Carsten Denkert1, Fenja Seither2, Andreas Schneeweiss3, Theresa Link4, Jens-Uwe Blohmer5, Marianne Just6, Pauline Wimberger4, Almuth Forberger7, Hans Tesch8, Christian Jackisch9, Sabine Schmatloch10, Mattea Reinisch11, Erich F Solomayer12, Wolfgang D Schmitt13, Claus Hanusch14, Peter A Fasching15, Kristina Lübbe16, Christine Solbach17, Jens Huober17, Kerstin Rhiem18, Frederik Marmé19, Toralf Reimer20, Marcus Schmidt21, Bruno V Sinn13, Wolfgang Janni22, Elmar Stickeler23, Laura Michel3, Oliver Stötzer24, Eric Hahnen18, Jenny Furlanetto2, Sabine Seiler2, Valentina Nekljudova2, Michael Untch25, Sibylle Loibl26. 1. Institute of Pathology, Philipps-Universität Marburg and University Hospital of Giessen and Marburg, Marburg, Germany; German Breast Group, Neu-Isenburg, Germany. Electronic address: carsten.denkert@uni-marburg.de. 2. German Breast Group, Neu-Isenburg, Germany. 3. Nationales Centrum für Tumorerkrankungen, Universitätsklinikum und Deutsches Krebsforschungszentrum, Heidelberg, Germany. 4. Department of Gynecology and Obstetrics, Universitätsklinikum Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany. 5. Breast Cancer Center, Charité Universitätsmedizin Berlin, Berlin, Germany. 6. Onkologische Schwerpunktpraxis Bielefeld, Bielefeld, Germany. 7. Institut für Pathologie, Universitätsklinikum Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany. 8. Onkologie Bethanien Krankenhaus Frankfurt, Frankfurt, Germany. 9. Department of Gynecology, Sana Klinikum Offenbach, Offenbach, Germany. 10. Brustzentrum Kassel, Elisabeth Krankenhaus, Kassel, Germany. 11. Interdisciplinary Breast Unit, Kliniken Essen Mitte, Essen, Germany. 12. Department of Gynecology, University of Saarland, Homburg, Germany. 13. Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Berlin, Germany. 14. Frauenklinik München, Rotkreuzklinikum München, München, Germany. 15. Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany. 16. DIAKOVERE Henriettenstift Gynäkologie, Hannover, Germany. 17. Department of Gynecology and Obstetrics, University Hospital Frankfurt, Frankfurt, Germany. 18. Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. 19. Medizinische Fakultät Mannheim, Universität Heidelberg, Universitätsfrauenklinik Mannheim, Germany. 20. Department of Obstetrics and Gynecology, University of Rostock, Rostock, Germany. 21. Department of Obstetrics and Gynecology, Universitätsmedizin Mainz, Mainz, Germany. 22. Department of Gynecology and Obstetrics, University Hospital Ulm, University of Ulm, Ulm, Germany. 23. Clinics for Gynaecology and Obstetrica, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany. 24. Hämatoonkologische Schwerpunktpraxis, München, Germany. 25. Breast Cancer Center, Department of Gynecology and Obstetrics, Helios-Klinikum Berlin Buch, Germany. 26. German Breast Group, Neu-Isenburg, Germany; Goethe University of Frankfurt, Frankfurt, Germany.
Abstract
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).
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 CancerAid (Deutsche Krebshilfe).
Authors: George Douganiotis; Loukas Kontovinis; Efrosini Markopoulou; Alexandra Ainali; Thomas Zarampoukas; Ioannis Natsiopoulos; Konstantinos Papazisis Journal: Cancer Diagn Progn Date: 2022-05-03
Authors: George Douganiotis; George Kesisis; Efthalia Lalla; Ippokratis Korantzis; Ioannis Boukovinas; Konstantinos Papazisis Journal: Cancer Diagn Progn Date: 2022-09-03