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.

[Silicone breast implants and breast cancer]. / Prothèses mammaires en silicone et cancer du sein.

The authors discuss the immunological and oncological risk of prefilled silicone gel breast implants. A comparative study of 146 patients undergoing breast reconstruction by silicone implant at the Institut Gustave-Roussy and 146 matched controls demonstrated the absence of any difference between the two groups concerning survival, local recurrence rate and metastases.

[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.

Use of a polyclonal antibody for the determination of the prognostic value of c-erbB-2 protein over-expression in human breast cancer.

A rabbit-specific polyclonal antibody was obtained raised to a synthetic peptide corresponding to the 1238-1255 C-terminal predicted sequence of the c-erbB-2 protein. This antibody was used in an immunohistochemical procedure to detect the c-erbB-2 protein on a series of 88 paraffin-embedded human breast carcinomas. In 14/88 cases (16%) the c-erbB-2 protein was found to be overexpressed (immunohistochemical score > 1) with a good concordance with the previously determined mRNA level (79/88 cases: 90%). Prognostic significance of c-erbB-2 protein overexpression as detected by immunohistochemistry was tested by the log-rank test. The relative risk of relapse is higher for patients with an immunohistochemical score > 1 (p = 0.00002). In a multivariate analysis of the c-erbB-2 immunohistochemical score was the only powerful parameter (p < 1 x 10(-3). In conclusion, this antibody seems to be a valuable tool in estimating the c-erbB-2 protein regarded in our series as a parameter able to identify a subgroup of operable breast cancer patients with a high risk of relapse.

Pattern of failure in patients with inflammatory breast cancer treated by alternating radiotherapy and chemotherapy.

BACKGROUND: Patients with inflammatory breast cancer have a high risk of developing a local recurrence and/or distant metastases. Treatment with combined chemotherapy and locoregional radiotherapy contributes to a decrease in both risks. This study presents treatment results and evaluates the pattern of failure when an alternating chemoradiotherapy schedule is used. METHODS: One hundred twenty-five patients with nonmetastatic inflammatory breast cancer were treated with an alternating schedule of radiotherapy and chemotherapy. All women recruited were younger than 70 years of age and had a T4d, histologically proven infiltrating carcinoma with N0 to N2 axillary disease. The protocol consisted of three cycles of induction chemotherapy with doxorubicin, vincristine, cyclophosphamide, methotrexate, and 5-fluorouracil followed by three series of locoregional radiotherapy, delivering a total dose of 65-75 Gy to the breast tumor. Five additional cycles of chemotherapy with 5-fluorouracil/doxorubicin/cyclophosphamide were to be administered in between the first two and after the third radiotherapy course. A 1-week gap was respected between each course of chemotherapy and each series of radiotherapy. RESULTS: Toxicity was moderate and this strategy proved feasible although most of the patients only received six instead of the eight planned cycles of chemotherapy. Eighty-two percent of the patients achieved a complete response at the end of the treatment. The cumulative 5-year local failure and distant metastasis rates were 27% and 53%, respectively. Assuming competing events, local failures, contralateral recurrences, and distant metastases were the first site of failure in 18%, 5%, and 38% of patients, respectively. The 5-year overall and disease free survival rates were 50% and 38%, respectively. The main prognostic factor was tumor size. CONCLUSIONS: Alternating high doses of radiotherapy and chemotherapy is a feasible treatment schedule and permits breast conservation. Disease free survival is comparable to that of recently published series. As the main causes of failure are distant metastases, higher dose chemotherapy should be evaluated, in an attempt to further improve overall survival.

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.

[Medullary carcinoma of the breast. What remains of this entity today?]. / Carcinome médullaire du sein. Que reste-t-il aujourd'hui de cette entité?

Identified half a century ago as a favorable prognostic form, medullary breast cancer was classified by Ridolfi in 1977 as necessarily combining 5 features: seemingly wall-circumscribed histological limits, a syncytial architecture in at least 75% of the areas examined, inflammation of the stroma containing diffuse lymphocytes and plasma cells, moderate or marked anisonucleosis and absence of tubular differentiation and/or an intraductal component. Defined is this way, it only accounts for one third of breast cancers with stromal invasion and its outcome is significantly more favorable. Although the reproducibility of this classification is not perfect, only the combination of morphological features prevail over the "new" biological characteristics.

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.

Estrogen receptors (ER) in human breast cancer. The significance of a new prognostic factor based on both ER protein and ER mRNA contents.

BACKGROUND: The response to endocrine therapy is not entirely predictable from the estrogen receptor (ER) and progesterone receptor (PgR) status of primary breast tumors. The authors previously proposed a new prognostic factor, ER.R, which was based on both ER protein and mRNA levels. A previous analysis of 88 primary breast carcinomas showed that ER.R permits the identification of a subset of ER-positive women with a higher risk of early relapse. The purpose of the present study was to confirm the prognostic significance of ER.R. METHODS: Estrogen receptor protein levels were determined for 171 patients with primary breast cancer either by radio-ligand binding assay (ER-LBA) or enzyme immunoassay (ER-EIA). Estrogen receptor, pS2, and c-erbB-2 mRNA were measured by Northern blot analysis. RESULTS: ER.R factor is determined by calculating the ratio of the values (ER protein in fentomoles per milligram of total proteins) to (ER mRNA in picograms per 4 micrograms of total RNA). A cutoff value of 1.5 (protein levels measured by ER-LBA) or 3 (protein levels measured by ER-EIA) discriminate the two ER.R1 (lower ratio) and ER.R2 (higher ratio) subgroups, which present a significantly lower and higher risk of early relapse, respectively. No association was found between ER.R status and either PgR status or c-erbB-2 and pS2 expression. According to a Cox multivariate analysis for disease free survival, the two stronger factors in predicting a poor prognosis were c-erbB-2 overexpression and ER.R2. In the present analysis, ER.R2 was a stronger predictor of recurrence than was ER negativity. CONCLUSIONS: In accordance with the authors' first published data, the analysis of a larger population with a longer follow-up showed that ER.R2 keeps its significance to predict a poorer outcome for a patient, regardless of which assay was used to quantify ER.

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.

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 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.

Surgical and chemotherapeutic treatment of hepatic metastases from carcinoma of the breast.

To date, no five year survival rates have been reported for patients with hepatic metastases (HM) from breast origin treated by chemotherapy or hormone therapy. This study was done to evaluate whether or not surgical excision of such metastatic disease associated with chemotherapy has any effect on such a poor prognosis. Between May 1985 and September 1988, 22 patients with a diagnosis of isolated (solitary or multiple) HM have been surgically treated. The therapeutic approach also included systemic preoperative and postoperative chemotherapy. Laparotomy findings for those 22 patients are presented. There were benign hepatic lesions in four patients (four different histologic types) and hepatectomy was done in two patients. Diffuse metastatic disease contraindicated any attempt at hepatic resection in six patients. Hepatectomy was possible in 12 patients. There was no postoperative mortality and minimal morbidity. One-half of the patients with metastases had one or more positive lymph nodes at the hepatic pedicule. Median survival time for 12 patients treated by hepatectomy was 37 +/- 9 months after hepatectomy and 42 +/- 3 months after the discovery of HM. Eleven patients had other metastases after an average period of 11.8 months after hepatectomy, and the liver was the first site of recurrence in eight. One patient underwent a hepatectomy twice. Two patients were free of disease 29 to 46 months postoperatively in spite of poor prognostic features on the excised specimen. Although the median survival time was two times better than with usual treatment, we believe this procedure is of doubtful benefit. In this situation, hepatectomy acts as cytoreductive surgical treatment, with the main limiting factor being the relatively low effectiveness of chemotherapy. This type of therapy can be applied only to a restricted number of patients, and if we decide to proceed with this study, we will have to modify the protocol of chemotherapy radically.

[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.

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.

Human breast cancer: identification of populations with a high risk of early relapse in relation to both oestrogen receptor status and c-erbB-2 overexpression.

We recently defined a new early prognostic factor, the ER+(R) status, which permits the discrimination of a group presenting a high risk of early relapse among the ER+ patients. This group was referred to as ER+(R2) in contrast to ER+(R1) which corresponded to the group of ER+ patients having a lower risk of early relapse. Taking into account the whole population including the ER- and inflammatory tumours, we have extended this view and showed that ER+(R) status is a significant predictor of disease-free survival. Determination of c-erbB-2 mRNA levels in the same series of tumours showed that high expression of c-erbB-2 mRNA is significantly correlated with ER-, inflammatory tumours and with lymph nodes involvement. Moreover, a multivariate analysis showed that c-erbB-2 mRNA overexpression was a significant predictor of early relapse (P = 0.02), as significant as ER negativity and ER+(R2). For ER+ patients a high level of c-erbB-2 mRNA constitutes a higher risk of relapse for both ER+(R1) and ER+(R2) patients. However, in the case of ER- patients, early relapses were strongly correlated with c-erbB-2 overexpression. The counterpart of this observation is that ER- patients with no overexpression of c-erbB-2 constitute a group with a relatively good prognosis.