Lobular Carcinoma of the Breast: A Comprehensive Review with Translational Insights
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ABSTRACT:
SUBMITTER: Batra H
PROVIDER: S-EPMC10670219 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.
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Project description:Invasive lobular carcinoma accounts for 5%-15% of all invasive breast cancers, with a marked increase in incidence rates over the past two decades. Distinctive biological hallmarks of invasive lobular carcinoma include the loss of cell adhesion molecule E-cadherin leading to cells with a discohesive morphology, proliferating into single-file strands and estrogen receptor positivity. These key molecular features can make diagnosis difficult, as invasive lobular carcinoma is challenging to detect both physically and with current standard imaging. Treatment of invasive lobular carcinoma strongly favors endocrine therapy due to low chemosensitivity and lower rates of pathological response as a result. This review will summarize the distinct biological and molecular features of invasive lobular carcinoma, focusing on the diagnostic challenges faced and the subsequent surgical and medical management strategies. Prospective therapeutic options will also be explored, highlighting how furthering our understanding of the unique biology of lobular breast carcinoma is essential in guiding and informing the treatment of patients in the future.
| S-EPMC7844138 | biostudies-literature
Project description:Invasive lobular carcinoma exhibits unique morphological features frequently associated with alterations in CDH1. Although some studies have identified abnormalities in adhesion factors other than E-cadherin, the molecular mechanisms underlying E-cadherin abnormalities in CDH1-unaltered invasive lobular carcinoma remain poorly understood. In this study, we investigated the molecular underpinnings of E-cadherin dysregulation in invasive lobular carcinoma in the absence of CDH1 gene alterations, using comprehensive bioinformatic analyses. We conducted a comparative study of CDH1-mutated and non-mutated invasive lobular carcinoma and evaluated the differences in mRNA levels, reverse-phase protein array, methylation, and miRNAs. We observed that invasive lobular carcinoma cases without CDH1 alterations exhibited a significantly higher incidence of the Claudin-low subtype (p < 0.01). The results of the reverse-phase protein array indicate no significant difference in E-cadherin expression between CDH1-mutated and non-mutated cases. Therefore, abnormalities in E-cadherin production also exist in CDH1 non-mutated invasive lobular carcinoma. Considering that there are no differences in mRNA levels and methylation status, post-translational modifications are the most plausible explanation for the same. Hence, future studies should focus on elucidating the mechanism underlying E-cadherin inactivation via post-translational modifications in CDH1 non-mutated invasive lobular carcinoma.
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Project description:To investigate the usefulness of imaging features for differentiating between small lobular carcinoma in situ (LCIS) and invasive lobular carcinoma (ILC). It included 52 female with LCISs (median 45 years, range 32-67 years) and 180 female with ILCs (median 49 years, range 36-75 years), with the longest diameter of ≤ 2 cm, who were evaluated between January 2012 and December 2016. All the female underwent mammography and ultrasonography. Twenty female with LCIS and 150 female with ILC underwent MRI. The clinical and imaging features were compared, and multivariate analysis was performed to identify the independent predictors of LCIS. Female with LCIS were also subgrouped by lesion size and compared with the female with ILC. Multivariate analysis showed that younger age [odds ratio (OR) = 1.100], smaller lesion size (OR = 1.103), oval or round shape (OR = 4.098), parallel orientation (OR = 5.464), and isoechotexture (OR = 3.360) were significant independent factors predictive of LCIS. The area under the receiver operating characteristic curve for distinguishing LCIS from ILC was 0.904 (95% confidence interval, 0.857-0.951). Subgroup analysis showed that benign features were more prevalent in female with smaller LCISs (≤ 1 cm) than in those with ILC. Small LCISs tend to demonstrate more benign features than small ILCs. Several imaging features are independently predictive of LCIS.
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Project description:The morphology of breast tumors is complicated and diagnosis can be difficult. We present here a novel diagnostic model which we validate on both array-based and RNA sequencing platforms which reliably distinguishes this tumor type across multiple cohorts. We also examine how this molecular classification predicts sensitivity to common chemotherapeutics in cell-line based assays. A total of 1845 invasive breast cancer cases in six cohorts were collected, split into discovery and validation cohorts, and a classifier was created and compared to pathological diagnosis, grade and survival. In the validation cohorts the concordance of predicted diagnosis with a pathological diagnosis was 92%, and 97% when inconclusively classified cases were excluded. Tumor-derived cell lines were classified with the model as having predominantly ductal or lobular-like molecular physiologies, and sensitivity of these lines to relevant compounds was analyzed. A diagnostic tool can be created that reliably distinguishes lobular from ductal carcinoma and allows the classification of cell lines on the basis of molecular profiles associated with these tumor types. This tool may assist in improved diagnosis and aid in explorations of the response of lobular type breast tumor models to different compounds.
| S-EPMC5355990 | biostudies-literature
Project description:PurposeThe purpose of this study was to investigate the expression of PD-L1 in invasive lobular carcinoma (ILC) and to determine its implications.MethodsTissue microarrays were constructed for 101 cases of ILC, and immunohistochemical staining for PD-L1 (using 22C3, SP142, and SP263 antibodies) was performed to examine the correlation between staining results and clinicopathologic parameters.ResultsThe positive cut-off values were defined as tumor cell (TC)≥1%, immune cell (IC)>0%, and IC≥1%. The range of PD-L1 TC positivity was 0.0-2.0%, with PD-L1 SP263 TC showing the highest positivity of 2.0%. The range of PD-L1 IC positivity was 0-21.8% for IC ≥ 1%, with PD-L1 22C3 IC showing the highest positivity. When PD-L1 IC was positive (IC≥1%), the highest antibody agreement was observed between SP263 and SP142 (OA = 93.1%), while the lowest agreement was observed between 22C3 and SP263 (OA = 73.3%, κ = 0.040). PD-L1 22C3 IC positivity (≥1%) was associated with high nuclear grade (p = 0.002), HER-2 positivity (p = 0.019), and pleomorphic type (p = 0.002).ConclusionPD-L1 expression in ILC shows a low TC positivity rate (0-2%) with various antibody clones and a variable IC positivity rate (0-21.8%). Pleomorphic type ILC exhibits higher PD-L1 IC positivity.
| S-EPMC11466385 | biostudies-literature
Project description:BackgroundBiopsy-proven breast lesions such as atypical ductal hyperplasia (ADH) or atypical lobular hyperplasia (ALH), lobular carcinoma in situ (LCIS) and flat epithelial atypia (FEA) increase subsequent risk of breast cancer (BC), but long-term risk has not been synthesized. A systematic review was conducted to quantify future risk of breast cancer accounting for time since diagnosis of these high-risk lesions.MethodsA systematic search of literature from 2000 was performed to identify studies reporting BC as an outcome following core-needle or excision biopsy histology diagnosis of ADH, ALH, LCIS, lobular neoplasia (LN) or FEA. Meta-analyses were conducted to estimate cumulative BC incidence at five-yearly intervals following initial diagnosis for each histology type.ResultsSeventy studies reporting on 47,671 subjects met eligibility criteria. BC incidence at five years post-diagnosis with a high-risk lesion was estimated to be 9.3 % (95 % CI 6.9-12.5 %) for LCIS, 6.6 % (95 % CI 4.4-9.7 %) for ADH, 9.7 % (95 % CI 5.3-17.2 %) for ALH, 8.6 % (95 % CI 6.5-11.4 %) for LN, and 3.8 % (95 % CI 1.2-11.7 %) for FEA. At ten years post-diagnosis, BC incidence was estimated to be 11.8 % (95 % CI 9.0-15.3 %) for LCIS, 13.9 % (95 % CI 7.8-23.6 %) for ADH, 15.4 % (95 % CI 7.2-29.3 %) for ALH, 17.0 % (95 % CI 7.2-35.3 %) for LN and 7.2 % (95 % CI 2.2-21.2 %) for FEA.ConclusionOur findings demonstrate increased BC risk sustained over time since initial diagnosis of high-risk breast lesions, varying by lesion type, with relatively less evidence for FEA.
| S-EPMC11415589 | biostudies-literature
Project description:BackgroundInvasive pleomorphic lobular carcinoma (PLC) of the breast is a subtype of invasive lobular cancer which compromises approximately 1% of all epithelial breast malignancies and is characterized by higher nuclear pleomorphism and poorer prognosis than classic invasive lobular cancer (ILC). Since PLC is more aggressive than classical ILC, we examined the underlying molecular alterations in this subtype of breast cancer to understand the possible benefit from targeted therapies.MethodsIn this study, we investigate the clinical characteristics and molecular alterations in 16 PLC from our institution. Additionally, we examined the clinical and genomic features in 31 PLC from the Cancer Genome Atlas (TCGA).ResultsOverall, our analysis of PLC found that 28% had activating ERBB2 mutations, 21% had ERBB2 amplification, and 49% activating PIK3CA mutations. Among cases from our institution, we found 19% with activating ERBB2 mutations, 25% had ERBB2 amplification, and 38% with activating PIK3CA mutations. In data from TCGA, 32% had activating ERBB2 mutations, 19% had ERBB2 amplification, and 55% had activating PIK3CA mutations. While classic ILC in TCGA had similar percentages of PIK3CA alterations compared to PLC, activating ERBB2 alterations were exceedingly rare, with no activating ERBB2 mutations and only one case with ERBB2 amplification. Interestingly, in further examining TCGA data which included FGFR1 and PTEN, 94% of PLC had alterations in ERBB2, FGFR1, or the PI3K pathway.ConclusionsOur results show a high frequency of ERBB2 and PIK3CA alterations in PLC and suggest all PLC should be tested for potential therapeutic targeting.
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Project description:Invasive lobular carcinoma (ILC) is a common breast cancer subtype that is often diagnosed at advanced stages and causes significant morbidity. Late-onset secondary tumor recurrence affects up to 30% of ILC patients, posing a therapeutic challenge if resistance to systemic therapy develops. Nonetheless, there is a lack of preclinical models for ILC, and the current models do not accurately reproduce the complete range of the disease. We created clinically relevant metastatic xenografts to address this gap by grafting the triple-negative IPH-926 cell line into mouse milk ducts. The resulting intraductal xenografts accurately recapitulate lobular carcinoma in situ (LCIS), invasive lobular carcinoma, and metastatic ILC in relevant organs. Using a panel of 15 clinical markers, we characterized the intratumoral heterogeneity of primary and metastatic lesions. Interestingly, intraductal IPH-926 xenografts express low but actionable HER2 and are not dependent on supplementation with the ovarian hormone estradiol for their growth. This model provides a valuable tool to test the efficiency of potential new ILC therapeutics, and it may help detect vulnerabilities within ILC that can be exploited for therapeutic targeting.
| S-EPMC10340059 | biostudies-literature
Project description:Breast cancer manifests in diverse forms, with particular reference to various cell types harboring different mutations and gene expression profiles. To elucidate the clonal relationship between cancer cells in tumors composed of both ductal and lobular phenotypes, two combined lobular and ductal carcinoma (CLDC) cases were analyzed, including one mixed ductal‑lobular carcinoma (MDL) lesion, by direct sequencing of the mitochondrial DNA D‑loop, digital PCR targeting of chromosomes 1q and 16q, as well as next‑generation sequencing. DNA was extracted from formalin‑fixed paraffin‑embedded tissue sections of different histological types, including invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, lobular carcinoma in situ, flat epithelial atypia, non‑neoplastic mammary gland and extramammary organs, using laser‑assisted microdissection. Mutations detected by the comprehensive cancer panel were validated by SYBR green allele‑specific quantitative PCR (RRM1, AKT1, PIK3CA, RALGDS, EGFR, TP53, IL21R, DPYD, SGK1, CDH1, TIMP3 and KMT2C). CLDC, which shared the basic genetic alterations of 1q gain or 16q loss, progresses to invasive lobular or ductual carcinoma with the accumulation of further mutations. Cancer cells contained in an MDL lesion shared closely related genetic alterations, suggesting that these cells have the same origin, despite different histological features, namely 'lobular' or 'ductal'. By contrast, multiple lesions located away from the main tumor, diagnosed as CLDC (excluding an MDL lesion) were not always identical with different genetic alterations, despite being diagnosed as ductal carcinoma in situ. Thus, MDL should be defined as a distinct category separate from CLDC, whose components of 'lobular' and 'ductal' may have the same cellular origin.
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