Exploratory analysis of PTEN deficiency by immunohistochemistry from the Phase III CAPItello-291 trial

Abstract Purpose: The PI3K/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. 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.

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Journal
Clinical Cancer Research
Published
2026-05-19
DOI
https://doi.org/10.1158/1078-0432.ccr-25-2965
Primary Topic
PI3K/AKT/mTOR signaling in cancer
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article
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article

Exploratory analysis of PTEN deficiency by immunohistochemistry from the Phase III CAPItello-291 trial

L. Zhukova, Eriko Tokunaga, J. Sohn, Петр Владимирович Криворотько et al.
Clinical Cancer Research
PI3K/AKT/mTOR signaling in cancer
article

Exploratory analysis of PTEN deficiency by immunohistochemistry from the Phase III CAPItello-291 trial

L. Zhukova, Eriko Tokunaga, J. Sohn, Петр Владимирович Криворотько, Ian Wadsworth, Henry Gómez, Agostina Nardone, Elza C. de Bruin, Nicholas C. Turner, Meena Okera, S C Howell, Dimple Das, Y H Park, Javier Cortés, Florence Dalenc, Tanya Wantenaar, Xichun Hu, Komal Jhaveri, Masakazu TOI, Hope S. Rugo, Sibylle Loibl, Celina D’Cruz, Mafalda Oliveira
article en

Abstract

Abstract Purpose: The PI3K/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. 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.

Clinical Cancer Research
City Of Hope National Medical Center (US), Royal Marsden NHS Foundation Trust (GB), Memorial Sloan Kettering Cancer Center (US), Yonsei University (KR), Samsung Medical Center (KR), University of Manchester (GB), Tokyo Metropolitan Komagome Hospital (JP), Moscow Clinical Scientific Center (RU), National Cancer Centre Japan (JP), Hospital Quirón Teknon (ES), Fudan University Shanghai Cancer Center (CN), National Hospital Organization Kyushu Cancer Center (JP), AstraZeneca (Australia) (AU), AstraZeneca (Singapore) (SG), Institute of Oncology NN Petrov (RU), EsSALUD (PE), Vall d'Hebron Hospital Universitari (ES), AstraZeneca (Switzerland) (CH), Institut Claudius Regaud (FR), German Breast group (DE), AstraZeneca (Poland) (PL), AstraZeneca (Spain) (ES), Manchester University (US)
Good health and well-being
Openalex Percentile: Top 7%
PI3K/AKT/mTOR signaling in cancer
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