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Published on: July 25, 2020
Exploratory Analysis of PTEN Deficiency by Immunohistochemistry from the Phase III CAPItello-291 Trial
Komal Jhaveri1, Hope S Rugo2, Javier Cortés3,4,5
1Memorial Sloan Kettering Cancer Center , Weill Cornell Medical College, New York, New York.
Purpose:
The phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) pathway is frequently activated in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer, with loss of phosphatase and tensin homolog (PTEN) activity contributing to this activation. Capivasertib is a potent pan-AKT inhibitor, approved in combination with fulvestrant for the treatment of HR-positive/HER2-negative locally advanced/metastatic breast cancer with one or more PIK3CA/AKT1/PTEN tumor alterations. Next-generation sequencing (NGS) is commonly used to identify patients with PIK3CA/AKT1/PTEN tumor alterations. However, the utility of immunohistochemistry (IHC) to identify patients with PTEN-deficient tumors has not been explored in this context.
Experimental Design:
This exploratory analysis was based on tumor samples collected from patients in the global phase III CAPItello-291 study.
Results:
PTEN IHC results were obtained for 367 tumor samples, with 70 (19.1%) identified as PTEN deficient by IHC. A total of 346 (94.3%) samples with a PTEN IHC test result also had NGS test results available for PIK3CA/AKT1/PTEN alteration status. When comparing PTEN deficiency by IHC with PTEN alteration status by NGS, the overall, positive, and negative percent agreements were 87.0% (301/346), 71.9% (23/32), and 88.5% (278/314), respectively. Exploratory analysis in patients with PTEN-deficient tumors by IHC (n = 70) showed improved progression-free survival in the capivasertib plus fulvestrant versus placebo plus fulvestrant treatment arm (median 9.3 vs. 3.7 months; hazard ratio: 0.52, 95% confidence interval, 0.28-0.90).
Conclusions:
These results suggest potential utility for IHC in determining tumor PTEN status in breast cancer and raise the possibility of IHC identifying additional patients who could benefit from treatment with capivasertib and fulvestrant.
Insights
Immunohistochemistry (IHC) can identify PTEN-deficient breast cancer tumors, potentially expanding eligibility for capivasertib and fulvestrant therapy. This method shows promise in guiding treatment decisions for advanced breast cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Biomarker Discovery
Background:
- The PI3K/AKT pathway is frequently activated in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer.
- Loss of phosphatase and tensin homolog (PTEN) activity contributes to this pathway's activation.
- Capivasertib, a pan-AKT inhibitor, is approved with fulvestrant for specific advanced breast cancer subtypes.
Purpose of the Study:
- To explore the utility of immunohistochemistry (IHC) in identifying PTEN-deficient tumors in advanced breast cancer.
- To compare PTEN deficiency by IHC with PTEN alteration status determined by next-generation sequencing (NGS).
- To assess the potential of IHC in identifying patients who may benefit from capivasertib plus fulvestrant therapy.
Main Methods:
- Exploratory analysis of tumor samples from the Phase III CAPItello-291 study.
- PTEN status assessed using both IHC and NGS.
- Comparison of IHC results with NGS-based PIK3CA/AKT1/PTEN alteration status.
Main Results:
- PTEN deficiency by IHC was observed in 19.1% (70/367) of samples.
- High agreement was found between PTEN IHC and NGS for PTEN alteration status (overall agreement 87.0%).
- In PTEN-deficient tumors (by IHC), capivasertib plus fulvestrant showed improved progression-free survival compared to placebo plus fulvestrant (median 9.3 vs 3.7 months).
Conclusions:
- IHC demonstrates potential utility for determining tumor PTEN status in breast cancer.
- IHC may identify additional patients eligible for capivasertib and fulvestrant treatment.
- This approach could enhance personalized treatment strategies for HR-positive/HER2-negative advanced breast cancer.
