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

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3036-3036
Author(s):  
A. Beano ◽  
E. Signorino ◽  
M. A. Polimeni ◽  
M. Mistrangelo ◽  
M. Ardine ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Nk Cells ◽  
Disease Progression ◽  
Mononuclear Cells ◽  
Metastatic Breast ◽  
Nk Activity ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Peripheral Blood Mononuclear ◽  
Effector Cells

3036 Background: Trastuzumab is a monoclonal antibody selectively directed against Her2 approved for the treatment of Her2 overexpressing breast cancer patients. Its proposed mechanisms of action include also a role in mediating antibody-dependent cellular cytotoxicity (ADCC), through the triggering of the FcγRIII on natural killer (NK) cells. This study addressed the correlation between overall NK function and clinical trastuzumab activity. Methods: Between March and September 2006 22 metastatic patients in treatment with trastuzumab alone (8 mg/kg load and then 6 mg/kg every 3 weeks until disease progression) as maintaining therapy after chemotherapy were analyzed for clinical and immunological responses. According to RECIST criteria, 14 patients obtained a response to trastuzumab, while 8 patients had a disease progression. Patient’s peripheral blood mononuclear cells were tested for cytotoxic activity against standard NK target (the MHC class I-negative K562 cell line) and trastuzumab-coated MCF7 (Her2-negative) and SKBR3 (Her2-positive) human cell lines in a 4-h 51Cr-release cytotoxicity assay in the presence of grading concentrations of effector cells. Results: NK activity was significantly (p<0.05) higher in responder compared to non responder patients at all the four effector:target (50:1 to 6:1) ratios tested. NK activity of non responder patients was significantly lower than that of 25 sex and age matched controls (p<0.02) and this was not merely due to chemotherapy- or tumor-associated immunosuppression, since the values of responder patients did not significantly differ from those of controls. ADCC activity against Her2-positive SKBR3 cells was also significantly higher in responder compared to non responder patients (p<0.05) and markedly so when compared to controls (p<0.001). Conclusions: The fact that, as shown here, normal levels of FcγR- independent and higher than normal levels of FcγR-dependent cytotoxicity are required for trastuzumab response, lends support to a paramount role of NK cells in the mechanism of action of this drug. No significant financial relationships to disclose.

Immunoglobulin G fragment C receptor polymorphisms and response to trastuzumab-based treatment in patients with HER-2/neu-positive metastatic breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13090-13090 ◽  
Author(s):  
A. Musolino ◽  
N. Naldi ◽  
B. Bortesi ◽  
M. Capelletti ◽  
D. Pezzuolo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Immunoglobulin G ◽  
Mononuclear Cells ◽  
Metastatic Breast ◽  
Cancer Cell Line ◽  
Breast Cancer Patients ◽  
Peripheral Blood Mononuclear ◽  
Immune Effector ◽  
Her 2

13090 Background: A potential mechanism of action of the humanized anti-HER-2/neu monoclonal antibody Trastuzumab involves antibody-dependent cellular cytotoxicity (ADCC) with the activation of immune effector cells via their immunoglobulin G fragment C receptors (FcγRs). Trastuzumab has been shown to engage both activation (FcγRIIIa; FcγRIIa) and inhibitory (FcγRIIb) antibody receptors on myeloid cells and several FcγR polymorphisms have been identified that may affect the antibody-dependent cytotoxicity of natural killer cells and macrophages. Methods: Forty consecutive HER-2/neu-positive (FISH+) metastatic breast cancer patients receiving a trastuzumab-based treatment (combined with paclitaxel for the majority) were examined for the FcγRIIIa 158 valine (V)/phenylalanine (F), FcγRIIa 131 histidine (H)/arginine (R), and FcγRIIb 232 isoleucine (I)/threonine (T) polymorphisms. A PCR-RFLP based assay using genomic DNA was performed for FcγRIIIa and FcγRIIa genotyping, while PCR-SSCP methods using complementary DNA were utilized for FcγRIIb. Patients’ peripheral blood mononuclear cells were drawn before treatment initiation and their trastuzumab-mediated killing function was measured by 51Cr release using a HER-2/neu-expressing human breast cancer cell line as a target. The results were then correlated with clinical outcome of these patients. Results: Median age was 60 years (range 26–83 years). Thirty-six (90%) patients received a trastuzumab-based treatment as first-line therapy. The overall clinical benefit rate (CR+PR+SD) was 65% (95% Confidence Interval: 62–71%), including 8 (20%) complete and 11 (27.5%) partial responses. Median survival was 22.3 mo with a median PFS of 7 mo. Trastuzumab-based treatment was well tolerated and no changes in cardiac function were observed. Conclusions: This study evaluates for the first time the potential role of FcγR polymorphisms in predicting response to trastuzumab-based treatment. Results according to this study purpose will be presented at the meeting. No significant financial relationships to disclose.

scholarly journals Epithelial/Mesenchymal Characteristics and PD-L1 Co-Expression in CTCs of Metastatic Breast Cancer Patients Treated with Eribulin: Correlation with Clinical Outcome

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3735
Author(s):  
Hara Polioudaki ◽  
Anastasia Mala ◽  
Eleni Gkimprixi ◽  
Maria A. Papadaki ◽  
Amanda Chantziou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Mononuclear Cells ◽  
Cox Regression ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Peripheral Blood Mononuclear ◽  
Cox Regression Analysis ◽  
Risk Of Death ◽  
Increased Risk

We aimed to evaluate the co-expression of PD-L1 and epithelial-mesenchymal markers in CTCs from metastatic breast cancer (MBC) patients and to determine if there is any relationship with patients’ outcome after eribulin treatment. Using cytospin preparations of peripheral blood mononuclear cells (PBMCs) from MBC patients treated with eribulin and a combination of immunocytochemistry and immunofluorescence, we quantified PD-L1, keratins and vimentin in single and cluster CTCs on days 1 and 8 of the first-treatment cycle. CTCs (n = 173) were found in 31 out of 38 patients. At baseline, the presence of cluster CTCs (p = 0.048), cluster mesenchymal CTCs (mCTCs) (p = 0.0003) or cluster PD-L1+mCTCs (p = 0.006) was associated with shorter overall survival (OS). In multivariate cox regression analysis, the detection of cluster mCTCs was the only parameter associated with increased risk of death (p = 0.024). On day 8 post-eribulin administration, PD-L1+mCTCs and especially single PD-L1+mCTCs decreased in 75% and 89% of patients, respectively. The detection of single PD-L1+mCTCs after eribulin treatment was correlated with shorter PFS (p = 0.047) and OS (p = 0.020). In conclusion, our study identified for the first time that cluster and single PD-L1+mCTCs subpopulations are of clinical significance in patients with MBC and highlighted the importance of CTC phenotyping during treatment with eribulin.

A pilot feasibility study to evaluate the efficacy of lapatinib in eliminating HER2-positive tumor cells circulating in peripheral blood of women with metastatic breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22105-e22105
Author(s):  
Sofia Agelaki ◽  
Antonia Kalykaki ◽  
Haris Markomanolaki ◽  
Galatea Kallergi ◽  
Kostas Kalbakis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Resistance Mechanism ◽  
Metastatic Breast ◽  
Her2 Status ◽  
Her2 Positive ◽  
Peripheral Blood Mononuclear ◽  
Prior Therapy ◽  
Egfr Expression

e22105 Background: EGFR and HER2 are expressed on CTCs from pts with breast cancer (BC). In this study we aimed to evaluate the efficacy of lapatinib, a dual EGFR and HER2 TK inhibitor, to eliminate HER2+ CTCs in metastatic BC. Methods: Pts with metastatic disease and HER2+ CTCs detected after disease stabilization or response to prior therapy were eligible. Pts received lapatinib till disease or CTC progression, whichever occurred first. Cytospins of peripheral blood mononuclear cells (PBMCs) were double stained with HER2 or EGFR along with cytokeratin antibody; 106 PBMCs/pt were analyzed for each molecule. Results: Twenty-two pts were enrolled; median age was 62.5 yrs, 2 had HER2+ primary, 12 (54.5%) had visceral disease and 8 (36.4%) had received ≥3 lines. Treatment was discontinued in 1 pt before the end of the 1st cycle due to toxicity and 1 withdrew consent after 3 cycles. A total of 119 courses were administered [median 4.0 (range, 0.5-26.0)]; disease evaluation revealed SD in 11 pts and PD in 10. HER2+ CTC counts declined in 18 (85.7%) pts during treatment [median time to nadir 1 mo (range, 1 – 5)]. After the 1st cycle, HER2+ CTCs decreased in 14 (66.7%) pts, increased in 6 (28.6%) and remained stable in 1 (4.7%). At baseline, 3444 HER2+ CTCs were detected (median 130), whereas after the 1st and 2nd cycles, 2281 (median 1) and 989 (median 2), respectively, were identified. The difference between baseline and post-1st or post-2nd cycle CTC counts was significant for all pts and for patients with SD but not in progressing pts. EGFR expression on CTCs was evaluated at the baseline and the end of treatment sample; in 6 of 8 pts with CTCs detected at both time points, the % EGFR+ CTCs/pt increased from a mean of 29.72% to 71.52%. Moreover, the % ratio of EGFR+ among the total CTCs increased from 17.08% to 37.59%. Conclusions: Lapatinib is effective in decreasing HER2+ CTCs in pts with metastatic BC, irrespective of the HER2 status of the primary. EGFR+ CTCs increase during treatment implicating EGFR as a possible resistance mechanism. The above results suggest that tailoring therapy according to targets present on CTCs represents an effective therapeutic strategy in BC. Clinical trial information: NCT00694252.

scholarly journals Clinical benefit of treatment after trastuzumab emtansine for HER2-positive metastatic breast cancer: a real-world multi-centre cohort study in Japan (WJOG12519B)

Breast Cancer ◽  
2021 ◽  
Author(s):  
Takamichi Yokoe ◽  
Sasagu Kurozumi ◽  
Kazuki Nozawa ◽  
Yukinori Ozaki ◽  
Tetsuyo Maeda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cohort Study ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Real World ◽  
Treatment Strategies ◽  
Metastatic Breast ◽  
Trastuzumab Emtansine ◽  
Breast Cancer Patients ◽  
Her2 Positive

Abstract Background Trastuzumab emtansine (T-DM1) treatment for human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer after taxane with trastuzumab and pertuzumab is standard therapy. However, treatment strategies beyond T-DM1 are still in development with insufficient evidence of their effectiveness. Here, we aimed to evaluate real-world treatment choice and efficacy of treatments after T-DM1 for HER2-positive metastatic breast cancer. Methods In this multi-centre retrospective cohort study involving 17 hospitals, 325 female HER2-positive metastatic breast cancer patients whose post-T-DM1 treatment began between April 15, 2014 and December 31, 2018 were enrolled. The primary end point was the objective response rate (ORR) of post-T-DM1 treatments. Secondary end points included disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), and overall survival (OS). Results The median number of prior treatments of post-T-DM1 treatment was four. The types of post-T-DM1 treatments included (1) chemotherapy in combination with trastuzumab and pertuzumab (n = 102; 31.4%), (2) chemotherapy concomitant with trastuzumab (n = 78; 24.0%), (3), lapatinib with capecitabine (n = 63; 19.4%), and (4) others (n = 82; 25.2%). ORR was 22.8% [95% confidence interval (CI): 18.1–28.0], DCR = 66.6% (95% CI 60.8–72.0), median PFS = 6.1 months (95% CI 5.3–6.7), median TTF = 5.1 months (95% CI 4.4–5.6), and median OS = 23.7 months (95% CI 20.7–27.4). Conclusion The benefits of treatments after T-DM1 are limited. Further investigation of new treatment strategies beyond T-DM1 is awaited for HER2-positive metastatic breast cancer patients.

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