Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2-overexpressing locally advanced breast cancers.
OBJECTIVE
Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be associated with trastuzumab resistance. Trastuzumab, the humanized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and lapatinib, an epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, are both established treatments for HER2-overexpressing breast cancers. Understanding of the cellular response to HER2-targeted therapies is needed to tailor treatments and to identify patients less likely to benefit.


METHODS
We evaluated the effect of trastuzumab or lapatinib in three HER2-overexpressing cell lines. We confirmed the in vitro observations in two neoadjuvant clinical trials in patients with HER2 overexpression; 35 patients received trastuzumab as a single agent for the first 3 weeks, then docetaxel every 3 weeks for 12 weeks (trastuzumab regimen), whereas 49 patients received lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel for 12 weeks before primary surgery (lapatinib regimen). Apoptosis, Ki67, p-MAPK, p-AKT, and PTEN were assessed by immunohistochemistry. Genomic DNA was sequenced for PIK3CA mutations.


RESULTS
Under low PTEN conditions, in vitro data indicate that lapatinib alone and in combination with trastuzumab was effective in decreasing p-MAPK and p-AKT levels, whereas trastuzumab was ineffective. In the clinical trials, we confirmed that low PTEN or activating mutation in PIK3CA conferred resistance to the trastuzumab regimen (P = .015), whereas low PTEN tumors were associated with a high pathologic complete response rate (P = .007).


CONCLUSIONS
Activation of PI3 kinase pathway is associated with trastuzumab resistance, whereas low PTEN predicted for response to lapatinib. These observations support clinical trials with the combination of both agents.
Lester and Sue Smith Breast Center, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Bhuvanesh
B
Dave
Ilenia
I
Migliaccio
M Carolina
MC
Gutierrez
Meng-Fen
MF
Wu
Gary C
GC
Chamness
Helen
H
Wong
Archana
A
Narasanna
Anindita
A
Chakrabarty
Susan G
SG
Hilsenbeck
Jian
J
Huang
Mothaffar
M
Rimawi
Rachel
R
Schiff
Carlos
C
Arteaga
C Kent
CK
Osborne
Jenny C
JC
Chang
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D017322:Clinical Trials, Phase II as Topic; D000077143:Docetaxel; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D043823:Taxoids / Q000008:administration & dosage; D014162:Transfection; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058534:Class I Phosphatidylinositol 3-Kinases; D000077143:Docetaxel; D000077341:Lapatinib; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D011799:Quinazolines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human