M Bates1, J Sperinde2, W J Köstler3, S M Ali4, K Leitzel5, E M Fuchs3, A Paquet6, Y Lie7, T Sherwood7, R Horvat8, C F Singer9, J Winslow2, J M Weidler7, W Huang7, A Lipton5. 1. Division of Clinical Research. Electronic address: mbates@monogrambio.com. 2. Division of Research and Development, Monogram Biosciences, South San Francisco, USA. 3. Clinical Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria. 4. Department of Medicine, Lebanon Veterans Affairs Medical Center, Lebanon. 5. Department of Medicine, Division of Hematology/Medical Oncology, Penn State Hershey Medical Center, Hershey. 6. Department of Translational Medicine and Biomarker Development, Division of Biostatics and Bioinformatics, Monogram Biosciences, South San Francisco, USA. 7. Division of Clinical Research. 8. Departments of Clinical Pathology. 9. Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.
Abstract
BACKGROUND: Patients with metastatic breast cancer (MBC) overexpressing HER2 (human epidermal growth factor receptor 2) are currently selected for treatment with trastuzumab, but not all patients respond. PATIENTS AND METHODS: Using a novel assay, HER2 protein expression (H2T) was measured in formalin-fixed, paraffin-embedded primary breast tumors from 98 women treated with trastuzumab-based therapy for MBC. Using subpopulation treatment effect pattern plots, the population was divided into H2T low (H2T < 13.8), H2T high (H2T ≥ 68.5), and H2T intermediate (13.8 ≤ H2T < 68.5) subgroups. Kaplan-Meier (KM) analyses were carried out comparing the groups for time to progression (TTP) and overall survival (OS). Cox multivariate analyses were carried out to identify correlates of clinical outcome. Bootstrapping analyses were carried out to test the robustness of the results. RESULTS: TTP improved with increasing H2T until, at the highest levels of H2T, an abrupt decrease in the TTP was observed. KM analyses demonstrated that patients with H2T low tumors [median TTP 4.2 months, hazard ratio (HR) = 3.7, P < 0.0001] or H2T high tumors (median TTP 4.6 months, HR = 2.7, P = 0.008) had significantly shorter TTP than patients whose tumors were H2T intermediate (median TTP 12 months). OS analyses yielded similar results. CONCLUSIONS: MBC patients with very high levels of H2T may represent a subgroup with de novo resistance to trastuzumab. These results are preliminary and require confirmation in larger controlled clinical cohorts.
BACKGROUND:Patients with metastatic breast cancer (MBC) overexpressing HER2 (humanepidermal growth factor receptor 2) are currently selected for treatment with trastuzumab, but not all patients respond. PATIENTS AND METHODS: Using a novel assay, HER2 protein expression (H2T) was measured in formalin-fixed, paraffin-embedded primary breast tumors from 98 women treated with trastuzumab-based therapy for MBC. Using subpopulation treatment effect pattern plots, the population was divided into H2T low (H2T < 13.8), H2T high (H2T ≥ 68.5), and H2T intermediate (13.8 ≤ H2T < 68.5) subgroups. Kaplan-Meier (KM) analyses were carried out comparing the groups for time to progression (TTP) and overall survival (OS). Cox multivariate analyses were carried out to identify correlates of clinical outcome. Bootstrapping analyses were carried out to test the robustness of the results. RESULTS: TTP improved with increasing H2T until, at the highest levels of H2T, an abrupt decrease in the TTP was observed. KM analyses demonstrated that patients with H2Tlow tumors [median TTP 4.2 months, hazard ratio (HR) = 3.7, P < 0.0001] or H2T high tumors (median TTP 4.6 months, HR = 2.7, P = 0.008) had significantly shorter TTP than patients whose tumors were H2T intermediate (median TTP 12 months). OS analyses yielded similar results. CONCLUSIONS:MBCpatients with very high levels of H2T may represent a subgroup with de novo resistance to trastuzumab. These results are preliminary and require confirmation in larger controlled clinical cohorts.
Authors: Noelia Martínez-Jañez; Ignacio Chacón; Ana de Juan; Luis Cruz-Merino; Sònia Del Barco; Isaura Fernández; Paula García-Teijido; Amalia Gómez-Bernal; Arrate Plazaola; José Ponce; Sonia Servitja; Pilar Zamora Journal: Breast Care (Basel) Date: 2016-02-08 Impact factor: 2.860
Authors: Kristine Kleivi Sahlberg; Vesa Hongisto; Henrik Edgren; Rami Mäkelä; Kirsi Hellström; Eldri U Due; Hans Kristian Moen Vollan; Niko Sahlberg; Maija Wolf; Anne-Lise Børresen-Dale; Merja Perälä; Olli Kallioniemi Journal: Mol Oncol Date: 2012-11-24 Impact factor: 6.603
Authors: Jeffrey S Larson; Laurie J Goodman; Yuping Tan; Lisa Defazio-Eli; Agnes C Paquet; Jennifer W Cook; Amber Rivera; Kristi Frankson; Jolly Bose; Lili Chen; Judy Cheung; Yining Shi; Sarah Irwin; Linda D B Kiss; Weidong Huang; Shannon Utter; Thomas Sherwood; Michael Bates; Jodi Weidler; Gordon Parry; John Winslow; Christos J Petropoulos; Jeannette M Whitcomb Journal: Patholog Res Int Date: 2010-06-28
Authors: Allan Lipton; Laurie Goodman; Kim Leitzel; Jennifer Cook; Jeff Sperinde; Mojgan Haddad; Wolfgang J Köstler; Weidong Huang; Jodi M Weidler; Suhail Ali; Alicia Newton; Eva-Marie Fuchs; Agnes Paquet; Christian F Singer; Reinhard Horvat; Xueguang Jin; Joyee Banerjee; Ali Mukherjee; Yuping Tan; Yining Shi; Ahmed Chenna; Jeff Larson; Yolanda Lie; Thomas Sherwood; Christos J Petropoulos; Stephen Williams; John Winslow; Gordon Parry; Michael Bates Journal: Breast Cancer Res Treat Date: 2013-08 Impact factor: 4.872
Authors: Antonio C Wolff; M Elizabeth H Hammond; David G Hicks; Mitch Dowsett; Lisa M McShane; Kimberly H Allison; Donald C Allred; John M S Bartlett; Michael Bilous; Patrick Fitzgibbons; Wedad Hanna; Robert B Jenkins; Pamela B Mangu; Soonmyung Paik; Edith A Perez; Michael F Press; Patricia A Spears; Gail H Vance; Giuseppe Viale; Daniel F Hayes Journal: Arch Pathol Lab Med Date: 2013-10-07 Impact factor: 5.534