Brigitte Zafrani

Prognostic factors of breast recurrence in the conservative management of early breast cancer: A 25-year follow-up☆

Between 1960 and 1980, 518 patients with T1, T2, N0, N1a, invasive breast cancer were treated by limited surgery at Institute Curie with (183 patients) or without (335 patients) axillary node dissection, followed by radiation therapy to breast and nodes. Median follow-up was 8.6 years (1.3 to 25 years). Fifty-six breast recurrences occurred, including 49 breast recurrences alone, 3 simultaneous breast and node recurrences, and 4 simultaneous breast recurrences and metastasis. Five-year, 10-year, and 15-year actuarial risks of breast recurrences were 7 +/- 1%, 11 +/- 1.5%, and 18 +/- 3%, respectively. Univariate analysis of 14 clinical and pathological prognostic factors revealed that local control in breast was significantly impaired by young age, premenopausal status, inadequate gross surgical excision, extensive ductal in situ component, and endolymphatic extension. On multivariate analysis with a Cox regression model, the most important contributors to local breast control in order of importance were age (p less than 10(-4), relative risk = 2.44), adequacy of surgery (p = 0.003, relative risk = 2.78), and endolymphatic extension (p = 0.03, relative risk = 2.98). The 5-year actuarial survival rate following breast recurrence was 73%, and was significantly worse when breast recurrence occurred in the first 3 years after treatment: 44% versus 87%, respectively (p less than 0.01). This study confirms the relationship between young age and low breast control rates, and demonstrates the importance of adequate initial surgical procedures. It emphasizes the adverse prognosis of early breast recurrences as compared to the relatively favorable outcome of late recurrences.

Characterization of chromosomal anomalies in human breast cancer: A comparison of 30 paradiploid cases with few chromosome changes

A comparison of chromosomal anomalies detected in 30 cases of breast cancer in females with near-diploid karyotypes is reported. The tumors, of which 20 were previously unpublished, were selected for the relatively low complexity of their karyotypes, among a sample of 118 cases. Almost all of the 151 structural rearrangements detected were unbalanced, and 67% of breakpoints were located in or had contact with heterochromatin. In cases with few anomalies, rearrangements of chromosomes 1 and/or 16 were very frequent, leading principally to a gain of 1q and loss of 16q. In cases with more anomalies (5-16), deletions involving 17p, 4p, 13, 6q, 8p, 9p, 11p, and 11q and gains of 1q and 8q were the most frequent. Homogeneously staining regions (HSR) were detected in 14 tumors, mostly on 8p (6/22) and chromosome 19 (3/22). No double minutes (dmin) were observed. We conclude that trisomy 1q and monosomy 16q are early chromosomal changes in breast cancer, whereas other deletions and gain of 8q are clearly secondary events.

Local control and survival of breast cancer treated by limited surgery followed by irradiation

Between 1960 and 1978, 324 patients with early breast cancer were treated by lumpectomy with or without axillary dissection followed by radiation therapy. All were followed for a minimum of 5 years. All patients were, retrospectively, classified T1, T2, N0, N1a, in the TNM (U.I.C.C.) Classification. The retrospective analysis of the local-regional patterns of failure revealed that young age (less than or equal to 32 years) and premenopausal status were associated with an increased rate of local failure, whereas tumor size and location showed no influence. No pathological features were associated with an increased risk of local recurrence, whether pathological subtypes, Scarff Bloom and Richardson grading, intraductal associated component, or vascular involvement. The absolute 5 year disease-free survival rate was 87% in patients who recurred and 93% in those who did not. The absolute 10 year disease-free survival rates were 75 and 82%, respectively. Therefore, these results confirm that loco-regional failure does not significantly influence the disease-free survival.

No significant predictive value of c- erbB-2 or p53 expression regarding sensitivity to primary chemotherapy or radiotherapy in breast cancer

To document whether c‐erbB‐2 over‐expression or p53 accumulation in tumour cells was predictive of response to chemo‐ or radiotherapy, we analyzed a population of patients with breast cancer assigned to neo‐adjuvant therapy (median follow‐up: 54 months). T2/T3‐N0N1b‐M0 tumours (329 cases) were treated either by FAC chemotherapy or by radiotherapy before surgery, and the clinical response was classified as complete or incomplete. Expression of c‐erbB‐2 and p53 was retrospectively evaluated by immunohistochemistry. Proliferation rate was assessed by means of MIB‐1 antibody and by S‐phase fraction. A complete response to chemotherapy was observed in 38/167 patients (23%). Complete response rate was 20% in c‐erbB‐2‐negative tumours, and rose to 31% in tumours with c‐erbB‐2 over‐expression, but this trend was not statistically significant. There was no correlation between p53 staining and response to treatment, whereas chemosensitivity was found correlated with histological grade and S‐phase. A complete response to radiotherapy was observed in 64 of the 156 evaluable patients (41%). Complete response rate was 41% in c‐erbB‐2‐ or p53‐negative tumours, 54% in tumours with c‐erb‐B‐2 over‐expression, and 44% in tumours with p53 accumulation. There was no correlation between response to radiotherapy and histological grade or proliferative rate. No prognostic value was found for c‐erbB‐2 or p53 expression, whereas the 5‐year survival rate was 85% for patients presenting a tumour with a low proliferating index (MIB‐1 < 10%), and 68% for patients presenting a tumour with a high proliferative index. In multivariate analysis, node status (RR = 2), MIB‐1 immunostaining (RR = 2), and tumour size (RR = 1.8) were found to be associated with survival. These results indicate that c‐erbB‐2 or p53 expression is not significantly associated with tumour response to neo‐adjuvant chemo/radiotherapy in our series of breast cancers. Int. J. Cancer (Pred. Oncol.) 79:27–33, 1998.

Breast cancer genetic evolution: I. Data from cytogenetics and DNA content.

SummaryA general scheme of chromosome alterations occurring during tumor progression is proposed from the cytogenetic study of 113 breast carcinomas. For 76 of these tumors, chromosome numbers and rate of chromosome rearrangements were correlated with DNA content studied by flow cytometry. A series of 536 cases was used as control for flow cytometry. The following evolution can be proposed: 1. occurrence of unbalanced rearrangements decreasing chromosome number and DNA content; 2. correlatively to the rate of chromosome rearrangements, formation of endoreduplications leading to hyperploid sidelines; 3. persistence of the near diploid cells and decrease of chromosome number to about 35 and of DNA index to .85; 4. more frequently, elimination of the near diploid cells and complete passage to hyperploidy; 5. further losses of chromosomes in the hyperploid tumors, whose karyotypes can decrease to about 55 chromosomes and a DNA index of 1.35; 6. eventually, occurrence of a second endoreduplication, leading to an apparent near tetraploidy. The rate of rearranged chromosomes may reach 80% in both near diploid tumors with 35–40 and hyperploid tumors with 55–65 chromosomes which can be regarded as those with the highest degree of tumor progression. It is shown that the increase of chromosome number and DNA index above diploidy is very limited, and that all tumors with more than 50 chromosomes and 1.35 DNA content passed through endoreduplication. This results in many possible losses of heterozygosity in these cases.

Conservative management of intraductal breast carcinoma with tumorectomy and radiation therapy

Between 1967 and 198354 patients with strictly noninvasive intraductal breast carcinoma were treated with tumorectomy and radiation therapy. Median follow‐up was 55 months. Three patients had a recurrence in the treated breast; two were noninvasiveand one was invasive. One patient died of disease. Actuarial 5‐year disease‐free survival rate was 95.2%. No axillary node recurrences occurred in patients treated with irradiation to the breast and regional nodes (34 patients)or in patients treated with breast irradiation alone (20 patients). These preliminary results suggest that combined tumorectomy and radiation therapy could be a valuable conservative alternative to mastectomy in the treatment of noninvasive intraductal breast carcinoma.

High sensitivity and specificity of immunohistochemistry for the detection of hormone receptors in breast carcinoma: comparison with biochemical determination in a prospective study of 793 cases

The hormone receptor (HR) status of breast cancer is an important prognostic factor and predictive parameter of the response to hormone therapy. Enzyme immunoassay (EIA) is currently the standard for determination of HR, but immunohistochemistry (IHC) represents a potentially useful alternative. We used IHC to determine HR status in a large prospective study and compared the results to those obtained by EIA. This study was designed to determine which technique should be used in daily practice in our institution which manages a large number of patients.

Consistency achieved by 23 European pathologists from 12 countries in diagnosing breast disease and reporting prognostic features of carcinomas

Abstract A detailed analysis of the consistency with which pathologists from 12 different European countries diagnose and classify breast disease was undertaken as part of the quality assurance programme of the European Breast Screening Pilot Network funded by the Europe against Cancer Programme. Altogether 107 cases were examined by 23 pathologists in 4 rounds. Kappa (κ) statistics for major diagnostic categories were: benign (not otherwise specified) 0.74, atypical ductal hyperplasia (ADH) 0.27, ductal carcinoma in situ (DCIS) 0.87 and invasive carcinoma 0.94. ADH was the majority diagnosis in only 2 cases but was diagnosed by at least 2 participants in another 14, in 9 of which the majority diagnosis was benign (explaining the relatively low κ for this category), DCIS in 4 (all low nuclear grade) and invasive carcinoma (a solitary 1-mm focus) in 1. The histological features of these cases were extremely variable; although one feature that nearly all shared was the presence of cells with small, uniform, hyperchromatic nuclei and a high nucleo-cytoplasmic ratio. The majority diagnosis was DCIS in 33 cases; κ for classifying by nuclear grade was 0.38 using three categories and 0.46 when only two (high and other) were used. When ADH was included with low nuclear grade DCIS there was only a slight improvement in κ. Size measurement of DCIS was less consistent than that of invasive carcinoma.The majority diagnosis was invasive carcinoma in 57 cases, the size of the majority being 100% in 49. The remainder were either special subtypes (adenoid cystic, tubular, colloid, secretory, ductal/medullary) or possible microinvasive carcinomas. Subtyping was most consistent for mucinous (κ, 0.92) and least consistent for medullary carcinomas (κ, 0.56). Consistency of grading using the Nottingham method was moderate (κ=0.53) and consistency of diagnosing vascular invasion, fair (κ=0.38). There was no tendency for consistency to improve from one round to the next, suggesting that further improvements are unlikely without changes in guidelines or methodology.

Strong Correlation between Results of Fluorescent In Situ Hybridization and Immunohistochemistry for the Assessment of the ERBB2 (HER-2/ neu ) Gene Status in Breast Carcinoma

ERBB2 (HER-2/neu) amplification and/or overexpression are associated with poor prognosis in node-positive breast carcinoma. Its prognostic value in node-negative cases and its predictive value for response to chemotherapy remain controversial. This may be related to the use of molecular methods, which are sensitive to dilution of tumor material by normal cells, or the use of nonstandardized immunohistochemistry (IHC) procedures, for the determination of the ERBB2 gene status. In addition, new therapeutic approaches that target the cells overexpressing ERBB2 are under development. These perspectives necessitate a reliable evaluation of the status of ERBB2 in individual tumors before the application of specific therapeutic strategies. Fluorescent in situ hybridization (FISH) and IHC allow the evaluation of the ERBB2 status specifically in tumor cells on archival material. We have analyzed a series of 100 invasive ductal breast carcinomas without lymph node invasion both by IHC, using the CB11 monoclonal antibody and a sensitive Auidin Biotin Complex (ABC) immunodetection system, and by FISH, using the Oncor Inform HER-2/neu (ERBB2) gene amplification detection system as reference technique. Complete concordance between the results of FISH and IHC was seen in 98% of the cases. ERBB2 amplification (more than four signals per nucleus) was observed in 12 of the 100 cases, and all but one showed an overexpression of the protein (membrane staining) by IHC. Conversely, ERBB2 expression was present in one case without gene amplification. In conclusion, ERBB2 overexpression detected by IHC is highly correlated to gene amplification detected by FISH. Thus, under standardized conditions, IHC is a reliable and economical test to assess the ERBB2 status in tumors. The use of FISH could be limited to the verification of the status of tumors displaying a weak membrane immunostaining.

Characteristic chromosomal imbalances in 18 near-diploid colorectal tumors

The cytogenetic study of 18 near-diploid colorectal tumors shows that the observed numerical and structural abnormalities resulted in recurrent chromosomal losses and gains. By order of decreasing frequencies, they are: monosomy 17p (16/18), partial or more frequently complete monosomy 18 (14/18), trisomy 20q (11/18), trisomy or tetrasomy 13 (10/18), monosomy lp and trisomies X and 8q (9/18). The absence of recurrent breakpoints in euchromatin contrasts with the high preponderance of breakage at various places of heterochromatic region. Because these tumors are characterized by very recurrent chromosomal imbalances, it is assumed that the observed chromosomal changes may be related to a recessive genetic determinism and to gene dosage imbalances.