Abstract
Breast cancer is the leading cause of cancer-related deaths among women worldwide,with the estrogen receptor-positive (ER+) subtype accounting for 70% of cases. Patientswith primary ER+ breast cancer are treated with endocrine therapy, while those withmetastatic disease receive combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy.Although this therapy has improved clinical outcomes, resistance is inevitable, and optimal subsequent therapy is unclear. Therefore, metastatic breast cancer remains an incurable disease. This Ph.D. project aimed to identify possible resistance mechanismsand monitor disease progression in patients receiving combined CDK4/6i and endocrinetherapy for advanced ER+ breast cancer.
The investigation into resistance mechanisms was tackled using two distinct methods. Byusing cell lines that were resistant to combined CDK4/6i and endocrine therapy, manuscript 1 identified high RET expression to be associated with CDK4/6i and endocrinetherapy resistance in ER+ breast cancer. Furthermore, targeting RET with a specific inhibitor significantly reduced cellular growth of resistant cell lines.
Manuscript 2 performed sequencing on paired tumor and blood samples before and aftertherapy, and this revealed pathogenic TP53 and PIK3CA mutations as potential mutations associated with resistance. Copy number variations of genes such as PDK1, weremore common. Serial analysis of circulating tumor DNA for mutant PIK3CA revealeddisease progression before clinical evidence in three of six patients 4-17 months prior todiagnosis of progression.
Collectively, our study suggests that RET inhibition in combination with CDK4/6i and endocrine therapy may be a promising therapeutic approach for advanced ER+ breast cancer patients who experience disease progression. Additionally, the use of serial circulating tumor DNA analysis could lead to earlier identification of progressive disease and beused for real-time monitoring of combined CDK4/6i and endocrine therapy response.
The investigation into resistance mechanisms was tackled using two distinct methods. Byusing cell lines that were resistant to combined CDK4/6i and endocrine therapy, manuscript 1 identified high RET expression to be associated with CDK4/6i and endocrinetherapy resistance in ER+ breast cancer. Furthermore, targeting RET with a specific inhibitor significantly reduced cellular growth of resistant cell lines.
Manuscript 2 performed sequencing on paired tumor and blood samples before and aftertherapy, and this revealed pathogenic TP53 and PIK3CA mutations as potential mutations associated with resistance. Copy number variations of genes such as PDK1, weremore common. Serial analysis of circulating tumor DNA for mutant PIK3CA revealeddisease progression before clinical evidence in three of six patients 4-17 months prior todiagnosis of progression.
Collectively, our study suggests that RET inhibition in combination with CDK4/6i and endocrine therapy may be a promising therapeutic approach for advanced ER+ breast cancer patients who experience disease progression. Additionally, the use of serial circulating tumor DNA analysis could lead to earlier identification of progressive disease and beused for real-time monitoring of combined CDK4/6i and endocrine therapy response.
| Translated title of the contribution | Molekylære markører associeret med resistens mod kombineret CDK4/6 hæmmer og endokrin behandling i avanceret østrogenfølsom brystkræft |
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| Original language | English |
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| Date of defence | 15. Jun 2023 |
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| Publication status | Published - 22. May 2023 |
Keywords
- breast cancer
- cancer
- estrogen positive
- CDK4/6 inhibitor