Identification of biomarkers of response to preoperative talazoparib monotherapy in treatment naïve gBRCA+ breast cancers
Abstract Germline mutations in BRCA1 or BRCA2 exist in ~2–7% of breast cancer patients, which has led to the approval of PARP inhibitors in the advanced setting. We have previously reported a phase II neoadjuvant trial of single agent talazoparib for patients with germline BRCA pathogenic variants w...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-05-01
|
| Series: | npj Breast Cancer |
| Online Access: | https://doi.org/10.1038/s41523-022-00427-9 |
| _version_ | 1797641843424362496 |
|---|---|
| author | Xuan Liu Zhongqi Ge Fei Yang Alejandro Contreras Sanghoon Lee Jason B. White Yiling Lu Marilyne Labrie Banu K. Arun Stacy L. Moulder Gordon B. Mills Helen Piwnica-Worms Jennifer K. Litton Jeffrey T. Chang |
| author_facet | Xuan Liu Zhongqi Ge Fei Yang Alejandro Contreras Sanghoon Lee Jason B. White Yiling Lu Marilyne Labrie Banu K. Arun Stacy L. Moulder Gordon B. Mills Helen Piwnica-Worms Jennifer K. Litton Jeffrey T. Chang |
| author_sort | Xuan Liu |
| collection | DOAJ |
| description | Abstract Germline mutations in BRCA1 or BRCA2 exist in ~2–7% of breast cancer patients, which has led to the approval of PARP inhibitors in the advanced setting. We have previously reported a phase II neoadjuvant trial of single agent talazoparib for patients with germline BRCA pathogenic variants with a pathologic complete response (pCR) rate of 53%. As nearly half of the patients treated did not have pCR, better strategies are needed to overcome treatment resistance. To this end, we conducted multi-omic analysis of 13 treatment naïve breast cancer tumors from patients that went on to receive single-agent neoadjuvant talazoparib. We looked for biomarkers that were predictive of response (assessed by residual cancer burden) after 6 months of therapy. We found that all resistant tumors exhibited either the loss of SHLD2, expression of a hypoxia signature, or expression of a stem cell signature. These results indicate that the deep analysis of pre-treatment tumors can identify biomarkers that are predictive of response to talazoparib and potentially other PARP inhibitors, and provides a framework that will allow for better selection of patients for treatment, as well as a roadmap for the development of novel combination therapies to prevent emergence of resistance. |
| first_indexed | 2024-03-11T13:51:33Z |
| format | Article |
| id | doaj.art-c1596f6b174a47a78043a40e8d62cdcd |
| institution | Directory Open Access Journal |
| issn | 2374-4677 |
| language | English |
| last_indexed | 2024-03-11T13:51:33Z |
| publishDate | 2022-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Breast Cancer |
| spelling | doaj.art-c1596f6b174a47a78043a40e8d62cdcd2023-11-02T08:33:42ZengNature Portfolionpj Breast Cancer2374-46772022-05-018111310.1038/s41523-022-00427-9Identification of biomarkers of response to preoperative talazoparib monotherapy in treatment naïve gBRCA+ breast cancersXuan Liu0Zhongqi Ge1Fei Yang2Alejandro Contreras3Sanghoon Lee4Jason B. White5Yiling Lu6Marilyne Labrie7Banu K. Arun8Stacy L. Moulder9Gordon B. Mills10Helen Piwnica-Worms11Jennifer K. Litton12Jeffrey T. Chang13Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at HoustonDepartment of Immunology, The University of Texas MD Anderson Cancer CenterDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer CenterDepartment of Anatomical Pathology, The University of Texas MD Anderson Cancer CenterDepartment of Systems Biology, The University of Texas MD Anderson Cancer CenterDepartment of Breast Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Genome Medicine, The University of Texas MD Anderson Cancer CenterDepartment of Cell, Developmental, and Cancer Biology, Knight Cancer Institute, Oregon Health and Science UniversityDepartment of Breast Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Breast Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Cell, Developmental, and Cancer Biology, Knight Cancer Institute, Oregon Health and Science UniversityDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Breast Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Integrative Biology and Pharmacology, University of Texas Health Science Center at HoustonAbstract Germline mutations in BRCA1 or BRCA2 exist in ~2–7% of breast cancer patients, which has led to the approval of PARP inhibitors in the advanced setting. We have previously reported a phase II neoadjuvant trial of single agent talazoparib for patients with germline BRCA pathogenic variants with a pathologic complete response (pCR) rate of 53%. As nearly half of the patients treated did not have pCR, better strategies are needed to overcome treatment resistance. To this end, we conducted multi-omic analysis of 13 treatment naïve breast cancer tumors from patients that went on to receive single-agent neoadjuvant talazoparib. We looked for biomarkers that were predictive of response (assessed by residual cancer burden) after 6 months of therapy. We found that all resistant tumors exhibited either the loss of SHLD2, expression of a hypoxia signature, or expression of a stem cell signature. These results indicate that the deep analysis of pre-treatment tumors can identify biomarkers that are predictive of response to talazoparib and potentially other PARP inhibitors, and provides a framework that will allow for better selection of patients for treatment, as well as a roadmap for the development of novel combination therapies to prevent emergence of resistance.https://doi.org/10.1038/s41523-022-00427-9 |
| spellingShingle | Xuan Liu Zhongqi Ge Fei Yang Alejandro Contreras Sanghoon Lee Jason B. White Yiling Lu Marilyne Labrie Banu K. Arun Stacy L. Moulder Gordon B. Mills Helen Piwnica-Worms Jennifer K. Litton Jeffrey T. Chang Identification of biomarkers of response to preoperative talazoparib monotherapy in treatment naïve gBRCA+ breast cancers npj Breast Cancer |
| title | Identification of biomarkers of response to preoperative talazoparib monotherapy in treatment naïve gBRCA+ breast cancers |
| title_full | Identification of biomarkers of response to preoperative talazoparib monotherapy in treatment naïve gBRCA+ breast cancers |
| title_fullStr | Identification of biomarkers of response to preoperative talazoparib monotherapy in treatment naïve gBRCA+ breast cancers |
| title_full_unstemmed | Identification of biomarkers of response to preoperative talazoparib monotherapy in treatment naïve gBRCA+ breast cancers |
| title_short | Identification of biomarkers of response to preoperative talazoparib monotherapy in treatment naïve gBRCA+ breast cancers |
| title_sort | identification of biomarkers of response to preoperative talazoparib monotherapy in treatment naive gbrca breast cancers |
| url | https://doi.org/10.1038/s41523-022-00427-9 |
| work_keys_str_mv | AT xuanliu identificationofbiomarkersofresponsetopreoperativetalazoparibmonotherapyintreatmentnaivegbrcabreastcancers AT zhongqige identificationofbiomarkersofresponsetopreoperativetalazoparibmonotherapyintreatmentnaivegbrcabreastcancers AT feiyang identificationofbiomarkersofresponsetopreoperativetalazoparibmonotherapyintreatmentnaivegbrcabreastcancers AT alejandrocontreras identificationofbiomarkersofresponsetopreoperativetalazoparibmonotherapyintreatmentnaivegbrcabreastcancers AT sanghoonlee identificationofbiomarkersofresponsetopreoperativetalazoparibmonotherapyintreatmentnaivegbrcabreastcancers AT jasonbwhite identificationofbiomarkersofresponsetopreoperativetalazoparibmonotherapyintreatmentnaivegbrcabreastcancers AT yilinglu identificationofbiomarkersofresponsetopreoperativetalazoparibmonotherapyintreatmentnaivegbrcabreastcancers AT marilynelabrie identificationofbiomarkersofresponsetopreoperativetalazoparibmonotherapyintreatmentnaivegbrcabreastcancers AT banukarun identificationofbiomarkersofresponsetopreoperativetalazoparibmonotherapyintreatmentnaivegbrcabreastcancers AT stacylmoulder identificationofbiomarkersofresponsetopreoperativetalazoparibmonotherapyintreatmentnaivegbrcabreastcancers AT gordonbmills identificationofbiomarkersofresponsetopreoperativetalazoparibmonotherapyintreatmentnaivegbrcabreastcancers AT helenpiwnicaworms identificationofbiomarkersofresponsetopreoperativetalazoparibmonotherapyintreatmentnaivegbrcabreastcancers AT jenniferklitton identificationofbiomarkersofresponsetopreoperativetalazoparibmonotherapyintreatmentnaivegbrcabreastcancers AT jeffreytchang identificationofbiomarkersofresponsetopreoperativetalazoparibmonotherapyintreatmentnaivegbrcabreastcancers |