Correlation between NK function and response to trastuzumab in metastatic breast cancer patients.
BACKGROUND
Trastuzumab is a monoclonal antibody selectively directed against Her2 and approved for the treatment of Her2 overexpressing breast cancer patients. Its proposed mechanisms of action include mediation of antibody-dependent cellular cytotoxicity (ADCC) by triggering FcgammaRIII on natural killer (NK) cells. This study addresses the correlation between overall NK function and trastuzumab's clinical activity.


METHODS
Clinical and immunological responses were assessed in 26 patients receiving trastuzumab monotherapy as maintenance management after chemotherapy (8 mg/kg load and then standard doses of 6 mg/kg every 3 weeks). Cytotoxic activity against the MHC class I-negative standard NK target K562 cell line and HER2-specific ADCC against a trastuzumab-coated Her2-positive SKBR3 cell line were assessed in peripheral blood mononuclear cells (PBMC) harvested after the first standard dose. After six months, seventeen patients were scored as responders and nine as non-responders according to the RECIST criteria, while Progression-Free Survival (PFS) was calculated during a 12 months follow-up.


RESULTS
The responders had significantly higher levels of both NK and ADCC activities (p < 0.05) that were not different from those of eleven normal controls. The NK activity of the non-responders was significantly (p < 0.05) lower than that of the normal controls. At twelve months, there was a marked correlation between PFS and NK activity only. PFS was significantly longer in patients with high levels of NK activity, whereas its pattern was unrelated to high or low ADCC activity.


CONCLUSIONS
One of the mechanisms of action of trastuzumab is NK cell-mediated ADCC lysis of the Her2-positve target cell. We show here that its potency is correlated with the short-term response to treatment, whereas longer protection against tumor expansion seems to be mediated by pure NK activity.
Beano
Alessandra
A
Dept of Medical Oncology, Molinette's Hospital, Turin, Italy, 2Laboratory of Tumour Immunology, Dept of Internal Medicine, Universityof Turin, Italy. gv.beano@accademiaservice.it
Signorino
Elena
E
Evangelista
Andrea
A
Brusa
Davide
D
Mistrangelo
Marinella
M
Polimeni
Maria Antonia
MA
Spadi
Rosella
R
Donadio
Michela
M
Ciuffreda
Libero
L
Matera
Lina
L
D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000737:chemistry; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000166:cytology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D009362:Neoplasm Metastasis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007376:Interleukin-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D000068878:Trastuzumab; C508053:ERBB2 protein, human