Screening with tumor markers: critical issues.

Reviewing the literature it would appear that tumor markers have often flattered to deceive. Early promise does not often seem to be borne out in extended trials. Despite apparently high specificity, very few markers are capable of assisting in a screening process. This brief review attempts to put the roles of tumor markers in perspective and explain how their misapplication has led to misunderstanding of their potential value in a clinical context. It also considers the theoretical basis for their use and highlights how misunderstanding of these can lead to flawed studies and application.

Markers of tumor burden : an overview.

Since ancient times, cancer has been known to humankind. The ancient Greeks and Romans have left us with writings in which various treatment options are discussed (1). Disease processes and causes were not well understood, however; the humoral pathology established by the ancient Greeks of the school of Galen in the second century ad was to survive virtually intact until the mid-nineteenth century. It is perhaps all the more remarkable then, that the first tumor marker-Bence Jones' protein in multiple myeloma-should come to light in what was still by and large the prescientific medical culture prevailing in 1845.

Serum amylase isoenzymes in patients undergoing operation for ruptured and non-ruptured abdominal aortic aneurysm.

OBJECTIVE: Previous work has suggested that hyperamylasemia in patients who undergo operation for ruptured abdominal aortic aneurysm (AAA) is associated with poor outcome. The aims of this study were to determine, for the first time, the source of serum amylase in such patients and to examine the prognostic significance of amylase isoenzyme expression. METHODS: This study was designed as a prospective clinical and laboratory study. The study consisted of 40 patients who underwent operation for ruptured AAA and 10 patients who underwent operation for non-ruptured AAA. The main outcome measures were serum total and pancreatic and salivary amylase activities determined with enzymatic colorimetric assay before operation and 6 hours after aortic clamp release. RESULTS: Five of 40 patients (12.5%) with rupture and one of 10 patients (10%) with non-rupture had elevated total amylase levels before operation, and seven of 31 patients (23%) with rupture and five of 10 patients (50%) with non-rupture had elevated total amylase levels after operation. The preoperative salivary amylase (P =.05) and postoperative pancreatic amylase (P <.02) levels were significantly lower in ruptured AAA as compared with non-ruptured AAA. The preoperative salivary amylase level was significantly lower in non-survivors of rupture, such that a level equal to or less than 45 U/L was associated with death in 11 of 13 patients (85%). CONCLUSION: These data do not support previous works that suggest that hyperamylasemia is associated with poor outcome in ruptured AAA. By contrast, a low preoperative salivary amylase level was associated with increased mortality in ruptured AAA and may be a marker of the severity of shock.

Serological markers for metastatic breast cancer.

Three serum markers, TPS, CA 15.3 and CEA, were used to monitor the response to treatment of 20 patients with metastatic breast cancer. At the time of the first evidence of metastases or at the time of progression of known metastatic disease, 84% of TPS values were above the reference limit, as compared to 74% for CA 15.3 and 84% for CEA. If the treatment instituted was effective, 60% of TPS values showed an early (within 2 or 3 weeks after commencement or change of therapy) reduction in level against only 27% of CA 15.3 and 27% of CEA levels. This suggests that TPS provides a more sensitive and earlier predictor of therapeutic response. In patients with clinical evidence of further progression of disease while on therapy, 86% of TPS values showed persistent elevation or increase, as compared to 71% of CA 15.3 levels and only 36% of CEA levels. It was also noted in these patients that TPS values rose earlier than either CA 15.3 or CEA. This indicates that TPS is a more reliable predictor of response to treatment than the other two markers. In addition, we found that, at the time of presentation, in women who had visceral metastases (liver, lung, or brain alone or in combination), 87% of TPS values were raised, as compared to 80% of CA 15.3 and 73% of CEA values. In women who had bone and soft tissue metastases at presentation, 75% of TPS values were elevated, against 50% of CA 15.3 and 75% of CEA values.(ABSTRACT TRUNCATED AT 250 WORDS)

The prognostic value of serum CA 125 in patients with advanced ovarian carcinoma: an analysis of 573 patients by the Medical Research Council Working Party on Gynaecological Cancer.

A number of studies have suggested that serum CA 125 levels may be an important prognostic factor for survival of patients with ovarian carcinoma. We investigated, in a large group of patients from 11 UK centers, which combination of CA 125 measurements provided the best prognostic index, and whether the predictive power could be improved by the addition of other factors. Analysis of the data from 248 patients showed that the absolute value of the third CA 125 sample was the single most important factor for predicting progression at 12 months, with the addition of residual bulk only slightly improving the predictive power. Seventy-four patients had CA 125> 70, and of these 57% were correctly predicted to progress or die within 12 months, but 43% remained alive and progression free. The best predictor for progression produced a false positive rate of 19%. We therefore conclude that prognostic information based upon CA 125 measurements up to the start of the third course of initial chemotherapy is not accurate enough to be used to manage individual patients.

The prognostic value of early CA125 serum assay in epithelial ovarian carcinoma.

We examined the prognostic value of early serum CA125 assay in 58 patients with advanced epithelial ovarian cancer together with residual disease, age, tumour grade, performance status, and the presence of ascites or adhesions at primary surgery. CA125 was a highly significant predictor of both progression free and overall survival after the first cycle and throughout primary chemotherapy. After the first cycle, CA125 was by far the most significant predictor of progression free survival (P < 0.0005). At this time, CA125 was a highly significant predictor of survival (P < 0.005), but did not add to performance status (P < 0.001) in multivariate analysis. We were able to identify three statistically-distinct prognostic groups. Patients in the upper quartile, with CA125 levels greater than 450 U ml-1, had a very poor median survival of 7 months. Patients in the lower quartile, with CA125 levels less than 55 U ml-1 had a good median survival of 23 months. Those in the two interquartile groups, who had CA125 levels ranging from 58-221 U ml-1 and 228-434 U ml-1, had relatively intermediate median survival times of 16 months and 15 months respectively. Although CA125 levels provided significant prognostic information, in the majority of patients CA125 merely confirmed overall clinical impression.

The value of the human milk fat globule membrane antigen HMFG2 in epithelial ovarian cancer monitoring: comparison with CA125.

We assayed serum HMFG2 in serial samples from 215 primary epithelial ovarian cancer patients using an 'in-house' single determinant ELISA, 45% of patients with stage I, 54% with stage II, 61% with stage III and 75% with stage IV disease had elevated serum HMFG2. Post-operative levels were significantly related with residual tumour volume (P < 0.005), and fell in the majority of responders, although the association with response to first-line chemotherapy was not significant. HMFG2 had a sensitivity of 50% specificity of 83%, accuracy of 61%, PVP of 86% and PVN of 45% for disease at second-look laparotomy. Serial levels gave a lead time to clinical relapse in 47% of patients who responded to therapy, including one patient with negative CA125 levels. HMFG, paralleled CA125 in many respects, although it was elevated in fewer patients. In a stepwise discriminant analysis, HMFG2 added to the discrimination of CA125 (r = 0.183, P < 0.005), although additional accurate information was only given in patients with advanced poorly differentiated serous cystadenocarcinoma. Given that HMFG2 is expressed in few patients who are CA125 negative it is unlikely that it will have a significant clinical impact upon patient management.