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Background: The PI3K/AKT pathway is activated through PIK3CA or AKT1 mutations and PTEN loss in breast cancer. We conducted a phase II trial with an allosteric AKT inhibitor MK-2206 in patients with advanced breast cancer who had tumors with PIK3CA/AKT1 mutations and/or PTEN loss/mutation.
Methods: The primary endpoint was objective response rate (ORR). Secondary endpoints were 6-month progression-free survival (6 m PFS), predictive and pharmacodynamic markers, safety, and tolerability. Patients had pre-treatment and on-treatment biopsies as well as collection of peripheral blood mononuclear cells (PBMC) and platelet-rich plasma (PRP). Next-generation sequencing, immunohistochemistry, and reverse phase protein arrays (RPPA) were performed.
Results: Twenty-seven patients received MK-2206. Eighteen patients were enrolled into the PIK3CA/AKT1 mutation arm (cohort A): 13 had PIK3CA mutations, four had AKT1 mutations, and one had a PIK3CA mutation as well as PTEN loss. ORR and 6 m PFS were both 5.6% (1/18), with one patient with HR+ breast cancer and a PIK3CA E542K mutation experiencing a partial response (on treatment for 36 weeks). Nine patients were enrolled on the PTEN loss/mutation arm (cohort B). ORR was 0% and 6 m PFS was 11% (1/9), observed in a patient with triple-negative breast cancer and PTEN loss. The study was stopped early due to futility. The most common adverse events were fatigue (48%) and rash (44%). On pre-treatment biopsy, PIK3CA and AKT1 mutation status was concordant with archival tissue testing. However, two patients with PTEN loss based on archival testing had PTEN expression on the pre-treatment biopsy. MK-2206 treatment was associated with a significant decline in pAKT S473 and pAKT T308 and PI3K activation score in PBMC and PRPs, but not in tumor biopsies. By IHC, there was no significant decrease in median pAKT S473 or Ki-67 staining, but a drop was observed in both responders.
Conclusions: MK-2206 monotherapy had limited clinical activity in advanced breast cancer patients selected for PIK3CA/AKT1 or PTEN mutations or PTEN loss. This may, in part, be due to inadequate target inhibition at tolerable doses in heavily pre-treated patients with pathway activation, as well as tumor heterogeneity and evolution in markers such as PTEN conferring challenges in patient selection.
Trial Registration: ClinicalTrials.gov, NCT01277757 . Registered 13 January 2011.
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http://dx.doi.org/10.1186/s13058-019-1154-8 | DOI Listing |
Med Anthropol
December 2024
Department of Social Anthropology, University of Barcelona, Barcelona, Spain.
This research asks what is being put to the test by breast and gynecological cancer predisposition testing in Spain beyond genes or cancer. By combining document analysis and fieldwork with national healthcare professionals and drawing on the anthropology and sociology of testing, I examine how the molecular relations of these tests extend to the political economy of the national healthcare system. I show how the capacity of these tests to produce a low-risk collective has paradoxical consequences for the political economy of the national healthcare system, unsettling professionals' concerns and spotlighting what is prioritized in personalized medicine strategies.
View Article and Find Full Text PDFDrug Dev Res
February 2025
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Five series of new 1,3,4-thiadiazole hybrids were designed and synthesized as promising EGFR inhibitors. Three human cancer cell lines were employed for testing each hybrid's in vitro antiproliferative efficacy; colon HCT-116, liver HepG-2 and breast MCF-7 using MTT assay. Comparing compound 9a to the reference doxorubicin, 9a shown superior activity to that of Dox with respect to MCF-7 (IC 3.
View Article and Find Full Text PDFJ Biochem Mol Toxicol
January 2025
Department of Translational Medicine, Clinical Research Centre, Skåne University Hospital, Lund University, Malmö, Sweden.
Berberine, an isoquinoline alkaloid derived from various medicinal plants, emerges as a potential therapeutic agent against diverse human diseases. It has particularly shown notable anticancer efficacy against breast, colorectal, lung, prostate, and liver cancer. Berberine results in inhibition of cancer cell proliferation, induction of apoptosis, and suppressing angiogenesis, positioning it as a versatile, multitargeted therapeutic tool against cancer.
View Article and Find Full Text PDFJ Mater Chem B
December 2024
ICGM, University of Montpellier, UMR-CNRS 5253, 34293 Montpellier, France.
We report the synthesis of multifunctional periodic mesoporous organosilica nanoparticles (PMO NPs) with substantial two-photon absorption properties and targeting capability for two-photon excitation fluorescence (TPEF) and photodynamic therapy (TPE-PDT). Prepared using an adapted sol-gel synthesis, the nanoplatforms integrated two silylated chromophores in their three-dimensional matrix to maximize non-radiative Förster resonance energy transfer from a high two-photon absorption fluorophore donor to a porphyrin derivative acceptor, leading to an enhanced generation of reactive oxygen species. Combinations of biodegradable and non-biodegradable bis(triethoxysilyl)alkoxysilanes were employed for the synthesis of the NPs, and the corresponding photophysical studies revealed high efficiency levels of FRET.
View Article and Find Full Text PDFFront Glob Womens Health
December 2024
WHO Department of Sexual and Reproductive Health and Research, World Health Organization, Geneva, Switzerland.
[This corrects the article DOI: 10.3389/fgwh.2024.
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