期刊
NPJ BREAST CANCER
卷 7, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41523-021-00251-7
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资金
- AstraZeneca
- Cancer Research UK
- Experimental Cancer Medicine Centre
- Biomedical Research Centre grants [RP-2016-07-028]
- NCI Cancer Center Support Grant [CCSG P30 CA08748]
- Breast Cancer Research Foundation
This study evaluated the efficacy and tolerability of oral capivasertib with fulvestrant in patients with PTEN-mutant ER+ metastatic breast cancer, showing that this treatment regimen is sensitive to the aggressive disease and can effectively improve clinical outcomes. Phenotypic and genomic differences were observed between fulvestrant-naive and -pretreated patients.
Five to ten percent of ER+ metastatic breast cancer (MBC) tumors harbor somatic PTEN mutations. Loss of function of this tumor-suppressor gene defines a highly aggressive, treatment-refractory disease for which new therapies are urgently needed. This Phase I multipart expansion study assessed oral capivasertib with fulvestrant in patients with PTEN-mutant ER+ MBC. Safety and tolerability were assessed by standard methods. Plasma and tumor were collected for NGS and immunohistochemistry analyses of PTEN protein expression. In 31 eligible patients (12 fulvestrant naive; 19 fulvestrant pretreated), the 24-week clinical benefit rate was 17% in fulvestrant-naive and 42% in fulvestrant-pretreated patients, with objective response rate of 8% and 21%, respectively. Non-functional PTEN was centrally confirmed in all cases by NGS or immunohistochemistry. Comutations occurred in PIK3CA (32%), with less ESR1 (10% vs 72%) and more TP53 (40% vs 28%) alterations in fulvestrant-naive versus fulvestrant-pretreated patients, respectively. PTEN was clonally dominant in most patients. Treatment-related grade >= 3 adverse events occurred in 32% of patients, most frequently diarrhea and maculopapular rash (both n=2). In this clinical study, which selectively targeted the aggressive PTEN-mutant ER+ MBC, capivasertib plus fulvestrant was tolerable and clinically active. Phenotypic and genomic differences were apparent between fulvestrant-naive and -pretreated patients.Trial registration number for the study is NCT01226316.
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