 amp (16%) and FGFR1 amp (7%). Comparing pts with early (0-5 yr, n=36) vs. late (5+ yr, n=38) recurrence showed CDH1 and ERBB2 SNVs were associated with early recurrence (odds ratio (OR)=0.18, p=0.0037, q=0.0394 and OR=0, p=0.0046, q=0.0394 respectively). Pts with liver metastases (mets) at the time of metastatic diagnosis (n=26) were more likely to have ERBB2 alteration (OR=14.1, p=0.001, q=0.0171). Comparing prevalence of gene alterations between ILC and NST, alteration in CDH1, PIK3CA, ERBB2, and MEN1 was more common in ILC while GATA3, TP53, FGFR1, ZNF217, CDKN2A, and IGF1R was more common in NST. mTTNT was not significantly different in pts who received ET + CDK4/6 inhibitor in the first line setting comparing ILC (9.5 mo [95% confidence interval (CI): 6.8-21.0]) to NST (10.2 mo [95% CI: 9.0-14.1]) (p=0.78) and mOS did not significantly differ between ILC (43.4 mo [95% CI: 38.3-not reached (NR)]) and NST (57.2 mo [95% CI: 41.8-78.8]) in this subset (p=0.74). There was no significant difference in mOS comparing all pts with ILC [4.2 yr (95% CI: 3.5-5.3)] to NST [4.3 yr (95% CI: 3.9-5.3)] (p=0.54). The presence of liver mets at diagnosis was associated with significantly shorter mOS in both ILC and NST (p<0.001) but there was no difference in mOS comparing pts with liver mets with ILC vs. NST (31.3 mo (95% CI 14.36-NR) vs 35.0 mo (95% CI: 28.5-41.4), [p=0.22]). Conclusion: Metastatic ILC has a unique genomic landscape which provides avenues for development of treatments designed specifically for this population. Pts with metastatic ILC had similar clinical outcomes to those with NST. Citation Format: K. Fanucci, S. Challa, Y. Li, G. Nader-Marta, A. Martin, M. Hughes, B. E. Johnson, L. Sholl, D. Dillon, B. Carroll, S. M. Tolaney, A. Cherniack, N. U. Lin, R. Jeselsohn. Genomic analysis of ER+/HER2- metastatic invasive lobular carcinoma (ILC) and clinical outcomes comparison with metastatic invasive carcinoma of no special type (NST) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-10-18.

Background: Circulating tumor cells (CTCs) have repeatedly been shown to carry independent prognostic information in metastatic breast cancer (MBC). A CTC count of 5 cells per 7.5 mL blood is a generally accepted cut-off, where MBCs with <5 CTCs are classified as MBCindolent and ≥5 CTCs as MBCaggressive. Furthermore, several studies have shown that the presence of CTC clusters add prognostic information to CTC count alone. Invasive lobular carcinoma (ILC) is the second most common histological breast cancer (BC) type (~10%). The vast majority of all BCs (~80%) are classified as invasive ductal carcinoma (IDC). Many distinguishing clinicopathological and genomic features have been identified between these two types, but in spite of this, current clinical management strategies and treatments are similar and mainly based on studies dominated by IDCs. The aim of this study was to explore potential differences in the distribution and prognostic significance of CTC count and CTC clusters in metastatic ILC vs. IDC, in a prospective observational study. Patients and methods: Between April 2011 and June 2016, 139 women with newly diagnosed metastatic ILC (N=28) and IDC (N=111) were included. CTCs and CTC clusters were detected, using CellSearch technology (Menarini Silicon Biosystems), at baseline (BL) before first-line systemic therapy, and during the first 6 months of follow-up (FU). The primary endpoint was progression-free survival (PFS) and the secondary endpoint overall survival (OS). Median FU time was 49 (27-93) months. Results: There was a highly significant (P<0.001) difference in the median CTC count between ILC (70, range 0-2598) and IDC (2, range 0-668) at BL, and presence of CTC clusters was also higher (36% vs. 18%, P=0.07). These differences between ILC and IDC persisted in the luminal A-like subgroup. The CTC count and CTC clusters declined in both ILC (median count 4, range 0-85; clusters: 4%) and IDC (median count 0, range 0-263; clusters: 12%) after 1 month of systemic treatment, but the decline was most pronounced in ILC. Seventy-nine percent of the ILCs and 46% of the IDCs were classified as MBCaggressive (CTC ≥5) at BL (P=0.003). The prognostic value of CTC ≥5 on PFS (HR 1.5, 95% CI 0.55-4.0, P=0.44) and OS (HR 2.4, 95% CI 0.71-8.3, P=0.16) in ILC was weak, whereas significant prognostic effects were seen in IDC (PFS: HR 1.7, 95% CI 1.2-2.6, P=0.007; OS: HR 2.1, 95% CI 1.3-3.3, P=0.002). With higher cut-offs the prognostic impact of CTC count on PFS/OS was significant also in ILC (CTC ≥20: HR 3.0, 95% CI 1.3-6.8, P=0.01 / HR 3.1, 95% CI 1.2-8.3, P=0.02) (CTC ≥80: HR 3.6, 95% CI 1.5-8.8, P=0.004 / HR 5.9, 95% CI 2.0-17.8, P=0.002) and the prognostic effect in IDC remained. The presence of ≥1 CTC cluster was a negative prognostic factor significantly associated with impaired survival in ILC (PFS: HR 4.6, 95% CI 1.7-12.4, P=0.003; OS: HR 4.9, 95% CI 1.7-13.8, P=0.003), whereas the effect was weaker in IDC (PFS: HR 1.2, 95% CI 0.69-2.0, P=0.55; OS: HR 1.9, 95% CI 1.1-3.3, P=0.02). First-line systemic treatment was similar in ILC vs. IDC (endocrine 46% vs. 39% and chemotherapy 54% vs. 61%) and the overall prognosis did not differ (PFS: HR 0.89, 95% CI 0.57-1.4, P=0.59; OS: HR 0.99, 95% CI 0.60-1.6, P=0.96). Conclusions: In this study of metastatic ILC and IDC, the CTC count at BL was remarkably higher in ILCs and the presence of CTC clusters was also more common, in spite of the fact that no difference in prognosis was seen. The prognostic value of the generally accepted CTC cut-off (≥5) was clearly weaker and the presence of CTC clusters stronger in ILC vs. IDC. A higher cut-off might be more suitable in ILCs in order to better discriminate between MBCindolent and MBCaggressive forms, and CTC clusters could potentially add prognostic information. Citation Format: Ulrik Christoffer Narbe, Pär-Ola Bendahl, Kristina Aaltonen, Mårten Fernö, Carina Forsare, Charlotte Levin Tykjær Jørgensen, Anna-Maria Larsson, Lisa Rydén. The distribution and prognostic significance of circulating tumor cells are different in invasive lobular carcinoma compared to invasive ductal carcinoma of the breast [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 P4-01-04.

Background: Activating mutations in ERBB2 (HER2) are enriched >4-fold in invasive lobular carcinoma (ILC) with a rate of up to 19% in metastatic ILC. ILC is a histologic subtype of breast cancer characterized by loss of E-cadherin (CDH1), suggesting a potential interaction between loss of CDH1 and mutations in ERBB2. Recent trials have demonstrated promising single agent efficacy using the irreversible pan-HER tyrosine kinase inhibitor (TKI), neratinib, in patients with metastatic ERBB2 mutant ILC. However, further studies on combination therapies with other anticancer agents are needed to increase response rate and progression free survival for these patients. HER2-targeted antibody drug conjugates (ADC), particularly trastuzumab deruxtecan (T-DXd), have shown great promise in HER2-low metastatic breast cancer. Yet, their efficacy as a single agent or with HER2 TKIs in HER2-low and -mutant ILC is unknown and warrants investigation. Methods: Past studies analyzing ERBB2 mutations used overexpression of ERBB2 mutant cDNA, but this approach does not faithfully recapitulate the human disease. To model ERBB2 missense mutations as found in human breast cancers, we used CRISPR-based prime editing to generate a panel of isogenic ILC cell lines and patient-derived organoids (PDO) harboring ERBB2 wild-type (WT) or ERBB2 mutations (S310F or V777L). Both of these ERBB2 mutations have been previously characterized and are known to be activating mutations. We then used them to test neratinib and other TKIs with ADCs, including T-DXd and trastuzumab emtansine (T-DM1). Results: We successfully introduced single copy, heterozygous activating ERBB2 mutations (S310F or V777L) into two ERBB2-nonamplified metastatic ILC cell lines (MDA-MB-134 and SUM44PE) and one ERBB2-nonamplified metastatic ILC PDO (IPM-BO-053). Positive clones carrying the mutations were verified by Sanger sequencing and droplet digital PCR and subsequently pooled together. We further demonstrated that these mutations hyperactivated HER2 and downstream signaling pathways. ILC cell lines harboring these mutations showed enhanced sensitivity to HER2 TKIs but not ADCs. In contrary, ERBB2 mutations did not alter responses of IPM-BO-053 PDOs to HER2 TKIs but significantly increased responses to ADCs. Interestingly, we also observed accelerated HER2 protein degradation upon heregulin stimulation in ERBB2 mutant ILC PDOs, suggesting activating ERBB2 mutations may enhance ADC/HER2 complex internalization, degradation, and release of payloads. Lastly, we explored drug synergy between HER2 TKIs and ADCs in isogenic IPM-BO-053 PDOs and found that combination of T-DXd and neratinib or afatinib showed synergy (Combination Index < 1). Conclusions: Although the reason for the discrepancies in drug response between ILC cell lines and PDOs is not clear, we hypothesize that response in 3D PDOs might be more faithfully representing response seen in patients. We will generate additional ILC PDOs with knock-in ERBB2 mutations to validate our findings. Irreversible HER2 TKIs, such as neratinib and afatinib, showed synergy with T-DXd in ERBB2 mutant ILC PDOs. This holds important therapeutic implications in light of current treatment options for ILC. In future experiments, we will test if neratinib or afatinib increases endocytic uptake of T-DXd using a fluorescently labeled endocytosis tracker. Further, an in-depth molecular characterization of our isogenic cell lines and PDOs models is ongoing to gain mechanistic insights into how activating ERBB2 mutations increase HER2 internalization and degradation. Our in vitro studies provide a strong foundation for in vivo testing of neratinib or afatinib with T-DXd for ERBB2 mutant ILC. Citation Format: Jie Bin Liu, Danielle Tseng, Jagmohan Hooda, Daniel Brown, Adrian Lee, Steffi Oesterreich. Predicting Response to HER2 Tyrosine Kinase Inhibitors and Antibody Drug Conjugates in HER2 Mutant Invasive Lobular Carcinoma Using CRISPR/Cas9 Knock-in Cell lines and Patient-derived Organoids [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 PO4-14-12.

1085 Background: Mixed invasive ductal lobular carcinoma (mIDC/ILC) is a poorly described subtype of invasive breast cancer, characterized by its composition of both ductal and lobular histopathology. It is unclear if individual or both components drive metastasis. Literature is sparse regarding sites of metastatic spread of this elusive subtype of invasive breast cancer. Methods: Cohorts of patients with mIDC/ILC, invasive ductal carcinoma (IDC), and invasive lobular carcinoma (ILC) were identified from the UPMC Network Cancer Registry. Among these, 46 patients with mIDC/ILC, 1,131 patients with IDC, and 145 patients with ILC seen at UPMC Magee Women’s Hospital from 1990 – 2017 were found to have developed distant metastasis during the course of their disease. The metastatic pattern of spread was compared between the cohorts. Formalin-fixed, paraffin-embedded patient samples from the metastatic sites of a portion of the mIDC/ILC cases (n = 19) was acquired and evaluated by H&E staining. Results: Patients with IDC were more likely than patients with ILC to have metastasis to the liver (p = 0.001) and lung (p < 0.001), and less likely to have metastasis to the peritoneum (p < 0.001). Patients with mIDC/ILC were more likely than patients with IDC to have peritoneal metastasis (p = 0.01), similar to patients with ILC. Compared to patients with ILC, patients with mIDC/ILC were more likely to have liver metastasis (p = 0.001), similar to patients with IDC. Evaluation of the metastatic lesions originating from mIDC/ILC displayed a spectrum of histopathology including mixed histology (n = 3), pure IDC (n = 3), pure ILC (n = 5), and indeterminate lesions with features of both IDC and ILC (n = 6). Two cases were uninterpretable due to significant crush artifact. Metastatic mIDC/ILC lesions with retained mIDC/ILC histology were found in vertebral, pleural, and skin tissues. Metastatic mIDC/ILC lesions with IDC histology were found in a cerebellar, liver, and chest wall lesion; whereas, those with ILC histology were found in bowel, omental fat, ovary, bone, and sacrum. Indeterminate histology metastatic lesions were found at liver, chest wall, cerebellar, and bone sites. Conclusions: mIDC/ILC metastasizes to a range of distant sites with a higher preference to the liver and peritoneum as compared to ILC and IDC, respectively. Metastatic lesions arising from mIDC/ILC tumors showed a spectrum of histologies, including mIDC/ILC, IDC, ILC and indeterminate lesions with features of both IDC and ILC. Ongoing genomics studies will provide further insight into development of metastases from mIDC/ILC tumors.

Background: Post-mastectomy radiation therapy (PMRT) can improve locoregional control and overall survival in patients with invasive breast cancer, particularly those with high-risk features such as ≥4 positive lymph nodes or T3-T4 tumors. However, data on the utilization and effectiveness of PMRT across different histological subtypes remain limited. Invasive lobular carcinoma (ILC), the second most common histologic subtype of breast cancer, differs from invasive ductal carcinoma (IDC) in its features and clinical outcomes, with more hormone receptor positive status and lower grade, but typically higher stage at presentation, higher risk of positive surgical margins, and propensity for late recurrences. Given the unique features of ILC, including a characteristic diffuse growth pattern, we hypothesized that more patients with ILC would receive PMRT, and, that the use of PMRT might have relatively greater survival benefit in patients with ILC than those with IDC. Methods: We used the National Cancer Database (NCDB) to identify patients diagnosed with pathologic stage I-III breast cancer between 2010 and 2020 who underwent mastectomy, with or without adjuvant radiation therapy. Patients who received neoadjuvant radiotherapy or intraoperative radiotherapy were excluded. We considered the following criteria to be an indication for PMRT: T3 tumor with age <50 years, T3 tumor with lymphovascular invasion (LVI), N2 or greater nodal involvement, positive surgical margins, tumor grade 3 with LVI, T1-2N2 category with tumor grade 3 or LVI. PMRT utilization was compared between ILC and IDC using chi-square analyses, and stratified by age, tumor stage, and receptor subtype. Multivariable Cox proportional hazards models were used to evaluate the association between PMRT and overall survival (OS), adjusting for age, T category, N category, hormone receptor/HER2 subtype, and tumor grade in ILC and IDC cohorts; a test of interaction between histology and PMRT was included to assess differential benefit. Results: Of 1,774,249 patients with stage I-III breast cancer in the NCDB, 472,499 patients met our eligibility criteria, of whom 94,359 (20%) had ILC and 378,140 (80%) had IDC. In total, 32% patients received PMRT, with significantly higher utilization rates in patients with ILC compared to IDC (37% vs 30%, p<0.001). In stratified analysis, ILC patients had more PMRT across receptor subtypes and age groups, but only within the stage III cohort, suggesting that higher stage is driving increased PMRT in ILC patients. Among patients meeting the indication for PMRT, those who received radiation had improved overall 5-year survival than those who did not (log-rank p<0.001). In separate multivariable models within the subgroups of ILC and IDC, the adjusted hazard ratio for death within 5-years in ILC patients was 0.66 (95% CI: 0.62-0.70, p<0.001) in those receiving PMRT compared to those who did not, while in IDC patients it was 0.74 (95% CI: 0.72-0.76, p<0.001), with a significant test of interaction (p=0.01), suggesting differential survival benefit by histologic subtype. Conclusion: PMRT is more frequently utilized in patients with ILC than those with IDC. While PMRT is associated with improved overall survival in both subtypes, the relative benefit of PMRT appears greater in patients with ILC than IDC, perhaps reflecting the greater risk of occult residual disease in those with diffusely growing tumors like ILC. These findings highlight the importance of considering histologic subtype when evaluating the role of PMRT and the need to tailor radiation strategies in lobular breast cancer. Citation Format: Y. Chen, A. Shui, C. Lee, A. Vertido, M. Kaur, J. Moya, E. Abeles, A. Quirarte, J. A. Mouabbi, N. Prionas, R. Mukhtar. Comparing Utilization and Survival Outcomes of Post-mastectomy Radiation Therapy in Invasive Lobular versus Ductal Carcinoma: A National Cancer Database Analysis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-07-19.

Mixed invasive ductal and lobular carcinoma (Mixed IDC/L) is a rare subtype (3-5%) of invasive breast cancer with elusive pathophysiology. This entity is characterized by a mixed population of both ductal and lobular components within an individual tumor. Few studies have been published to date which compare Mixed IDC/L to invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) from a histopathologic perspective. Available literature on this topic is sparse and has been conflicting with regards to outcomes, and no studies to date describe the response of Mixed IDC/L to neoadjuvant chemotherapy. Patients with ILC have been shown to have lower response rates to neoadjuvant chemotherapy as compared to patients with IDC, which in turn leads to lower rates of successful breast conserving surgery and higher rates of re-excision due to positive margins. We aimed to compare Mixed IDC/L to pure ILC with regards to response to neoadjuvant chemotherapy and the need for repeat surgical intervention. We identified 26 patients with Mixed IDC/L and 113 patients with ILC who received neoadjuvant chemotherapy at our institution between 1990 – 2017. At baseline, the groups had a similar median age, as well as ER H-score, PR H-score, and Ki-67 index. There was no statistical difference in rates of pathologic complete response (pCR) or percent tumor volume reduction post therapy between the two groups. Similarly, the percent of patients that required re-excision was not statistically different. Interestingly, the metastatic pattern was similar between the groups and included sites of dissemination such as the peritoneal cavity and omentum, which are not common sites of metastasis for IDC. These findings suggest that Mixed IDC/L tumors behave similarly to ILC with regard to their response to neoadjuvant chemotherapy and patterns of metastatic spread. These findings support a prominent role for the lobular component in this mixed subtype in driving biology, including response to neoadjuvant therapy and metastatic dissemination. Ongoing efforts are directed towards incorporating data from the IDC cohort, as well as evaluation of changes in histology, ER/PR H-scores, and Ki-67 levels as a result of therapy. These data may imply that Mixed IDC/L tumors may behave clinically more like ILC than IDC, but larger studies are needed to study this rare breast cancer subtype. Citation Format: Azadeh Nasrazadani, Jennifer M Atkinson, Yujia Li, Priscilla F McAuliffe, Rachel C Jankowitz, Leisha A Emens, George C Tseng, Adrian V Lee, Norman Wolmark, Steffi Oesterreich, Peter C Lucas. Mixed invasive ductal and lobular carcinoma (IDC/L) behaves similarly to invasive lobular carcinoma (ILC) with regard to neoadjuvant chemotherapy response and metastatic dissemination [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 P2-16-26.

Clinicopathologic differences between histological subtypes of invasive breast cancer are increasingly being appreciated. Mixed invasive ductal lobular carcinomas (mDLC) are thought to be composed of both ductal and lobular components, and we sought to determine whether mDLC clinically align more closely with invasive ductal (IDC) or invasive lobular (ILC) carcinoma subtypes or if they display intermediate or unique features dissimilar to either type. Key clinical and histologic parameters were compared between cohorts of patients with mDLC (N = 410), IDC (N = 12,979), and ILC (N = 1,569) identified from cancer registry data of a single large healthcare system.Patients with mDLC were older (59 years (49 - 68)) than those with IDC (57 years (48 - 67), p = 0.014)) and younger than those with ILC (61 years (51 - 70), p = 0.006). Tumor size in mDLC was larger (19mm (12 - 27)) than IDC (16mm (10 - 25), p < 0.001) and smaller than ILC (20mm (12 - 35), p = 0.036). Similar to ILC, mDLC were more likely than IDC to be ER+ (92% vs 78% in IDC, p < 0.001), and less likely to be HER2+ (8% vs 15% in IDC, p = 0.04). mDLC were also similar to ILC with regards to higher likelihood of diagnosis at higher stage (p < 0.001), yet with lower grade (p < 0.001), at diagnosis as compared to IDC. Heatmap visualization, as well as dimension reduction by multidimentional scaling (MDS), demonstrates significant overlap of the mDLC and ILC cohorts. Furthermore, an elastic net regression model based on clinicopathologic parameters predicts mDLC to align more closely with ILC than IDC. For patients for whom oncotype Dx scores were available, there was a trend for enrichment of low risk RS scores with rare high-risk RS tumors in mDLC, similar to ILC. With regards to response to neoadjuvant chemotherapy, a subset of the aforementioned cohorts who had received neoadjuvant chemotherapy, mDLC (N = 17), IDC (N = 180), and ILC (N = 57), were compared. Among patients in whom breast conserving surgery (BCS) was attempted, patients with IDC were more likely to have a successful BCS than those with ILC, with less margin positivity thereby avoiding re-excision and/or completion mastectomy (70% vs 32%, respectively; p = 0.003). Successful BCS was achieved with mDLC 56% of the time, although compared to IDC and ILC statistical significance was not reached. In a limited cohort receiving neoadjuvant endocrine therapy (mDLC (N = 7), IDC (N = 37), and ILC (N = 21)) no differences with regard to rates of successful BCS were identified. Pathologic complete response rates (pCR) were additionally evaluated, although small study numbers precluded our ability to perform statistical analysis.Collectively, the aforementioned findings support a higher concordance between mDLC and ILC as compared to IDC. It is feasible that the lobular component of mDLC tumors is predominant, leading to the observed histopathologic similarities noted between mDC and ILC cohorts. We are planning meta-analyses including data from other institutions, and molecular studies to further understand complexities of mDLC.The authors acknowledge grant support from ASCO Conquer Cancer (to NW and AN). Citation Format: Azadeh Nasrazadani, Yujia Li, Yusi Fang, Osama Shah, Jennifer M Atkinson, Joanna S Lee, Priscilla F McAuliffe, Adrian V Lee, George Tseng, Peter Lucas, Steffi Oesterreich, Norman Wolmark. Mixed invasive ductal lobular carcinomas (mDLC) are clinically more similar to invasive lobular carcinoma (ILC) than to invasive ductal carcinoma (IDC) [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 PS7-15.

Benefits of endocrine therapy in treating hormone receptor (HR)-positive (HR+) BC are well recorded in clinic. However, ~40% to 50% of HR+ patients eventually developed to endocrine resistance and disease relapsed. Fulvestrant, a selective estrogen receptor degrader (SERD) is approved to treat HR+ metastatic breast cancer in patients with disease progression after endocrine therapy. However, due to its poor bioavailability, it is given by intramuscular injection, which makes inconvenience in administration. Additionally, approximately 14% of hormone positive patients with advanced breast cancer are diagnosed with brain metastases, while, at present, there are no FDA-approved systemic therapies for the treatment of breast cancer brain metastases. Therefore, to develop a new generated oral and brain-penetrant SERD to overcome these challenges is believed to be needed. SCR6106, discovered and currently being developed by Simcere, is a novel, potent, orally delivered and non-steroidal SERD that both antagonizes and degrades ERα. SCR6106 showed high potency on inducing ERα protein degradation (DC50=0.29 nM) and anti-proliferation (IC50=0.43 nM) in MCF7 cells. In addition, SCR6106, showed high activities on ERα degradation and anti-proliferation in a panel of ER+ breast cancer cell lines. Meanwhile, ER target genes transcription were evaluated and SCR6106 exhibit strong suppressive phenotype in T-47D. SCR6106 demonstrated more potent than fulvestrant on anti-tumor growth in vivo. In MCF7 xenograft model, SCR6106 at 3 mpk QD induced 113% tumor growth inhibition (TGI), compared to fulvestrant 56.8% TGI at 250 mpk. Compared to fulvestrant, SCR6106 demonstrated stronger ERα degradation and inhibition of ER target genes transcription in tumors, which was consistent with anti-tumor activities. SCR6106 displayed good oral bioavailability in multiple pre-clinical species, which supports its oral administration in human. Significantly, SCR6106 possess a high BBB permeability, the B/P ratio is more than 4 in pre-clinical species. The exposure of SCR6106 observed in mouse brain is much higher than the IC90 value of anti-proliferation (MCF7), and SCR6106 demonstrated anti-tumor activities in a MCF-7 intracranial tumor xenograft model. In conclusion, SCR6106 is a novel, potent and oral SERD, which demonstrated anti-tumor activities in vitro and in vivo. It showed high potential ability to cross the blood-brain barrier, and could be used to treat HR+ patients with brain metastasis. Citation Format: Feng Zhou, Lei Liu, Guimei Yang, Peng Gu, Liting Xue, Wenqing Yang, Ping Chen, Renhong Tang. SCR6106, an oral and brain penetrant SERD demonstrated anti-tumor activities in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1070.

To investigate the prognosis of females with invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and mixed invasive ductal and lobular carcinoma (IDLC) according to hormone receptor (HR) and HER2 status. Data of 171,881 patients from the SEER database were analyzed. Propensity score matching was used to balance the covariates. Breast cancer-specific survival (BCSS) and overall survival (OS) of IDC, ILC, and IDLC were investigated. Patients with ILC were older, had lower tumor grade, higher tumor stage, larger tumor size, more nodal metastasis, higher estrogen receptor(+), lower HER2(-), and less likely to receive partial mastectomy and chemotherapy compared with IDC and IDLC. ILC and IDLC showed better prognosis than IDC after matching by Kaplan-Meier curves. Multivariate Cox regression showed better OS of ILC and IDLC compared with IDC with hazard ratio and a 95% confidence interval of 0.84 (0.77-0.90) and 0.91 (0.83-1.00), respectively. For HR(+)HER2(-) subgroup, ILC showed better OS than IDC; IDC showed worse BCSS and OS than IDLC. For HR(+)HER2(+); ILC showed better OS compared with IDLC; there were no survival differences of IDC, ILC, and IDLC for HER2(+). For HR(-)HER2(-), ILC and IDC showed better BCSS and OS compared with IDLC by multivariate analysis. The prognoses of female patients with IDC, ILC or IDLC were associated with the molecular subtypes of breast carcinoma. Management decisions should be based on pathological types and molecular subtypes.

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.