Abstract
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.
Highlights
Breast cancer (BC) is the most frequently diagnosed malignancy and the leading cause of cancer mortality in women[1], with estrogen-receptor-positive (ER+), human epidermal growth factor receptor 2 negative (HER2–) BC being the most common BC subtype[2]
Loss of function of Phosphatase and tensin homolog (PTEN) is associated with poor prognosis in BC6,7 and the ER+ HER2– subtype (Fig. 1) and has been implicated in resistance to endocrine therapy and CDK4/6 and PI3Kα inhibitors[8,9,10,11,12]
Patient demographics and disease characteristics In total, 32 patients with PTEN-mutant ER+ metastatic BC (MBC) were enrolled across eight sites in six countries, of whom 31 patients
Summary
Breast cancer (BC) is the most frequently diagnosed malignancy and the leading cause of cancer mortality in women[1], with estrogen-receptor-positive (ER+), human epidermal growth factor receptor 2 negative (HER2–) BC being the most common BC subtype[2]. Within this heterogeneous subtype, 5–10% harbor somatic mutations in PTEN, a frequently mutated tumorsuppressor gene in human cancer[3,4]. Loss of function of PTEN is associated with poor prognosis in BC6,7 and the ER+ HER2– subtype (Fig. 1) and has been implicated in resistance to endocrine therapy and CDK4/6 and PI3Kα inhibitors[8,9,10,11,12]. An understanding of both de novo and acquired driver tumor genomic alterations may unlock precision medicine approaches for patients with this disease
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