Targeted immunotherapy for HER2-low breast cancer with 17p loss
Authors: Xinna Zhang
Kathy D Miller
Milan Radovich
Kevin Van der Jeught
Yifan Sun
Xiongbin Lu
Bin He
Bryan P Schneider
Yujing Li
Michael Kulke
Tianhan Dong
Torsten Hechler
Andreas Pahl
Journal: Science Translational Medicine (2021)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: HER2-low breast cancer; drug targets; chromosome 17p loss; TP53; gene expression changes
Affiliations: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Heidelberg Pharma Research GmbH, Ladenburg 68526, Germany., Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Departments of Surgery and Urology, Immunobiology and Transplant Science Center, Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USA., Department of Medicine, Weill Cornell Medicine of Cornell University, New York, NY 10065, USA., Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.  ., Indiana University Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Abstract:  The clinical challenge for treating HER2 (human epidermal growth factor receptor 2)-low breast cancer is the paucity of actionable drug targets. HER2-targeted therapy often has poor clinical efficacy for this disease due to the low level of HER2 protein on the cancer cell surface. We analyzed breast cancer genomics in the search for potential drug targets. Heterozygous loss of chromosome 17p is one of the most frequent genomic events in breast cancer, and 17p loss involves a massive deletion of genes including the tumor suppressor TP53 Our analyses revealed that 17p loss leads to global gene expression changes and reduced tumor infiltration and cytotoxicity of T cells, resulting in immune evasion during breast tumor progression. The 17p deletion region also includes POLR2A, a gene encoding the catalytic subunit of RNA polymerase II that is essential for cell survival. Therefore, breast cancer cells with heterozygous loss of 17p are extremely sensitive to the inhibition of POLR2A via a specific small-molecule inhibitor, α-amanitin. Here, we demonstrate that α-amanitin-conjugated trastuzumab (T-Ama) potentiated the HER2-targeted therapy and exhibited superior efficacy in treating HER2-low breast cancer with 17p loss. Moreover, treatment with T-Ama induced immunogenic cell death in breast cancer cells and, thereby, delivered greater efficacy in combination with immune checkpoint blockade therapy in preclinical HER2-low breast cancer models. Collectively, 17p loss not only drives breast tumorigenesis but also confers therapeutic vulnerabilities that may be used to develop targeted precision immunotherapy. 

Retracted: No

PubPeer comments:
 **Preliminary note:** Another article from one of the authors was retracted because the study did not obtain an approval from a Comitu00e9 de Protection des Personnes (CPP) before to start. Which is a serious breach to the French Health Law related to research in humans. In France, CPPs are the only IRBs that can approve prospective researches in human. **Comment on this study:** The ethics statement mentions that : * This research was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. All participants gave their formal, written consent, and were fully debriefed after the experiment. Participation was voluntary and participants could quit the experiment at any time without negative consequences. All data were analyzed and stored anonymously. * This statement describes a prospective research in humans. In France, all prospective research in humans intended to increase the knowledge in sciences must obtain an approval from a CPP before to start. This type of study MUST obtain an approval from a CPP before to start the recruitment. But the article do not mention any CPP approval before to start. As an example, and to support the comment made here, this [other study] from a different team in France explored the physical physical exercise as a treatment. Which is a similar concept as this study. This french team obtained an approval from a CPP before to start their prospective research in human. The authors of the article commented here should have done the same ethics procedure. As a reminder, the lack of CPP approval is a serious breach to the French Health Law related to research in humans and it could be a cause for the retraction of the article. Furthermore, the Declaration of Helsink (article 23) requires to obtain an ethics approval for all study in humans and to be in compliance with the local law. The ethics statement don t provide enough details to ensure the study is in compliance with the Declaration of Helsinki. As a consequence, can the author detail the ethics procedure and confirm that a CPP approval have been obtained prior to the study. If not, can the author confirm a CPP approval has been requested first and detail the answer of the CPP (request number, date of CPP answer, name of the CPP that provide the answer, etc...). Considering the participants were the student of the institution, some could have been minors and the approval from parents should have been requested. Can the authors provide the age range of all participants (min and max). ,