Pure Invasive Lobular Carcinoma Research Articles

Accelerated Partial Breast Irradiation for Early-Stage Invasive Lobular Carcinoma

Purpose: Invasive lobular carcinoma (ILC) represents 10-15% of invasive breast cancers with limited representation among trials of accelerated partial breast irradiation (APBI). Contemporary guidelines advise against treating ILC with APBI given a paucity of supportive evidence. Here, we evaluated oncologic outcomes among patients with ILC treated with APBI. Methods: Patients treated from 2010 –2022 with APBI following breast conserving surgery for ILC (or mixed ILC with other histologies) were ascertained from a prospectively-maintained institutional database. All patients received external beam APBI to 40Gy in 10 daily fractions. Outcomes of interest included local recurrence (LR) and overall survival (OS). Results: Of 1248 patients who underwent APBI at our center, the study cohort comprised 132 (11%) who had ILC, either exclusively or mixed with another histology (median age 63). Median tumor size was 1.1cm (IQR: 0.8, 1.5), nearly all had estrogen receptor positive disease (99%) and received endocrine therapy (91%), and most underwent sentinel node biopsy (89%) with the remainder having no axillary surgery. At 530 person-years and a median follow-up of 39 months, two LRs were observed yielding a 48-month cumulative incidence of LR of 3.0% (95% CI 0.56 –9.5%). Both events arose in patients with mixed lobular histology (none arose in patients with pure ILC). Two unrelated deaths were also observed yielding a 48-month overall survival of 98% (95% CI: 95% - 100%) Conclusion: Among patients with ILC who received APBI following BCS, we observed a 4-year LR rate of 3%. No regional or distant recurrences were observed, and overall survival was excellent. The safety of APBI for ILC will require confirmation among larger trials with longer follow-up, although the excellent outcomes observed here are consistent with those seen for invasive ductal carcinomas among contemporary trials of APBI.

Abstract PO1-06-06: Underestimation of metastatic spread in patients with lobular breast cancer: results from the post-mortem tissue donation program UPTIDER

Abstract Background: Invasive lobular carcinoma (ILC) accounts for 15% of all invasive breast cancers (BC) and has a peculiar metastatic spread in comparison to BC of no-special type. Since ILC is less likely to disrupt normal tissue architecture and is usually non-mass forming, imaging of ILC lesions entails many challenges. Insights into pathologic versus radiological metastatic invasion can lead to better diagnostic and monitoring tools for patients with ILC. Here, we compare microscopical findings during autopsy with clinical findings prior to death in patients with metastatic ILC included in our post-mortem tissue donation program UPTIDER (NCT04531696). Methods: UPTIDER was started in November 2020 in University Hospitals Leuven/KU Leuven with inclusion of patients with stage IV BC who were willing to participate. One of the predefined subgroups consisted of patients with primary pure (i.e. not mixed) ILC. Samples were taken from different macroscopically invaded and non-invaded sites. Clinical data on disease progression, imaging, biochemistry and treatment regimens were extracted from patient files. The number of samples that were preregistered as pathological served as a surrogate for lesions that were seen on imaging performed during the treatment of the patient. These samples are compared to microscopical findings of the autopsy. Results: Since the start of UPTIDER, an autopsy has been performed on 6 patients with pure ILC (26.1% of all autopsies). Median age at initial diagnosis was 52 years (range: 37 – 80 years). Three patients (50.0%) had stage IV disease at diagnosis, the others relapsed on average 162.7 months (range: 55 – 358 months) after initial diagnosis. The average time between clinical occurrence of metastases and death was 44.8 months (range: 15 – 83 months). Median number of treatment lines for stage IV disease was 5 (median endocrine lines 2; median chemotherapy regimens 3.5). To follow disease evolution, computed tomography of thorax and abdomen was used for 4 (66.7%) patients and whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) for the remaining 2 (33.3%). Median time between last premortem imaging and death was 5.9 weeks (range: 1.6 – 16.6 weeks). At autopsy, a median of 26 unique metastases (range: 12-36) were sampled per patient. Table 1 gives an overview on the unique microscopically invaded metastases that were sampled per patient. Only 47.3% of the sampled unique metastases was preregistered. Of all unique metastases, 26.7% appeared macroscopically normal during autopsy. Tissues that appeared normal but turned out to be microscopically infiltrated included liver, stomach, adrenal glands, heart, pericardium, visceral and subcutaneous fat tissue. There were 2 patients with normal appearing, microscopically infiltrated livers. In these patients, elevation of γGT and transanimases was seen in the months prior to death. Conclusions: The disease burden of metastatic ILC reported on premortem imaging does not reflect the microscopical findings at autopsy. One of the priorities of metastatic ILC research should be the development of diagnostic tools to better estimate the extent of the disease. Future analyses of the performed postmortem MRIs in our study can aid in improving the interpretation of WB-DWI/MRI for patients with ILC. For now, clinicians should consider that unexplained clinical and/or biochemical findings might indicate progression of ILC. Table 1: patient overview on performed imaging and unique metastases sampled during autopsy CT = computed tomography; ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; pt = patient; WB-DWI MRI = whole-body diffusion-weighted magnetic resonance imaging *exclusion of samples of patient 2012 since no preregistration was performed for this patient due to unexpected death Citation Format: Karen Van Baelen, Gitte Zels, Maxim De Schepper, Marion Maetens, Josephine Van Cauwenberge, Tatjana Geukens, Kristien Borremans, François Richard, Amena Mahdami, Ha-Linh Nguyen, Sophia Leduc, Anirudh Pabba, Ann Smeets, Ines Nevelsteen, Patrick Neven, Hans Wildiers, Vincent Vandecaveye, Wouter Van Den Bogaert, Giuseppe Floris, Christine Desmedt. Underestimation of metastatic spread in patients with lobular breast cancer: results from the post-mortem tissue donation program UPTIDER [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 PO1-06-06.

Abstract PO2-07-09: Early stage invasive lobular breast cancer is underestimated on conventional imaging including MRI

Abstract Background: Invasive lobular carcinoma (ILC), representing 15% of all invasive breast cancers, is characterized by loss or dysfunction of the adhesion molecule E-cadherin. This leads to an infiltrative growth pattern that is unlikely to disrupt the normal architecture of breast tissue. As a result, ILC is often non-mass forming and imaging is limited in correctly diagnosing stage I-III ILC. Mammography is believed to underestimate ILC, while MRI tends to overestimate the extent of ILC. The aim of this retrospective study was to correlate radiological with pathological findings. Methods: All patients diagnosed with stage I-III pure (i.e. not mixed) ILC between January 2000 and December 2020 who underwent primary surgery in University Hospitals Leuven, were included. Data on patient characteristics, preoperative imaging and pathology were collected from the patient files. Imaging and pathology measurements were compared by use of Pearson correlation coefficient, Whitney U test or Chi-square test. Weighted kappa statistics were used to assess agreement. Since the techniques of mammography and ultrasound have evolved in the past 20 years, different time periods were considered in sub-analyses (2000-2004, 2005-2009, 2010-2014, 2015-2020). Results: In total 1029 patients were included. Median age at diagnosis was 61.0 years (range 32.0 – 95.0 years). The breast density score determined on mammogram was Bi-RADS type A for 52 (5.1%) patients, B for 238 (23.1%) patients, C for 235 (22.8%) patients and D for 141 (13.7%) patients. Density score was missing from the reports of the remaining patients (n=363, 35.3%). Contrast enhanced breast magnetic resonance imaging (MRI) was performed in 709 (68.9%) patients. An increase in preoperative use of MRI was seen over the years. In comparison to tumor size reported by pathology, all imaging techniques underestimated the tumor size. The mean difference in largest tumor size compared to pathology was 14.64 ± 21.15 mm for mammography, 18.19 ± 21.66 mm for ultrasound and 9.93 ± 20.63 mm for MRI. A higher breast density level and a larger tumor size were significantly associated with a larger difference between diameter on pathology versus mammography (ρ=0.102, p-value 0.025 and ρ=0.530, p-value < 0.001 respectively). Changes over different time periods are shown in Table 1 for mammography and ultrasound. There was an agreement on unifocality versus multifocality between pathology and mammography for 81.2% of the patients. In 52.1% of the 236 cases where multifocality was reported on MRI, only 1 lesion was reported by the pathologist. Multifocality was seen on pathology in 12.0% of the 460 cases that were seen as unifocal lesions on MRI. Considering adenopathies, the false positive rate of ultrasound was 3.0%. However, the false negative rate was 68.3%. Conclusions: The local extent of ILC is underestimated by conventional imaging techniques. Unlike previous reports, our results suggest that tumor size of ILC is also underestimated by MRI. Ultrasound was inferior to mammography and MRI in estimating tumor size in our series. It was confirmed that MRI tends to overestimate the number of foci which might lead to unnecessary secondary ultrasounds and biopsies. The presurgical underestimation of lymph node involvement might increase the need of secondary surgeries. It is crucial to address these limitations in imaging of ILC and to prioritize the development of enhanced imaging techniques to improve diagnostic accuracy for these patients. Table 1: difference between imaging techniques and pathology by year of diagnosis Citation Format: Kaat Van Herck, Karen Van Baelen, Chantal Van Ongeval, Valerie Celis, Helen De Boodt, Machteld Keupers, Renate Prevos, Giuseppe Floris, Ines Nevelsteen, Ann Smeets, Thaïs Baert, Sileny Han, Hans Wildiers, Annouschka Laenen, Christine Desmedt, Patrick Neven. Early stage invasive lobular breast cancer is underestimated on conventional imaging including MRI [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 PO2-07-09.

62P KI67 in ER+HER2-negative pure invasive lobular breast carcinoma (ILC). What’s the best Ki67 threshold to differentiate prognosis?

62P KI67 in ER+HER2-negative pure invasive lobular breast carcinoma (ILC). What’s the best Ki67 threshold to differentiate prognosis?

Abstract P4-03-11: Population-based survival outcomes of pure vs mixed invasive lobular breast carcinoma in Ontario, Canada

Abstract Purpose: We aim to determine incidence and survival rates of pure vs mixed invasive lobular breast carcinoma between 1990 and 2020 in the province of Ontario, Canada. We further evaluated patient and tumour factors that predict survival for invasive lobular carcinoma (ILC). Methods: Using population-based administrative healthcare datasets at Institute of Clinical Evaluative Sciences (ICES) Ontario, we calculated the crude 5-year incidence rates of pure ILC versus invasive ductal carcinoma (IDC) versus mixed ILC-IDC in the province of Ontario, Canada between 1990 and 2020. Kaplan-Meier survival curves were generated to determine the 5-, 10-, 15- and 20-year survival for ILC (and mixed ILC-IDC) as compared with IDC. Survival curves were compared using the log-rank test and stratified by stage. Using a multivariable Cox proportional hazards regression analysis, we identified patient (e.g. demographic, geographic, socioeconomic) and tumour (grade, stage, receptor subtype) factors that predicted survival for patients with ILC. Statistical analysis was performed using SAS® and P values < 0.05 were considered statistically significant. Results: We identified 18,551 (8%) pure ILC, 10,234 (4%) mixed ILC-IDC and 192,371 (81%) IDC cases. The crude incidence of pure ILC increased from 55.7 per 100,000 in 1990 to 80.2 per 100,000 in 2020. The crude incidence of mixed ILC-IDC peaked in the mid-2000s at 48.6 per 100,000 and subsequently declined to 32.1 per 100,000 in 2020. There was a significant difference in overall survival between the three breast cancer subtypes. Over a 30-year follow-up period (mean 9.3 +/- 7.3 years), overall survival of mixed ILC-IDC mirrors the survival of pure IDC, while women with pure ILC have inferior survival compared with IDC beginning after 10 years of follow-up (P < .001). The 20-year overall survival was 40% for ILC and 50% for IDC and mixed ILC-IDC. Older age > 55 years (vs. 50-54 years, P < .0001), lowest neighborhood income quintile (HR 1.1, P = .038), geographic location within Ontario (P < .01) and increasing Elixhauser Comorbidity Index score (P < .0001) predicted worse overall survival for ILC patients. Conversely, the increasing number of mammograms received in the five years prior to diagnosis predicted better overall survival (P < .0001). When stratified by cancer stage, the worse survival in ILC (compared with IDC and mixed ILC-IDC) was only observed for stage III patients (P = .01). Stage III and IV disease, grade 3 histology and ER/PR negativity predicted worse survival (P < .01). Conclusion: The crude incidence of ILC is increasing over time. Over a 30-year follow-up period (mean 9.3 +/- 7.3 years), ILC had worse overall survival compared with IDC and mixed ILC-IDC, particular stage III patients. Patient demographic and tumour factors predict overall survival in ILC. While treatment paradigms for ILC mirror that for IDC, our data demonstrates worse overall survival for ILC and a need for more research and treatments focused on improving long-term survival for ILC patients. Citation Format: David Lim, Vasily Giannakeas, Steven Narod, Kelly Metcalfe. Population-based survival outcomes of pure vs mixed invasive lobular breast carcinoma in Ontario, Canada [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-11.

Abstract P3-05-04: Absence of Lobular Carcinoma In Situ, a Poor Prognostic Marker in Invasive Lobular Carcinoma

Abstract Background: Lobular carcinoma in situ (LCIS) is known to be a risk factor for the development of invasive lobular carcinoma (ILC). Recent genetic analysis indicates that LCIS is a facultative precursor of ILC. It was reported that ~50% of ILC co-occur with LCIS, however it is unclear whether patients with this co-occurrence behave similarly to patients with pure ILC. Methods: We retrospectively searched for patients treated at MD Anderson Cancer Center with a diagnosis of stage I-III ILC in our prospectively collected electronic database. Patients were divided into 2 groups: those with ILC with co-occurring ipsilateral LCIS (ILC/LCIS) and those with pure ILC without a histologically detected co-occurring ipsilateral in situ lesion (ILC alone). We obtained data on demographics, tumor size (T), lymph nodes (N) involvement, estrogen (ER), progesterone (PR) receptor status, HER2 expression, Ki67, treatment received, distant recurrence and survival status. The Kaplan-Meier product-limit method was used to compare distant recurrence-free survival (DRFS) and overall survival (OS) between the two groups. Multivariate analysis using Cox regression was used to assess association between co-variables and recurrence/survival. Results: We identified 4,217 patients with stage I-III ILC treated at MDACC between 1966 and 2021. 45% of cases (n = 1,881) had co-existing LCIS. 90% of ILCs were classical and 96% of LCIS were classical. Overall, the median age was 56 years, 95% of cases were ER+, 80% PR+, 5% HER2+. 40% of cases were T1, 60% N0 and 70% of tumors with available Ki67 data had low Ki67 (< 20%). Around 65% underwent mastectomy, 20% received neoadjuvant chemotherapy, and 35% received adjuvant chemotherapy. Statistically and numerically, ILC alone tended to have more T4 and N3 disease (P < 0.001), more ER/PR negative disease (P = 0.0002), more HER2+ disease (P = 0.010), higher Ki67 (P = 0.005), more non-classical ILC subtype (P = 0.04) and more exposure to neoadjuvant chemotherapy (P = 0.0002) than the ILC/LCIS group. The median follow-up time was 6.5 years. Patients with ILC co-existing with LCIS had better DRFS (28.0 vs 14.3 years, Hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.47 – 0.59, P < 0.0001) and better OS (18.9 vs 13.7 years, HR 0.62, 95% CI 0.56 – 0.69; P < 0.0001). Multivariate (MV) analysis showed the absence of LCIS to be a poor prognostic factor along with a higher T and higher N for distant recurrence and overall survival (Table 1). Conclusion: The findings of this study suggests that the co-existence of LCIS with ILC is a good prognostic factor and that further studies are warranted to understand this phenomenon. Table 1. Multivariate Analysis between Clinico-Pathological Variables and Distant Recurrence-free Survival/Overall Survival Citation Format: Jason Mouabbi, Akshara Singareeka Raghavendra, Matthias Christgen, Amy Hassan, Gabriel N. Hortobagyi, Debu Tripathy, Rachel M. Layman. Absence of Lobular Carcinoma In Situ, a Poor Prognostic Marker in Invasive Lobular Carcinoma [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-04.

Abstract P3-05-40: Association of body mass index with clinicopathological features and survival in patients with primary ER+/HER2- invasive lobular breast cancer

Abstract Background: Invasive lobular carcinoma (ILC) represents up to 15% of all breast carcinomas. The majority of ILC express the estrogen receptor (ER) and have no amplification/overexpression of the human epidermal growth factor receptor 2 (HER2). A high body mass index (BMI) has been associated with an increased risk of developing ILC in postmenopausal women, similar to what is seen for breast cancer of no special type (NST). It is however unknown if BMI impacts the clinicopathological features and the prognosis of ILC. Methods: We performed a multicentric retrospective study in 5 European centers of patients diagnosed between January 2000 and December 2020 with ER+/HER2- non-metastatic pure (i.e., not mixed) ILC. Patient and tumor characteristics and event-related data were collected. BMI was categorized into underweight (≤18.5kg/m2), lean (>18.5kg/m2 and < 25kg/m2), overweight (≥25kg/m2 and < 30kg/m2) and obese (≥30kg/m2). The association of BMI as either a continuous or a categorical variable with clinicopathological variables was assessed using linear regression or ordinal logistic regression, respectively. Median follow-up was calculated using the reverse Kaplan-Meier estimator. Survival analyses using univariable (stratified by center) and multivariable (adjusted for all included variables and stratified by center) Cox regression were performed to evaluate the association of BMI with disease free survival (DFS), distant recurrence free survival (DRFS) and overall survival (OS). DFS and DRFS were analyzed in the presence of death without event as the competing risk. Results: The data of 2476 patients were collected and BMI was available for 2346 patients. In total, 1299 (55%) patients were lean, 638 (27%) overweight and 339 (14%) obese. Underweight patients only represented 3% of all patients and were thus excluded from further analyses. A higher age at diagnosis, higher grade, larger tumor size, nodal involvement and multifocality were significantly associated with higher BMI (Table 1). The median follow-up was 8,5 years (interquartile range 59.24 – 142.13 months). In univariable analysis, higher BMI was associated with worse survival outcomes (Table 2). However, this association was not seen in multivariable analysis while grade, tumor size and nodal involvement were still prognostic for all endpoints. Similar results were seen with BMI as a continuous variable. Conclusion: Larger tumors and nodal involvement were more likely to be found in patients with ER+/HER2- ILC with higher BMI which might be explained by a delayed diagnosis in these patients. Higher grade also seemed to be associated with higher BMI. In multivariable analyses, BMI was not found to be an independent prognostic factor. Tumor grade, tumor size, and nodal status remained strongly prognostic for survival outcomes in multivariable survival analyses which is consistent with their known prognostic importance in luminal tumors. We hypothesize that the prognostic effect of BMI is mediated through these variables for patients with ER+/HER2- ILC. Table 1. Association of clinicopathological features of ER+/HER2- ILC with categorical BMI. Table 2. Association of categorical BMI and other clinicopathological features of ER+/HER2- ILC with survival. Citation Format: Karen Van Baelen, Ha-Linh Nguyen, François Richard, Anne-Sophie Hamy, Aullène Toussaint, Fabien Reyal, Anne Salomon, Luc Dirix, Peter Vermeulen, Hilde Wuyts, Maria Karsten, Adam D. Dordevic, Guilherme Nader Marta, Evandro de Azambuja, Christos Sotiriou, Denis Larsimont, Ottavia Amato, Marion Maetens, Maxim De Schepper, Tatjana Geukens, Sileny Han, Thaïs Baert, Kevin Punie, Hans Wildiers, Chantal Remmerie, Ann Smeets, Ines Nevelsteen, Giuseppe Floris, Elia Biganzoli, Patrick Neven, Christine Desmedt. Association of body mass index with clinicopathological features and survival in patients with primary ER+/HER2- invasive lobular breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-40.

MRI background parenchymal enhancement in patients with invasive lobular carcinoma: Endocrine hormonal treatment effect.

High background parenchymal enhancement (BPE) levels and asymmetric distribution could cause diagnostic uncertainty due to morphological similarity to breast cancer, especially invasive lobular carcinoma (ILC). We investigated BPE in ILC patients, its association with the tumor hormonal profile, and the effect of endocrine treatment (ET). The analysis included all MRI examinations performed at our institution between 2010 and 2019 for ILC-diagnosed patients. Baseline study and the first follow-up study were reviewed. Digital medical records were reviewed to retrieve demographics/pathology results/treatment information. BPE and fibroglandular tissue were assessed qualitatively on the contralateral breast according to the criteria of the Breast Imaging Reporting and Data System (BI-RADS). The study included 129 patients. Most (91%) had pure ILC. All received ET; 12% also received chemotherapy; 90% had surgery first; 70% by breast conservation. On the baseline MRI, 70% had mild or moderate BPE; whereas, on the follow-up study, the majority (59%) had minimal BPE. Most BPE reductions were by 2 degrees. In the baseline study, additional biopsies were required in 59% of cases, and in 17%, a short-term follow-up was recommended. In the follow-up study, biopsies were recommended in 10%, and a short-term follow-up was requested in 16%. A correlation between progesterone receptor intensity index and baseline BPE level was observed (r =0.3, p =0.004). ILC patients usually exhibit high BPE. ET decreases BPE, and therefore may decrease false-positive interpretations. Additional research is needed to explore whether study can be performed on ET without compromising sensitivity. ∙ High background parenchymal enhancement levels reduces breast MRI sensitivity, yielding high false positive rates especially when reporting cases of invasive lobular carcinoma [ILC].∙Treatment of ILC with endocrine therapy reduces background parenchymal enhancement and thus could decrease these false-positive interpretations.

Abstract PD14-03: Genetic and epigenetic basis of invasive lobular carcinomas lacking CDH1-alterations

Abstract Introduction: Invasive lobular carcinoma (ILC) is the most prevalent histologic special type of breast cancer, representing ~15% of invasive breast cancers. ILCs are mostly hormone receptor-positive and diagnosed histologically based on their distinctive discohesive growth pattern, dispersed single cells or line of cells invading the stroma. ILCs commonly show biallelic inactivation of a CDH1 (~65%), a tumor suppressor gene that is mapped to 16q22.1 and encodes for E-cadherin, a critical component of the epithelial adhesion complex. Massively parallel sequencing and pathologic studies have shown that a subset of ILCs (up to 15%) may lack CDH1 loss-of-function (LOF) mutations/deletions and retain E-cadherin expression, despite their distinctive lobular phenotype. The genetic and epigenetic underpinning of ILCs lacking CDH1 alterations has yet to be defined. Here we sought to define the mechanistic basis of the lobular phenotype in ILCs lacking CDH1 LOF genetic alterations or CDH1 gene promoter methylation and to determine the repertoire of epigenetic and genetic alterations of CDH1-wildtype ILCs. Materials and methods: Reanalysis of the CDH1 gene status in 364 primary ILCs, previously subjected to clinical massively parallel sequencing, was performed to identify all primary ILCs lacking bi-allelic CDH1 alterations. The hematoxylin and eosin stained slides of all identified ILCs lacking bi-allelic CDH1 alterations were reviewed by two pathologists and primary pure ILCs lacking bi-allelic CDH1 alterations were curated. We evaluated the presence of genetic alterations in genes playing essential roles in epithelial adhesion included in the clinical sequencing panel of up to 505 genes. The presence of CDH1 promoter methylation in 18 ILCs lacking bi-allelic CDH1 alterations with available formalin-fixed, paraffin-embedded (FFPE) material was assessed using methylation-specific PCR (MSP) and bisulfite sequencing. Results: We identified 23/364 (6.3%) primary ILCs lacking bi-allelic CDH1 alterations, of which 65.3% and 34.7% were classic and pleomorphic lobular variants, respectively. In 18 cases with available FFPE material, our analyses revealed that 67% (12/18) of ILCs lacking bi-allelic CDH1 alterations displayed biallelic CDH1 inactivation via promoter methylation and 16q loss. Furthermore, we observed that 1/23 ILC lacking bi-allelic CDH1 alterations had bi-allelic inactivation of AXIN2. We then extended our query to all invasive breast carcinomas subjected to clinical sequencing, including the ones initially categorized as invasive breast carcinoma “type unknown”, and observed that the three additional cases with pathogenic LOF AXIN2 alterations were ILCs lacking bi-allelic CDH1 alterations. Conclusions: The lobular phenotype in ILCs can be due to CDH1 promoter methylation or genetic alterations affecting other genes related to epithelial cell adhesion, such as AXIN2 LOF mutations. Whole-genome sequencing analyses of ILCs whose molecular basis has not been identified by targeted sequencing are warranted. Citation Format: Fatemeh Derakhshan, Higinio Dopeso, Arnaud Da Cruz Paula, Pier Selenica, Antonio Marra, Edaise M da Silva, Andrea Gazzo, Shirin Issa Bhaloo, Dara S Ross, Anne Grabenstetter, Sarat Chandarlapaty, Pedram Razavi, Hannah Y. Wen, Hong Zhang, Edi Brogi, Britta Weigelt, Fresia Pareja, Jorge S. Reis-Filho. Genetic and epigenetic basis of invasive lobular carcinomas lacking CDH1-alterations [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 PD14-03.

Accuracy of Preoperative Breast MRI Versus Conventional Imaging in Measuring Pathologic Extent of Invasive Lobular Carcinoma.

To determine whether invasive lobular carcinoma (ILC) extent is more accurately depicted with preoperative MRI (pMRI) than conventional imaging (mammography and/or ultrasound). After IRB approval, we retrospectively identified women with pMRIs (February 2005 to January 2014) to evaluate pure ILC excluding those with ipsilateral pMRI BI-RADS 4 or 5 findings or who had neoadjuvant chemotherapy. Agreement between imaging and pathology sizes was summarized using Bland-Altman plots, absolute and percent differences, and the intraclass correlation coefficient (ICC). Rates of underestimation and overestimation were evaluated and their associations with clinical features were explored. Among the 56 women included, pMRI demonstrated better agreement with pathology than conventional imaging by mean absolute difference (1.6 mm versus -7.8 mm, P < 0.001), percent difference (10.3% versus -16.4%, P < 0.001), and ICC (0.88 versus 0.61, P = 0.019). Conventional imaging more frequently underestimated ILC span than pMRI using a 5 mm difference threshold (24/56 (43%) versus 10/56 (18%), P < 0.001), a 25% threshold (19/53 (36%) versus 10/53 (19%), P = 0.035), and T category change (17/56 (30%) versus 7/56 (13%), P = 0.006). Imaging-pathology size concordance was greater for MRI-described solitary masses than other lesions for both MRI and conventional imaging (P < 0.05). Variability of conventional imaging was lower for patients ≥ the median age of 62 years than for younger patients (SD: 12 mm versus 22 mm, P = 0.012). MRI depicts pure ILC more accurately than conventional imaging and may have particular value for younger women.

Abstract PS17-05: Relationship between body mass index and tumor subtype by menopausal status: An analysis in women with lobular carcinoma of the breast

Abstract Background: Invasive lobular carcinoma (ILC) is the second most common type of breast cancer and is primarily estrogen receptor (ER)-positive. Compared to invasive ductal carcinoma, ILC is more strongly associated with risk factors that modulate sex steroid hormones, including obesity and use of hormone replacement therapy. Studies also suggest that body mass index (BMI) and metabolic syndrome may impact the molecular characteristics of ILC. We evaluated the relationship between BMI, metabolic syndrome, and tumor characteristics by menopausal status in a single institution cohort of women with newly diagnosed ILC. Methods: We retrospectively evaluated ILC cases from an institutional database of patients treated between 1996 and 2020. We excluded cases with mixed ILC/IDC histology, and those with triple negative or human epidermal growth factor-2 overexpressing disease. BMI was calculated as (weight kg)/(height m)^2 and was evaluated continuously and categorically with 20-24.9 as normal weight, 25-30 as overweight, and &amp;gt;30 as obese. Metabolic syndrome was defined as having any 3 of the following 5 factors: obesity, hypertension, hypercholesterolemia, hypertriglyceridemia, or diabetes mellitus. Oncotype Dx Recurrence Scores (RS) were recorded in the subset for whom scores had been obtained clinically. Data were analyzed in Stata 14.2. Results: Of the 481 ILC cases studied, 147 (30.5%) were pre-menopausal at diagnosis, while 334 (69.5%) were post-menopausal, with mean ages of 48 and 64.9 years (p&amp;lt;0.0001). Most tumors (79.5%) were both ER-positive and progesterone receptor (PR)-positive. Post-menopausal women had significantly more ER-positive/PR-negative ILC than premenopausal women (25.3% vs 9.9%, p&amp;lt;0.001), were more likely to have a BMI in the overweight/obese category (53.6% vs 40.1%, p=0.016), and were more likely to have metabolic syndrome (21.9% vs 6.8%, p&amp;lt;0.001). Of the 143 cases with an Oncotype RS, 69.9% were intermediate, 21.7% were low, and 8.4% were high risk. Post-menopausal women had significantly higher RS than premenopausal women when RS was treated as a continuous variable (16.9 vs 13.8, p=0.007). Among postmenopausal women, overweight/obesity status was associated with lower RS while those with normal weight had a greater proportion of high RS tumors (p=0.027). There was no association between BMI and RS in the pre-menopausal population. Similarly, there was no association between metabolic syndrome and tumor subtype in either group. Conclusions: In this cohort of women with ER-positive pure ILC, we found that post-menopausal ILC had higher rates of overweight/obesity, metabolic syndrome, and numerically higher RS than pre-menopausal ILC. However, within the post-menopausal group, higher BMI was anti-correlated with RS whereas BMI had no impact on pre-menopausal ILC RS. Since obesity is associated with worse outcomes for breast cancer, these findings are unexpected and raise the possibility that the hormonal pathogenesis and estrogenic drive behind ILC differs in pre- vs post-menopausal women, consistent with their different PR positivity rates, possibly due to the more local production of estrogen from higher breast adiposity in post-menopausal women relative to the greater systemic ovarian production of estrogen in pre-menopausal women. These findings have potential implications for both ILC prevention and adjuvant therapy strategies. CharacteristicsPremenopausal (n=147)Postmenopausal (n=334)P valueAge, mean (SD)48 (5.5)64.9 (9.7)&amp;lt;0.0001Body mass index0.016BMI&amp;lt;25, n (%)88 (59.9%)155 (46.4%)BMI 25-30, n (%)39 (26.5%)105 (31.4%)BMI&amp;gt;30, n (%)20 (13.6%)74 (22.2%)Metabolic syndrome present, n (%)10 (6.8%)73 (21.9%)&amp;lt;0.001ILC StageNSI, n (%)86 (58.9%)224 (68.3%)II, n (%)40 (27.4%)61 (18.6%)III, n (%)20 (13.7%)43 (13.1%)ILC GradeNS1, n (%)49 (34.3%)93 (28.3%)2, n (%)88 (61.5%)222 (67.5%)3, n (%)6 (4.2%)14 (4.2%)Hormone Receptor Status&amp;lt;0.001ER+/PR+128 (90.1%)236 (74.7%)ER+/PR-14 (9.9%)80 (25.3%)21-gene Recurrence Score in women with BMI&amp;lt;250.020Low, n (%)10 (25%)2 (6%)Intermediate, n (%)28 (70%)24 (72.7%)High, n (%)2 (5%)7 (21.3%)21-gene Recurrence Score in women with BMI&amp;gt;25NSLow, n (%)6 (28.5%)11 (26.8%)Intermediate, n (%)15 (71.5%)27 (65.9%)High, n (%)0 (0%)3 (7.3%)SD, standard deviation, NS, not significant. Citation Format: Harriet Rothschild, Laura Esserman, Christopher Benz, Rita Mukhtar. Relationship between body mass index and tumor subtype by menopausal status: An analysis in women with lobular carcinoma of the breast [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 PS17-05.

Metastatic behavior of mixed invasive ductal lobular carcinoma (mIDC/ILC).

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&amp;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 &lt; 0.001), and less likely to have metastasis to the peritoneum (p &lt; 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.

Mitotic score and pleomorphic histology in invasive lobular carcinoma of the breast: impact on disease-free survival.

Pleomorphic invasive lobular carcinoma (ILC) has long been thought to have worse outcomes than classic ILC and is therefore often treated with chemotherapy. However, recent data question the utility of the pleomorphic designation, as the poor outcomes seen may be related to other associated high-risk features. Importantly, mitotic count may better define a subset of ILC with high risk of recurrence. We sought to determine the impact of pleomorphic histology versus mitotic count on disease-free survival (DFS) in pure ILC. Additionally, we evaluated whether pleomorphic histology was associated with receipt of chemotherapy when adjusting for other factors. We analyzed a cohort of 475 patients with stage I-III pure ILC. We used Kaplan-Meier estimates, and Cox proportional hazards and logistic regression for multivariate analyses. Pleomorphic histology was confirmed by central pathology review. In a multivariate model, pleomorphic histology was not associated with reduced DFS. Only mitotic score, receptor subtype, and pathologic stage were independently and significantly associated with DFS. Patients with pleomorphic ILC were significantly more likely to receive chemotherapy than patients with classic ILC (adjusted odds ratio 2.96, p = 0.026). The pleomorphic designation in ILC does not have clinical utility and should not be used to determine therapy. Rather, mitotic count identified clear prognostic groups in this cohort of pure ILC.

Abstract P2-16-26: 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 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.

Abstract PD7-06: Molecular subtypes of invasive lobular breast cancer in the I-SPY2 TRIAL

Abstract Background: Invasive lobular carcinoma (ILC) of the breast has distinct histological and molecular variations compared to invasive ductal carcinoma (IDC), including absence of the adhesion protein E-cadherin. Recently, molecular subtypes within ILC have been described, with an analysis from The Cancer Genome Atlas (Ciriello et al) identifying three distinct groups within ILC based on gene expression—reactive-like, immune-related, and proliferative. In this study, we applied this 60-gene classifier to a locally advanced cohort of ILC and mixed ILC/IDC cases from patients screening for the I-SPY 2 neoadjuvant chemotherapy trial. Methods: The I-SPY 2 TRIAL is open to women with more locally advanced, clinically/molecularly (as assessed by MammaPrint) high risk breast cancer. HR+HER2- MammaPrint Low risk patients ineligible for I-SPY 2 randomization are invited to join a MP Low risk registry. 131 ILC and mixed ILC/IDC tumors from these cohorts (I-SPY 2: n=80; low risk registry: n=51) with pre-treatment Agilent microarrays were available for analysis. We used the Classification to Nearest Centroid technique to assign TCGA subtype to our cohort. We assessed association between TCGA subtype, clinical covariates and response to therapy using a chi-square test. We also evaluated the Euclidean distance between each sample and the three subtype centroids. In an exploratory analysis, we used consensus clustering based on the 1000 most varying genes within the HR+HER2- I-SPY ILC cases to generate new unsupervised groupings, and assessed the concordance with the TCGA reactive-like, immune-related and proliferative subtype assignments. Results: Of the 131 patients included, most (79%) were HR+HER2-, 11% were HR+HER2+, 2% were HR-HER2+ and 8% were HR-HER2- for a total of 10% HR-. 66 were pure ILC, while 65 were mixed ILC/IDC. Upon applying the TCGA 60-gene classifier, the distribution of ILC subtypes was as follows: 33 (25%) were classified as reactive-like, 50 (38%) were immune-related, and 48 (37%) were proliferative. 64% of triple negative cases were reactive-like; while the HR+HER2- and HER2+ cases were more likely to be in the proliferative or immune-related subtype (p=0.037). Among the 80 I-SPY 2 cases, the overall pathologic complete response rate was low (16%) but equivalent to the overall HR+HER2- I-SPY2 population (16%). This did not differ across the groups defined by the TCGA ILC subtypes (p=0.79). Interestingly, a subset of cases assigned as reactive-like and immune-related were of similar distance to the proliferative subtype centroid as patients assigned to the proliferative subtype. When we used consensus clustering to identify new subsets within our locally advanced ILC cohort, our unsupervised groupings had only 32% concordance with the TCGA ILC subtype assignments. Conclusion: The low concordance between our consensus cluster groupings and the TCGA subtype groupings may reflect underlying differences within a locally advanced cohort of ILC cases, like I-SPY, that may not be captured in the 60-gene classifier developed from the overall lower stage TCGA cohort. These findings suggest that considerable molecular heterogeneity exists in lobular cancers, which merits further investigation. Citation Format: Zhu Z, Yau C, Chien AJ, Haddad T, Esserman LJ, van't Veer L, Mukhtar RA, I-SPY2 Consortium. Molecular subtypes of invasive lobular breast cancer in the I-SPY2 TRIAL [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD7-06.

Outcomes of Breast Cancer (Invasive Lobular and Ductal Carcinoma) Treated with Boost Intraoperative Electron Radiotherapy Versus Conventional External Beam Radiotherapy

Background: Breast conserving surgery (BCS) and its following radiotherapy is an accepted therapeutic method for patients with invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC). Objectives: The aim of this study was to investigate the effect of intraoperative electron radiotherapy on women with breast cancer (invasive lobular and ductal carcinoma). Methods: Between August 2013 and September 2017, 968 patients, who were referred to Cancer Research Center, Shahid Beheshti University of Medical Sciences with invasive breast cancer, were treated with breast-conserving surgery and radiotherapy. Of those, 426 patients received a tumor bed boost with intraoperative electron radiotherapy (IOERT) during lumpectomy (58 patients with pure invasive lobular carcinoma, 239 patients with pure invasive ductal carcinoma, and 129 patients with other diagnoses). 542 patients received a tumor bed boost with conventional external beam radiotherapy post lumpectomy (24 patients with pure invasive lobular carcinoma, 418 patients with pure invasive ductal carcinoma, and 100 patients with other diagnoses). The patients were followed up to 49 months. A comprehensive list of clinical and pathologic features was evaluated for all patients. We retrospectively analyzed outcomes of breast cancer treated with boost intraoperative electron radiotherapy (pure ILC and IDC groups) and in other group treated with boost conventional external beam radiotherapy (pure ILC group). Results: None of the ILC patients had recurrence in the two groups. The four-year survival rate for ILC patients was 100%, but in the IDC group the survival rate was 97%. Survival analyses showed patients with IDC had a higher risk of ipsilateral breast tumor recurrence (IBTR) and metastasis. Conclusions: Overall, the rates of IBTR and metastasis in the ILC boost IOERT group were significantly low. This finding suggests that IOERT technique deployment in ILC had no inferiority compared with the control group.

197P - A propensity score analysis exploring the impact of the addition of adjuvant chemotherapy (aCT) to hormone therapy (aHT) in a multi-center series of resected luminal early stage pure invasive lobular breast carcinoma (ILC)

197P - A propensity score analysis exploring the impact of the addition of adjuvant chemotherapy (aCT) to hormone therapy (aHT) in a multi-center series of resected luminal early stage pure invasive lobular breast carcinoma (ILC)

Next-generation targeted sequencing (NGTS) investigating CDK4 as a prognostic driver in pure invasive lobular breast carcinoma (ILC): Preliminary results in early-stage patients (pts) stratified according to a validated clinico-pathological model.

542Background: The aim of this analysis was to investigate the distribution of molecular abnormalities and their potential role as therapeutic targets (with particular regard to CDK4/6 alterations)...

A propensity score analysis exploring the impact of adjuvant chemotherapy (aCT) in 739 patients (pts) affected by early stage pure Invasive Lobular breast Carcinoma (ILC)

A propensity score analysis exploring the impact of adjuvant chemotherapy (aCT) in 739 patients (pts) affected by early stage pure Invasive Lobular breast Carcinoma (ILC)

204P - ESR1, Ph-mTOR, CDK4/6 and PD-L1 expression as prognostic (and potentially druggable) drivers for pure invasive lobular breast carcinoma (ILC): Preliminary results of prognostic outliers according to a clinical-pathological model

204P - ESR1, Ph-mTOR, CDK4/6 and PD-L1 expression as prognostic (and potentially druggable) drivers for pure invasive lobular breast carcinoma (ILC): Preliminary results of prognostic outliers according to a clinical-pathological model