TY - JOUR
T1 - Efficacy and determinants of response to her kinase inhibition in her2-mutant metastatic breast cancer
AU - Smyth, Lillian M.
AU - Piha-Paul, Sarina A.
AU - Won, Helen H.
AU - Schram, Alison M.
AU - Saura, Cristina
AU - Loi, Sherene
AU - Lu, Janice
AU - Shapiro, Geoffrey I.
AU - Juric, Dejan
AU - Mayer, Ingrid A.
AU - Arteaga, Carlos L.
AU - de la Fuente, Macarena I.
AU - Brufksy, Adam M.
AU - Spanggaard, Iben
AU - Mau-Sørensen, Morten
AU - Arnedos, Monica
AU - Moreno, Victor
AU - Boni, Valentina
AU - Sohn, Joohyuk
AU - Schwartzberg, Lee S.
AU - Gonzàlez-Farré, Xavier
AU - Cervantes, Andrés
AU - Bidard, François Clement
AU - Gorelick, Alexander N.
AU - Lanman, Richard B.
AU - Nagy, Rebecca J.
AU - Ulaner, Gary A.
AU - Chandarlapaty, Sarat
AU - Jhaveri, Komal
AU - Gavrila, Elena I.
AU - Zimel, Catherine
AU - Selcuklu, S. Duygu
AU - Melcer, Myra
AU - Samoila, Aliaksandra
AU - Cai, Yanyan
AU - Scaltriti, Maurizio
AU - Mann, Grace
AU - Xu, Feng
AU - Eli, Lisa D.
AU - Dujka, Melanie
AU - Lalani, Alshad S.
AU - Bryce, Richard
AU - Baselga, José
AU - Taylor, Barry S.
AU - Solit, David B.
AU - Meric-Bernstam, Funda
AU - Hyman, David M.
N1 - Funding Information:
We would like to thank patients and their families for participating in this study. Editorial support, not including writing, was provided by L. Miller and D. Carman (Miller Medical Commu-nications Ltd.). This work was funded by Puma Biotechnology. M. Scaltriti is funded by NIH grant R01 CA190642, the Breast Cancer Research Foundation, Stand Up To Cancer (Cancer Drug Combination Convergence Team), the V Foundation, and the National Science Foundation. Authors from Memorial Sloan Kettering were funded by NIH grant P30 CA008748.
Funding Information:
We would like to thank patients and their families for participating in this study. Editorial support, not including writing, was provided by L. Miller and D. Carman (Miller Medical Commu- nications Ltd.). This work was funded by Puma Biotechnology. M. Scaltriti is funded by NIH grant R01 CA190642, the Breast Cancer Research Foundation, Stand Up To Cancer (Cancer Drug Combination Convergence Team), the V Foundation, and the National Science Foundation. Authors from Memorial Sloan Kettering were funded by NIH grant P30 CA008748.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2020/2
Y1 - 2020/2
N2 - HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. SIGNIFICANCE: HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer.
AB - HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. SIGNIFICANCE: HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer.
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U2 - 10.1158/2159-8290.CD-19-0966
DO - 10.1158/2159-8290.CD-19-0966
M3 - Article
C2 - 31806627
AN - SCOPUS:85079077280
SN - 2159-8274
VL - 10
SP - 198
EP - 213
JO - Cancer discovery
JF - Cancer discovery
IS - 2
ER -