Clinical evaluation of new serum tumor markers CA M26 and CA M29 in patients with primary breast cancer

Serum CA M26 and CA M29 values were determined in 125 women: 46 patients with primary breast cancer, 49 patients with benign breast disease, and 30 controls. The mean CA M26 and CA M29 values in breast cancer patients were higher than in patients with benign breast disease and in control subjects. When we set the cut-off level at 40 kU/1 for CA M26, 15/46 (33%) of all breast cancer patients, 11/20 (55%) of breast cancer patients with axillary node involvement, 1/1 breast cancer patient with distant metastases, 4/49 (8%) of patients with benign breast disease, and 7/30 (23%) of control subjects were above this cut-off level. For comparison, at the cut-off level of 10 kU/1 the CA M29 test was positive in 30/46 (65%) cancer cases, in 16/20 (80%) of cancer patients with nodal involvement, in 9/49 (18%) of the patients with benign breast disease, and in 10/30 (33%) of control subjects. Patients with axillary nodal metastasis showed higher values than patients without metastasis in both tests. When we used a cut-off level of 15 kU/1 for CA M29, 24% (11/46) of all breast cancer patients, 35% (7/20) of breast cancer patients with axillary node involvement, 4% (2/49) of patients with benign breast disease, and 0% of control subjects were above this cut-off level. The combination of CA M26 at the 40 kU/l cut-off level and CA M29 at the 10 kU/l cut-off level reached the diagnostic sensitivity of 0.65, specificity of 0.78, and efficiency of 0.72. In breast cancer detection among patients with breast problems serum marker CA M29 reached the sensitivity of 0.65 at the specificity level of 0.82. Our results suggest that the CA M29 marker alone is as good as the panel of two markers (CA M26, CA M29) in breast cancer diagnostics. Thus it seems that CA M29 is a promising serum tumor marker in breast cancer.     

Evaluation of CA M26, CA M29, CA 15-3 and CEA as circulating tumor markers in breast cancer patients

The clinical utility of CA M26 and CA M29 was studied in 116 breast cancer patients and compared with results for CA 15-3 and carcinoembryonic antigen (CEA). The highest sensitivities for breast cancer detection were achieved with CA 15-3 (0.60) and CEA (0.56), but this was compromised by a relative lack of specificity (0.87 and 0.88 for CA 15-3 and CEA, respectively). Sensitivities attained with CA M26 (0.47) and CA M29 (0.53) were lower, but there was an excellent specificity (1.00) for each assay in this series of benign patients. Tumor marker elevations were appreciable with advanced disease such that 82 of 91 patients (90%) with active metastatic breast cancer exhibited at least one abnormal test value. Longitudinal studies demonstrated that CA M26, CA M29, CA 15-3 and CEA complement each other and combinations of these markers reflect disease status better than individual tests.     

Serum markers for primary and recurrent breast cancer: BCM-EIA, CAM 26 and CAM 29.

Three sandwich enzyme immunoassays were used to evaluate serum from 93 women: 20 normal, 20 with benign breast disease, 22 with primary and 31 with recurrent breast cancer. Using the three assays, breast cancer mucin enzyme immunoassay (BCM-EIA) carcinoma-associated mucin antigen (CAM) 26 and CAM 29, both singly and in combination, we were unable to establish meaningful cut-offs to differentiate between patients with or without breast cancer. The sensitivity and specificity for BCM-EIA were 90% and 40%, for CAM 26, 89% and 42%, and for CAM 29, 91% and 66%, respectively. Serial serum specimens from 29 patients with recurrent breast cancer were assayed. At recurrence, an increase of 25% or more in marker level over the previous value was found in 24/29 (83%) BCM results, 14/29 (48%) CAM 26 results and 12/29 (41%) CAM 29 results. Prior to clinical detection of recurrence, stepwise increases in BCM and CAM 26 marker levels were seen up to 299 days prior to clinical detection of recurrence. We conclude that these markers may help in the early detection of recurrent breast cancer.     

Significance of serum tumor markers in monitoring advanced breast cancer patients treated with systemic therapy: A prospective study

OBJECTIVE: The significance of serum tumor markers in monitoring advanced breast cancer patients is still controversial. To clarify this issue, the Tumor Marker Study Group of the Japanese Breast Cancer Society conducted a prospective study. METHODS: Patients with advanced breast cancer who were treated with systemic therapy between January and December 2002 were recruited from five collaborative institutes in Japan. The patients were monitored every four weeks using three serum tumor markers, CEA, CA 15-3 and NCC-ST-439 during the therapy. RESULTS: Findings from 108 eligible patients were analyzed. The pretreatment positivity rates were 51.9% for CEA, 50% for CA 15-3, and 34.3% for NCC-ST-439. The changes in each marker level at 8 and 12 weeks but not at 4 weeks after the start of therapy seemed to correlate with the response to therapy in pretreatment marker-positive patients but not in negative patients. The Cox proportional hazard model revealed a greater than 20% reduction in CEA, CA 15-3 or NCC-ST-439 levels at 4, 8 and/or 12 weeks after the start of therapy to be an independent predictive factor for longer time-to-progression (TTP) in pretreatment marker-positive patients. CONCLUSION: This prospective study supported the findings obtained from our previous retrospective study that in pretreatment marker-positive patients 1) the changes in serum tumor marker levels after the start of therapy correlate with the response to therapy; and 2) a greater than 20% reduction in the tumor marker levels was a favorable predictive factor for TTP during systemic therapy. When the pretreatment serum level of these markers is over the respective cut-off value, sequential measurement of them may be useful for evaluating the efficacy of treatment as well as monitoring the outcome of patients with advanced breast cancer.     

Cancers of the breast,endometrium and ovary: Geographic correlations

Patterns of incidence of breast, endometrial and ovarian cancer show strong similarities in both international and inter-regional comparisons, similarities readily confirmed by the calculation of coefficients of correlation. Migrant studies suggest that environmental factors are more important than genetic differences between populations. Correlation studies have shown that dietary factors can explain much of the international variation, and most suspicion has fallen on dietary fat. Differences in fertility between populations also correlate with the variations in incidence. For breast cancer, the latter may be an important determinant of variation within countries in the premenopausal age group, with dietary differences accounting for variations in post-menopausal rates internationally. There is scope for improving upon earlier studies, and for investigating the relative contributions of diet and fertility to the geographic patterns of endometrial and ovarian cancers.     

CA15-3, CASA,MSA, and TPS as diagnostic serum markers in breast cancer

Summary This is the first comparison of the three mucin based tests CA15-3, CASA, and MSA, and the cytokeratin-related TPS assay in breast cancer. The mucin markers were superior to TPS in receiver-operator analysis, though no marker was of use in the diagnosis of malignancy due to low sensitivity. Using cutpoints that gave 95% specificity in benign disease (n = 83), corresponding sensitivities in pre-treatment breast cancer (n = 123: 13in situ, 54 stage I, 45 stage II, 4 stage III, 7 stage IV) were 17% (CA15-3), 16% (CASA), 13% (MSA), and 8% (TPS), with a strong relationship between marker levels and disease stage. These assays did not always detect the same patients, and the use of CA15-3 combined with CASA gave the highest sensitivity (23%), though this was not significantly better than the use of CA15-3 alone. Despite detecting similar antigens, these assays can show markedly different responses in some patients, indicating that one mucin-based test cannot be sub-stituted for another.     

The effect of adjuvant hormonal therapy on the endometrium and ovary of breast cancer patients

Objective

To investigate the effect of adjuvant hormonal therapy on the endometrium and ovary of breast cancer patients.

Methods

A retrospective review was performed on the 207 patients who had taken tamoxifen or anastrozole, as adjuvant hormonal therapy after breast cancer surgery between January 2003 and December 2006. Gynecologic surveillance constituted of ultrasonographic exam of the endometrial thickness and ovarian cyst formation. The patients were classified into three groups and analyzed; premenopausal/postmenopausal women receiving tamoxifen and women receiving anastrozole.

Results

Mean duration of follow up was 20.6±6.6 months. There was no difference of mean endometrial thickness before hormonal therapy among the three groups (p=0.327). In women receiving tamoxifen, the endometrium was continuously thickened in proportion to the duration of the therapy irrespective of menopausal status while it remained unchanged in women receiving anastrozole (p<0.05). Endometrial biopsies were performed in 28 patients receiving tamoxifen. The most common histologic finding was proliferative endometrium in premenopausal women (7/21) and atrophic endometrium in postmenopausal women (6/7). There was no case of endometrial cancer in both groups. Ovarian cyst was found in 32 women and the most were developed in premenopausal women receiving tamoxifen (30/32). All of them showed benign nature on transvaginal ultrasonographic findings.

Conclusion

Women undergoing adjuvant hormonal therapy after breast cancer surgery exhibited changes in the endometrium and ovary. However most changes were not a serious problem in this study and frequent gynecologic surveillance in these patients needs further investigation.     

Combined evaluation of serum CA 125 and CAM 29 in patients with epithelial ovarian cancer.

We examined 92 patients with epithelial ovarian cancer and 262 patients with benign ovarian diseases undergoing laparotomy. On the basis of a nonparametric method, antigen levels corresponding to prefixed 95% specificity values in a group of 674 women with benign gynecologic diseases were taken as cutoff limits (88.8 U/ml for CA 125 and 13.7 U/ml for CAM 29). Moreover, CA 125 and CAM 29 levels were measured serially during and after chemotherapy in 26 women selected from the patients with advanced epithelial ovarian cancer. At diagnosis, serum CA 125 was as sensitive as serum CAM 29 for nonmucinous tumors, but more sensitive than serum CAM 29 for mucinous tumors. The association of the two markers seemed to give no advantage over the CA 125 assay alone in the diagnosis of epithelial ovarian cancer. In monitoring the response to chemotherapy and follow-up of patients with epithelial ovarian cancer, changes in CA 125 levels correlated with the clinical course of disease better than changes in CAM 29 levels, and the serum CA 125 assay was more reliable than the serum CAM 29 assay in the early detection of tumor progression. In conclusion, serum CAM 29 did not seem to represent a complementary assay to serum CA 125 in the management of patients with epithelial ovarian cancer.     

Prevention of cancers of the breast, endometrium and ovary

A central epidemiological feature of cancers of the breast, endometrium and ovary is the sharp slowing down in their rate of increase with age around the time of menopause. The incidence of these tumors by the age of 70 years would be between fourfold and eightfold increased if the rapid increase with age seen in young women continued into old age. These phenomena can be explained by the different effects of ovarian hormones on cell division rates in the relevant tissues. Models of these effects provide a plausible explanation of most of the known epidemiology of each of the cancers, including the increase in breast cancer risk from menopausal estrogen-progestin therapy. Some recent epidemiological findings in endometrial and ovarian cancer suggest new avenues for possible chemoprevention of these cancers.     

Multiple primary cancers of the breast,endometrium and ovary

The association between cancers of the breast, endometrium and ovary is reviewed, using mainly population-based data from the cancer registries in Denmark and Connecticut, U.S.A. Breast cancer patients had an approximately three-fold increased risk of developing a cancer in the contralateral breast. The risk of breast cancer was also elevated following cancers of the corpus uteri and ovary, with relative risk (RR) estimates of about 1.5 from 1 to 4 years after the diagnosis of the first primary cancer. An increased risk of cancer of the corpus uteri subsequent to breast cancer was found in Connecticut, but not in Denmark. After an ovarian cancer, the risk of cancer of the corpus uteri was also elevated (RR = 1.6–2.3). An increased risk of ovarian cancer was observed subsequent to breast cancer (RR = 1.3–1.7), whereas the ovarian cancer risk decreased with time since the diagnosis of a cancer of the corpus uteri, probably reflecting treatment involving oophorectomy.     

Comparison of breast cancer mucin (BCM) and CA 15-3 in human breast cancer

Summary The Breast Cancer Mucin (BCM) enzyme immunoassay utilizes two monoclonal antibodies (Mab), M85/34 and F36/22, for the identification of a mucin-like glycoprotein in serum of breast cancer patients. We have compared BCM with CA 15-3, another member of the human mammary epithelial antigen family.Serum BCM was evaluated in 151 and CA 15-3 in 134 patients with breast cancer, in 30 normal controls, in 9 pregnant women, and in 13 cancer patients (non-breast). Neither the normal controls nor the pregnant women had BCM levels > 25 U/ml. In contrast, 87 of 115 patients (75%) with metastatic breast cancer had BCM levels > 25 U/ml. All control persons had CA 15-3 levels < 25 U/ml, but 2 out of 9 pregnant women (22%) had levels > 25 U/ml. Seventy-four out of 97 patients (76%) with metastatic breast cancer had CA 15-3 levels > 25 U/ml.A statistically significant correlation was found between BCM and CA 15-3 in the breast cancer patient group (r = 0.883, p < 0.001, n = 134) and in the normal control group (r = 0.743, p < 0.001, n = 30). BCM and CA 15.3 both showed no correlation with CEA in breast cancer patients (r = 0.060, n = 81; and r = 0.146, n = 78, respectively). BCM had a range of sensitivity similar to that of the CA 15-3 RIA.Our results suggest that BCM may be a useful new marker for monitoring the clinical course of patients with breast cancer. Furthermore, in the evaluation of breast cancer patients, marker pands depending on disease stage may be a better choice than any single parameter in the evaluation of breast cancer patients.     

Evaluation of serum tumor markers in patients with advanced or recurrent breast cancer

Summary Serum CA15-3, CEA, and BCA225 concentrations were determined in 98 patients with advanced or recurrent breast cancer in an attempt to correlate elevation with clinical status. The rate of serum positivity was 68.4% (67/98), 55.1% (54/98), and 43.9% (43/98) for CA15-3, CEA, and BCA225, respectively. After a 4 weeksinterval, a 20% change of tumor marker concentration from the preceding assay correlated significantly with clinical findings. Significant elevation was predictive of new recurrence or tumor regrowth after complete remission, especially in patients with bone metastasis. The 20% change in concentration at 4 weeks was also useful in patients with tumor marker concentrations persistently beneath the cut-off level for positive. Serological evaluation of tumor markers in patients with advanced or recurrent breast cancer should seek to document 20% changes over a 4 week interval.The cooperative group is organized from Surgery departments of Ena Byoin National Sanatorium, director Tetsuo Hotta; National Health Insurance Sakishima Hospital, Tsutoh Niwa; Nagoya City Johoku Hospital, director Hiroshi Itoh; Toyokawa City Hospital, director Kazuo Shibata; Nagoya City Higashi Hospital, director Hironori Tanaka; Toyota Memorial Hospital, director Shoji Karamatsu; Nagoya City Johsai Hospital, director Katsumi Nakamae; Sakuragaoka Branch Toyohashi Municipal Hospital, director Koji Matsuo; National Health Insurance Kamiyahagi Hospital, director Kaoru Kondo     

Tumor markers CEA, CA19-9 and CA125 in monitoring of response to systemic chemotherapy in patients with advanced gastric cancer

BACKGROUND: To evaluate whether tumor markers can be used to assess response to systemic chemotherapy, we analyzed preliminarily the relationship between the response to chemotherapy based on serial imaging and on change in serum tumor marker level of CEA, CA19-9 and CA125. METHODS: We analyzed 26 patients with advanced gastric cancer in whom at least one of the tumor markers CEA, CA19-9 and CA125 was elevated before systemic chemotherapy with regard to the relationship between the change in serum tumor marker level and response assessment by imaging studies throughout the treatment course. A responder was defined as showing a > or = 50% drop in tumor marker level for more than 4 weeks. RESULTS: The sensitivity and negative predictive value of falling tumor marker level after chemotherapy for a partial response in imaging was 100%. When patients were categorized as responders or non-responders, a significant correlation was observed between the assessment of response by tumor markers and by imaging studies. The survival time of responders assessed by tumor markers was significantly longer than that of non-responders. CONCLUSIONS: The measurement of tumor markers might be useful in monitoring response and in predicting the prognosis of patients with advanced gastric cancer treated with systemic chemotherapy. Tumor markers may be used as a means of monitoring treatment in patients when in an imaging study it is difficult to assess response to chemotherapy in clinical practice. Further studies are required to confirm these findings.     

Nutritional factors and cancers of the breast,endometrium and ovary

From an overview of epidemiological evidence on nutrition, diet and cancers of the breast, endometrium and ovary, the following indications can be drawn:

• •— Overweight and obesity are causally related to endometrial and post-menopausal breast cancer, and may account for as much as one third of the cases of endometrial and one tenth of breast cancer in Europe. It is not known whether obesity or overweight early in life has any role on breast cancer risk, nor whether obesity influences ovarian carcinogenesis. Overweight tends to be associated with an unfavourable prognosis for breast cancer.
• •— Despite extensive research, the available knowledge on diet and breast cancer is largely inconsistent, and the results from ecological and individual-based studies are contradictory in relation to fat, proteins, total energy, alcohol, etc.
• •— There are only scanty data on diet and endometrial or ovarian cancer, which tend to suggest role for fat (or animal fat) in the risk of these neoplasms.
• •— The evidence on diet and breast, ovarian and endometrial carcinogenesis is still too scanty or inconsistent to be of any practical preventive value. Thus, the only clear indication for prevention is that a reduction of overweight would avoid a substantial number of cases of endometrial and post-menopausal breast cancer.

     

Abnormal expression of M1/MUC5AC mucin in distal colon of patients with diverticulitis, ulcerative colitis and cancer

The abnormal expression of gastric M1/MUC5AC mucin in precancerous lesions and colon cancer evidenced by immunohistochemistry led us to check for its presence in the mucus obtained directly from patients undergoing surgery for cancerous (adenocarcinoma) or inflammatory (diverticulitis or ulcerative colitis) diseases. In parallel, the authors quantified aberrant crypt foci (ACF) and their immunolabelling by M1/MUC5AC in mucosae of cancer and diverticulitis patients. Immuno-Radio-Metric Assay of M1/MUC5AC mucin developed by the authors was used to detect M1/MUC5AC mucin in the colonic mucus scraped from surgical specimens. M1/MUC5AC mucin was detected in the mucus of 51/69 (74%) patients with colon adenocarcinoma, versus 7/27 (26%) patients with diverticulitis (threshold: 30 units of M1 mucin per mg protein, area under ROC curve: 0.80). M1/MUC5AC was present in significantly (p < 0.001) larger amounts in the mucus of cancer versus diverticulitis patients. All (10/10) patients with ulcerative colitis tested showed levels above the threshold and their mucosae were strongly labelled with the anti-M1/MUC5AC antibody by immunohistochemistry. Patients with cancer exhibited 3 fold more ACF than those with diverticulitis, but no significant difference was observed in the mean size and M1/MUC5AC expression pattern of ACF between these two groups. The expression of M1/MUC5AC was in correlation with their size. In macroscopically normal mucosa, ACF were the most important source of M1/MUC5AC mucin. Testing of M1/MUC5AC can enhance the detection of precancerous lesions and colon cancer.     

Combined measurement of serum sialyl Lewis X with serum CA15-3 in breast cancer patients

BACKGROUND: Serum CA15-3 has been one of the most reliable tumor markers used in monitoring breast cancer patients; however, its sensitivity in detecting metastases is limited. To increase its sensitivity, the combined measurement of other tumor markers with CA15-3 was investigated. METHODS: Serum CA15-3, carcinoembryonic antigen (CEA) and sialyl Lewis X (CSLEX) were simultaneously measured in a prospective series of 455 postoperative breast cancer patients with or without metastasis. The diagnostic parameters sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for detecting metastases were compared. The correlation of values between pairs of tumor markers was analyzed. The efficacy of combined measurement of two different tumor markers was also evaluated. RESULTS: The sensitivity for detecting metastases was 61.5, 56.9 and 52.3%; specificity was 97.2, 93.6 and 96.2%; PPV was 78.4, 59.7 and 69.4%; NPV was 93.8, 92.9 and 92.4%; and accuracy was 92.1, 88.8 and 89.9% for CA15-3, CEA and CSLEX, respectively. The values for CA15-3 were significantly correlated with those for CEA (P < 0.001) but not those for CSLEX. The combined measurement of CSLEX and CA15-3 increased the sensitivity by 17.0% but that of CEA and CA15-3 increased the sensitivity by only 10.8%. All diagnostic parameters for the combined measurement of CSLEX and CA15-3 were higher than those for the combined measurement of CEA and CA15-3. CONCLUSIONS: These findings suggest that CSLEX may be more useful than CEA in combination with CA15-3 in monitoring breast cancer patients. The results of this study suggest that CSLEX may be more useful than CEA in combination with CA15-3 in monitoring breast cancer patients.