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Verma C.,University of Nottingham | Kaewkangsadan V.,University of Nottingham | Eremin J.M.,Lincoln Breast Unit | Cowley G.P.,PathLinks | And 3 more authors.
Journal of Translational Medicine | Year: 2015

Background: NK cells contribute to tumour surveillance, inhibition of growth and dissemination by cytotoxicity, secretion of cytokines and interaction with immune cells. Their precise role in human breast cancer is unclear and the effect of therapy poorly studied. The purpose of our study was to characterise NK cells in women with large (≥3 cm) and locally advanced (T3-4, N1-2, M0) breast cancers (LLABCs) undergoing neoadjuvant chemotherapy (NAC) and surgery, and to ascertain their possible contribution to a pathological complete response (pCR). Methods: Women with LLABCs (n = 25) and healthy female donors [HFDs (n = 10)] were studied. Pathological responses in the breast were assessed using established criteria. Blood samples were collected pre and post NAC and surgery. Flow cytometry and labelled monoclonal antibodies established absolute numbers (AbNs) and percentages (%) of NK cells, and expressing granzyme B/perforin and NKG2D. In vitro NK cytotoxicity was assessed and NK cells and cytokines (IL-2, INF-γ, TGF-β) documented in tumours using immunohistochemical techniques. Data was analysed by SPSS. Results: Women with LLABCs had significantly reduced AbNs (160.00 ± 40.00 cells/μl) but not % of NK cells, compared with HFDs (NK: 266.78 ± 55.00 cells/μl; p = 0.020). NAC enhanced the AbN (p = 0.001) and % (p = 0.006) of NK cells in patients with good pathological responses. Granzyme B+/perforin+ cells were significantly reduced (43.41 ± 4.00%), compared with HFDs (60.26 ± 7.00%; p = 0.003). NAC increased the % in good (p = 0.006) and poor (p = 0.005) pathological responders. Pretreatment NK cytotoxicity was significantly reduced in good (37.80 ± 8.05%) and poor (22.80 ± 7.97%) responders (p = 0.001) but remained unchanged following NAC. NK-NKG2D+ cells were unaltered and unaffected by NAC; NKG2D expression was increased in patients with a pCR (p = 0.001). Surgery following NAC was not beneficial, except in those with a pCR. Tumour-infiltrating NK cells were infrequent but increased peritumourally (p = 0.005) showing a significant correlation (p = 0.004) between CD56+ cells and grade of response. Tumour cytokines had no effect. Conclusion: Women with LLABCs have inhibited blood innate immunity, variably reversed by NAC (especially with tumour pCRs), which returned to pretreatment levels following surgery. These and in situ tumour findings suggest a role for NK cells in NAC-induced breast pCR. © 2015 Verma et al. Source


Walker L.G.,University of Hull | Eremin J.M.,Lincoln County Hospital | Aloysius M.M.,University of Nottingham | Vassanasiri W.,Lincoln County Hospital | And 18 more authors.
BMC Cancer | Year: 2011

Background: Weekly docetaxel has occasionally been used in the neoadjuvant to downstage breast cancer to reduce toxicity and possibly enhance quality of life. However, no studies have compared the standard three weekly regimen to the weekly regimen in terms of quality of life. The primary aim of our study was to compare the effects on QoL of weekly versus 3-weekly sequential neoadjuvant docetaxel. Secondary aims were to determine the clinical and pathological responses, incidence of Breast Conserving Surgery (BCS), Disease Free Survival (DFS) and Overall Survival (OS).Methods: Eighty-nine patients receiving four cycles of doxorubicin and cyclophosphamide were randomised to receive twelve cycles of weekly docetaxel (33 mg/m2) or four cycles of 3-weekly docetaxel (100 mg/m2). The Functional Assessment of Cancer Therapy-Breast and psychosocial questionnaires were completed.Results: At a median follow-up of 71.5 months, there was no difference in the Trial Outcome Index scores between treatment groups. During weekly docetaxel, patients experienced less constipation, nail problems, neuropathy, tiredness, distress, depressed mood, and unhappiness. There were no differences in overall clinical response (93% vs. 90%), pathological complete response (20% vs. 27%), and breast-conserving surgery (BCS) rates (49% vs. 42%). Disease-free survival and overall survival were similar between treatment groups.Conclusions: Weekly docetaxel is well-tolerated and has less distressing side-effects, without compromising therapeutic responses, Breast Conserving Surgery (BCS) or survival outcomes in the neoadjuvant setting.Trial registration: ISRCTN: ISRCTN09184069. © 2011 Walker et al; licensee BioMed Central Ltd. Source


Verma C.,University of Nottingham | Kaewkangsadan V.,University of Nottingham | Eremin J.M.,Lincoln Breast Unit | Cowley G.P.,PathLinks | And 4 more authors.
Journal of Translational Medicine | Year: 2015

Background: NK cells contribute to tumour surveillance, inhibition of growth and dissemination by cytotoxicity, secretion of cytokines and interaction with immune cells. Their precise role in human breast cancer is unclear and the effect of therapy poorly studied. The purpose of our study was to characterise NK cells in women with large (≥3 cm) and locally advanced (T3-4, N1-2, M0) breast cancers (LLABCs) undergoing neoadjuvant chemotherapy (NAC) and surgery, and to ascertain their possible contribution to a pathological complete response (pCR). Methods: Women with LLABCs (n = 25) and healthy female donors [HFDs (n = 10)] were studied. Pathological responses in the breast were assessed using established criteria. Blood samples were collected pre and post NAC and surgery. Flow cytometry and labelled monoclonal antibodies established absolute numbers (AbNs) and percentages (%) of NK cells, and expressing granzyme B/perforin and NKG2D. In vitro NK cytotoxicity was assessed and NK cells and cytokines (IL-2, INF-γ, TGF-β) documented in tumours using immunohistochemical techniques. Data was analysed by SPSS. Results: Women with LLABCs had significantly reduced AbNs (160.00 ± 40.00 cells/μl) but not % of NK cells, compared with HFDs (NK: 266.78 ± 55.00 cells/μl; p = 0.020). NAC enhanced the AbN (p = 0.001) and % (p = 0.006) of NK cells in patients with good pathological responses. Granzyme B+/perforin+ cells were significantly reduced (43.41 ± 4.00%), compared with HFDs (60.26 ± 7.00%; p = 0.003). NAC increased the % in good (p = 0.006) and poor (p = 0.005) pathological responders. Pretreatment NK cytotoxicity was significantly reduced in good (37.80 ± 8.05%) and poor (22.80 ± 7.97%) responders (p = 0.001) but remained unchanged following NAC. NK-NKG2D+ cells were unaltered and unaffected by NAC; NKG2D expression was increased in patients with a pCR (p = 0.001). Surgery following NAC was not beneficial, except in those with a pCR. Tumour-infiltrating NK cells were infrequent but increased peritumourally (p = 0.005) showing a significant correlation (p = 0.004) between CD56+ cells and grade of response. Tumour cytokines had no effect. Conclusion: Women with LLABCs have inhibited blood innate immunity, variably reversed by NAC (especially with tumour pCRs), which returned to pretreatment levels following surgery. These and in situ tumour findings suggest a role for NK cells in NAC-induced breast pCR. © 2015 Verma et al. Source


Background: Host defences play a key role in tumour growth. Some of the benefits of chemotherapy may occur through modulation of these defences. The aim of this study was to define the status of regulatory cells in women with large and locally advanced breast cancers (LLABCs) undergoing neoadjuvant chemotherapy (NAC) and surgery. Methods: Bloods were collected from patients (n = 56) before, during and following NAC, and surgery. Controls (n = 10) were healthy, age-matched females donors (HFDs). Blood mononuclear cells (BMCs) were isolated and T regulatory cells (Tregs) (n = 31) determined. Absolute numbers (AbNs) of Tregs and myeloid-derived suppressor cells (MDSCs) were ascertained from whole blood (n = 25). Reverse transcriptase polymerase chain reaction analysis determined Treg mRNA (n = 16). In vitro production of Th1, Th2 and Th17 cytokines (n = 30), was documented. Patients were classified as clinical responders by magnetic resonance mammography after two cycles of NAC and as pathological responders using established criteria, following surgery. Results: Patients with LLABCs had significantly increased circulating Tregs (≥ 6 fold AbN and percentage (%)) and MDSCs (≥ 1.5 fold AbN (p = 0.025)). Percentage of FOXP3+ Tregs in blood predicted the response of the LLABCs to subsequent NAC (p = 0.04). Post NAC blood Tregs (%) were significantly reduced in patients where tumours showed a good pathological response to NAC (p = 0.05). Blood MDSCs (granulocytic, monocytic) were significantly reduced in all patients, irrespective of the pathological tumour response to chemotherapy. NAC followed by surgery failed to restore blood Tregs to normal levels. MDSCs, however, were reduced to or below normal levels by NAC alone. Invitro Th1 profile (IL-1β, IL-2, INF-γ, TNF-α) was significantly reduced (p ≤ 0.009), whilst Th2 (IL-4, IL-5) was significantly enhanced (P ≤ 0.004). Th1 and Th2 (IL-5) were unaffected by NAC and surgery. IL-17A was significantly increased (p ≤ 0.023) but unaffected by chemotherapy and surgery. Conclusion: Women with LLABCs have abnormal blood regulatory cell levels (Tregs and MDSCs) and cytokine profiles (Th1, Th2, Th17). NAC followed by surgery failed to abolish the abnormal Treg and Th profiles. There was a significant correlation between the circulatory levels of Tregs and the pathological response of the breast cancers to NAC. © 2013 Verma et al.; licensee BioMed Central Ltd. Source

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