TY - JOUR
T1 - Functional Mapping of AKT Signaling and Biomarkers of Response from the FAIRLANE Trial of Neoadjuvant Ipatasertib plus Paclitaxel for Triple-Negative Breast Cancer
AU - Shi, Zhen
AU - Wulfkuhle, Julia
AU - Nowicka, Malgorzata
AU - Gallagher, Rosa I.
AU - Saura, Cristina
AU - Nuciforo, Paolo G.
AU - Calvo, Isabel
AU - Andersen, Jay
AU - Passos-Coelho, José Luis
AU - Gil-Gil, Miguel J.
AU - Bermejo, Begona
AU - Pratt, Debra A.
AU - Ciruelos, Eva M.
AU - Villagrasa, Patricia
AU - Wongchenko, Matthew J.
AU - Petricoin, Emanuel F.
AU - Oliveira, Mafalda
AU - Isakoff, Steven J.
N1 - Funding Information:
Z. Shi reports other support from Roche/Genentech outside the submitted work. J. Wulfkuhle reports other support from Theralink Technologies outside the submitted work. M. Nowicka reports personal fees from F. Hoffmann-La Roche Ltd during the conduct of the study, as well as personal fees from F. Hoffmann-La Roche Ltd outside the submitted work. C. Saura reports personal fees and other support from Astra-Zeneca, Daiichi Sankyo, Eisai, Exact Sciences, Novartis, Pfizer, Pierre Fabre, Puma, Roche Farma, and SeaGen, as well as personal fees from Byondis B.V., Exeter Pharma, F. Hoffmann-La Roche Ltd, MediTech, Merck Sharp & Dohme, Philips, PintPharma, Sanofi-Aventis, and Zymeworks outside the submitted work. P.G. Nuciforo reports grants from F. Hoffmann-La Roche Ltd during the conduct of the study, as well as personal fees from Bayer, MSD, and Novartis outside the submitted work. J. Andersen reports personal fees from Genentech, AstraZeneca/Daiichi Sankyo, Puma, Gilead/ Immunomedics, SeaGen, Merck, Novartis, Athenex, Biotheranostics, Myriad, and Genomic Health outside the submitted work. J.L. Passos-Coelho reports personal fees from Roche Pharmaceuticals outside the submitted work. M.J. Gil-Gil reports personal fees from Novartis, Daiichi Sankyo, Pfizer, AstraZeneca, and F. Hoffmann-La Roche Ltd outside the submitted work. B. Bermejo reports personal fees from Novartis, F. Hoffmann-La Roche Ltd, Pierre Fabre, and MSD outside the submitted work. E.M. Ciruelos reports personal fees from Roche Farma, Eli Lilly and Company, Novartis, AstraZeneca DS, MSD, and Pfizer outside the submitted work. P. Villagrasa reports other support from GNE during the conduct of the study; P. Villagrasa also reports personal fees from Nanostring, as well as other support from REVEAL GENOMICS S.L. outside the submitted work. M.J. Wongchenko reports other support from Genentech and F. Hoffman-La Roche Ltd outside the submitted work. E.F. Petricoin reports personal fees from Theralink Technologies, Inc. and Perthera, Inc. during the conduct of the study, as well as personal fees from Theralink Technologies, Inc. and Perthera, Inc. outside the submitted work; in addition, E.F. Petricoin has a patent 6,969,614 issued and with royalties paid from The United States of America as represented by the Department of Health and Human Services. M. Oliveira reports grants from Genentech during the conduct of the study. M. Oliveira also reports grants, personal fees, and non-financial support from F. Hoffman-La Roche Ltd, AstraZeneca, and Novartis; grants and personal fees from SeaGen, GlaxoSmithKline, and PUMA Biotechnology; personal fees from Pfizer, Guardant Health, iTEOS, and MSD; grants from Genentech, Immunomedics, Boehringer Ingelheim, Cascadian Therapeutics, Sanofi-Aventis, Piqur, and Zenith Epigenetics;
Publisher Copyright:
© 2021 The Authors.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - Purpose: Despite extensive genomic and transcriptomic profiling, it remains unknown how signaling pathways are differentially activated and how tumors are differentially sensitized to certain perturbations. Here, we aim to characterize AKT signaling activity and its association with other genomic or IHC-based PI3K/AKT pathway biomarkers as well as the clinical activity of ipatasertib (AKT inhibitor) in the FAIRLANE trial. Experimental Design: In FAIRLANE, 151 patients with early triple-negative breast cancer (TNBC) were randomized 1:1 to receive paclitaxel with ipatasertib or placebo for 12 weeks prior to surgery. Adding ipatasertib did not increase pathologic complete response rate and numerically improved overall response rate by MRI. We used reverse-phase protein microarrays (RPPA) to examine the total level and/or phosphorylation states of over 100 proteins in various signaling or cell processes including PI3K/AKT and mTOR signaling. One hundred and twenty-five baseline and 127 on-treatment samples were evaluable by RPPA, with 110 paired samples at both time points. Results: Tumors with genomic/protein alterations in PIK3CA/ AKT1/PTEN were associated with higher levels of AKT phosphorylation. In addition, phosphorylated AKT (pAKT) levels exhibited a significant association with enriched clinical benefit of ipatasertib, and identified patients who received benefit in the absence of PIK3CA/AKT1/PTEN alterations. Ipatasertib treatment led to a downregulation of AKT/mTORC1 signaling, which was more pronounced among the tumors with PIK3CA/AKT1/PTEN alterations or among the responders to the treatment. Conclusions: We showed that the high baseline pAKT levels are associated with the alterations of PI3K/AKT pathway components and enriched benefit of ipatasertib in TNBC.
AB - Purpose: Despite extensive genomic and transcriptomic profiling, it remains unknown how signaling pathways are differentially activated and how tumors are differentially sensitized to certain perturbations. Here, we aim to characterize AKT signaling activity and its association with other genomic or IHC-based PI3K/AKT pathway biomarkers as well as the clinical activity of ipatasertib (AKT inhibitor) in the FAIRLANE trial. Experimental Design: In FAIRLANE, 151 patients with early triple-negative breast cancer (TNBC) were randomized 1:1 to receive paclitaxel with ipatasertib or placebo for 12 weeks prior to surgery. Adding ipatasertib did not increase pathologic complete response rate and numerically improved overall response rate by MRI. We used reverse-phase protein microarrays (RPPA) to examine the total level and/or phosphorylation states of over 100 proteins in various signaling or cell processes including PI3K/AKT and mTOR signaling. One hundred and twenty-five baseline and 127 on-treatment samples were evaluable by RPPA, with 110 paired samples at both time points. Results: Tumors with genomic/protein alterations in PIK3CA/ AKT1/PTEN were associated with higher levels of AKT phosphorylation. In addition, phosphorylated AKT (pAKT) levels exhibited a significant association with enriched clinical benefit of ipatasertib, and identified patients who received benefit in the absence of PIK3CA/AKT1/PTEN alterations. Ipatasertib treatment led to a downregulation of AKT/mTORC1 signaling, which was more pronounced among the tumors with PIK3CA/AKT1/PTEN alterations or among the responders to the treatment. Conclusions: We showed that the high baseline pAKT levels are associated with the alterations of PI3K/AKT pathway components and enriched benefit of ipatasertib in TNBC.
UR - http://www.scopus.com/inward/record.url?scp=85125729523&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-2498
DO - 10.1158/1078-0432.CCR-21-2498
M3 - Article
C2 - 34907082
AN - SCOPUS:85125729523
SN - 1078-0432
VL - 28
SP - 93
EP - 1003
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 5
ER -