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Aim: To investigate in a prospective study the prognostic value of serum HER2 extracellular domain (ECD) level in patients with primary breast cancer overexpressing HER2 treated with adjuvant chemotherapy and trastuzumab., Patients and Methods: All the patients treated for primary breast cancer with chemotherapy and adjuvant trastuzumab from April 1, 2005 to December 31, 2006 at the Centre de Lutte Contre le Cancer de Haute Normandie were enrolled in this prospective study. HER2 ECD was measured in frozen serum by a commercial kit with a cut-off value of 15 ng/ml., Results: Sixty-five patients were enrolled. Seven patients (11%) had an elevated serum HER2 ECD level (mean=25.1 ng/ml, range 15.1-38.9 ng/ml). During follow-up, 13 patients (20%) developed metastases and seven patients (11%) died. Death was related to breast cancer metastases in six patients (9%). Out of the seven patient with elevated serum HER2 ECD level, five (71%) developed metastases and three (43%) died of metastases during follow-up. Multivariate analysis showed that elevated serum HER2 ECD level was the unique factor for both disease-free survival (p<0.0006) and overall survival (p=0.008) in this series., Conclusion: Elevated serum HER2 ECD level is a strong prognostic factor in primary breast cancer overexpressing HER2 treated with adjuvant therapy of trastuzumab. In addition, our results suggest that it could predict failure of adjuvant therapy of trastuzumab.

This clinical report illustrates the usefulness of routine CA 15.3 assay during the follow-up of patients treated for invasive breast cancer. This patient presented an isolated elevation of CA 15.3 eighteen months after initial treatment of inflammatory breast cancer. The scientific committee for breast cancer decided to modify the hormonotherapy, even without clinical or radiological event (tomodensitometry, echography, scintigraphy). The prompt CA 15.3 normalization persisted for more than seven years. When CA 15.3 levels increased again, a positron emission tomodensitometry was performed and revealed pulmonary nodes. The sole modification of hormone treatment, based upon isolated increase of CA 15.3, led to seven years of clinical and biological stability for our patient with probable pulmonary metastases.

Background: Quality control results for serum MUC-1/CA 15-3 assays have always shown large discrepancies., Methods: This multicentre study of 15 methods (labelled M1-M15) measured coded sera from 35 patients with breast cancer without recurrence (group 1), 46 patients at 1st metastasis (group 2), and 39 patients with advanced metastases (group 3). Results were compared using parametric statistics, ANOVA, principal component analysis, and receiver operating characteristic (ROC) curves., Results: Mean MUC-1/CA 15-3 concentrations varied widely (75.1-303.0 U/mL, 24.8%) among methods. The false positive (FP) rate for group 1 was 8/521 (1.5%); for group 2 and group 3 false negative (FN) results were 21/680 (3.1%) and 11/583 (1.9%), respectively. Using the ROC cut-offs, we found no FPs for group 1 and no FNs for group 3. However, group 2 showed 16 FNs. All p-values for Pearson's correlation were <0.0001 between methods, except for M11. When comparing methods using different antibodies, discordance rates reached a maximum of 15.2%. Principal component analysis revealed a grouping of methods using: CanAg monoclonal antibodies (mAbs) (M2, M7 and M12); Centocor/Fujirebio mAbs (M3-M6, M8-M10, M14-M15) and Biomira mAbs (M1 and M13); and Centocor/Fujirebio mAbs (M11)., Conclusions: Results were more consistent among methods using the same antibody type. Principal component analysis showed that antibody type was the strongest determinant of immunoassay results.

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.

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.

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.

pS2 protein assay was performed with Elsa-pS2 kit (CIS-Biointernational) on a group of 1,065 patients with operable breast cancer who underwent breast surgery in the years 1982 through 1990. The median follow-up was 57 months. This group included exclusively infiltrating ductal carcinoma with primary surgery. Age mean was 58 yr; T0-T1, 33.6%; T2-T4, 66.4%; Differentiation grade I, 29%; node negative, 53%; estrogen receptor (ER) positive, 62.4%; progesterone receptor (PR) positive, 55.2%; mean tumor size, 2.4 cm; local recurrence, 5.2%; metastasis, 17.5%. pS2 values varied from 0.1 to 707 ng/mg of cytosol protein (median, 5.6; mean 24.5; 95th percentile 112 ng/mg p). There was no significant relationship between the mean level of pS2 and age, tumor size, nodal status, whereas pS2 was related to histological grade (P < 10(-3)), ER (P < 10(-5)), and PR (P < 10(-5)). By using 2 ng/mg p as pS2 cutoff, 77/391 (19.7%) of ER+PR+ tumors were pS2-, and 122/345 (35.4%) of ER-PR-tumors were pS2+; with this cutoff, a strong relationship existed between pS2 and overall survival, but not between pS2 and relapse-free survival. With Cox multivariate analysis, pS2 protein was classified after lymph node status, histological size, ER, differentiation grade, age, clinical stage, PR. In patients with axillary lymph node involvement (N+), pS2 status could discriminate between good and bad prognosis, specially for patients with small tumors (< 2 cm) and with less than seven invaded nodes. This study showed that pS2 protein was a poor prognostic factor in comparison with classical factors.

This retrospective study shows the advantage of the CA 15.3 assay for the early detection of relapse in breast cancer. It involved 473 women with invasive canalar carcinoma who had local recurrence or metastasis and/or an elevation of CA 15.3 (> 35 kU/l). The positive predictive value is excellent (97.7%). Sensitivity is poor for local relapse (13.7%), but a marker elevation at this time is a good prognostic factor of further distant metastasis (88%). It is better in the case of distant metastasis (74%), especially in bone and and liver localizations. CA 15.3 measurement at two month intervals may allow an early detection in 40% of distant metastasis. These results confirm the need of trials to test the benefits in terms of survival of early treatment of breast cancer metastasis only proved by CA 15.3 elevation, without any clinical or radiological finding.

This study concerns 645 patients first treated with surgery for unilateral, non metastatic, invading breast cancer. Intratumoral estrogen receptor and progesterone level were determined in every case. Level greater than 5 fmoles/mg cytosolic protein was considered as positive for both receptors. Univariate analysis has pointed out a significant linkage between overall survival and the following factors: age, clinical size of the tumor, histopathological grading SBR, clinical and histological lymph node involvement, capsular tear, RO and RP status. Statistical significance of menopausal status is borderline. Number of tumor foci is not significant. Likewise, disease free survival was correlated to the same factors. Multivariate analysis (Cox), secondarily pointed out that overall survival was strongly related to age, size of the tumor, lymph node involvement, capsular tear, histopathological grading SBR, menopausal status and RP. Multivariate analysis of the disease free survival revealed that it was strongly related to age, tumor size, lymph node involvement, capsular tear, grading SBR and RP. An interaction has been pointed out between Ro and menopausal status: Ro greater than 5 fmoles/mg cytosolic protein carry its own prognostic weight (Cox) and lengthen overall survival only for post menopausal women. A prognostic score, taking into account all of these factors has been calculated for both overall survival and disease free survival, and enabled us to isolate 4 groups of patients with good, intermediate and bad prognosis. These 2 models have been validated on an independent group of patients according to the sample test procedure. This results indicate that hormonal receptors carry their own prognostic weight in operable breast cancer (only for postmenopausal women for RO), and should be taken into account when adjuvant therapies are indicated after surgical treatment for breast cancer, in association with other more usual prognostic factors.

From October 1977 to December 1983, estrogen receptor (ER) and progesterone receptor (PR) levels were measured in 645 tumors from women with primary, unilateral, nonmetastatic breast cancer. All of them were treated surgically. Some received adjuvant radiotherapy, adjuvant chemotherapy, or adjuvant hormonotherapy. A level of greater than 5 fmol/mg cytosolic protein was considered as positive for both ER and PR. Unifactorial analysis, using Kaplan and Meier estimates and the log-rank test, revealed that disease-free survival (DFS) and overall survival (SV) were both strongly related to age, tumor size, nodal status, nodal effraction, histopathologic grading (SBR), ER, and PR. Menopausal status and number of intramammary tumor foci were not significant. Multifactorial analysis, using Cox's model, revealed a strong relationship between SV and age (poor prognosis [pp]: less than or equal to 37 years old), menopausal status (pp: postmenopausal) tumor size, nodal status (pp: N+ greater than 3), nodal effraction, ER (pp: less than or equal to 5 fmol/mg), histopathologic grading (pp: SBR = 3), and PR (pp: less than or equal to 5 fmol/mg). Similarly, multifactorial analysis revealed a strong correlation between DFS and age, tumor size, nodal status, nodal effraction, histopathologic grading, and PR. A prognostic score taking into account these prognostic factors was calculated for DFS and SV. Analysis of this score allowed us to divide our patients into four significantly different (P less than 0.0001) groups with high, intermediate, and low risk of relapse. Our procedure was then validated using the sample test technique. These results show that both ER and PR have their own prognostic weight and should be considered, among other classic prognostic factors, when adjuvant therapies are indicated after surgical treatment of breast cancer.