Immunotherapy and breast cancer.
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Animals↗
Biomedical subjects
D W Miles
Publications and source records attributed to D W Miles.
Role of nitric oxide in tumour progression: lessons from human tumours.
Varied cellular expression and localisation of nitric oxide synthase (NOS) isoforms has been shown in human cancers, including tumours of the breast, ovary, stomach, cervix and central nervous system. Mapping of NOS expression within tumour tissue from breast and gastric cancers shows inducible NOS (iNOS) is expressed predominantly in stromal (macrophage and endothelial) cells, although the level of NOS activity is at least 1-2 orders of magnitude lower than the enzyme activity associated with cytotoxicity and apoptosis. There is evidence that the intratumoural environment may provide chemoattractant signals for monocyte-macrophage recruitment and their subsequent activation via expression of interleukin-4, IgE, and CD23. Such signals lead to induction of iNOS in human macrophages in vitro. The correlation between NOS activity and grade for breast cancer suggests that NO may provide a positive growth signal within the tumour microenvironment. In vivo studies showing increased growth rate, vascular density and invasiveness of a human tumour cell line transfected to constitutively express iNOS support this. Furthermore, in vivo administration of a highly selective inhibitor of iNOS limited invasion and growth rate of iNOS transfected tumours and other murine tumours expressing this isoform. Inhibition of NO generation in the intratumoural microenvironment may prove a useful cancer therapy by preventing angiogenesis, invasion and metastasis.
Disease Progression↗
Family history and survival in premenopausal breast cancer.
The clinicopathological characteristics of breast cancer in 95 women between the ages of 24 and 45 years with a family history of breast cancer were compared with tumours from 329 women with sporadic disease matched for age and year of diagnosis. There was a trend for the family history patients to have slightly smaller tumours (mean size 2.49 cm) than the controls (mean 3.04 cm) (Mann-Whitney test, P = 0.09). A significantly greater proportion of the familial cases had grade III infiltrating ductal carcinoma than did the controls (40% vs 27%; chi2(1) = 5.64, P = 0.02). Despite this, there were more cases of operable node-negative disease among the study group than among the controls (48% vs 32%; chi2(1) = 8.2, P = 0.004). There was a highly significant survival advantage for patients with a family history (chi2 = 22.4, P < 0.001). Five- and 10-year survival rates were 92% and 87% for those with a family history compared with 70% and 54% for those in the control group. This survival advantage was maintained when patients with operable disease only were considered. In multivariate analysis, which included age, tumour size, stage, histological grade and family history, family history was an independent predictor of favourable prognosis and, in a Cox model, was associated with a relative risk of survival of 6.11 (95% CI 2.81-13.28). These results suggest that familial breast cancer has a more favourable clinical course than the more common sporadic forms of the disease.
Adult↗
Persistent induction of nitric oxide synthase in tumours from mice treated with the anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid.
An anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA) induced nitric oxide synthase (NOS) in the tumour, spleen, thymus and small intestine, but not in the lung, liver, kidney, heart or skeletal muscle in B6D2F1 mice bearing subcutaneous colon 38 tumours. This pattern of induction is distinct from that caused by agents such as endotoxin, muramyl dipeptide or Corynebacterium parvum. The induction of NOS (iNOS) in the tumour was more persistent (maximal at 3 days) than in other tissues (maximal at 12 h). Immunohistochemical staining suggested that iNOS was located in macrophages and endothelial cells within and around the tumour. Treatment with 5,6-MeXAA also caused substantial increases in plasma nitrite and nitrate (NOx) concentrations that peaked at 8-12 h after 5,6-MeXAA. The increase in plasma NOx was prevented by a NOS inhibitor N-iminoethyl-L-ornithine (L-NIO), indicating that it was due to enhanced production of NO. Tumour-bearing mice were more responsive than controls to 5,6-MeXAA both in their plasma NOx increase and in their lower maximally tolerated dose. L-NIO was unable to prevent the complete tumour necrosis and regression caused by 5,6-MeXAA at a dose that substantially inhibited the increase of plasma NOx. In conclusion, the experimental anti-tumour agent 5,6-MeXAA induced NO synthesis in tumour-associated macrophages and in immunologically active tissues in parallel with its effects on tumour growth. The experiments with a non-selective NOS inhibitor L-NIO, however, suggest that NO is not a significant component in the mechanism of the anti-tumour action of 5,6-MeXAA in this particular model.
Animals↗
p53 immunohistochemical staining and survival after adjuvant chemotherapy for breast cancer.
We have investigated the relationship between immunohistochemically determined p53 status and outcome in 277 women with node-positive primary breast cancer who, following tumour excision and axillary clearance, were randomised to receive either 6 cycles of cyclophosphamide/methotrexate/S-fluorouracil (CMF) (n = 130) or no such post-operative treatment (n = 147). Follow-up data (median = 9 years) were available on all patients. A significant association was found between p53 status and survival. Patients with p53-positive tumours had a less favourable outcome than those with p53-negative disease. Women receiving adjuvant CMF chemotherapy had a significantly more favourable outcome compared to those who did not. The effect was seen both in women with p53-positive and p53-negative tumours; multivariate analysis showed relative risks for overall survival attributable to chemotherapy of 2.3 (95% CI 1.2-4.3) for women with p53-positive tumours and of 2.1 (95% CI 1.4-3.0) for those with p53-negative tumours. Thus, adjuvant chemotherapy with CMF is associated with a survival benefit in women with node-positive breast cancer irrespective of immunohistochemically determined p53 status.
Adult↗
Development and evaluation of a predictive model for the effect of temperature and water activity on the growth rate of Vibrio parahaemolyticus.
The growth rates of four strains of Vibrio parahaemolyticus were measured and compared in a model broth system. The results for the fastest growing strain, based on 77 combinations of temperature and water activity (aw) using NaCl as the humectant, were summarised in the form of a predictive mathematical model. The model, of the square-root type includes a novel term to describe the effects of super-optimal water activity, and can be used to predict generation times for the temperature range (8-45 degrees C) and water activity range (0.936-0.995) which permit growth of Vibrio parahaemolyticus. Predicted generation times from the model were compared to literature data, using bias and accuracy factors, for both laboratory media and foods. The model was shown to give realistic growth estimates, with a bias value of 1.01, and an accuracy factor of 1.38.
Models, Biological↗
The localization of the insulin-like growth factor receptor 1 (IGFR-1) in benign and malignant breast tissue.
Insulin-like growth factors (IGFs) play an important role in normal cellular growth and development and have been implicated in the regulation of tumour growth. Two receptors are recognized, IGFR-1 and IGFR-2, of which one, IGFR-1, is a transmembrane heterodimer structurally similar to the insulin receptor. Studies using ligand-binding assays have suggested that the proportion of human breast carcinomas expressing IGFR-1 varies between 39 and 93 per cent and all suggest a lower level of IGFR-1 expression in benign mammary epithelia. As there is this variation between studies and since no study appears to have examined the immunohistochemical localization of IGFR-1 within breast tissue, a series of 79 infiltrating ductal carcinomas, 11 infiltrating lobular carcinomas, three cases of pure ductal carcinoma in situ (DCIS), seven fibroadenomas, and eight normal breast specimens have been studied utilizing the monoclonal antibody alpha IR3. IGFR-1 localized to the epithelial component of 90 per cent of the carcinomas, with only cytoplasmic (21 per cent), only membrane (5 per cent), or a mixture of both cytoplasmic and membrane (64 per cent) staining patterns. In some tumours, distinct basolateral distribution of the receptor was observed. Invasive lobular carcinoma showed significantly less labelling than ductal (P = 0.0009). There was a significant correlation between the level of IGFR-1 immunostaining with both oestrogen receptor (P < 0.001) and progesterone receptor (P = 0.0018) positivity within the malignant group. All normal mammary epithelium showed strong labelling, which was often at an intensity matching that of the most strongly labelled carcinoma and occasionally visualized as basolateral staining of the luminal cells. Weak to moderate staining of endothelial cells was also observed. It is concluded that IGFR-1 immunoreactivity is found in the majority of breast carcinomas, where it correlates most closely with oestrogen receptor status. The high intensity labelling of normal cells seen in this study contrasts with the low levels inferred from ligand-binding-based techniques and emphasizes the importance of the morphological approach in the investigation of novel molecules.
Breast↗
A randomised phase II study of sialyl-Tn and DETOX-B adjuvant with or without cyclophosphamide pretreatment for the active specific immunotherapy of breast cancer.
Studies in animal models of mouse mammary carcinoma have shown that ovine submaxillary mucin, which carries multiple sialyl-Tn (STn) epitopes, is effective in stimulating an immune response and inhibiting tumour growth. In similar studies using carbohydrate antigens, pretreatment with low-dose cyclophosphamide has been shown to be important in modulating the immune response to antigen possibly by inhibiting suppresser T-cell activity. In a clinical trial assessing the efficacy and toxicity of synthetic STn, patients with metastatic breast cancer were randomised to receive 100 micrograms STn linked to keyhole limpet haemocyanin (KLH) with DETOX-B adjuvant given by subcutaneous injection at weeks 0, 2, 5 and 9 with or without low-dose cyclophosphamide (CTX, 300 mg m-2) pretreatment, 3 days before the start of immunotherapy. Patients with responding or stable disease after the first four injections were eligible to receive STn-KLH at 4 week intervals. The main toxicity noted was the development of subcutaneous granulomata at injection sites. Of 23 patients randomised, 18 received four injections, 5 patients having developed progressive disease during the initial 12 week period. Two minor responses were noted in the 18 patients who received four active specific immunotherapy (ASI) injections and a further five patients had stable disease. Six patients continued ASI at 4 week intervals and a partial response was noted in a patient who had previously had stable disease. All patients developed IgG and IgM responses to sialyl-Tn and levels of IgM antibodies were significantly higher in those patients who were pretreated with CTX. Measurable tumour responses have been recorded following ASI with STn-KLH plus DETOX and the immunomodulatory properties of low-dose CTX have been confirmed.
Adjuvants, Immunologic↗
Adhesion molecule expression and leucocyte trafficking following immunotherapy with recombinant interleukin-2.
The relevant anti-tumour mechanisms of recombinant interleukin-2 (rIL-2) in vivo are unclear but an influx of T-lymphocytes and macrophages has been noted in regressing lesions. One of the dose limiting toxicities of rIL-2 is the development of a capillary leak syndrome attributed to widespread endothelial activation. Changes in expression of endothelial and leucocyte-associated adhesion molecules were assessed in tumour and uninvolved skin in patients with metastatic breast cancer receiving rIL-2. Increased expression of intracellular adhesion molecule-1, its leucocyte-associated ligand, leucocyte function associated molecule-1, vascular cell adhesion molecule and its ligand, very late after activation antigen-4 as well as members of the selectin family of adhesion molecules, were noted in uninvolved skin following rIL-2. Expression of these adhesion molecules was noted in tumour stroma before rIL-2 but little change was observed following rIL-2 infusion. An influx of monocytes and T-lymphocytes (expressing the IL-2 receptor and of the memory subtype) and a lower number of neutrophils was noted in uninvolved skin following rIL-2. Although monocytes and T-lymphocytes were present in tumour stroma before rIL-2 no changes were observed following infusion. The changes noted in the dermis contrast with those seen at tumour sites and may partly explain the low therapeutic index of rIL-2.
Aged↗
Enhancing the effect of THERATOPE STn-KLH cancer vaccine in patients with metastatic breast cancer by pretreatment with low-dose intravenous cyclophosphamide.
THERATOPE (Biomira Inc., Edmonton, AB, Canada) STn-KLH cancer vaccine induces strong antibody titers against both the synthetic STn epitope and against a natural mucin, OSM, which expresses STn-like epitopes. In prospective, randomized studies in patients with metastatic breast cancer treated at two cancer centers, the effect of different low-dose, immunomodulatory cyclophosphamide (cyclo) pretreatments on the response to THERATOPE STn-KLH was compared. Patients were randomized to receive either intravenous cyclo 300 mg/m2 on day -3, or oral cyclo 50 mg daily from days -14 to -3 inclusive, or no cyclo, before THERATOPE treatments. The anti-STn and anti-OSM antibody titers were higher in the patients who received cyclo intravenously before THERATOPE. Patients treated with cyclo intravenously and THERATOPE STn-KLH cancer vaccine lived significantly longer (projected median survival of 19.7 months versus actual median survival of 12.6 months, p = 0.0176) than those treated with the same STn vaccine with oral or no cyclo. Although it is not clear how the anti-STn antibody response modifies tumor biology, we noted that patients in the intravenously administered cyclo group had a lower percentage of patients showing progressive disease at 9 weeks, and that there was an inverse correlation between serum anti-STN antibody titer and growth of measurable tumors. There was no correlation between tumor growth and anti-KLH antibody titers. These data are consistent with a therapeutic effect of THERATOPE STn-KLH cancer vaccine and support development of a phase III study to explore this further.
Adenocarcinoma↗
Images in clinical medicine. Transverse leukonychia.
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Antibiotics, Antineoplastic↗
Expression of sialyl-Tn in gastric cancer: correlation with known prognostic factors.
Sialyl-Tn (STn) is a core region carcinoma-associated carbohydrate determinant expressed on cancer-associated mucins. Expression of STn has been associated with poor prognosis in colon and ovarian cancer, independent of other prognostic factors such as tumour grade, stage or histological type. Recent studies have suggested that STn expression may be an independent prognostic variable in gastric cancer. We have examined 158 patients with gastric cancer using the antibody B72.3 (Biomira, Edmonton, Alberta, Canada). Of these, 110 patients (70%) expressed STn. Expression of STn did not correlate with tumour differentiation or the Ming classification, but expression was noted more frequently in the relatively good prognosis intestinal type of tumours (chi 2 = 6.9, P = 0.03). Conversely, early-stage cancers showed a significantly lower frequency of expression than more advanced cases (chi 2 = 13.75, P = 0.003). In this patient group, STn expression did not influence survival, and in multivariate regression analysis only tumour stage and Lauren classification were found to be independent prognostic variables.
Antigens, Tumor-Associated, Carbohydrate↗
Nitric oxide synthase activity in human breast cancer.
Nitric oxide (NO) is generated by a family of isoenzymes (NO synthases) expressed in a wide range of mammalian cells. We have recently reported NO synthase expression in human gynaecological cancers. In this study we have assessed the activity and distribution of NO synthase in a series of human breast tumours and in normal breast tissue. Calcium-dependent (constitutive) and -independent (inducible) NO synthase activity, as well as NO biosynthesis, was high in invasive tumours compared with benign or normal tissue. Furthermore, for invasive ductal carcinomas, NO biosynthesis was significantly greater for grade III compared with grade II tumours. Immunohistochemical investigations revealed immunolabelling with a monoclonal antibody to murine inducible NO synthase predominantly within tumour-associated macrophages. Immunolabelling with a polyclonal antiserum raised against rat brain NO synthase was also observed in vascular endothelial and myoepithelial cells. Thus NO synthase is expressed in human breast tumours, where its presence correlates with tumour grade.
Amino Acid Oxidoreductases↗
Expression of tumour necrosis factor (TNF alpha) and its receptors in benign and malignant breast tissue.
As well as having anti-tumour activity in animal models. TNF alpha has been implicated in the promotion of tumour invasion and metastasis. Expression and localization of TNF alpha mRNA and protein has been investigated in a series of benign and malignant breast tissues. TNF alpha mRNA was expressed in a minority of cells (< 0.5%) in 4/11 cases of benign breast tissue and in a higher proportion of invasive carcinomas (43/49 cases). Expression of TNF alpha mRNA was focal and confined to the tumour stroma. The presence of TNF alpha was confirmed by immunohistochemistry and again was predominantly stromal. Expression of mRNA and protein localized to infiltrating macrophages defined by the antibody EBM/11 in adjacent sections and using 2-colour immunofluorescence. Although the average number of macrophages per high-power field did not vary among invasive carcinomas of different histological type or grade, the number of cells expressing TNF alpha increased with increasing tumour grade. Immunodetectable p75 TNF receptor and to a lesser extent p55 receptor was present on cells of the mononuclear infiltrate and on the endothelium of invasive carcinomas, but not on the tumour cells themselves.
Breast↗
Expression of sialyl-Tn predicts the effect of adjuvant chemotherapy in node-positive breast cancer.
Sialyl-Tn (STn) is a carcinoma-associated carbohydrate determinant expressed on cancer-associated mucins and has the structure NANA alpha(2-6)alpha GalNAc. Expression of STn in colon and ovarian cancer is associated with a poor prognosis independent of tumour grade, stage or histological type. We have examined 237 cases of primary breast cancer for expression of this antigen using the antibody HB-STn (Dako). The frequency of STn expression was 31% in the whole group, 36% in the node-negative and 28% in the node-positive group. Survival was lower, but not significantly so, in the STn-positive group (P = 0.07), but this effect was highly significant for patients with node-positive disease (P < 0.002), the curves for node-negative disease being coincident (P = 0.31). In node-positive disease the effect was limited to those receiving adjuvant chemotherapy (P = 0.001). In a multivariate (Cox) analysis on the whole group STn staining, combined with adjuvant chemotherapy, showed a highly significant correlation with survival. In STn-negative cases, adjuvant chemotherapy improved survival (relative risk 2.3, 95% confidence intervals 1.4-3.9), whereas adjuvant chemotherapy did not influence survival in patients which expressed STn (relative risk 1.1, 95% confidence intervals 0.6-2.2). Thus, by either direct or indirect mechanisms, STn positivity appears to be a marker of resistance to adjuvant chemotherapy.
Antigens, Tumor-Associated, Carbohydrate↗
Received dose-intensity: a randomized trial of weekly chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer.
PURPOSE: A prospective randomized trial to determine if granulocyte colony-stimulating factor (G-CSF) could increase the received dose-intensity (RDI) of weekly chemotherapy in patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Forty patients with SCLC with good prognostic features (all patients with limited disease [LD], and extensive-disease [ED] patients with Eastern Cooperative Oncology Group [ECOG] 0 or 1 and plasma alkaline phosphatase levels < 1.5 times the upper limit of normal) were randomized to receive weekly chemotherapy with or without G-CSF. G-CSF (5 micrograms/kg) was self-administered subcutaneously on days when chemotherapy was not given. Chemotherapy consisted of cisplatin 50 mg/m2 intravenously (IV) on day 1 and etoposide 75 mg/m2 IV on days 1 and 2 alternating weekly with ifosfamide 2 g/m2 IV (with mesna) and doxorubicin 25 mg/m2 on day 1, for a total of 12 courses. Dose modifications (dose reductions and treatment delays) were made according to defined hematologic criteria. RESULTS: Dose reductions were made at some point during treatment in 12 of 17 patients in the control arm and in 11 of 23 patients in the G-CSF arm (P = .20). The proportion of patients experiencing dose reductions due to leukopenia was significantly higher in the control arm (nine of 17) compared with the G-CSF arm (four of 23, P < .04). Cycle delays due to leukopenia were similar in both arms of the study. The RDI was 82% of projected in the control arm (95% confidence interval [CI], 79% to 84%) and 84% in patients receiving G-CSF (95% CI, 82% to 87%) (P value not significant). CONCLUSION: In this randomized trial, G-CSF significantly decreased dose reductions due to neutropenia. However, administration of G-CSF did not decrease dose reductions or treatment delays to a level that would allow an increase in received dose-intensity. Nonhematologic toxicities such as increased creatinine concentration also prevented an increase in the RDI in the G-CSF arm.
Adult↗
Diagnosis and management of malignant pleural effusion.
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Humans↗
Activity of type IV collagenases in benign and malignant breast disease.
Using zymography and computer assisted image analysis, we have measured the levels of type IV collagenases in biopsies from normal breast, and benign and malignant breast disease. The 92 kDa form was present in three of 11 cases of normal/benign disease, three of nine grade I tumours, four of 12 grade II tumours, but 11 of 11 grade III tumours. Mean levels were higher in grade III tumours (P < 0.0001). When the levels of 72 kDa collagenase and its active 62 kDa form were considered together, there was no difference between the benign and malignant cases (P = 0.55), but the amount of active enzyme, considered as a proportion of the 62 + 72 kDa forms, was significantly higher in malignant disease (P = 0.003). There was also a trend towards a higher proportion of active enzyme with increasing tumour grade (P < 0.0001). In situ hybridisation and immunohistochemistry studies showed that that mRNA and protein for the 92 kDa enzyme was primarily found in the tumour stroma. mRNA for the 72 kDa enzyme was also found in stromal areas. This study demonstrates a clear relationship between production of Type IV collagenases and malignant breast disease. Inhibitors of these enzymes may be of value in preventing metastatic disease.
Breast↗