Summary report of the Standards, Options and Recommendations for the use of serum tumour markers in breast cancer: 2000.
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Biomarkers, Tumor↗
Biomedical subjects
M F Pichon
Publications and source records attributed to M F Pichon.
Serum chromogranin-A in advanced prostate cancer.
OBJECTIVE: To determine the value of serum chromogranin A (CgA), a marker of neuroendocrine differentiation, for monitoring prostate cancer: CgA levels were related to three other tumour markers, i.e. total prostate-specific antigen (tPSA), prostatic acid phosphatase (PAP), neurone-specific enolase (NSE), and to testosterone, to assess the importance of hormone withdrawal. PATIENTS AND METHODS: Serum samples (218) were obtained from 118 patients with prostate cancer, including 111 patients with advanced prostate cancer: 103 presented to our centre for systemic radionuclide therapy of painful skeletal metastases. CgA concentrations were measured using a new immunoradiometric assay (IRMA: Cis Bio International, Gif sur Yvette, France) and a threshold of 70 ng/mL was determined after receiver operating characteristic curve analysis. Testosterone was also measured with an IRMA assay; tPSA, PAP and NSE were assayed using the time-resolved amplified cryptate emission. RESULTS: Serum marker levels were high in 64% of the patients for CgA, 24% for NSE, 89% for tPSA and 81% for PAP. Patients resistant to endocrine treatments and with elevated tPSA (i.e. hormone-independent) showed increased CgA and NSE in 62% and 29%, respectively. Patients with hormone-dependent prostate cancer (i.e. with a normal tPSA level) had elevated CgA in 59% but no abnormal NSE. All patients of the latter group except one showed clinical progression of their disease. However, the mean (SD) concentrations of CgA in hormone-independent (146) or hormone-dependent (22) patients, at 185.3 (449.1) and 160.9 (293.9) ng/mL, respectively, were not statistically different (P=0.8, Mann-Whitney U-test). For 30 patients, blood samples were drawn and markers measured before and after systemic radionuclide therapy. There was a significant increase in the CgA and tPSA concentrations after treatment (P=0.0146 and 0.0025, respectively). CONCLUSIONS: In association with tPSA, serum CgA appears to be a promising marker for monitoring patients with prostate cancer.
Acid Phosphatase↗
Prospective evaluation of Ki-67 labeling in predicting the recurrence and progression of superficial bladder transitional cell carcinoma.
PURPOSE: We studied a series of superficial transitional cell carcinoma of the bladder to assess whether the Ki-67 labeling index predicts recurrence and progression in a cohort of patients treated by transurethral resection alone or receiving adjuvant intravesical bacillus Calmette-Guerin therapy (BCG). MATERIALS AND METHODS: From 1989 to 1990, we prospectively studied 70 consecutive cases of superficial transitional cell carcinoma of the bladder using Ki-67 immunostaining. The tumors were 43 pTa and 27 pTl. Thirteen were treated with transurethral resection only and 57 received adjuvant intravesical BCG. The median follow-up times was 64 months. The threshold index values of Ki-67 for recurrence and progression were determined using ROC curves. The relative predictive values of the Ki-67 labeling index and tumor characteristics for recurrence and progression were evaluated using Cox's proportional hazards model. RESULTS: A cutoff value of 13% was determined. The recurrence free survival rate at 5 years was 68% for cases with a Ki-67 labeling index of 13 or higher and 71% for those with an index of less than 13 (NS). The progression-free survival rate at 5 years was 43% in cases with an index of 13 or higher and 89% in those with an index of less than 13 (p<0.0001). Using multivariate analysis the Ki-67 labeling index is an independent risk factor for tumor progression with a relative risk of 4.61 (p<0.05). CONCLUSION: When BCG is used for high and intermediate risk superficial bladder cancers, the Ki-67 labeling index is an independent predictive factor of progression but not of recurrence.
Adult↗
Detection of occult disease in breast cancer using fluorodeoxyglucose camera-based positron emission tomography.
An isolated increase of blood tumor marker CA 15.3 in breast cancer is considered a sensitive indicator for occult metastatic disease but by itself is not sufficient for initiating therapeutic intervention. We investigated the potential of camera-based positron emission tomography (PET) imaging using [18F]-fluorodeoxyglucose (FDG) to detect clinically occult recurrences in 132 female patients (age, 35-69 years) treated for breast cancer, all presenting with an isolated increase in blood tumor marker CA 15.3 without any other evidence of metastatic disease. FDG results were correlated to pathology results or to a sequentially guided conventional imaging method. One hundred nineteen patients were eligible for correlations. Positive FDG scans were obtained for 106 patients, including 89 with a single lesion and 17 with 2 or more lesion. There were 92 true-positive and 14 false-positive cases, 10 of which became true positive within 1 year. Among the 13 negative cases, 7 were false negative and 6 were true negative. Camera-based PET using FDG has successfully identified clinically occult disease with an overall sensitivity of 93.6% and a positive predictive value of 96.2%. The smallest detected size was 6 mm for a lymph node metastasis (tumor to nontumor ratio, 4:2). FDG camera-based PET localized tumors in 85.7% of cases suspected for clinically occult metastatic disease on the basis of a significant increase in blood tumor marker. A positive FDG scan associated with an elevated CA 15.3 level is most consistent with metastatic relapse of breast cancer.
Adult↗
[Standards, options and recommendations for blood tumor markers in thyroid cancers].
CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centers (FNCLCC), the 20 French Cancer Centers and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To define, according to the definitions of the Standards, Options and Recommendations project, the characteristics of the main tumor markers in thyroid cancer and the potential role of these markers in the management of patients with this malignancy. METHODS: Data were identified by searching Medline and the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to 55 independent reviewers, and to the medical committees of the 20 French Cancer Centers. RESULTS: The main recommendations are: 1) Thyroglobulin is a serum tumor marker for the monitoring of operated thyroid differentiated neoplasms (standard). 2) It is essential to know if the patient is under TSH stimulation or under thyroid suppression therapy to interpret thyroglobulin results (standard). 3) Thyroglobulin assay must be performed regularly during the monitoring of differentiated thyroid neoplasms (standard, level of evidence B2), should be coupled with the measurement of anti-thyroglobulin antibodies concentration using a sensitive method (standard, level of evidence B2). 4) Thyroglobulin assay should not be performed to detect or diagnose differentiated thyroid neoplasms (standard, level of evidence B2). 5) The methods used to assay thyroglobulin must have a limit of detection lower than 3 mug.l- 1 (standard, expert agreement). 6) Calcitonin is a marker for medullary thyroid cancer (standard). 7) Its assay, associated with RET gene study if indicated, enables medullary thyroid cancer to be diagnosed. 8) The pentagastrin test is essential to diagnose familial forms of medullary thyroid cancer. 9) All analyses for each patient must be performed in the same laboratory, using the same technique (standard, expert agreement). 10) Calcitonin and carcinoembryonic-antigen are serum markers for the monitoring of medullary thyroid cancer and allow the detection of recurrent disease (standard).
Antibodies, Neoplasm↗
[Standards, options and recommendations for tumor markers in colorectal cancer].
CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the French National Federation of Comprehensive Cancer Centers (FNCLCC), the 20 French Cancer Centers and specialists from French Public University or General Hospitals, and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome of cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To define, according to the definitions of the Standards, Options and Recommendations project, the characteristics of the main tumor markers in colorectal cancer and their potential role in the management of patients with this malignancy. METHODS: Data were identified by searching Medline and the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to 117 independent reviewers, and to the medical committees of the 20 French Cancer Centers. RESULTS: The main recommendations for the tumor markers in colorectal cancer are: 1) The carcinoembryonic antigen (CEA) is the reference serum marker (standard). 2) All the analyses for a given patient must be performed in the same laboratory, using the same technique (standard, expert agreement). 3) CEA or CA 19-9 should not be used for screening or diagnosis (standard, level of evidence B2). 4) High initial serum concentration of CEA is of bad predictive value (standard, level of evidence C). CEA is an independent prognostic factor of survival in colorectal cancers with lymph node metastases (standard, level of evidence B2). 5) CEA is the most sensitive biological parameter for the screening of hepatic metastases (standard, level of evidence B2). 6) CEA serum concentration before palliative chemotherapy is an independent prognostic factor of survival (standard, level of evidence B2). The combination of CEA assay with imagery techniques and clinical examination can help monitor the response to palliative chemotherapy (standard), in particular in non measurable disease (standard, expert agreement). 7) In 65% of the cases, CEA is the first indicator of relapse (standard, level of evidence B2). CEA is the choice marker for monitoring patients with colorectal cancer (standard, level of evidence B2). 8) A sustained biological follow-up including CEA assay can be used to predict the operability of recurring tumors (standard, level of evidence B2). Nevertheless, no survival advantage has been shown (standard).
Antigens, Tumor-Associated, Carbohydrate↗
Serum sICAM-1 (soluble intercellular adhesion molecule-1) and M-CSF (macrophage colony-stimulating growth factor) throughout monitoring of 34 non-serous ovarian cancers.
PURPOSE: Evaluation of serum ICAM-1 (soluble intercellular adhesion molecule-1) and M-CSF (macrophage colony-stimulating growth factor) determinations for monitoring patients with non-serous ovarian cancers. METHODS: ELISA assay of sICAM-1 (cut-off 235 ng/ml) and M-CSF (cut-off 450 pg/ml) in 190 blood samples from 34 patients. RESULTS: In pre-treatment sera (n=17), sICAM-1 was over the cut-off in 12/17 (70.6%), M-CSF in 14/17 (82.4%) and CA 125 in 12/16 (75%). sICAM-1 was related only to age at diagnosis (p=0.0008). M-CSF was positively correlated to FIGO stage (p=0.04) CA 125 was elevated in 90.9% of adenocarcinomas (p=0.033 vs other). None of the 3 biological markers were related to other clinico-pathological criteria. Among disease-free patients, higher median concentrations of sICAM-1 and M-CSF were recorded under adjuvant treatment than without (p=0.014, and p=0.08, respectively). After relapse, the highest levels of sICAM-1, M-CSF and CA 125 were observed in progressive disease (46/53, 86.8% (p=0.014), 51/53 96.2% (p=0.008) and 46/52 88.5% (p>0.05), respectively). CONCLUSION: In non-serous ovarian cancers, sICAM-1 although elevated in most cases, is not useful for monitoring. Serum M-CSF is a valuable marker when ovarian tumours do not express CA 125.
Adenocarcinoma↗
[Standards, Options and Recommendations (SOR) for tumor markers in breast cancer. SOR Working Group].
CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To define, according to the definitions of the Standards, Options and Recommendations project, the characteristics of various tumour markers in breast cancer and the potential role of these markers in the management of patients with this malignancy. METHODS: Data were identified by searching Medline and the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to 43 independent reviewers, and to the medical committees of the 20 French Cancer Centres. RESULTS: The main recommendations are: 1) CA 15.3 and CEA are the serum tumour markers most often used in breast cancer (standard). 2) If the CA 15.3 is raised at presentation, there is no place for the measurement of other tumour markers (standard, expert agreement). 3) All analyses for each patient must be performed in the same laboratory, using the same technique (standard, expert agreement). 4) CA 15.3 should not be used for screening or diagnosis. 5) The level of CA 15.3 before treatment is a recognised prognostic factor, the independent value of which has not been proven (standard, level of evidence C). 6) If the initial value of CA 15.3 is greater than 50 kU.L(-1), disseminated disease should be actively sought before any treatment decisions are made (standard, expert agreement). 7) An initial elevation of CA 15.3 that does not return to normal, reflects a lack of response to treatment and is a strong adverse prognostic factor (standard, level of evidence C). 8) The accuracy of tumours markers (especially CA 15.3) as early indicators of metastatic disease is well recognised (standard) but the clinical benefit has not been established. 9) There is a correlation between tumour markers and clinical response in the treatment of metastatic disease (level of evidence C). The level of CA 15.3 in metastatic disease does not predict response to treatment.
Biomarkers, Tumor↗
[1959-1999: from serum markers to 18-FDG in oncology. The experience of the René-Huguenin Center].
Blood tumour markers are widely used in the follow up of patients treated for a malignant tumour. In many cases where the tumour associated marker is increasing the clinical and radiological evaluations remain normal. PET and CDET-scan with 18-FDG have been demonstrated as powerful tools in oncology and their use in such situations may give a new appraisal on the development of the disease. Seventy patients with an isolated increasing of a tumour associated marker (CEA or CA19.9, CA15.3, CA125) were tested. Accuracy and sensitivity of the method were 82.8 and 96.5%, specificity 25%, and positive and negative predictive values 50% and 87%. Focusing on breast carcinomas and CA15.3 as well as ovarian cancers and CA125, the sensitivity and the predictive value are reaching 100%. Patients exhibiting a tumor target associated to an increasing in blood tumour marker may be treated earlier with dedicated protocols.
Adult↗
Cancer of the uterine cervix: sensitivity and specificity of serum Cyfra 21.1 determinations.
PURPOSE: The purpose was to evaluate the usefulness of serum Cyfra 21.1 assay for the monitoring of patients with uterine cervix cancer. METHODS: Pre-treatment sera and complete follow-up of the patients were available for SCC and Cyfra 21.1 for 79 patients Another group of 50 patients was studied to evaluate the specificity, sensitivity, negative or positive predictive values of the markers. The cut-off value for Cyfra 21.1 (1.1 ng/ml) was established by ROC curve analysis. RESULTS: A positive or negative concordance between SCC and Cyfra 21.1 was observed in 65.8% of the cases. Positive SCC and negative Cyfra 21.1 were found in 22.8% of the sera, while the inverse was observed in 11.4% of the cases. The mean concentrations of SCC and Cyfra 21.1 were correlated to FIGO stages, with Cyfra 21.1 being elevated in 100% of stages III and IV. Cyfra 21.1 was also correlated with the extension of the cancer, and to the presence of metastases. The mean concentrations of both markers were significantly higher in the sera of patients with constant progression (P < or = 0.0019). Analysis of 186 results from 91 patients followed-up with a median of 3.29 years showed a sensitivity of 89.5% for Cyfra 21.1, 75.0% for SCC, and a specificity of 86.4% and 99.1%, respectively. The positive predictive values were 91.9% for Cyfra 21.1 and 98.3% for SCC, and the negative predictive values 92.7% and 85.2%, respectively. Median lead times, calculated from the records of 18 selected patients with complete resection of the tumour, were found to be 60 days for Cyfra 21.1 and 50 days for SCC (P > 0.05). CONCLUSION: In cervical cancer Cyfra 21.1 is very well-correlated to the tumour burden and the extent of the disease. In the case of recurrence, this marker rises more often than SCC. We therefore propose the use of Cyfra 21.1 for the monitoring of cervical cancer.
Adult↗
[Long-term prognostic role of steroid receptors in cancer of the breast].
We screened for the prognostic value of estrogen receptor (ER) and progesterone receptor (PR) through a multicentric study of 2,257 operable breast cancer patients who did not received adjuvant therapy. Three hundred and seven local-regional recurrences, 105 metachronous contralateral breast cancer, 589 metastases and 537 deaths from cancer had been diagnosed with a median follow-up of 8.5 years. A total of 69% of the tumors were ER positive and 54% PR positive. For statistical analysis, 1,665 patients were studied because of complete clinical and biological data. In univariate analysis, ER and PR status were of prognostic value for the metastases-free interval (MFI) and the overall survival (OS). In multivariate analysis (Cox proportional hazard model), only the ER status showed a significant difference between positive and negative groups regarding the MFI and OS. By using Cox regression model with time-dependent covariates, we show that the predictive value of ER status of the primary tumor decreases by approximately 20% per year, losing its significance after 8 years of follow-up. These results show that ER and PR status have a relatively limited predictive value and their major interest remain in the domain of therapeutic decision.
Adult↗
[Follow-up of treated cancers of the ovary].
The main goal of the follow up in ovarian cancer is to achieve an early detection of recurrence after a complete remission or to assess the antitumoral efficiency of the treatment used. When the tumoral antigen CA125 is expressed by the primary tumor, the most sensitive test is the sequentially evaluation of the CA125 in the blood. An increasing slope of the serous CA125 is related to disease progression which must be confirmed by imaging techniques including immunoscintigraphy.
CA-125 Antigen↗
Prognostic value of steroid receptors after long-term follow-up of 2257 operable breast cancers.
The prognostic value of oestrogen receptor (ER) and progesterone receptor (PR) was estimated through a multicentric study of 2257 operable breast cancer patients followed up for a median of 8.5 years. None of the patients had received adjuvant therapy. The series included 33.3% stage I patients, 57.1% stage II, 5.7% stage IIIa and 2.4% stage IIIb. At the end point of the study 589 metastases and 537 deaths from cancer were recorded. Receptor measurements were performed by radiolgand assay according to a uniform protocol. A total of 68.8% of the tumous were ER positive and 54.0% PR positive ( > or = 10 fmol mg-1 cytosol protein). In univariate analysis, ER and PR status (positive/negative) were of prognostic value (P < 0.001) for the disease-free interval (DFI), the metastases-free interval (MFI) and the overall survival (OS). The OS of the patients after a first metastasis was also significantly different between ER-positive and -negative tumours (P < 0.001). In multivariate analysis (Cox proportional hazard model, 1665 patients), only the ER status showed a significant difference (P < 0.01) between positive and negative groups regarding the DFI, MFI and OS. By using Cox non-proportional, time-dependent models, we show that the predictive value of ER status of the primary tumour decreases by approximately 20% per year, losing its significance after 8 years of follow-up. Overall, when compared with TNM and histological grading, ER and PR status have a low prognostic value, their major interest remaining solely in the domain of therapeutic decision.
Adult↗
Clinical significance of the estrogen regulated pS2 protein in mammary tumors.
A third of breast cancers are estrogen dependent and respond to endocrine therapy. The estrogen receptor (ER) was the first marker used to predict the responses to treatment, and two-thirds of ER positive tumors show a favourable response. Several estrogen-regulated proteins were further studied in a search to enhance the prediction accuracy of ER status: progesterone receptors, 24-K heat shock protein, cathepsin D, and recently pS2 protein. The pS2 gene, also named BCEI, pNR-2 [4], Md2, was first identified by two groups using differential screening of a complementary DNA library derived from a human breast carcinoma cell line (MCF-7) grown with and without estrogens. Later on two independent English groups and a Japanese group identified a gene similar to pS2. The pS2 mRNA, relatively abundant (0.8%) in the MCF-7 cell line when stimulated by estrogens, encodes a cystein-rich, 84 aminoacids peptide which is secreted by breast cancer cells. The expression of the pS2 gene, pS2 protein assays in tumor cytosols and more recently pS2 detection by immunocytochemistry, have been described in several series of breast cancers.
Aromatase Inhibitors↗
Immunohistochemistry of pS2 in normal human breast and in various histological forms of breast tumours.
Expression of pS2 was studied by immunocytochemistry in normal breast tissue (n = 20), benign tumours (n = 9) and 145 breast cancers representative of the different histological types. pS2 immunostaining was scored as negative (D1 = 0-5% stained cells), positive (D2 = 5-75% stained cells) or highly positive (D3 > 75% stained cells). pS2 protein was evident in all normal breast samples examined. Six of nine benign lesions showed pS2 staining. In both cases, immunostaining was weaker than in breast cancers. Of breast cancers, 77/145 (53.1%) were pS2 positive, including 33.1% with intense staining. The presence of pS2 was not correlated with the age of patients, the size of the primary tumour, or lymph node status, but was correlated with histological grading and nuclear grading. pS2 expression was also correlated with menopausal status and oestrogen receptor status (59% of receptor-positive tumours were pS2 positive), but not to progesterone receptor status. pS2 expression in breast carcinomas is not a characteristic of specific histological types. Although this protein is predominantly expressed in oestrogen receptor-positive and differentiated tumours, it shows oestrogen-independent expression in about 30% of cases.
Aged↗
[Circulating tumor markers].
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Biomarkers, Tumor↗
Prognostic value of progesterone receptor after long-term follow-up in primary breast cancer.
In a previous study of a series of 105 patients with primary breast cancer we found that the progesterone receptor (PgR) status was an important prognostic factor for early recurrences. 95 patients from the same series were followed-up for a median of 9.5 years and reassessed for the prognostic value of PgR status by univariate and multivariate statistical methods. In univariate analysis, the disease-free interval was only related to the lymph-node status. For overall survival, PgR and combined PgR-ER (oestradiol receptor) status had a prognostic value (P = 0.035 and 0.05, respectively). Moreover, PgR status was found to be discriminant for the survival of the node-negative patients (P = 0.017). In multivariate analysis, ER and PgR status were not significant, indicating that receptor status is not a powerful predictor of the course of breast cancer.
Adult↗
Oestrogen receptor negative-progesterone receptor positive phenotype in 1,211 breast tumours.
From 1,211 breast cancers, 15 oestrogen receptor (ER) negative-progesterone receptor (PgR) positive breast cancers by conventional dextran coated charcoal steroid binding assays in cytosol were reassessed using Elisa techniques with monoclonal antireceptors antibodies in the cytosolic and nuclear fractions, and immunocytochemistry on cryostat sections. Three categories of results were found in this series. Two tumours were false negative ER due to receptor sites occupancy by hormonal contraceptive treatment. A second group of ten tumours, with high PgR concentrations and immunoreactive ER, corresponds to non ER-binding forms of receptors. One PgR positive tumour was found to be devoid of PgR by using monoclonal antiPgR antibodies might contain a progesterone binding cyst protein. Only two tumours were found to be true ER negative-PgR positive by all methods. This rare phenotype deserves further study of the regulation of the PgR gene.
Adult↗