Chromatin accessibility landscape and active transcription factors in primary human invasive lobular and ductal breast carcinomas.

BACKGROUND: Invasive lobular breast carcinoma (ILC), the second most prevalent histological subtype of breast cancer, exhibits unique molecular features compared with the more common invasive ductal carcinoma (IDC). While genomic and transcriptomic features of ILC and IDC have been characterized, genome-wide chromatin accessibility pattern differences between ILC and IDC remain largely unexplored. METHODS: Here, we characterized tumor-intrinsic chromatin accessibility differences between ILC and IDC using primary tumors from The Cancer Genome Atlas (TCGA) breast cancer assay for transposase-accessible chromatin with sequencing (ATAC-seq) dataset. RESULTS: We identified distinct patterns of genome-wide chromatin accessibility in ILC and IDC. Inferred patient-specific transcription factor (TF) motif activities revealed regulatory differences between and within ILC and IDC tumors. EGR1, RUNX3, TP63, STAT6, SOX family, and TEAD family TFs were higher in ILC, while ATF4, PBX3, SPDEF, PITX family, and FOX family TFs were higher in IDC. CONCLUSIONS: This study reveals the distinct epigenomic features of ILC and IDC and the active TFs driving cancer progression that may provide valuable information on patient prognosis.

Gastric metastasis before diagnosis of primary invasive lobular breast carcinoma: a rare case presentation from Pakistan.

Metastatic spread of invasive lobular breast carcinoma to stomach is rare especially before diagnosis of primary breast cancer. Incorrect diagnosis might result in delay of appropriate treatment for breast cancer. Recognition of this possibility enables better clinical management. A 62-year-old female presented with upper gastrointestinal symptoms and weight loss and was referred to a gastroenterologist for investigation. At the time of initial diagnosis of stomach cancer, patient was asymptomatic for breast cancer. Multiple gastric biopsies taken showed features suspicious of metastatic breast cancer. Consequently, the initial provisional diagnosis of stomach cancer changed into metastatic invasive lobular breast carcinoma. These findings were corroborated radiologically. The patient was treated with letrozole and zoledronic acid as first-line therapy for one year. Residual metastatic breast cancer was present in the gastric mucosa. The patient was treated with endocrine therapy containing ribociclib and treatment was ineffective confirmed by PET-CT scan. But her symptoms have resolved completely despite her presentation with stage IV. We present rare case of initial presentation of gastric metastasis before diagnosis of a primary invasive lobular breast carcinoma. Correct diagnosis and appropriate treatment were accomplished through initial clinical suspicion, accurate histological examination, and endoscopy together with analysis of disease-specific biomarkers.

Nomograms to predict the long-term prognosis for non-metastatic invasive lobular breast carcinoma: a population-based study.

Invasive lobular breast carcinoma (ILC) is one potential subset that "clinicopathologic features" can conflict with "long-term outcome" and the optimal management strategy is unknown in such discordant situations. The present study aims to predict the long-term, overall survival (OS) and cancer-specific survival (CSS) of ILC. The clinical information of patients with non-metastatic ILC was retrieved from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2020. A total of 31451 patients were enrolled and divided into the training cohort (n=22,017) and validation cohort (n=9434). The last follow-up was December, 31, 2020 and the median follow-up period was 99 months (1-203). Age, marriage, estrogen (ER) status, progesterone (PR) status, grade, tumor size, lymph node ratio (LNR) and combined summary (CS) stage were prognostic factors for both OS and CSS of ILC, whereas chemotherapy and radiation were independent protect factors for OS. The nomograms exhibited satisfactory discriminative ability. For the training and validation cohorts, the C-index of the OS nomogram was 0.765 (95% CI 0.762-0.768) and 0.757 (95% CI 0.747-0.767), and the C-index of the CSS nomogram were 0.812 (95% CI 0.804-0.820) and 0.813 (95% CI 0.799-0.827), respectively. Additionally, decision curve analysis (DCA) demonstrated that the nomograms had superior predictive performance than traditional American Joint Committee on Cancer (AJCC) TNM stage. The novel nomograms to predict long-term prognosis based on LNR are reliable tools to predict survival, which may assist clinicians in identifying high-risk patients and devising individual treatments for patients with ILC. Our findings should aid public health prevention strategies to reduce cancer burden. We provide two R/Shiny apps ( https://ilc-survival2024.shinyapps.io/osnomogram/ ; https://ilc-survival2024.shinyapps.io/cssnomogram/ ) to visualize findings.

Construction of immune score and its prognostic value in invasive lobular carcinoma of the breast using computational pathology analysis.

BACKGROUND: Previous studies have shown that high level of TILs in invasive lobular carcinoma (ILC) is associated with poor prognosis, contrary to that in TNBC and HER2-positive breast cancer. METHODS: The densities of six immune cell markers and three immune checkpoints in the ILC microenvironment were detected by computational pathology analysis. Then, the LASSO cox regression model was used to construct an immune score (IS) and further evaluate its prognostic value. RESULTS: In our ILC cohort, the low density of CD4, CD8, CD20, CD56, CD68, FOXP3, PD-1, and PD-L1 had significantly longer disease-free survival (DFS) and overall survival (OS); however, the low density of CTLA-4 was associated with shorter DFS and OS. Based on this, an IS was constructed, and patients with low-IS had significantly prolonged DFS (p < 0.0001) and OS (p < 0.0001). Multivariate analysis revealed that IS was an independent prognostic indicator for DFS and OS. Further analysis showed that IS may increase the prognostic value of TNM stage. We further explored the prognostic role of CD68 and FOXP3 in the transcriptional level and the corresponding ISm in the METABRIC dataset, and found that low proportion of CD68 and FOXP3 and their ISm were associated with longer OS, and ISm was also an independent prognostic factor for OS. CONCLUSION: IS was a promising biomarker to distinguish the prognosis in ILC patients.

The uncharted role of HER2 mutant alleles in breast cancer.

Somatic HER2 mutations are a novel class of therapeutic targets across different cancer types. Treatment with the tyrosine kinase inhibitor (TKI) neratinib as a single agent continues to be evaluated in HER2-mutant metastatic disease. However, responses are heterogeneous, with frequent early progression. Herein, we discuss the under-explored effects of individual HER2 mutant alleles on therapeutic response, a role for HER2 mutation in metastatic propensity, and differences in patient outcomes in ER+ invasive lobular carcinoma (ILC) versus invasive ductal carcinoma (IDC). The preclinical efficacy of additional agents is also discussed, particularly the pan-HER inhibitor poziotinib.

Descriptive Study and Surgical Management Among Infiltrating Lobular Carcinoma Patients Admitted to King Abdulaziz Medical City From 2000 to 2017: A Retrospective Cross-Sectional Study.

INTRODUCTION: Invasive lobular carcinoma (ILC) is the second most common histologic type of breast carcinoma. The etiology of ILC is unknown; however, many contributing risk factors have been suggested. Treatment of ILC can be divided into local and systemic. Our objectives were to assess the clinical presentations, risk factors, radiological findings, pathological types, and surgical options for patients with ILC treated at the national guard hospital. Identify the factors associated with metastasis and recurrence. METHODS: Retrospective cross-sectional descriptive study at a tertiary care center in Riyadh. All adult patients aged 16 years and above, from different nationalities, and both genders, were diagnosed with ILC from 2000 to 2017 and followed up at KAMC. The sampling technique was a non-probability consecutive technique. Among 1066 patients identified, 91 patients were diagnosed with ILC over seventeen years study period. RESULTS: The median age at the primary diagnosis was 50. On the clinical examination, 63 (71%) cases were found to have palpable masses which was the most suspicious finding. On radiology, the most encountered finding was speculated masses which were seen in 76 (84%). Regarding the pathology, unilateral breast cancer was seen in 82 while bilateral breast cancer was found only in eight. For the biopsy, a core needle biopsy was the most commonly used in 83 (91%) patients. The most documented surgery for ILC patients was a modified radical mastectomy. Metastasis in different organs was identified with the musculoskeletal system being the commonest site. Different significant variables were compared between patients with or without metastasis. Skin changes, post-operative invasion, estrogen, progesterone, and HER2 receptors were significantly associated with metastasis. Patients with metastasis were less likely to have conservative surgery. Regarding the Recurrence and five years survival, out of 62 cases, 10 had recurrence within five years, which was more prevalent in patients who had fine needle aspiration, excisional biopsy, and nulliparous patients. CONCLUSION: To our knowledge, this is the first study to exclusively describe ILC in Saudi Arabia. The results of this current study are highly important, as these results provide baseline data of ILC in the capital city of Saudi Arabia.

Expression analysis of novel long non-coding RNAs for invasive ductal and invasive lobular breast carcinoma cases.

AIM: Long non-coding RNAs (LncRNAs) serve as important regulatory molecules of gene expression and protein functionality at multiple biological levels, and their deregulation plays a key role in tumorigenesis including in breast cancer metastasis. Therefore, in this study, we aim to compare the expression of novel lncRNAs in the landscape of invasive ductal carcinoma (IDC) and invasive lobular (ILC) carcinoma of breast. MAIN METHODS: We have designed an in-silico approach to find the lncRNAs that regulate the breast cancer. Then, we used the clinical samples to carry out the verification of our in silico finding. In the present study, the tissues of breast cancer were deparaffinized. RNA was extracted by the TRIzole method. After synthesizing cDNA from the extracted RNA, expression levels of lncRNAs were analyzed by qPCR using primers specifically designed and validated for the targeted lncRNAs. In this study, breast biopsy materials from 41 female patients with IDC and 10 female patients with ILC were examined histopathological and expression changes of candidate lncRNAs were investigated in line with the findings. The results were analyzed using IBM SPSS Statistics 25 version. RESULTS: The mean age of the cases was 53.78 ± 14.96. The minimum age was 29, while the maximum age was 87. While 27 of the cases were pre-menopausal, 24 cases were post-menopausal. The number of hormone receptor-positive cases was found to be 40, 35, and 27 for ER, PR, and cerb2/neu, respectively. While the expressions of LINC00501, LINC00578, LINC01209, LINC02015, LINC02584, ABCC5-AS1, PEX5L-AS2, SHANK2-AS3 and SOX2-OT showed significant differences (p < 0.05), the expressions of LINC01206, LINC01994, SHANK2-AS1, and TPRG1-AS2 showed no significant differences (p > 0.05). In addition, it was determined that the regulation of all lncRNAs could be able to involve in the development of cancer such as the NOTCH1, NFKB, and estrogen receptor signalings. CONCLUSION: As a result, it was thought that the discovery of novel lncRNAs might be an important player in the diagnosis, prognosis and therapeutic development of breast cancer.

Evaluation of an Artificial Intelligence System for Detection of Invasive Lobular Carcinoma on Digital Mammography.

Introduction Early breast cancer detection with screening mammography has been shown to reduce mortality and improve breast cancer survival. This study aims to evaluate the ability of an artificial intelligence computer-aided detection (AI CAD) system to detect biopsy-proven invasive lobular carcinoma (ILC) on digital mammography. Methods This retrospective study reviewed mammograms of patients who were diagnosed with biopsy-proved ILC between January 1, 2017, and January 1, 2022. All mammograms were analyzed using cmAssist® (CureMetrix, San Diego, California, United States), which is an AI CAD for mammography. The AI CAD sensitivity for detecting ILC on mammography was calculated and further subdivided by lesion type, mass shape, and mass margins. To account for the within-subject correlation, generalized linear mixed models were implemented to investigate the association between age, family history, and breast density and whether the AI detected a false positive or true positive. Odds ratios, 95% confidence intervals, and p-values were also calculated. Results A total of 124 patients with 153 biopsy-proven ILC lesions were included. The AI CAD detected ILC on mammography with a sensitivity of 80%. The AI CAD had the highest sensitivity for detecting calcifications (100%), masses with irregular shape (82%), and masses with spiculated margins (86%). However, 88% of mammograms had at least one false positive mark with an average number of 3.9 false positive marks per mammogram. Conclusion The AI CAD system evaluated was successful in marking the malignancy in digital mammography. However, the numerous annotations confounded the ability to determine its overall accuracy and this reduces its potential use in real-life practice.

A Rare Case of a Chylous Pleural Effusion as the Initial Manifestation of Synchronous Tumors.

Multiple primary malignancies (MPMs) are defined as two or more histopathologically distinct malignancies in the same individual. MPMs are classified as synchronous when tumors are diagnosed within six months of each other. The most common malignancies in MPMs are melanoma, breast, lung, and prostate cancer. Synchronous lymphoma and solid tumors are relatively rare. In these cases, a multi-disciplinary approach to treatment is essential. The early detection of additional primary malignancies such as myeloid and lymphatic tumors will enable prompt management with curative intent. The authors present a case of diffuse B-cell non-Hodgkin lymphoma and invasive lobular breast carcinoma presented as a chylous pleural effusion.

Mammographically Occult Invasive Lobular Carcinoma With Intradermal Invasion.

While shortcomings in the detection of invasive lobular carcinoma (ILC) continue to be studied, research is ongoing to determine detection rates using current breast imaging modalities in combination with physical examination findings. In the following case report, we describe the rare presentation of a patient diagnosed by punch biopsy with grade III, estrogen receptor (ER)-/progesterone receptor (PR)-positive invasive lobular carcinoma with intradermal invasion. This patient presented with findings similar to inflammatory breast cancer (IBC) including pain in the left nipple, skin warmth, and erythema circumferentially encompassing approximately two-thirds of the left breast. This case study is of significance as, to date, it is the first report of an invasive lobular carcinoma that presented clinically as inflammatory breast cancer and was occult on both diagnostic mammography and ultrasound. While imaging remains the primary method of breast cancer detection, it is important to note that clinical findings of dermal invasion of the breast may prompt further investigation with a biopsy and close follow-up, regardless of imaging results.

Pleomorphic Invasive Lobular Cancer of the Breast Presenting with Orbital Metastasis: A Case Report.

BACKGROUND: Orbital metastasis of breast cancer is an unusual condition, especially in the absence of a previous diagnosis of primary breast cancer. The main MRI findings in patients with orbital metastasis are retroorbital soft tissue with thickening of extraocular muscles. Paradoxical enophthalmos secondary to fibrosis can be seen. CASE REPORT: In this case report, we present a 75-year-old female patient with left eye pain and blurred vision and retraction. Although there was no evidence of malignancy in the biopsy of the orbita; since the patient's complaints continued despite idiopathic pseudotumor treatment, mammography was recommended to rule out the possibility of breast cancer metastasis. Her mammography revealed a suspicious lesion in the left breast and proved to be pleomorphic invasive lobular cancer. CONCLUSION: Breast cancer metastasis should be kept in mind in women with pseudotumor -like the involvement of the orbita.

Metastatic Infiltrating Lobular Breast Cancer to the Colon Diagnosed Through Routine Bowel Screening in a 67-Year-Old Female.

Breast cancer most commonly metastasizes to the bone, lung, liver, and brain. The colon is an uncommon site for metastases and its symptoms are variable. A 67-year-old female with a history of breast cancer was referred for colonoscopy following a positive fecal occult blood test (FOBT); there were no discrete lesions concerning for primary colonic cancers or metastasis; however, a random biopsy revealed metastatic breast cancer. The possibility of colonic metastases must be considered when assessing positive FOBT in a patient with previous breast cancer.

Invasive Lobular Carcinoma in Premenopausal Woman: A Delayed Diagnosis Due to Socio-Cultural Factors Prevalent in Pakistan.

A 41-year-old premenopausal woman presented to the outpatient department with a diagnosis of invasive lobular carcinoma. She noticed a lump a year back but did not seek medical attention due to many socio-cultural factors prevalent in Pakistan that prevent her from seeking medical attention earlier. She came in for a check-up after increasing in size of the lump. The bilateral mammogram showed large areas of asymmetrical density in the left upper quadrant. It was followed by an ultrasound-guided biopsy which confirmed the diagnosis of invasive lobular carcinoma. Due to stage 3, it was recommended to have CT and an MRI of the breast to assess the extent of the disease. Tissue immunohistochemistry was also requested, which came back as ER-positive, PR-positive, and HER2/neu negative. MRI of the breast revealed a 4.2 x 3.3cm heterogeneously enhancing asymmetric mass-like enhancement area within the left breast outer quadrant with an adjacent spiculated nodular lesion measuring 2.2 cm. CT chest/abdomen/pelvis with contrast showed left breast with minimal parenchymal asymmetry and a small 9 mm node seen in the left axilla. There was no evidence of metastasis. The patient was started on neoadjuvant therapy to minimize systemic disease, followed by mastectomy. This case highlights socio-cultural factors prevalent in Pakistan that lead to delays in the diagnosis and treatment of invasive lobular carcinoma. The outcome had been better if the patient sought medical attention sooner at an earlier stage. We also propose strategies to raise awareness in Pakistan for the timely diagnosis and treatment of breast cancer.

Atlas of Lobular Breast Cancer Models: Challenges and Strategic Directions.

Invasive lobular carcinoma (ILC) accounts for up to 15% of all breast cancer (BC) cases and responds well to endocrine treatment when estrogen receptor α-positive (ER+) yet differs in many biological aspects from other ER+ BC subtypes. Up to 30% of patients with ILC will develop late-onset metastatic disease up to ten years after initial tumor diagnosis and may experience failure of systemic therapy. Unfortunately, preclinical models to study ILC progression and predict the efficacy of novel therapeutics are scarce. Here, we review the current advances in ILC modeling, including cell lines and organotypic models, genetically engineered mouse models, and patient-derived xenografts. We also underscore four critical challenges that can be addressed using ILC models: drug resistance, lobular tumor microenvironment, tumor dormancy, and metastasis. Finally, we highlight the advantages of shared experimental ILC resources and provide essential considerations from the perspective of the European Lobular Breast Cancer Consortium (ELBCC), which is devoted to better understanding and translating the molecular cues that underpin ILC to clinical diagnosis and intervention. This review will guide investigators who are considering the implementation of ILC models in their research programs.

Uncommon metastases of invasive lobular breast cancer to the endometrium: a report of two cases and review of the literature.

Although it is known that breast cancer can metastasize to many organ sites, metastasis to the uterus is uncommon and usually occurs during widespread metastatic disease. Lobular carcinoma is not the most common histological subtypes of breast carcinoma, but it is the most frequent histologic type that causes gastrointestinal, gynecological and peritoneal metastases. The main symptoms of the uterine metastasis depend on the anatomic involvement site. Abnormal uterine bleeding is by far the most important symptom.We highlight the importance of the follow up of patient with breast cancer. A rapid endometrial sampling for confirmation of the diagnosis, should be performed when the routine gynecological follow-up revealed any abnormality. We report two original observations of endometrium metastases of invasive lobular carcinoma of the breast which we detected during follow-up.

ERBB2 mutations associated with solid variant of high-grade invasive lobular breast carcinomas.

ERBB2 and ERBB3 somatic gain-of-function mutations, which may be targeted by anti-ERBB2 therapies, were reported by high-throughput sequencing studies in 1% and 2% of invasive breast cancers respectively. Our study aims to determine ERBB2 and ERBB3 mutations frequencies in grade 3 and/or ERBB2-positive invasive lobular breast carcinomas (ILC). All the 529 ILC surgically-excised registered at Institut Curie in the years 2005 to 2008 were reviewed. Thirty-nine grade 3 ERBB2-negative ILC and 16 ERBB2-positive ILC were retrieved and subjected to Sanger sequencing of the ERBB2 and ERBB3 activation mutation hotspots (ERBB2: exons 8, 17, 19, 20, 21; ERBB3: exons 3, 6, 7, 8). Among the 39 grade 3 ERBB2-negative ILC, six tumors were found to have at least one detectable ERBB2 activating mutation (incidence rate: 15%, 95%CI [4%-27%]). No ERBB2 mutation was found among the 16 ERBB2-positive ILC. No ERBB3 mutation was found in any of the 55 ILC. ERBB2 mutations were statistically associated with solid ILC features (p=0.01). Survival analyses showed no significant prognostic impact of ERBB2 mutations. Our study demonstrates that high grade ERBB2-negative ILC display a high frequency of ERBB2 mutations, and should be subjected to systematic genetic screening.