The DESTINY-Breast04 clinical trial is currently investigating whether trastuzumab deruxtecan (T-DXd) is effective in HER2-low as well as HER2-positive breast cancer. This highlights the interest in treatment strategies for patients with HER2-low breast cancer. The current study was therefore designed to determine the frequency of HER2-low among all breast cancers, and to compare the prognosis of HER2low patients with that of HER2-negative patients. MethodsWe retrospectively reviewed the biological data from 4,918 of 4,977 primary breast cancer patients who attended our institute. We quanti ed the overall frequency of breast cancer patients with a new HER2-low subtype that was de ned by an immunohistochemistry score of IHC1+ or IHC2+/ISH-. We then compared the clinical characteristics and prognosis of HER2-low patients with that of patients who did not have HER2 ampli cation (HER2-0). ResultsLow HER2 expression was found in 3169 (64.4%) patients; 2860 (58.1%) were HR-positive and 309(6.3%) were HR-negative. Among HER2-0 patients, 681(13.9%) were HR-positive and 157(3.2%) were HRnegative. The HER2-0 group tended to have more poor prognostic factors than the HER2-low group, irrespective of HR status. There were no statistically signi cant differences between the prognosis of HER2-low and HER2-0 patients, regardless of HR status. However, patients in the HER2-low group tended to have better prognosis than those in the HER2-0 group. ConclusionHER2-low patients did not have a signi cantly different prognosis than HER2-0 patients, regardless of HR status. However, we should consider tailoring therapies for patients with HRE2-low early breast cancer according to their HR status.

Cancer tissues reflect a greater number of pathological characteristics of cancer compared to cancer cells, so the evaluation of cancer tissues can be effective in determining cancer treatment strategies. Mass spectrometry imaging (MSI) can evaluate cancer tissues and even identify molecules while preserving spatial information. Cluster analysis of cancer tissues’ MSI data is currently used to evaluate the phenotype heterogeneity of the tissues. Interestingly, it has been reported that phenotype heterogeneity does not always coincide with genotype heterogeneity in HER2-positive breast cancer. We thus investigated the phenotype heterogeneity of luminal breast cancer, which is generally known to have few gene mutations. As a result, we identified phenotype heterogeneity based on lipidomics in luminal breast cancer tissues. Clusters were composed of phosphatidylcholine (PC), triglycerides (TG), phosphatidylethanolamine, sphingomyelin, and ceramide. It was found that mainly the proportion of PC and TG correlated with the proportion of cancer and stroma on HE images. Furthermore, the number of carbons in these lipid class varied from cluster to cluster. This was consistent with the fact that enzymes that synthesize long-chain fatty acids are increased through cancer metabolism. It was then thought that clusters containing PCs with high carbon counts might reflect high malignancy. These results indicate that lipidomics-based phenotype heterogeneity could potentially be used to classify cancer for which genetic analysis alone is insufficient for classification.

Background Fibromatosis-like metaplastic carcinoma (FLMCa), classified as a metaplastic carcinoma of the breast, is a very rare type of metaplastic carcinoma. We report a case of FLMCa that was difficult to diagnose. Case presentation The patient was a 56-year-old postmenopausal woman who presented with a left-sided breast mass. A 1.3-cm irregular mass was found in the lower outer quadrant of the left breast on breast ultrasonography. She underwent core needle biopsy and vacuum-assisted biopsy, but the pathological findings only revealed inflammatory cell infiltration and a high level of fibrosis, with no malignant findings. At 3 months follow-up, she underwent a repeat breast ultrasonography, which revealed an increase in the size of the mass to 1.8 cm, and a repeat core needle biopsy, which showed a few spindle cells and squamous cells positive for cytokeratin (CK)5/6 and AE1/AE3, leading to the suspicion of FLMCa. Since the amount of tissue was insufficient to establish a definitive diagnosis, she underwent a lumpectomy. We found low-grade and slightly atypical spindle cells and partly atypical spindle cell carcinoma and squamous cell carcinoma. CK5/6 and α-SMA were positive, thus confirming FLMCa. Because the margins on the edge of the nipple side and anterior side were “ink on tumor”, she underwent a mastectomy and sentinel lymph node biopsy. After the surgery, she received adjuvant chemotherapy. At 3 years and 8 months of follow-up, no recurrent or metastatic lesions were identified in her body. Conclusions FLMCa should be considered in the differential diagnosis when collagenous fibers are proliferating and malignancy is clinically suspected. Immunohistochemical analysis may be helpful in confirming this diagnosis.

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