Chemotherapy Modulates Endocrine Therapy-Related Resistance Mutations in Metastatic Breast Cancer
Dabo Zhou1, Quchang Ouyang1, Liping Liu1
1The Affiliated Cancer Hospital of Xiangya Medical School, Central South University / Hunan Cancer Hospital, Changsha, 410013, China; Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital, Changsha, 410013, China; Department of Breast Cancer Medical Oncology, the Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha 410013, China.
Purpose:
Accumulation of PIK3CA, ESR1, and GATA3 mutations results in resistance to endocrine therapy in breast cancer patients; however, the response of these genes to chemotherapy is unclear. Therefore, we sought to evaluate the genetic response of circulating tumor DNA (ctDNA) to chemotherapy in metastatic breast cancer patients.
Methods:
The mutation frequency of 1021 genes was examined prior to chemotherapy in ctDNA of 44 estrogen receptor-positive metastatic breast cancer patients. These genes were evaluated again in a subset of patients (n=24) following chemotherapy. Mutation frequency was defined as the percentage of mutations found in ctDNA compared to total cell-free DNA.
Results:
Prior to chemotherapy, PIK3CA was the most commonly mutated gene, with mutation found in 22 of the metastatic breast cancer patients. Following chemotherapy, 16 patients exhibited progressive disease (PD), and 8 patients experienced no progression (non-PD). PIK3CA mutation frequency increased in 56.25% (9/16) of the PD patients but decreased in 62.5% (5/8) of the non-PD patients. As a result, more PD patients exhibited increased PIK3CA mutation frequency than non-PD patients (56.25% vs 0%, P=.002). Further, ESR1 and GATA3 mutations correlated with PIK3CA mutation. Interestingly, patients receiving the mTOR inhibitor everolimus exhibited a lower progression rate (0% vs 62.5%, P=.001), and the combination of everolimus and chemotherapy effectively suppressed PIK3CA, ESR1, and GATA3 gene mutations.
Conclusion:
Together, these results suggest that mTOR inhibition may be a useful chemotherapy adjuvant to suppress chemotherapy-induced gene mutations that render tumors resistant to endocrine therapy in metastatic breast cancer patients with PD.
Insights
Chemotherapy can increase PIK3CA mutations in metastatic breast cancer, leading to resistance. mTOR inhibitors like everolimus, combined with chemotherapy, may suppress these mutations and improve outcomes for patients with progressive disease.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Endocrine therapy resistance in breast cancer is linked to PIK3CA, ESR1, and GATA3 mutations.
- The impact of chemotherapy on these specific gene mutations in circulating tumor DNA (ctDNA) remains unclear.
Purpose of the Study:
- To investigate the genetic response of ctDNA to chemotherapy in metastatic breast cancer patients.
- To evaluate changes in PIK3CA, ESR1, and GATA3 mutation frequencies following chemotherapy.
Main Methods:
- Analyzed mutation frequency of 1021 genes in ctDNA from 44 estrogen receptor-positive metastatic breast cancer patients before and after chemotherapy.
- Correlated mutation frequency changes with disease progression and treatment response.
Main Results:
- PIK3CA was the most frequent mutation pre-chemotherapy.
- Progressive disease post-chemotherapy was associated with increased PIK3CA mutation frequency (56.25%).
- Everolimus combined with chemotherapy suppressed PIK3CA, ESR1, and GATA3 mutations and reduced progression rates.
Conclusions:
- mTOR inhibition may serve as an effective adjuvant therapy to chemotherapy.
- This approach could overcome chemotherapy-induced mutations driving endocrine therapy resistance in metastatic breast cancer with progressive disease.
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