A new approach allowing an early prognosis in breast cancer: the ratio of estrogen receptor (ER) ligand binding activity to the ER-specific mRNA level.

We have performed a quantitative analysis of steady-state levels of ER-mRNA for 88 untreated, primary breast carcinomas. We compared the amount of specific mRNA with the amount of ER receptor measured, through ligand binding activity, by calculating the ratio R = [ER-protein/ER-mRNA]. This analysis showed that the relative level of ER-mRNA displayed a large range of values partly related to the concentration of ER-protein. We found a greater percentage of tumors with a high R ratio value in the tumor population containing elevated levels of ER-protein. A statistical analysis performed on a homogeneous population of 63 patients shows no correlation between the R ratio, lymph-node involvement and histological grade. However, R appears to be significantly related to the risk of relapse within a relatively short period of time following the first observation. An R value higher than 1.5 appears to constitute a significant and early prognostic factor of recurrence (P = 0.003).

The importance of histologic grade in long-term prognosis of breast cancer: a study of 1,010 patients, uniformly treated at the Institut Gustave-Roussy.

In a study of 1,010 patients with solitary, unilateral, nonmetastatic breast cancer, the histologic grade, assessed by a multifactorial analysis (Cox model) to study its significance with other prognostic factors, was found to be an important, independent factor. For 612 operable patients, two laboratory characteristics, the number of histologically positive nodes and the histologic grade, were the most valuable predictors. These two factors alone form a predictive index that may be an excellent and simple guide for the clinical decision of subsequent therapy. For 398 patients with inoperable breast cancer (ie, tumor greater than or equal to 7 cm, N2-3, inflammatory, skin fixation, and clinically rapidly growing forms), the histologic grade (performed on drill or cutting needle biopsy) was again a most important (and with inflammatory forms the most important) predictor of prognosis in these patients. Our data support that performing our modified histoprognostic grading of Scarff and Bloom is simple, reproducible, incurs no additional cost, may be carried out in the simplest histology laboratory, and finally, defines an important risk factor in all patients. It should be routine for all breast cancer specimens. Furthermore, studies of adjuvant therapy should stratify patients for this variable.

Primary chemotherapy in the treatment of inflammatory breast carcinoma: a study of 230 cases from the Institut Gustave-Roussy.

We report the largest series of induction chemotherapy for inflammatory breast carcinoma (IBC). Results of two chemotherapy protocols with radiation therapy (RT) (170 patients) are compared with results with radiation alone (60 patients) in the treatment of this disease. From 1973 to 1975, 60 patients (control, group C) received RT (45 Gy and 20 to 30 Gy boost) and hormonal manipulation. From 1976 to 1980, 91 patients (group A) were treated with induction chemotherapy: Adriamycin (Adria Laboratories, Columbus, Ohio), vincristine, and methotrexate (AVM) and RT on a cyclical schedule; and maintenance chemotherapy: vincristine, cyclophosphamide, and 5-fluorouracil (5-FU) (VCF). From 1980 to 1982, 79 patients (group B) received induction chemotherapy, Adriamycin, vincristine, cyclophosphamide, methotrexate, and 5-FU (AVCMF) and RT on a cyclical schedule and VCF maintenance. Hormonal manipulation was performed in all groups. Disease-free survival at 4 years was 15% for group C, 32% for group A, and 54% for group B (P less than .005 group C v group A, less than .00001 group C v group B, and less than .01 group A v group B). Total survival at 4 years was 42% for group C, 53% for group A, and 74% for group B (P = .17 group C v group A, less than .00001 group C v group B, and less than .001 group A v group B). Clinical assessment of tumor aggressiveness, nodal status, type of chemotherapy administered, and early response to chemotherapy (by third course) were all prognostic factors. There is an important, highly statistically significant benefit in terms of both disease-free survival and total survival observed in patients treated with the addition of chemotherapy compared with radiation alone in IBC.

Is the negative prognostic value of high oestrogen receptor (ER) levels in postmenopausal breast cancer patients due to a modified ER gene product?

Recently, it was found that, among post menopausal breast cancer patients receiving no adjuvant therapy, the highest oestrogen receptor (ER) levels (ER++) as opposed to the intermediate ER levels (ER+) indicated a poorer prognosis in terms of recurrence-free survival (Thorpe et al. Eur J Cancer 1993, 29A, 971-977). In the present study, we confirm, in a series of 218 node negative, postmenopausal patients in whom ER was determined using a one-dose saturating method, that ER+ tumours have a more negative effect on disease-free survival (DFS) than ER+ tumours (P = 0.02). In another series of 87 ER positive, postmenopausal patients, we found a significant correlation (P = 0.04) between the ER level and ER+R ratio (ER protein/ER-specific mRNA): the higher the ER level, the more numerous the high ER+R ratio cases (ER+R > 1.5), reflecting an imbalance between the ER protein level and ER-specific mRNA. From these results, we hypothesise that high ER levels related to a high ER+R ratio suggest the presence of a modified ER gene product.

Radiotherapy alone in breast cancer. I. Analysis of tumor parameters, tumor dose and local control: the experience of the Gustave-Roussy Institute and the Princess Margaret Hospital.

This retrospective study involved 463 breast cancer patients treated by radiotherapy alone at the Princess Margaret Hospital and at the Institut Gustave-Roussy. These patients either had operable tumors, but were unfit for general anesthesia, or had inoperable tumors due to local contraindications to surgery. Results were analyzed according to tumor response, local recurrence rate, tumor size, tumor fixation, nodal fixation and tumor dose. Conventional statistical analysis of local control showed two significant factors: tumor dose and tumor size. Multivariate analysis permitted to define an "individual risk" (IR) of local recurrence according to three independent factors: tumor size, tumor fixation, and nodal fixation. It was shown that the IR was a good prognostic factor for local control. Increase in tumor dose gave a similar effect in the local recurrence relative risk for all the IR groups. According to the slope of the dose-effect curve, it was deduced that a dose increase of 15 Gy can decrease the relative risk of local recurrence 2-fold. In fact, it was shown that tumor dose was the most significant independent factor on local control, able to produce up to a 10-fold increase compared to 2-fold decrease for tumor size. If the IR of local recurrence is known, a theoretical predictive value on local control, taking into account the tumor dose, can be determined according to the present data.

Long-term risk of sarcoma following radiation treatment for breast cancer.

Between 1954 and 1983, 7620 patients were treated for breast carcinoma at Institut Gustave Roussy (France). Of these patients, 6919 were followed for at least 1 year. Out of these, 11 presented with sarcomas thought to be induced by irradiation, 2 of which were Steward-Treves Syndrome, and 9 of which were sarcomas within the irradiated fields. All histological slides were reviewed and a comparison with those of breast cancer was done. The sites of these sarcomas were: parietal wall, 1 case; second costal cartilage, 1 case; infraclavicular region, 1 case; supraclavicular region, 2 cases; internal third of the clavicle, 2 cases; axillary region 2 cases; and the internal side of the upper arm (Stewart-Treves syndrome), 2 cases. The median age of these 11 patients at the diagnosis of sarcomas was 65.8 (49-83). The mean latent period was 9.5 years (4-24). Three patients underwent radical mastectomy and nine modified radical mastectomy. Only one patient received chemotherapy. The radiation doses received at the site of the sarcoma were 45 Gy/18 fr. for 10 cases and 90-100 Gy for 1 case (due to overlapping between two fields). The histology was as follows: malignant fibrous histiocytoma, 5 cases; fibrosarcoma, 3 cases; lymphangiosarcoma, 2 cases; and osteochondrosarcoma, 1 case. The median survival following diagnosis of sarcoma was 2.4 years (4 months-9 years). Two patients are still alive: one with recurrence of her breast cancer, the other in complete remission, with 7 and 3 years follow-up, respectively. All other patients died from their sarcomas. The cumulative incidence of sarcoma following irradiation of breast cancer was 0.2% (0.09-0.47) at 10 years. The standardized incidence ratio (SIR) of sarcoma (observed n# of cases (Obs)/expected n# of cases (Exp) computed from the Danish Cancer Registry for the same period) was 1.81 (CI 0.91-3.23). This is significantly higher than one, with a p = 0.03 (One Tailed Exact Test). The mean annual excess (Obs-Exp)/100.000 person-years at risk during the same period/(100,000) was 9.92. This study suggests that patients treated by radiation for breast cancer have a risk of subsequent sarcomas that is higher than the general population. However, the benefit from adjuvant radiation therapy in the treatment of breast cancer exceeds the risk of second cancer; therefore, the potential of radiation-induced sarcomas should not be a factor in the selection of treatment for patients with breast cancer.

Alternating radiotherapy and chemotherapy in non-metastatic inflammatory breast cancer.

Ninety-nine patients presenting with non-metastatic inflammatory breast cancer were treated with an alternating protocol of radiotherapy and chemotherapy. The alternating schedule consisted of 8 courses of combined chemotherapy, including doxorubicin, vincristine, cyclophosphamide, methotrexate and 5-Fluorouracil, and 3 series of loco-regional radiotherapy delivering a total dose of 65 to 75 Gy to the breast tumor, 65 Gy to the axilla, and 50 Gy to the supraclavicular and internal mammary chain lymph nodes. Radiotherapy was started after the third course of chemotherapy. A 1-week gap was respected between each course of chemotherapy and each series of radiotherapy. Seventy-five percent of patients were in complete remission at the end of this induction treatment. The 3-year local control was 72% and the 3-year overall survival rate was 70%. An isolated local recurrence was observed in only 4% of patients. Approximately one-half of patients developed distant metastases. These results show that alternating radiotherapy and chemotherapy schedules deserve further investigation in locally advanced breast cancer.

Radiotherapy alone in breast cancer. Analysis of tumor and lymph node radiation doses and treatment-related complications. The experience of the Gustave-Roussy Institute and the Princess Margaret Hospital.

This retrospective analysis was conducted on breast cancer patients treated by radiotherapy alone at The Princess Margaret Hospital and at the Institut Gustave-Roussy. These patients had either operable tumors, but were unfit for general anesthesia, or had inoperable tumors due to local contraindications to surgery. Previous results showed that a radiation dose increase of 15 Gy can decrease the relative risk of tumor or lymph node recurrence twofold. In this third report, the same data were analyzed to determine the treatment-related complication rates and to correlate these to the radiation dose levels. Overall results were analyzed on 453 patients, but detailed analyses on complications were conducted on 372 patients not developing local recurrence in the first 6 months of follow-up. Each complication was graded on a 3-level previously defined scale. Most frequent complications were skin changes of different degrees, which were usually asymptomatic. More disabling complications were arm edema, impaired shoulder mobility, rib fractures and brachial plexopathy. The incidence of disabling complications was low. The only factor significantly increasing the risk of complications was the radiation dose level to the tumor and axilla. Technical factors such as overlapping fields should also be taken into account. As the more effective control of tumor and lymph nodes obtained in patients treated with higher radiation doses is counterbalanced by an increase in the complication rate, the dose to be delivered for each patient should be carefully chosen according to individual risk factors.

Long-term effect of internal mammary chain treatment. Results of a multivariate analysis of 1195 patients with operable breast cancer and positive axillary nodes.

A multivariate analysis on 1195 patients with operable breast cancer and histologically positive axillary nodes treated by mastectomy and complete axillary dissection at the Institut Gustave-Roussy between 1958 and 1978 suggests a beneficial effect of treatment of the internal mammary chain (IMC) on the risks of death and distant metastasis for the patients with medial tumors. For these patients, surgical IMC dissection and post-operative irradiation have similar effects on both the risk of death and of distant metastasis. For the patients with lateral tumors, no beneficial effect of the treatment of the IMC on these two risks was observed. Postoperative irradiation to the IMC, axilla, chest wall and supraclavicular nodes significantly decreases the risk of locoregional recurrences independent of the tumor site and surgical management of the lymph nodes.

Radical radiotherapy alone in non-operable breast cancer: the major impact of tumor size and histological grade on prognosis.

This retrospective study involved 319 non-operable breast cancer patients treated by radiotherapy alone with doses of 65 Gy at the Institut Gustave-Roussy (IGR). These patients either had operable tumors but were unfit for general anesthesia or had inoperable tumors due to local contraindications. Most of them had advanced tumors: 21% less than 7 cm; 30% N2 or N3; 30% with inflammatory carcinomas. The 5- and 10-year survival was 40 and 19%, respectively. The local and distant relapse-free rate was 56 and 33% at 5 years and 44 and 28% at 10 years respectively. Results were analyzed according to tumor size, clinical node involvement, histologic grade, age, skin invasion and tumor dose. A multivariate analysis demonstrated that tumor size (p = 10(-3)) and histological grade (HG) (p = 10(-2)) were both significant factors predicting local relapse. Histological grade (p = 10(-3)), tumor size (p = 10(-2)) and clinical node involvement (p = 10(-2)) were the most significant factors predicting distant relapses. An individual risk (IR) of local recurrence and of distant recurrence was defined according to the above factors and was demonstrated to be good prognostic index. Tumor doses above 80 Gy did not increase local control. We recommend the general use of histological grading as it seems important for prediction of local and distant control in patients treated by radiotherapy alone.

Limited small cell lung cancer treated by combined radiotherapy and chemotherapy: evaluation of a grading system of lung fibrosis.

A grading system of radiological fibrosis was defined and applied by four observers for the reading of 218 posterior-anterior chest X-rays of 78 patients. These patients with limited small cell lung cancer were treated from May 1980 to July 1983 in two consecutive alternating radiotherapy-chemotherapy schedules. Chest X-rays performed at each 6-month interval were read by each observer. A second reading was performed the day after. The analysis of results showed that in spite of some systematic variations in intra- and inter-observations, the proposed grading system had a good reproducibility. The radiological lung fibrosis score progressed between 6 and 12 months but was stable after one year of follow-up. There was no difference in the score of lung fibrosis between the two protocols which delivered a total dose of 45 and 55 Gy to the mediastinum. There was no significant correlation between the radiological changes and clinical symptoms.

Can breast reconstruction with gel-filled silicone implants increase the risk of death and second primary cancer in patients treated by mastectomy for breast cancer?

An increased risk of cancer and autoimmune disease associated with gel-filled silicone implants has been suggested recently, but these possible detrimental effects have not been adequately studied in patients with breast cancer. In order to evaluate these effects, we have studied 146 patients with breast cancer treated by mastectomy at the Gustave Roussy Cancer Institute between 1965 and 1983 and who received a gel-filled silicone implant for immediate or delayed breast reconstruction between 1976 and 1984. These patients were compared with 146 matched controls with breast cancer who were treated in the same center by mastectomy without breast reconstruction and were matched for age at diagnosis (within 10 years), year of diagnosis (within 3 years), stage, histologic type of the tumor, histopathologic grade, and nodal status. The relative risks of death, relapse, and second primary cancer were estimated by means of the Cox proportional hazards model stratified on age at diagnosis. The risks of distant metastasis and death due to breast cancer were significantly lower in the breast reconstruction group than in the control group. The risks of local recurrence, second breast cancer, and second primary cancer in another site than the breast were not significantly different between the two groups of patients. Our results do not support the hypothesis of a detrimental effect of gel-filled silicone implants either in the course of breast cancer or in the risk of death due to other diseases.

Does long-term exposure to gel-filled silicone implants increase the risk of relapse after breast cancer?

BACKGROUND: An increased risk of cancer and autoimmune diseases associated with gel-filled silicone implants, debated by FDA experts since 1991, has given rise to a profusion of literature on the subject. However, such effects have not been adequately investigated in patients with breast cancer. In a previous report we compared 146 breast cancer patients with gel-filled silicone implants for breast reconstruction to 146 control patients in whom no reconstruction had been performed. The observed results were reassuring, as the evolution of the disease after 10 years was better in the reconstruction group than in the control group. We now report the end results of this study with a median follow-up of 13 years after the breast reconstruction (range, 10-20 years). METHOD: The relative risks of detrimental events were estimated with Cox's Proportional Hazards Model, with stratification according to age at diagnosis. RESULTS: The risks of locoregional recurrences and distant metastasis were significantly lower in the BR group than in the control group. The risks of death, of a second breast cancer and of a second primary cancer at a site other than the breast were not significantly different between the two groups of patients. CONCLUSION: Long-term follow-up of patients exposed to gel-filled silicone implants confirms the absence of detrimental effects after breast cancer. The power of our study is, however, below that required to detect a very slight increase in the risks studied.

[Current data on radiotherapy of breast cancer]. / Données actuelles sur la radiothérapie du cancer du sein

At the Symposium in Teheran two aspects of radiotherapy in mammary cancer came up for discussion: post-operative radiotherapy and the possibilities of conservative treatment, combining tumorectomy ("lumpectomy", "tylectomy ") for stage 1 cases. The place of post-operative irradiation was discussed in relationship to the appearance of local recurrences, metastases and the survival rates available from published data (therapeutic trials and retrospective studies) and in relationship with a population of 206 cases treated at the Gustave Roussy Institute between 1963 and 1966. The possible relationship between post-operative irradiation and immunity were mentioned. With identical wide surgical excision the essential role of post-operative irradiation consists of diminishing in a significant fashion the level of local recurrences. With more restricted surgery of the simple mastectomy type one asks whether irradiation could not replace radical node dissections. It should be reserved for the bad N+ cases. A retrospective study of 44 cases coded T1 NO/N1 MO/PevO treated by tumorectomy and cobalt 60 was compared with 44 matching cases which differed only in their local treatment which consisted of wide surgical excision. The survival actuarial rate at 8 years is 88.6% for the more conservatively treated group compared with 73% for the radical group. In order to provide a quite impartial result a WHO therapeutic trial was begun in 1972.

[Enzymo-immunoassay of progesterone receptors in human breast lesions and tumors. Comparison with a biochemical method]. / Enzymo-immunodosage des récepteurs à la progestérone dans les lésions et tumeurs mammaires humaines comparison à la méthode biochimique.

The determination of progesterone receptors (RP) was performed on 80 benign and malignant human breast tumors with a single saturating dose method (10 nM) using dextran-coated charcoal (PR-Bio) and an enzymo-immunoassay (PgR-EIA). There was a significant correlation between the 2 methods qualitatively (P less than 0.001) and quantitatively (r = 0.79). However the results were significantly higher using the PgR-EIA method than the PR-Bio method (P = 0.04) with a regression line Y = 0.81 x +0.58.

[Bilateralization of breast cancer]. / Bilatéralisation des cancers du sein.

1,271 patients with breast cancer treated at the Institut Gustave Roussy between 1967 and 1972 and with a minimum follow-up of 10 years, have been studied in order to analyse the risk factors for bilateralization. Patients with metastases at presentation (160) who have an incidence of bilateralization at two years of 20% have been excluded since the contralateral tumor is regarded as part of the metastatic process. For 1,111 patients, non-metastatic at presentation, the following factors have been studied: age, T-stage, N-stage, tumor grade, tumor growth rate (doubling tumor size in less than six months) and the presence of inflammatory signs. Of these factors, only advanced T stage, fixed axillary lymphadenopathy and the presence of inflammatory sign were associated with a significantly increased risk of bilateralization. For patients presenting with T1 tumors the incidence of bilateralization is 19% at 10 years but this is probably because relatively more of these patients lived long enough to develop a second cancer. A more detailed histopathological study was performed on 682 patients whose tumors were operable at presentation and for whom the following histological characteristics are known: type, grading (Scarff and Bloom), number of axillary nodes involved by tumor and anatomical size of the tumor. None of these characteristics was found to increase the risk of bilateralization. Comparing the two breast tumors (and excluding those with a diffuse infiltration in either breast) in 74 patients in whom the exact tumor site was known, in only 7, was the second tumor a "mirror-image" of the first. Overall, MO patients with bilateral tumors have a decreased survival compared with those with unilateral tumors. For those patients operable at presentation, the 10 year survival is 51% and 63%. The conclusions of this study are that there are two populations of patients with bilateral breast cancer: Those in whom the controlateral tumor is part of a generalized metastatic process and occurs particularly in those with a poor prognosis (metastases at presentation, inflammatory carcinomas, fixed lymphadenopathy). Those in whom there is a relatively long interval (5-10 years) between the development of the two tumors who have not any metastases. This population particularly comprises patients with T1 tumors thus for whom continuing clinical and mammographic follow-up is justified.

[The anatomopathological factors of prognostic value in breast cancer]. / Les facteurs anatomo-pathologiques du pronostic des cancers du sein.

A prospective study on the progress of 356 women with unilateral carcinoma of the breast treated throughout at the Institut Gustave-Roussy, by a Halsted or Patey type radical mastectomy. Between 1-1-68 and 31-12-71 293 patients without any previous treatment were operated on, and 63 after irradiation according to the dosage-schedule then in force. In the first group no prognostic importance could be attached to the character of the tumour margin nor to its stroma. Two features thought to be bound up with survival on first analysis were not found to have significance when the other prognostic factors were kept constant and these are microscopic spread of tumour outside the nipple and transcapsular spread of tumour in the axillary nodes. Only four parameters were found to have a real prognostic value and these were the size of the tumour, its Bloom grading, microscopic spread to the nipple and the number of nodes invaded, with a threshold at three involved nodes. With regard to irradiated carcinomas, whose number were really too small for such an intense analysis, only two parameters were related to survival: Bloom grading and the number of axillary nodes invaded.

Combined overexpression of c-erbB-2 protein and epidermal growth factor receptor (EGF-R) could be predictive of early and long-term outcome in human breast cancer: a pilot study.

In order to determine the prognostic value of c-erbB-2 protein and Epidermal Growth Factor Receptor (EGF-R), we used an immunohistochemical procedure with specific antibodies on paraffin-embedded material from a series of 73 operable breast cancer carcinomas. c-erbB-2 protein (c-erbB-2 score > 1) was overexpressed in 10/73 cases (14%) and EGF-R (EGF-R ratio > 1) in 42/73 cases (58%). c-erbB-2 overexpression was correlated with tumour size (P < 0.02) and lymph-node involvement (P = 0.05) whereas EGF-R overexpression did not correlate with any of the variables tested. The relative risk of relapse was respectively 1 vs 4.5 (P = 0.001) for patients with a negative (0-1) or positive (> 1) c-erbB-2 score and 1 vs 3 for patients with an EGF-R ratio < or = 1 and > 1 (P = 0.03). Moreover, c-erbB-2 protein overexpression is more specifically an early factor of poor prognosis whereas EGF-R overexpression is a long-term factor of poor prognosis. Patients with an early good prognosis (c-erbB-2 score = 0-1) are found to relapse with time when EGF-R is overexpressed. In a multivariate analysis including axillary lymph-node status, histological grade, tumour size, ER status, c-erbB-2 score, EGF-ratio and hormonal treatment, c-erbB-2 overexpression was the most powerful parameter (P = 0.001) followed by EGF-R overexpression (P = 0.02). We concluded that, in our series, the combined determination of c-erbB-2 protein and EGF-R appeared to be a prognostic indicator whereby both early and long term prognosis could be determined in breast cancer patients.

[Diagnosis of local recurrence after conservative treatment of breast cancer. A comparative study of a series of 50 cases]. / Diagnostic des récidives locales après traitement conservateur du cancer du sein. Etude comparée d'une série de 50 cas.

In order to determine the diagnostic features of recurrences after conservative treatment of breast cancer, 100 files have been studied. Fifty cases of glandular recurrence have been analysed and compared to 50 control cases of same stage, age and follow-up, without recurrence. In 58% of cases, the diagnosis was established during the course of a visit requested by the patient. In 84% of the cases the recurrence was found to be within the tumorectomy zone. The significant glandular pains, mammary density and deformation, nipple retractions and the radiological evidence of microcalcifications and irregular opacities seem to be strongly indicative of recurrence. The simultaneous clinical and radiological expression of recurrence was not noted in more than 52% of cases.

[Efficacy of massage and mobilization of the upper limb after surgical treatment of breast cancer]. / Efficacité du massage et de la mobilisation du membre supérieur après traitement chirurgical du cancer du sein.

We have compared different modes of rehabilitation after breast cancer surgery on a population of 257 patients treated at the Institute Gustave-Roussy in 1990 and 1991. The mode of rehabilitation was randomized according to a 2 X 2 design, between physiotherapy alone, shoulder movement alone, both or neither. Treatment began the day after breast surgery and continued for 7 days. Afterwards, all patients had physiotherapy and shoulder movements until the end of hospitalisation. Treatment efficacy was evaluated at day 7 by the volume of lymph drained, and by degree of shoulder movement. The volume of lymph collected by day 7 was reduced in the physiotherapy groups, but was not modified in the groups with shoulder movement. The degree of motion was larger in the group who had had both physiotherapy and shoulder movement. The frequencies of complications at day 7 and later were similar in the four treatment groups, but locoregional pain was less frequent in the two groups with shoulder movement than in the two other groups. An early treatment including both physiotherapy and shoulder movement seems advisable.