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Background: The development of anti-HER2 antibody-drug conjugates opens new therapeutic options for patients with breast cancer, including patients with low expression of HER2. To characterise this new breast cancer subtype, we have compared the clinical and molecular characteristics of HER2-low-positive and HER2-zero breast cancer, including response to neoadjuvant chemotherapy and prognosis., Methods: In this pooled analysis of individual patient data, we evaluated a cohort of 2310 patients with HER2-non-amplified primary breast cancer that were treated with neoadjuvant combination chemotherapy in four prospective neoadjuvant clinical trials (GeparSepto, NCT01583426; GeparOcto, NCT02125344; GeparX, NCT02682693; Gain-2 neoadjuvant, NCT01690702) between July 30, 2012, and March 20, 2019. Central HER2 testing was done prospectively before random assignment of participants in all trials. HER2-low-positive status was defined as immunohistochemistry (IHC) 1+ or IHC2+/in-situ hybridisation negative and HER2-zero was defined as IHC0, based on the American Society of Clinical Oncology/College of American Pathologists guidelines. Disease-free survival and overall survival data were available for 1694 patients (from all trials except GeparX) with a median follow-up of 46·6 months (IQR 35·0-52·3). Bivariable and multivariable logistic regression models and Cox-proportional hazards models were performed based on a predefined statistical analysis plan for analysis of the endpoints pathological complete response, disease-free survival, and overall survival., Findings: A total of 1098 (47·5%) of 2310 tumours were HER2-low-positive and 1212 (52·5%) were HER2-zero. 703 (64·0%) of 1098 patients with HER2-low-positive tumours were hormone receptor positive, compared with 445 (36·7%) of 1212 patients with HER2-zero tumours (p<0.0001). HER2-low-positive tumours had a significantly lower pathological complete response rate than HER2-zero tumours (321 [29·2%] of 1098 vs 473 [39·0%] of 1212, p=0·0002). Pathological complete response was also significantly lower in HER2-low-positive tumours versus HER2-zero tumours in the hormone receptor-positive subgroup (123 [17·5%] of 703 vs 105 [23·6%] of 445, p=0·024), but not in the hormone receptor-negative subgroup (198 [50·1%] of 395 vs 368 [48·0%] of 767, p=0·21). Patients with HER2-low-positive tumours had significantly longer survival than did patients with HER2-zero tumours (3-year disease-free survival: 83·4% [95% CI 80·5-85·9] vs 76·1% [72·9-79·0]; stratified log-rank test p=0·0084; 3-year overall survival: 91·6% [84·9-93·4] vs 85·8% [83·0-88·1]; stratified log-rank test p=0·0016). Survival differences were also seen in patients with hormone receptor-negative tumours (3-year disease-free survival: 84·5% [95% CI 79·5-88·3] vs 74·4% [70·2-78.0]; stratified log-rank test p=0·0076; 3-year overall survival: 90·2% [86·0-93·2] vs 84·3% [80·7-87·3], stratified log-rank test p=0·016), but not in patients with hormone receptor-positive tumours (3-year disease-free survival 82·8% [79·1-85·9] vs 79·3% [73·9-83·7]; stratified log-rank test p=0·39; 3-year overall survival 92·3% [89·6-94·4] vs 88·4% [83·8-91·8]; stratified log-rank test p=0·13)., Interpretation: Our results show that HER2-low-positive tumours can be identified as new subgroup of breast cancer by standardised IHC, distinct from HER2-zero tumours. HER2-low-positive tumours have a specific biology and show differences in response to therapy and prognosis, which is particularly relevant in therapy-resistant, hormone receptor-negative tumours. Our results provide a basis for a better understanding of the biology of breast cancer subtypes and the refinement of future diagnostic and therapeutic strategies., Funding: German Cancer Aid (Deutsche Krebshilfe)., Competing Interests: Declaration of interests CD reports grants from European Commission H2020, German Cancer Aid Translational Oncology, German Breast Group, during the conduct of the study; personal fees from Novartis, Roche, MSD Oncology, Daiichi Sankyo, AstraZeneca, Molecular Health, and Merck, and grants from Myriad, outside the submitted work. CD is the cofounder of Sividon diagnostics. CD has a patent VMScope digital pathology software with royalties paid, a patent WO2020109570A1-cancer immunotherapy pending, and a patent WO2015114146A1 and WO2010076322A1-therapy response issued. AS reports grants from Celgene, Roche, and AbbVie; personal fees from Roche, AstraZeneca, Celgene, Novartis, MSD, Tesaro, Lilly, and Roche, outside the submitted work. TL receives payment or honoraria from Tesaro, MSD, Roche, Novartis, Pfizer, Amgen, Clovis, and Lilly; receives support for travel costs from Roche, Pfizer, MSD, Celgene, and Clovis; reports participation on an Advisory Board from Roche, Tesaro, Amgen, MSD, Pfizer, Lilly, Myriad, Esai, and GSK, outside the submitted work. J-UB reports personal fees from AstraZeneca, Exact Sciences, Amgen, MSD Oncology, Lilly, Novartis, Sysmex, Roche, and Sonoscape, outside the submitted work. PW reports personal fees from Amgen, AstraZeneca, MSD, Novartis, Pfizer, PharmaMar, Roche, Teva, Eisai, Clovis, and Tesaro, outside the submitted work. HT reports consulting fees and travel costs from Pierre Fabre, Pfizer Pharma, Mundipharma, ClinSol, Novartis, Lilly, Grünenthal, Vifor, AstraZeneca, Mylan, and AMGEN; payment or honoraria from Vifor, Novartis, AstraZeneca, ClinSol, Mundipharma, Lilly, and Amgen; participation on an Advisory Board from Novartis, Bristol Myers Squibb, AstraZeneca, Molecular Health, Pfizer, Roche, Grünenthal, and Mylan; and is part of a leadership or fiduciary role in Arbeitskreis klinische Studien. ASCO, BNHO, DGHO, DKG, ESMO, Deutsche Gesellschaft für Senelogie. CJ receives payment or honoraria from Roche, AstraZeneca, Novartis, Lilly, Exact Sciences, and Pierre Fabre; recieves support for travel costs from Roche and AstraZeneca, reports participation on an Advisory Board from Roche, Lilly, and AstraZeneca. MR reports consulting fees from Roche, Novartis, Lilly, and Somatex; receives payment or honoraria from Novartis, Roche, Lilly, Somatex, and AstraZeneca; recieves support for travel costs from Novartis, Pfizer, and Celgene. EFS receives payment or honoraria from AstraZeneca, Pfizer, Celgene, Roche, and Amgen; support for travel costs from Amgen, AstraZeneca, Celgene, Clovis Oncology, Eisai, Erbe, Gedeon, Richter, Genomic Health, Jenapharm, Johnson Johnson, KLS Martin, Matramed, Medac, Mentor, Novartis, Pfizer, Pharma Mar, MSD, Roche, Samsung, Storz, Tewa, Vifor, Medconcept, and Thieme; is part of a leadership or fiduciary role of University of Saarland, Germany, society for German Gynecological Endoscopy. CH reports personal fees from Pfizer, Roche, Novartis, Lilly, AstraZeneca, Celgene, outside the submitted work. PAF reports personal fees from Novartis, Pfizer, Daiichi-Sankyo, AstraZeneca, Eisai, Merck Sharp & Dohme, Lilly, Pierre Fabre, Seattle Genetics, Roche, and Hexal, and grants from Biontech and Cepheid, during the conduct of the study. KL receives payment from Roche, Pfizer, MSD, Novartis, Lilly, and Genomic Health, support for travel costs from Roche, and reports participation on an Advisory Board from Roche, MSD, and Esai. JH reports research grants to institution from Celgene, Novartis, and Hexal; consulting fees from Lilly, Novartis, Roche, Pfizer, Hexal, AstraZeneca, MSD, Celgene, and Abbvie; receives payment from Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Celgene, Eisai, and Abbvie; recieves support for travel costs from Roche, Pfizer, Novartis, Celgene, and Daiichi. TR reports consulting fees from Pfizer, honoraria for presentations from AstraZeneca and receives payment from Pfizer, Roche, and Novartis. MS reports grants from AstraZeneca, BioNtech, Eisai, German Breast Group, Genentech, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, and Roche; consulting fees from AstraZeneca, Eisai, Lilly, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche, and SeaGen; receives payment or honoraria from AstraZeneca, Novartis, Pfizer, Roche, and SeaGen; support for travel costs from Pfizer and Roche; has planned patents, issued or pending from EP 2951317 B1 and EP 2390370 B1; reports participation on an Advisory Board from AstraZeneca, Eisai, Lilly, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche, and SeaGen; medical writing support from Roche. WJ reports grants and personal fees from Sanofi-Aventis, Novartis, Lilly, Pfizer, Roche, Chugai, AstraZeneca, MSD, and Daiichi Sankyo, during the conduct of the study. ES reports consulting fees from Roche and AstraZeneca; receives payment or honoraria from Roche, Pfizer, Novartis, and Astra Zeneca; support for travel costs from Roche, Pfizer, and Daiko. SSe reports reimbursement of travel costs from Novartis and personal fees from Roche, Mundipharma, and Amgen, outside the submitted work. MU reports personal fees and non-financial support from Abbvie, Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Lilly Int, MSD Merck, Mundipharma, Myriad Genetics, Odonate, Pfizer, Roche Pharma, Sanofi Aventis Deutschland, TEVA Pharmaceuticals, Novartis, and Clovis Oncology; personal fees from Bristol Myers Squibb, Lilly Deutschland, PUMA Biotechnology, Pierre Fabre, Seattle Genetics, outside the submitted work. SL reports grants or fundings from Amgen, AstraZeneca, Celgene, Novartis, Immunomedics, Pfizer, Roche, DSI Trevor, Vifor, Abbvie, Cepheid, Seagen, and VM Scope; receives payment or honoraria from AstraZeneca, Roche, Novartis, Pfizer, Prime/Medscape, Puma, and Samsung; has planned patents, issued or pending from EP14153692.0; reports participation on an Advisory Board from Amgen, AstraZeneca, DSI, Roche, Merck, Pfizer, BMS, SeaGen, Eirgenix, Celgene, Abbvie, Lilly, GlaxoSmithKline, and Pierre Fabre; is part of a leadership or fiduciary role from BIG. All other authors report no conflicts of interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background/aim: Presence of circulating tumor cells (CTCs) is associated with impaired survival in metastatic breast cancer (MBC). This study was designed to evaluate whether assessment of serum HER2 (sHER2) levels provide additional prognostic information in MBC., Materials and Methods: Two hundred and fifty-three MBC patients were enrolled in this multicentre trial. CTCs were detected before the start of first- or later-line treatment using the CellSearch system. sHER2 was determined using ELISA., Results: ≥5 CTCs were detected in 122 of 245 evaluable patients (49.8%). One hundred and nineteen of 251 patients (47%) had sHER2 levels above 15 ng/ml. Median overall survival (OS) was 16.3 months in patients with elevated sHER2; median OS in patients with non-elevated sHER2 has not been reached (p=0.001). Patients with ≥5 CTCs were more likely to present with elevated sHER2 (61% vs. 33% in those with <5 CTC; p<0.001). In patients with HER2-negative tumors, elevated sHER2 was associated with shorter OS and PFS; in HER2-positive patients with OS only. Including sHER2, CTC status and established prognostic factors into a multivariate analysis, only the presence of CTCs and higher-line of therapy remained independent predictors of OS., Conclusion: Elevated levels of sHER2 are associated with worse survival, irrespective of the HER2 status of the tumor. However, sHER2 does not provide additional prognostic information in patients with known CTC status., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Triple-negative breast cancer (TNBC) is characterized by a strong heterogeneity with regard to tumour biology as well as in the clinical course of the disease. This study aimed to analyse whether there are any prognostic factors enabling prediction of the clinical outcome in patients with TNBC. Particularly, the impact of Her2-neu score 0 versus Her2-neu score 1 and 2 on survival was investigated., Materials and Methods: We retrospectively studied a cohort of 1013 patients with TNBC, diagnosed at seven hospitals between May 2002 and February 2015. We studied the impact of Her2-neu scores (0 vs. 1 or 2 with negative FISH) on disease-free survival (DFS) and overall survival (OS)., Results: 1013 patients were included in this study. 447 (44.13 %) of them had a T2-4 tumour. A total of 314 (31.00 %) were nodal-positive and 714 (70.48 %) had high-grade tumours. The Her2-neu score of all participating patients was determined. 588 (58.05 %) of them had a Her2-neu score 0, and 425 (41.95 %) had a score of 1 or 2. This study shows that TNBC patients with a Her2-neu score 0 had a significantly poorer outcome regarding DFS (p = 0.0001) and OS (p = 0.0051) compared to a score of 1 or 2. In contrast, grading did not seem to have any prognostic value for women with TNBC., Conclusion: The Her2-neu score 0 might be considered as an innovative prognostic factor for patients with TNBC indicating poor clinical outcome.

Purpose: Many patients with triple negative breast cancer (TNBC) have a poor outcome, but not all of them. This study has the aim to analyse the prognostic impact of tumour size, nodal status, grading, Her2-neu (human epithelial growth factor receptor 2) score and Ki-67 index. The main goal of this analysis is to find out if there are any differences in survival between patients with TNBC and a Her2-neu score 0 versus 1+2., Experimental Design: Retrospectively, we studied a cohort of 121 patients with TNBC, diagnosed at the Saarland University Medical Center between December 2004 and June 2013. We compared the disease-free survival (DFS) and overall survival (OS) in those women on the basis of the different Her2-neu scores (0 versus 1 or 2 with negative FISH)., Results: One hundred and twenty one patients were included in this study. 58.68 % of them had a T2-4 tumour. 39.67 % were nodal positive and 67.77 % had high-grade tumours. The Her2-neu score was determined in 119 patients. 54.62 % of them had a score 0. In the 103 patients with a Ki-67 determination, the mean index was 44.5 %. We found that tumour size, nodal status and Her2-neu score are important prognostic factors. Patients with a Her2-neu score 0 had a significantly poorer outcome regarding DFS and OS. In contrast, the expression level of Ki-67 and the grading do not seem to have any prognostic value in TNBC., Conclusion: Besides tumour stage, grading and nodal status, the Her2-neu score 0 is able to function as a prognostic factor in patients with TNBC.

Background: Persistence of disseminated tumor cells (DTCs) is observed in 10 to 15% of breast cancer patients and is associated with poor prognosis. These patients might benefit from secondary adjuvant targeted therapy. The aim of this study was to assess HER2 status of persistent DTCs to determine whether the use of HER2-targeted agents might be a therapeutic option in patients with tumor cell persistence., Patients and Methods: Bone marrow was obtained from 85 primary breast cancer patients intraoperatively and after completion of systemic treatment (median follow-up of 13 months; range: 6-30 months). Immunofluorescence double staining was used for identification of cytokeratin-positive, HER2-positive cells., Results: A total of 31 out of 85 (36%) patients had DTCs preoperatively. Out of 85 (16%) patients, 14 were DTC positive after completion of surgery and adjuvant cytotoxic therapy. Five of these patients had HER2-positive DTCs, however, the corresponding tumor was HER2 positive in only one case. The remaining nine patients with HER2-negative DTCs had HER2-negative primary tumors., Conclusion: HER2-positive DTCs can be detected in patients with HER2-negative tumors, even after adjuvant therapy. Such patients may benefit from (secondary) HER2-targeted therapy in an adjuvant setting.

Background: The persistence of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients is associated with poor prognosis. Preliminary studies indicated that these patients might benefit from secondary adjuvant targeted therapy. HER2 protein is suggested as one of the most promising targets. The aims of this study were (1) to determine the HER2 status of DTC in BM of breast cancer patients and (2) to compare the HER2 status of DTC and corresponding primary tumors., Methods: BM aspirates from 137 primary breast cancer patients were included into the study. A double staining procedure was used for the identification of cytokeratin-positive (CK)/HER2 positive cells. HER2 status of the primary tumor was immunohistochemically assessed by the HERCEP-test., Results: In 46 of 137 (34%) breast cancer patients CK-positive cells were detectable in BM. DTC with HER2 positivity were found in 20 (43%) of these patients. The HER2 expression on DTC was heterogeneous in 7 of 17 (41%) patients. Concordance rate of HER2 status between primary tumor and DTC was 62%. In 12 of 20 patients with HER2 negative tumors HER2 positive DTC were detected., Conclusions: HER2 positive DTC can be detected in patients with HER2 negative primary tumors. Therefore, the antigenic profile of DTC may be considered for treatment decision since these patients might actually benefit from trastuzumab. However, the HER2 overexpression on DTC is heterogeneous in individual patients which may reduce the efficacy of an immunotherapy based strategy directed against HER2-antigen only.

Background: The presence of cytokeratin (CK)-positive cells in the bone marrow (BM) of breast cancer patients is an independent prognostic marker for long-term survival. While the exact nature of these cells remains under investigation, their persistence after chemotherapy is linked to decreased survival, making them a potential therapeutic target. Targeted therapy using the her2 antibody has been shown to improve survival in breast cancer patients. We studied the her2 expression in the BM of 105 patients with CK-positive cells present and compared it with results from the primary tumor., Materials and Methods: BM cytospins were stained to detect CK-positive cells. In 105 patients with detectable CK-positive cells, additional staining with her2 antibody was performed. Using an automated imaging system, the her2 slides were evaluated based on the criteria of the International Society for Cellular Therapy. RESULTS were correlated with the her2 status of the primary tumor. Furthermore, the presence of her2 mRNA was examined in a subset of 27 patients using RT-PCR., Results: On 22/105 (21%) cytospins with CK-positive cells, her2-positive cells could be detected. The positivity rate for RT-PCR was 15%. Her2 overexpression on the primary tumor was 26/105 (25%). Correlation with the BM status was as follows: Hercep score 0 to 1+: 79 patients, 10 with positive BM for her2 (12%). Hercep scores 2+ to 3+: 26 patients, 12 with her2-positive bone marrows (46%) (p=0.001)., Conclusion: Her2-positive cells were detected in the BM of 15-21% of patients who were also CK-positive using immunocytochemistry and RT-PCR. Correlation exists between the presence of her2 on the primary tumor, the hercep score and the presence of her2- positive cells in the BM both with RT-PCR and immunocytochemistry. Despite this correlation, in 12.6% of patients with a her2-negative primary tumor, her2-positive cells could be detected in the BM.

Background: Serum HER2 testing allows the determination of the real-time HER2 status of breast cancer patients. The aim of this investigation was to study (i) whether changes of serum HER2 status occur during the clinical course of breast cancer and (ii) to evaluate the prognostic significance of serum HER2 status, at the time of first diagnosis of primary breast cancer and at the onset of metastatic disease, for survival after relapse (SAR)., Materials and Methods: HER2 serum levels were retrospectively measured in 152 breast cancer patients at the time of first diagnosis of breast cancer and at the onset of metastatic disease by enzyme immunoassay., Results: Twenty-seven out of 152 (18%) patients had elevated HER2 serum levels at the time of first diagnosis of breast cancer. In contrast, 56 out of 152 (37%) patients showed elevated serum HER2 levels when metastases were diagnosed. A change of serum HER2 status during clinical course was observed in 43 out of 152 (28%) patients. Serum HER2 status at the time of first diagnosis of breast cancer had no impact on survival after relapse (SAR) (p = 0.4). However, the median SAR for serum HER2-positive patients at the onset of metastatic disease was significantly shorter (8 months, 95% CI: 3-12) compared to patients serum HER2-negative at this time (18 months, 95% CI: 14-22) (p < 0.01)., Conclusion: Serum HER2 status can change during the course of disease. Therefore, the serum HER2 status should be re-evaluated at the time of diagnosis of metastatic disease to optimize treatment decisions.