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Correlation between NK function and response to trastuzumab in metastatic breast cancer patients.

Beano A, Signorino E, Evangelista A, Brusa D, Mistrangelo M, Polimeni MA, Spadi R, Donadio M, Ciuffreda L, Matera L - J Transl Med (2008)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept of Medical Oncology, Molinette's Hospital, Turin, Italy, 2Laboratory of Tumour Immunology, Dept of Internal Medicine, Universityof Turin, Italy. gv.beano@accademiaservice.it

ABSTRACT

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.

Subjects and 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.

Conclusion: 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.

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Related in: MedlinePlus

Time to tumor progression is not correlated with the ADCC activity. A cut-off of 10%, 6% and 4% cytotoxicity was arbitrarly chosen to discriminate between high and low levels ADCC at the three E:T ratios of 50:1, 25:1 and 12:1 respectively and a stratified PFS curve was created from these values. The pattern of the two curves and the Log-Rank test p values demonstrated that time to tumor progression was not correlated with the ADCC.
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Figure 7: Time to tumor progression is not correlated with the ADCC activity. A cut-off of 10%, 6% and 4% cytotoxicity was arbitrarly chosen to discriminate between high and low levels ADCC at the three E:T ratios of 50:1, 25:1 and 12:1 respectively and a stratified PFS curve was created from these values. The pattern of the two curves and the Log-Rank test p values demonstrated that time to tumor progression was not correlated with the ADCC.

Mentions: The Kaplan-Meier PFS curve showed that 25% and 50% of patients were in PD at 6 and 12 months respectively (Fig. 5). ROC analysis was used to provide an optimal cut-off for discrimination of high an low NK and ADCC activities at the three E:T ratios and stratified PFS curves were created. Results show that patients with higher levels of NK activity are significantly less likely to relapse within twelve months (Log-Rank test p-values 0.168, 0.033 an 0.024 at the 50:1, 25:1 and 12:1 E:T ratios respectively (Fig. 6). By contrast, the advantage of a high ADCC activity is only evident at six months. At twelve months, the percentage of relapsing patients with either a high or a low initial ADCC activity is 50% (Fig. 7).


Correlation between NK function and response to trastuzumab in metastatic breast cancer patients.

Beano A, Signorino E, Evangelista A, Brusa D, Mistrangelo M, Polimeni MA, Spadi R, Donadio M, Ciuffreda L, Matera L - J Transl Med (2008)

Time to tumor progression is not correlated with the ADCC activity. A cut-off of 10%, 6% and 4% cytotoxicity was arbitrarly chosen to discriminate between high and low levels ADCC at the three E:T ratios of 50:1, 25:1 and 12:1 respectively and a stratified PFS curve was created from these values. The pattern of the two curves and the Log-Rank test p values demonstrated that time to tumor progression was not correlated with the ADCC.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2415031&req=5

Figure 7: Time to tumor progression is not correlated with the ADCC activity. A cut-off of 10%, 6% and 4% cytotoxicity was arbitrarly chosen to discriminate between high and low levels ADCC at the three E:T ratios of 50:1, 25:1 and 12:1 respectively and a stratified PFS curve was created from these values. The pattern of the two curves and the Log-Rank test p values demonstrated that time to tumor progression was not correlated with the ADCC.
Mentions: The Kaplan-Meier PFS curve showed that 25% and 50% of patients were in PD at 6 and 12 months respectively (Fig. 5). ROC analysis was used to provide an optimal cut-off for discrimination of high an low NK and ADCC activities at the three E:T ratios and stratified PFS curves were created. Results show that patients with higher levels of NK activity are significantly less likely to relapse within twelve months (Log-Rank test p-values 0.168, 0.033 an 0.024 at the 50:1, 25:1 and 12:1 E:T ratios respectively (Fig. 6). By contrast, the advantage of a high ADCC activity is only evident at six months. At twelve months, the percentage of relapsing patients with either a high or a low initial ADCC activity is 50% (Fig. 7).

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept of Medical Oncology, Molinette's Hospital, Turin, Italy, 2Laboratory of Tumour Immunology, Dept of Internal Medicine, Universityof Turin, Italy. gv.beano@accademiaservice.it

ABSTRACT

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.

Subjects and 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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus