Invasive Lobular Breast Carcinoma

Most invasive lobular breast carcinomas (ILBCs) are luminal-type carcinomas with an HER2-negative phenotype (ERBB2 or HER2 un-amplified) and CDH1 mutations. Rare variants include ERBB2-amplified subtypes associated with an unfavorable prognosis and less response to anti-HER2 targeted therapies. We analyzed the clinicopathological and molecular features of ERBB2-amplified ILBC and compared these characteristics with ERBB2-unamplified ILBC. A total of 253 patients with ILBC were analyzed. Paraffin-embedded formalin-fixed tumor samples from 250 of these patients were added to a tissue microarray. Protein expression of prognostic, stem cell and breast-specific markers was tested by immunohistochemistry (IHC). Hybrid capture-based comprehensive genomic profiling (CGP) was performed for 10 ILBCs that were either fluorescent in situ hybridization (FISH) or IHC positive for HER2 amplification/overexpression and 10 ILBCs that were either FISH or IHC negative. Results were compared with a CGP database of 44,293 invasive breast carcinomas. The CGP definition of ERBB2 amplification was five copies or greater. A total of 17 of 255 ILBC (5%) were ERBB2 amplified. ERBB2-amplified ILBC had higher tumor stage (p < 0.0001), more frequent positive nodal status (p = 0.00022), more distant metastases (p = 0.012), and higher histological grade (p < 0.0001), and were more often hormone receptor negative (p < 0.001) and more often SOX10 positive (p = 0.005). ERBB2 short variant sequence mutations were more often detected in ERBB2-unamplified tumors (6/10, p = 0.027), whereas CDH1 mutations/copy loss were frequently present in both subgroups (9/10 and 7/10, respectively). Amplification of pathogenic genes were more common in HER2-positive ILBC (p = 0.0009). CDK12 gene amplification (≥6 copies) was detected in 7 of 10 ERBB2-amplified ILBC (p = 0.018). There were no CDK12 gene amplifications reported in 44,293 invasive breast carcinomas in the FMI Insights CGP database. ERBB2-amplified ILBC is a distinct molecular subgroup with frequent coamplification of CDK12, whereas ERBB2 sequence mutations occur only in ERBB2-unamplified ILBC. CDK12/ERBB2 co-amplification may explain the poor prognosis and therapy resistance of ERBB2-amplified ILBC.

Positron Emission Tomography (PET) has been growing in usage for patients with breast cancer, due to an increased number of FDA-approved PET radiotracers pertinent to patients with breast cancer as well as increased prospective evidence for the value of these agents. The leading PET radiotracer for patients with breast cancer is 18F-fluorodeoxyglucose (18F-FDG), which measures glucose metabolism. There is prospective evidence for the use of 18F-FDG PET in systemic staging of newly diagnosed locally advanced breast cancer (stages IIB-IIIC), monitoring breast cancer treatment response, and detecting breast cancer recurrence, particularly in no special type (NST) breast cancer. 16α-18F-fluoro-17β-Fluoroestradiol (18F-FES) is a radiolabeled estrogen which evaluates estrogen receptor (ER) accessible for estrogen binding. There is prospective evidence supporting 18F-FES PET as a predictive biomarker for selecting patients with metastatic breast cancer for endocrine therapies. 18F-FES PET has also been shown to be valuable in the evaluation of ER status of lesions which are difficult to biopsy, for evaluation of ER status in lesions that are equivocal on other imaging modalities, and for selecting optimal dosage of novel ER-targeted systemic therapies in early clinical trials. Multiple investigators have suggested 18F-FES PET will have an increasing role for patients with invasive lobular breast cancer (ILC), which is less optimally evaluated by 18F-FDG PET. Sodium 18F-Fluoride (18F-NaF) evaluates bone turnover and has been effective in evaluation of malignancies which commonly metastasize to bone. In patients with metastatic breast cancer, 18F-NaF PET/CT has demonstrated superior sensitivity for osseous metastases than 99mTc-MDP or CT. In addition to these three FDA-approved PET radiotracers, there are multiple novel radiotracers currently in clinical trials with potential to further increase PET usage for patients with breast cancer.

CDH1 (E-cadherin) bi-allelic inactivation is the hallmark alteration of breast invasive lobular carcinoma (ILC), resulting in its discohesive phenotype. A subset of ILCs, however, lack CDH1 genetic/epigenetic inactivation, and their genetic underpinning is unknown. Through clinical targeted sequencing data reanalysis of 364 primary ILCs, we identified 25 ILCs lacking CDH1 bi-allelic genetic alterations. CDH1 promoter methylation was frequent (63%) in these cases. Targeted sequencing reanalysis revealed 3 ILCs harboring AXIN2 deleterious fusions (n = 2) or loss-of-function mutation (n = 1). Whole-genome sequencing of 3 cases lacking bi-allelic CDH1 genetic/epigenetic inactivation confirmed the AXIN2 mutation and no other cell-cell adhesion genetic alterations but revealed a new CTNND1 (p120) deleterious fusion. AXIN2 knock-out in MCF7 cells resulted in lobular-like features, including increased cellular migration and resistance to anoikis. Taken together, ILCs lacking CDH1 genetic/epigenetic alterations are driven by inactivating alterations in other cell adhesion genes (CTNND1 or AXIN2), endorsing a convergent phenotype in ILC.