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Qianming Bai,1– 3,&ast; Hong Lv,1– 3,&ast; Longlong Bao,1– 3,&ast; Yu Yang,1– 3 Xin Zhang,4 Heng Chang,1– 3 Tian Xue,1– 3 Min Ren,1– 3 Xiaoli Zhu,1– 3 Xiaoyan Zhou,1– 3,&ast; Wentao Yang1– 3,&ast; 1Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China; 3Institute of Pathology, Fudan University, Shanghai, 200032, People’s Republic of China; 4Department of Pathology, Fudan University Zhongshan Hospital, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wentao Yang; Xiaoyan Zhou, Department of Pathology, Fudan University Shanghai Cancer Centre, 270 Dong’an Road, Shanghai, 200032, People’s Republic of China, Tel +86-18017312353 ; +86-18017312385, Email yangwt2000@163.com; xyzhou100@163.comPurpose: To investigate the HER2 status and clinicopathological features in invasive breast cancer with HER2 ≥ 4.0 and < 6.0, which has always been controversial.Methods: Forty breast cancer cases with HER2 ≥ 4.0 and < 6.0 by fluorescence in situ hybridization (FISH) were collected and classified into two groups based on the HRE2/CEP17 ratio (Group A: ≥ 2.0, n=22; Group B: < 2.0, n=18). Clinicopathological characteristics, HER2 status, risk classification, and molecular typing were further analyzed and compared by 21-Gene expression assay and MammaPrint plus BluePrint test.Results: The majority of cases in both groups were invasive carcinoma (NOS), with histological grade II, HR+, Ki-67 ≥ 20%, HER2 2+, and a high risk of recurrence, although younger patients and lymph node metastases were more common in Group A. Surprisingly, all HR+ breast cancers in both groups were classified as luminal-type, HR− cases were all basal-type or unknown, and the index of HER2 in all cases was < 0.000 using the BluePrint test, which indicated that HER2 status should be negative. Furthermore, the level of HER2 mRNA expression in all cases of both groups was < 10.7, which was defined as HER2 negative by the 21-Gene expression assay. In addition, 10 patients of Group A received anti-HER2 neoadjuvant therapy; only one patient with HR- achieved Grade 5 based on the Miller-Payne system, whereas none of the patients achieved pathological complete response (pCR) based on the Residual Cancer Burden system.Conclusion: Group A breast cancer, which has always been unquestionably diagnosed as HER2 amplification, was more likely to be HER2 negative and derived less benefit from anti-HER2 neoadjuvant chemotherapy. Group A breast cancer should be distinguished from classical HER2-positive breast cancers when assessing HER2 FISH, and a larger cohort of Group A patients should be included in further studies.Graphical Abstract: Keywords: breast cancer, HER2, FISH, 21-gene expression assay, MammaPrint plus BluePrint

Mingkai Gong,1 Xiangping Liu,2 Wu Yang,3 Hongming Song,1 Xian Zhao,1 Xiancheng Ai,1 Shuo Wang,1 Haibo Wang1 1Center of Diagnosis and Treatment of Breast Disease, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China; 2Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China; 3Department of International Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of ChinaCorrespondence: Haibo WangCenter of Diagnosis and Treatment of Breast Disease, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of ChinaEmail hbwang66@126.comBackground: Cancer metabolism and specifically lipid metabolism play an important role in breast cancer (BC) progression and metastasis. However, the role of lipid metabolism-associated genes (LMGs) in the prognosis of breast cancer remains unknown.Methods: The expression profiles and clinical follow-up information of 1053 BC were downloaded from The Cancer Genome Atlas (TCGA), and metabolic genes were downloaded from the Gene Set Enrichment Analysis (GSEA) dataset. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were performed on the differentially expressed metabolism-related genes. Then, the formula of the metabolism-related risk model was composed, and the risk score of each patient was calculated. The breast cancer patients were divided into high-risk and low-risk groups with a cutoff of the median expression value of the risk score, and the prognostic analysis was also used to analyze the survival time between these two groups. Finally, we analyzed the expression, interaction and correlation among the lipid metabolism-associated genes risk model.Results: The results from the prognostic analysis indicated that the survival was significantly poorer in the high-risk group than in the low-risk group in TCGA, and single-sample gene set enrichment analysis (ssGSEA) shows it is plausible that lipid metabolism is highly correlated with tumor immunity.Conclusion: Lipid metabolism-associated genes may become a new prognostic indicator predicting the survival of BC patients. The prognostic genes (n = 16) may help provide new strategies for tumor therapy.Keywords: bioinformatics, lipid metabolism-associated genes, breast cancer, lipid metabolism, TCGA