Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER Study.
Ado-Trastuzumab Emtansine
/ administration & dosage
Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized
/ administration & dosage
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Apoptosis
Biomarkers, Tumor
/ genetics
Breast Neoplasms
/ drug therapy
Cell Proliferation
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Middle Aged
Prognosis
Receptor, ErbB-2
/ antagonists & inhibitors
Retrospective Studies
Survival Rate
Trastuzumab
/ administration & dosage
Tumor Cells, Cultured
HER2+ breast cancer
T-DM1 efficacy
Trastuzumab/pertuzumab blockade
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
10 Dec 2020
10 Dec 2020
Historique:
received:
04
09
2020
accepted:
02
12
2020
entrez:
11
12
2020
pubmed:
12
12
2020
medline:
7
9
2021
Statut:
epublish
Résumé
HER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines. The biology of HER2 was investigated in vitro through sequential exposure of resistant HER2 + breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2 + ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models. We herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p = 0.0006 and 0.03 for OS and PFS2, respectively). Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.
Sections du résumé
BACKGROUND
BACKGROUND
HER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines.
METHODS
METHODS
The biology of HER2 was investigated in vitro through sequential exposure of resistant HER2 + breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2 + ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models.
RESULTS
RESULTS
We herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p = 0.0006 and 0.03 for OS and PFS2, respectively).
CONCLUSIONS
CONCLUSIONS
Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.
Identifiants
pubmed: 33302999
doi: 10.1186/s13046-020-01797-3
pii: 10.1186/s13046-020-01797-3
pmc: PMC7731769
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Biomarkers, Tumor
0
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
pertuzumab
K16AIQ8CTM
Trastuzumab
P188ANX8CK
Ado-Trastuzumab Emtansine
SE2KH7T06F
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
279Subventions
Organisme : Regina Elena Cancer Institute
ID : Intramural Grant
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