The role of a new monoclonal antibody assay in the detection of recurrent breast cancer

The immunoradiometric assay "CA 15-3", recently developed to measure a breast tumor-associated antigen, gave a mean serum value of 13.8 U/ml (S.D. 6.2) for this antigen in 156 non-cancer controls (36 biopsies for a benign breast lesion and 120 healthy controls). Setting a cut-off value of 30 U/ml (specificity 99.3%), only 3 out of 58 primary breast cancer cases were positive. In metastatic breast cancer, 11 out of 33 cases with limited recurrence (33.3%) and 36 out of 56 cases with extensive recurrence (64.3%) gave abnormal values in this assay, above the cut-off point, with an overall sensitivity of 52.8%; the difference between the sensitivity values in the two groups of recurrent cases was statistically significant (P less than 0.01). According to the findings of the present study, CA 15-3 has no role in the detection of primary breast cancer, but its usefulness in disease monitoring can be hypothesized, as circulating levels of the antigen seem to be dependent on the tumor mass.     

Circulating CA 15.3 levels in breast cancer. Our present experience

CA 15.3 is an antigen expressed by human breast carcinoma cells, and defined by two monoclonal antibodies, 115D8 and DF3. We used IRMA to determine the circulating serum levels of CA 15.3 in 1178 subjects with breast cancer, non-breast malignancies, benign diseases and controls. A threshold level of 40 U/ml was established with 140 healthy controls and 650 patients with benign diseases (respectively 0% subjects and 1.5% patients had abnormal antigen levels). Elevated CA 15.3 was found in 12 of 184 patients with malignancies different from breast cancer (6.5%), either epithelial carcinomas with distant metastases, mainly in the liver, or primary liver tumors. Breast cancer patients (n = 204) were analysed by prior therapy, UICC stage and WHO response to therapy. Eight of 134 (5.9%) patients with stage II or III breast cancer at presentation and no evidence of disease (NED) had elevated CA 15.3. All of 22 patients with stage IV breast cancer not responding to therapy (SD and PD) had antigen levels greater than 40 U/ml, as did 10 of 34 (29.4%) stage IV patients in objective response (CR + PR). Three of 14 pretreatment patients had abnormal marker levels, and they later proved to have distant metastases. Serum CA 15.3 values were statistically different (p less than 0.01) in NED (20.6 +/- 11.2 U/ml), CR + PR (33.5 +/- 24.0 U/ml), stable disease (98.8 +/- 50.4 U/ml) and progressive disease (greater than 200 U/ml) breast cancer patients. Our results suggest that circulating CA 15.3 antigen levels agree with the stage of breast cancer and with the response to therapy.     

MCA in patients with breast cancer: correlation with CEA and CA15-3

MCA serum levels were determined in 27 healthy subjects, 136 with benign pathology (42 breast) and in 289 patients with cancer (247 active). The last group includes 223 patients with breast cancer (96 without metastases, 89 with metastases and 38 no-evidence of disease). CEA and CA15-3 serum levels were determined in all the patients with breast diseases. The mean levels of MCA were 4.7 + 2.4 U/ml in the control group, considering less than 11 U/ml as normal. MCA values were abnormal in 15.4% of patients with benign pathology, mainly in those with liver cirrhosis (8/20) and lung diseases (4/20). In the majority of these cases, the rise was only moderate, lower than 15 U/ml in 97.5% of patients. In malignant diseases, important increments were found in breast cancer (19.8% Mo, 77.5% M1) and ovarian cancer stages III-IV (44.4%). When we compared MCA serum levels with CA15-3 and CEA in breast pathology, a similar specificity was observed: 92.3%, 92.3% and 100% in cases with benign pathology and 92.1%, 94.7%, and 97.4% in NED patients, respectively. MCA and CA15-3 sensitivity was similar in breast cancer without metastases (19.8%) and lower for CEA (16.7%). In patients with breast cancer without metastases, we found a relation between positivity of these tumor markers and prognostic factors (tumor size, nodal involvement). The disease free interval in patients with locoregional breast cancer was shorter in cases with abnormal presurgical levels of some of the tumor markers, but only the difference from MCA was significant (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of CA 15-3 and CEA in diagnosis and monitoring of breast cancer

In order to assess the utility of the tumor-associated antigen CA15-3 in the diagnosis of breast cancer, this new tumor marker was measured pre-operatively in 1342 patients. This group comprised 509 patients with malignant disease (134 with breast cancer and 375 with other malignancies not involving the breast) and 833 patients with benign surgical diseases (95 patients with fibroadenoma of the breast, 738 with other benign diseases). The results were compared with those for carcino-embryonic antigen (CEA) in the diagnosis of breast cancer. CA15-3 was above the normal limits of 25 U/ml in 31% of the patients with breast cancer, in 22% of patients with other malignancies, and in 9% of patients with benign diseases. CEA was elevated in 26% of patients with breast cancer (greater than 3 ng/ml). CA15-3 levels were above 50 U/ml in 13% of the breast cancer patients, in 6% of patients with other malignancies, and in 0.2% of the patients with benign diseases. There was a good correlation between CA15-3 level and tumor stage in breast cancer. CA15-3 serum levels were over 50 U/ml in respectively 0%, 2%, 13%, and 73% of the patients with stages I, II, III, and IV. CA15-3 and CEA were also determined in 671 patients who had received initial curative surgery of breast cancer, and who regularly attended our follow-up clinic. CA15-3 was found to be more sensitive than CEA in detecting recurrences of breast cancer.(ABSTRACT TRUNCATED AT 250 WORDS)     

CA 549 as a marker in breast cancer.

CA 549 is one of several carcinoma associated mucin antigens proposed as a breast cancer tumor marker. In this study, the performance characteristics of the CA 549 assay were validated and the clinical utility of the test was compared with that of other breast cancer markers including CA 15-3, CA M26, CA M29 and carcinoembryonic antigen. The upper limit of normal was established as 15.5 U/ml based on data for 250 control subjects apparently free of disease. Overall, CA 549 had a low negative predictive value (0.51) due to a low sensitivity in the detection of early breast cancer. However, the test had a high positive predictive value (0.93) reflecting a high specificity for the disease. In 56 patients with advanced breast cancer, the sensitivity was 0.71 for CA 549 alone and 0.79-0.84 for CA 549 combined with any of the other markers studied.     

CA 15.3 and CEA plasma level monitoring in patients with breast cancer

CA 15.3 and CEA were determined in the serum of 217 patients with early and advanced breast carcinoma. CA 15.3 was high (greater than 30 U/ml) in 1/6 (17%) patients with stage I-II primary tumor, in 4/77 (5%) patients without clinical signs of disease after mastectomy, in 67/102 (65%) patients with advanced disease in progression, and in 13/32 (41%) patients with advanced disease not in progression and undergoing therapy. The corresponding incidences of pathological CEA values (greater than 2.5 ng/ml) were 33, 8, 55 and 14%. The combination of the two markers brings about a certain improvement in the sensitivity for recognising patients with advanced disease in progression (79/102 = 77%). The presence of high values of CA 15.3 is statistically correlated to the prevalent site of metastases (bone and viscera greater than soft tissues). Monitoring the two markers during antitumor therapy in 36 patients showed good accordance (56%) between CA 15.3 changes and response to therapy. The decrease of the marker in patients who achieved partial remission was statistically significant. In conclusion, CA 15.3 is more sensitive than CEA in recognising patients with advanced disease in progression and gives better accordance with the response to therapy. The simultaneous use of the two markers may be useful in the follow-up of operated patients and in monitoring the disease during treatment.     

Circulating macrophage colony stimulating factor as a marker of tumour progression

Tumour expression of the macrophage colony stimulating factor (CSF-1 or MCSF) has been associated with an adverse prognosis in breast cancer, through an effect on the promotion of metastasis. The aim of the present study was to evaluate the clinical relevance of high circulating CSF-1 levels in patients with newly diagnosed breast tumours and correlate CSF-1 with clinico-pathological parameters. A secondary aim was to also measure CSF-1 in patients with other tumour types and at different stages of disease. Using a commercially available ELISA, pre-treatment plasma levels of CSF-1 were assessed, in 471 consecutive patients diagnosed with breast tumours, in 70 patients with newly diagnosed cancer of the head & neck, in 32 men with prostate cancer metastatic to bone and in 39 women with advanced metastatic breast cancer. Mean CSF-1 levels were significantly higher in patients with locally advanced (p <.015) or metastatic breast tumours (p <.048) and in a group of primary breast cancer patients (n = 26) selected for intensive chemotherapy because of multiple adverse tumour characteristics (p <.0002). Mean CSF-1 was also higher in patients younger than 35 years (p <.02) and in post-menopausal patients (p <.03). There was no significant association with tumour histologic type, grade, or other individual histopathologic parameters. No significant association was found between pre-treatment CSF-1 and overall/relapse free survival. Median CSF-1 levels were dramatically higher in patients with newly diagnosed tumours of the head & neck (604 pg/ml), in men with prostate cancer metastatic to bone (627 pg/ml) and women with advanced metastatic breast cancer (867 pg/ml) than those seen in patients with newly diagnosed breast tumours (334 pg/ml). Our data support the hypothesis that CSF-1 may play a functional role in tumour progression to metastasis as has previously been reported in animal models.     

Relationship of CA 125 and CA 19.9 with lung carcinoma histological subtype: preliminary study

The aim of this work was to study the possible utility of simultaneous determination of CA 125 and CA 19.9 in patients with lung cancer. Serum levels of both markers were studied in 87 patients without metastases (Mo), 72 patients with distant metastases (MT) and 15 cases without clinical evidence of disease after primary treatment (NED). Sixty-five tumors were epidermoid, 34 were adenocarcinomas, 24 were cell undifferentiated carcinomas and 51 were small-cell carcinomas. Sera from 75 healthy subjects and 20 patients with benign lung disease were used as controls. The cut-off values used were 35 and 37 U/ml for CA 125 and CA 19.9, respectively. CA 125 and CA 19.9 serum levels were within normal limits in all control patients. In NED patients these markers were not elevated, except in one with chronic liver disease who showed elevated CA 19.9 (76 U/ml). Twenty-five percent of Mo lung cancer patients and 40.3% of MT cases had CA 19.9 over 37 U/ml. Abnormally high levels of CA 125 were found in 18.7% and 22.9% of Mo and MT patients, respectively. Sixty percent of patients with large cell undifferentiated carcinoma had elevated CA 125 (mean 176 U/ml) compared to 15.4% of patients with all other histological types of tumors combined (54.3 U/ml, p less than 0.01). CA 19.9 serum levels were also more often elevated in patients with large cell undifferentiated carcinomas (50%, 7/14 cases) than in other histological types (30%, 36/120 patients), but the difference was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)     

CA 15.3 as a tumour marker in breast cancer

CA 15.3 is an antigenic determinant associated with human mammary carcinomas. Two murine monoclonal antibodies have been raised against the determinants, and an immunoradiometric assay (IRMA-Kit, Centocor, USA) has been developed to determine the antigen levels in plasma of cancer patients. Based on the 99% confidence limit of healthy women, plasma values above 30 U/ml are considered abnormal. Plasma samples from 357 women were examined in the present study. Healthy females (n = 84) ranged below the cut-off level between less than 10 and 29 U/ml. Higher values were found in 12.5% of benign breast diseases and in 23.6% of breast cancer patients, including all stages. Depending on the stage of the disease, there were elevated levels in 11% of operable breast cancer patients preoperatively, in 7% of the cases with no evidence of disease after primary treatment and in 63.5% of patients with disseminated mammary carcinoma. In metastasized breast cancer the frequency and the degree of abnormal titers were closely related to the extent of the metastatic disease. Follow-up examinations of 63 patients under cytotoxic therapy showed CA 15.3 changes correlating well with the clinical course in up to 90% of the antigen positive cases. The present data indicate that CA 15.3 may be useful in the surveillance of breast cancer patients. However in our study one third of the patients with metastatic breast cancer did not show any increase in CA 15.3 and must be regarded as antigen negative.     

CA-125 monitoring during chemotherapy for ovarian cancer

Serum CA-125 was determined in 60 patients with variously extended ovarian cancer and monitored during and after chemotherapy. The study indicates that: 1) prechemotherapy CA-125 shows the presence of an active disease with an accuracy greater than 85%. The antigen is elevated in 97% of patients with greater than 2 cm disease, but sensitivity is low (67%) in patients with minimal residual disease (less than 2 cm); 2) changes in CA-125 correspond well with the response to chemotherapy. CA-125 becomes negative in every patient having clinical CR and increases in every patient with progressive disease. These changes can indicate the type of response some months ahead of time; 3) CA-125 indicates in advance the recurrence of the disease after an objective remission: 4) In the conditions studied CA-125 basal levels do not seem to have prognostic value as regarding either response or survival.     

Comparative trial of endocrine versus cytotoxic treatment in advanced breast cancer.

Ninety-two women with advanced breast cancer were allocated at random to receive either cytotoxic or endocrine treatment. Out of 45 women included in the cytotoxic treatment group, 22 (49%) achieved complete or partial remission of their disease, whereas of the 47 included in the endocrine treatment group, only 10 (21%) achieved such remission. Significantly longer survival times in the cytotoxic treatment group were most apparent among premenopausal women, 75% of such patients responding to cytotoxic drugs (median survival 46 weeks) compared with only 11% benefiting from ovarian ablation (median survival 12 weeks). In postmenopausal women with predominantly soft-tissue disease, however, additive hormonal treatment with tamoxifen produced remission rates and survival times equivalent to those produced by cytotoxic drugs.     

c-erbB-2 in serum of patients receiving fractionated paclitaxel chemotherapy.

Humanized anti-c-erbB-2 antibodies (Herceptin) in a weekly schedule are a new therapeutic option for the treatment of c-erbB-2-positive, advanced breast cancer (ABC). Addition of Herceptin to first-line chemotherapy for c-erbB-2 overexpressing ABC increased anticancer activity in a randomized phase III trial. However, except from standard UICC response criteria, there are hitherto no recommendations as to how to monitor Herceptin therapy. In a therapy optimizing study with weekly dose-intensified paclitaxel monotherapy (schedule: 90 mg/m2 weekly x 6, q9w), we correlated the clinical course of stage IV breast cancer in UICC criteria with the course of the shed c-erbB-2 protein fragment and the CA 27.29 serum level. Serum samples were taken weekly from 35 patients to measure the serum c-erbB-2 and CA 27.29 protein levels over time. Up to now, 10 patients (28.5%) are c-erbB-2 positive (> 15 U/mL), with a median baseline protein expression of 65 U/mL. While the overall response rate in the study is 36%, the response rate among c-erbB-2-positive patients is 62%, indicating a high sensitivity of c-erbB-2 positive patients to dose-intense paclitaxel treatment. In all responders the c-erbB-2 serum level decreased below the detection limit either before the clinical diagnosis of response or by the end of the next cycle. However, the normalization of the c-erbB-2 serum level was not specific for responders as patients with stable or progressive disease presented normalized levels or a > 50% decrease of the baseline level, too. The courses of the c-erbB-2 protein levels correlated closely with the courses of CA 27.29. The decrease in the serum c-erbB-2 oncoprotein level might indicate a regression of c-erbB-2 positive tumor load. This may even happen in progressive disease according to UICC criteria when the c-erbB-2-negative tumor fraction progresses while the c-erbB-2-positive fraction is controlled. Another explanation would be that the mechanisms of c-erbB-2 shedding change under chemotherapy, with less of the c-erbB-2 protein fragment being released to the serum, which would make the c-erbB-2 positive tumor cells a better target for anti-c-erbB-2 antibody treatment.     

TPS monitoring in metastatic breast cancer.

The management of metastatic breast cancer patients reflects the heterogeneous nature of the disease. While patients may benefit from hormonal treatment, in most cases more toxic chemotherapy is applied in the advanced stages. The pretreatment levels of TPS in patients with metastatic breast cancer are correlated with prognosis. Decreasing TPS levels (> 50%) during treatment are indicative of response. The fastest decrease in TPS levels is obtained in patients with a favorable prognosis. Increasing TPS levels (> 25%) predict disease progression with a considerable lead time (median 8 months). The clinical impact of these observations is discussed in this paper.     

Locally advanced breast cancer in Saudi Arabia: high frequency of stage III in a young population

In the Kingdom of Saudi Arabia (KSA), breast cancer constitutes 18% of all cancers in Saudi women. Whilst locally advanced breast cancer disease is unusual in Western countries, it constitutes more than 40% of all non-metastatic breast cancer in KSA. The relative frequency of locally advanced disease among our breast cancer population and the lack of a uniform consensus in the literature about its optimal management have prompted this retrospective analysis of the medical records of patients with Stage III breast cancer patients seen at King Faisal Specialist Hospital and Research Center between 1981 and 1991. In all, 315 patients were identified. Their median age ±SD was 46±11.6 years which is distinctly different from the 60–65 years median age in industrial Western nations. Most patients were younger than 50 years (64%) and premenopausal (62%). Patients were approximately equally divided between Stage III A and Stage III B Patients received multimodality treatment, including surgery., adjuvant chemotherapy, tamoxifen, and adjuvant radiotherapy. Sixty-one patients were excluded from survival analysis as they were considered lost to follow-up. Of the remaining 254 patients, 73 (29%) were alive and disease free, and 18 patients (7%) were alive but, with evidence of the disease. The remaining 163 (64%) had died from breast cancer or its related complications. Their median overall survival (OS) was 54 months, (95%, Cl, 27 to 121 months) and the median progression-free survival (PFS) was 28.8 months (95% Cl, 14.2 to 113 months). Cox proportional hazard, model identified Stage III B and the number of positive axillary lymph nodes as poor predictors of OS and PFS. Radiotherapy was the only adjuvant modality that affected survival favourably. The prognosis of patients with Stage III disease remains poor despite the use of a multimodality approach. The overall young age of our patients may have contributed to the poor outcome. Moreover, the adverse effect of Stage III B disease (as compared with Stage III A) and axillary nodal status was evident. Whilst the favourable effect of radiotherapy on survival was demonstrated, the lack of independent efficacy of other modalities (adjuvant chemotherapy and tamoxifen) or the apparent deleterious effect of neoadjuvant chemotherapy should be addressed with discretion in such retrospective analysis. Optimal management of patients with locally advanced breast cancer disease should be appraised in well designed, prospective, randomised studies.     

The significance of CA19-9 tumor antigen in the serum of patients with carcinomas

The concentration of serum CA19-9TM in 101 patients with colorectal adenocarcinoma (CRC), and 109 patients with carcinomas of lung, breast, stomach and pancreas and hepatoma, and 40 normal healthy controls including an equal number of smokers and nonsmokers were determined by solid phase radioimmunoassay of CA19-9 assay kits (Centocor). Of the normal sera, only 1 out of 40 (2.5%) was over 37.6 U/ml. No significant difference of CA19-9 levels was found between smokers (14.4 +/- 9.0 U/ml) and non-smokers (16.0 +/- 10.2 U/ml) of normal control. In patients sera, the mean value of CA19-9 levels was significantly higher in patients with Dukes B (P less than 0.05) and in patients with Dukes C and D (P less than 0.001) than the normal healthy control (15.2 +/- 10.2 U/ml). Analysis of serum CEA concentrations has shown a similar result in patients with all Dukes staged CRC. The CA19-9 levels was also significantly elevated in patients with gastric carcinoma, lung carcinoma, hepatoma, and especially in patients with pancreatic carcinoma (P less than 0.0001). The levels of CA19-9 elevated in 50% (22/44) of patients with advanced CRC while the elevation was 8 of 43 (18.6%) patients with localized CRC. A comparison of CA19-9 and CEA assays showed no correlation (r = 0.125) between the two assays. Although the CA19-9 assay (26.4%) was less sensitive than the CEA assay (51.7%), the specificity of CA19-9 assay (97.5%) was better than that of CEA assay (87.5%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum levels of IL-6 type cytokines and soluble IL-6 receptors in active B-cell chronic lymphocytic leukemia and in cladribine induced remission

We have investigated the serum concentrations of interleukin-6 (IL-6) and two IL-6 family cytokines-oncostatin M (OSM) and leukemia inhibitory factor (LIF)-in 63 patients with B-cell chronic lymphocytic leukemia (B-CLL) and 17 healthy controls using the enzyme-linked immunosorbent assay (ELISA) method. Simultaneously, we measured the serum levels of the soluble forms of two subunits of the IL-6 receptor complex-ligand binding glycoprotein 80 (sIL-6R) and glycoprotein 130 (sgp130). The cytokines and receptors were evaluated in 25 untreated patients and 38 patients treated with cladribine (2-CdA), as well as in 17 healthy controls. We have correlated the serum levels of these proteins with Rai's clinical stage of the disease, the response to 2-CdA treatment and some hematological parameters. We have also evaluated the correlation of the IL-6 serum level with the concentration of OSM and IL-6 soluble receptors. IL-6 was measurable in 62/63 (98.4%), OSM in 20/25 (80%) of untreated and 14/38 (37.8%) of the treated patients. sIL-6R and sgp130 were detectable in all 63 patients and LIF in none of the CLL patients. IL-6 serum level in untreated patients was not significantly different as compared to its concentration in the control group (P>0.05). However, in the patients treated with 2-CdA the IL-6 level was significantly lower (P<0.02), and the lowest concentration was found in the patients with complete remission (CR; median 1.4pg/ml; P<0.02). The concentration of sIL-6R was significantly higher in untreated (median 61.8 ng/ml) and treated (median 50.1 ng/ml) CLL patients when compared to normal persons (median 41.2 ng/ml; P=0.04; P<0.001, respectively). There was no difference between the sIL-6R levels in the patients with CR and the healthy controls. In non-responders sIL-6R concentration was the highest and similar to its level in the untreated patients. OSM level was higher in the untreated patients (median 1.8pg/ml) than in the normal controls (median 0.0pg/ml; P<0.001) and in the CR patients (median 0.0pg/ml; P<0.03). The serum concentration of sgp130 was similar in the untreated (median 480 pg/ml) and treated (median 470 pg/ml) patients, as well as in the healthy persons (median 420 pg/ml; P>0.05). We have found significant positive correlation between the levels of sIL-6R and the lymphocytes count in CLL patients (p=0.423; P<0.001). In addition, sIL-6R and OSM serum concentrations correlated also with CLL Rai stage. In conclusion, the serum level of IL-6, OSM and sIL-6R, but not LIF and sgp130, are useful indicators of CLL activity.     

Expression of periostin in the serum of NSCLC and its function on proliferation and migration of human lung adenocarcinoma cell line (A549) in vitro

Periostin is over expressed in many epithelial malignant cancers, including lung cancer, breast cancer, ovarian cancer and colon cancer. It is related with the progression and migration of breast and ovarian cancer cells in vitro. The aim of this study was to investigate the serum level of periostin in non-small cell lung cancer (NSCLC) and its relationship with established biological and prognostic factors by enzyme-linked-immunosorbent serologic assay. We also observe the function of periostin on the proliferation and migration of human lung adenocarcinoma cell line (A549) and discuss the mechanism. The mean value for serum periostin (POSTN) was elevated in NSCLC patients (242.84 ± 5.33 pg/ml) compared to the normal healthy volunteers (215.66 ± 11.67 pg/ml) (p = 0.030). The serum level of periostin of NSCLC patients had no connection with gender, age, pathological type, TNM stage, lymph node status, tumor size and invasiveness. We constructed a plasmid named pEGFP-N1/POSTN expressing full-length human periostin. Transfecting the plasmid to A549 cells and periostin was efficiently expressed in transfected A549 cells. Our data showed that periostin could promote the proliferation and migration of A549 cells by inducing vimentin and N-cadherin expression and downregulating E-cadherin expression. These results strongly suggest that periostin is a novel molecular which play an important role during the progression and development of NSCLC.     

The biological tumor markers' myopia: a model with CA 125 and second-look in ovarian cancer

Preoperative CA 125 levels were measured in 36 patients with advanced epithelial ovarian carcinoma in clinical response undergoing a second-look operation. All the patients had positive levels (greater than 35 U/ml) of this tumor marker at diagnosis. The correlation between antigen levels and disease status at surgery revealed a sensitivity of this assay of 0.55 (only 11/20 patients still with tumor had positive levels) and a specificity of 0.94 (15/16 patients with no tumor had less than 35 U/ml). The predictive value of a positive test was 0.92. This method unfortunately proved unable to recognize microscopic residual tumor burden, less than 0.5 cm.     

Aromatase inhibitors in the treatment of breast cancer

A number of inhibitors of estrogen synthesis are now becoming available which could be of value in the treatment of breast cancer. 4-Hydroxyandrostenedione (4-OHA), the first of these compounds to enter the clinic has been found to be effective in postmenopausal patients who have relapsed from tamoxifen. Thus, in studies of 240 patients, 26% patients experienced partial or complete response to treatment. An additional 25% patients had disease stabilization. 4-OHA is a potent selective, steroidal inhibitor which causes inactivation of aromatase in vitro. It is effective in reducing concentrations of ovarian estrogens in rats and of ovarian and peripheral estrogens in non-human primate species. The compound has been shown to lower serum estrogen levels in postmenopausal breast cancer patients. However, not all of these patients experienced disease remission, suggesting that their tumors were hormone insensitive rather than that the dose of 4-OHA was suboptimal. In trials of patients who had not received prior tamoxifen treatment, 4-OHA (250 mg i.m. every 2 weeks) was found to induce complete or partial tumor regression in 33% of patients. The response of patients was not significantly different from that observed in patients treated with tamoxifen (30 mg o.d) of 37%. No significant difference between treatments was observed for disease stabilization, the duration of response or median survival. Several other steroidal aromatase inhibitors have been studied, such as 7-substituted androstenedione derivatives. MDL 18962 [10-(2-propynyl)estr-4-ene-3,17-dione] and FCE 24304 (6-methylen-androsta-1,4-diene-3,17-dione) are currently in clinical trials. Non-steroidal inhibitors of cytochrome P-450 enzymes, such as imidazole and triazole derivatives have been developed which are highly selective for aromatase. Three triazoles which are very potent and selective inhibitors are vorazole (6-[(4-chlorophenyl)(1H-1,2,4-triazol-1-yl)-methyl]1-methyl-1H-benzotriazole R 76713, arimidex 2,2′[5-( -1,2,4-triazol-1-yl methyl)-1,3-phenylene]bis(2-methylpropiononitrile) (ZD1033) and letrozole 4-[1-(cyanophenyl)-1-(1,2,4-triazolyl)methyl]benzonitril (CGS 20267). These compounds reduce serum estradiol concentration to undetectable levels in breast cancer patients. These highly potent inhibitors provide the opportunity to determine whether a further degree of estrogen suppression will be important in producing greater clinical response. With the recent approval of 4-OHA in several countries and the introduction of the potent new compounds, aromatase inhibitors either alone or in combination with the antiestrogen are likely to improve the treatment of breast cancer.