J.C. Durand

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.

Age as prognostic factor in premenopausal breast carcinoma

Whether or not young age at diagnosis is an adverse prognostic factor in breast cancer has long been controversial, in part because much previous work has not taken due account of menopausal status and confounding factors. We have analysed the influence of age on prognosis in a consecutive series of 1703 patients with stage I-III breast cancer. All were premenopausal and all were treated in one centre (Institut Curie, Paris) between 1981 and 1985. Mean age was 44 years (range 23-55) and median follow-up was 82 months. Younger patients had significantly lower survival rates and higher local and distant relapse rates than older patients. The hazard rate of relapse decreased over time in the youngest age group (< or = 33) to reach that of older patients after 5 years. The relation between the hazard of recurrence and age was a continuous one, best fitted by a log-linear function and indicating a 4% decrease in recurrence for every year of age. Multivariate analysis of both survival and disease-free interval demonstrated that the worse prognosis of young age was independent of other factors such as clinical tumour size, clinical node status, histological grade, hormone receptor status, locoregional treatment procedure, and adjuvant systemic therapy. This difference in outlook has yet to be explained biologically but it does suggest the need for a closer look at the natural history of breast cancer in young women.

Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: Preliminary results of a randomised trial: S6

The aim of this study was to assess a potential advantage in survival by neoadjuvant as compared to adjuvant chemotherapy. 414 premenopausal patients with T2-T3 N0-N1 M0 breast cancer were randomised to receive either four cycles of neoadjuvant chemotherapy (cyclophosphamide, doxorubicin, 5-fluorouracil), followed by local-regional treatment (group I) or four cycles of adjuvant chemotherapy after primary irradiation +/- surgery (group II). Surgery was limited to those patients with a persisting mass after irradiation, and aimed to be as conservative as possible. 390 patients were evaluable. With a median follow-up of 54 months, we observed a statistically significant difference (P = 0.039) in survival in favour of the neoadjuvant chemotherapy group. A similar trend was seen when the time to metastatic recurrence was evaluated (P = 0.09). At this stage, no difference in disease-free interval or local recurrence between these two groups could be observed. The mean total dose of chemotherapy administered was similar in both groups. On average, group I had more intensive chemotherapy regimes (doxorubicin P = 0.02) but fewer treatment courses (P = 0.008) as compared to the treated patients in group II. Haematological tolerance was reduced when chemotherapy succeeded to exclusive irradiation. Breast conservation was identical for both groups at the end of primary treatment (82 and 77% for groups I and II, respectively). Of the 191 evaluable patients in the neoadjuvant treatment arm, 65% had an objective response (> 50% regression) following four cycles of chemotherapy. The objective response rate to primary irradiation (55 Gy) was 85%. Improved survival figures in the neoadjuvant treatment arm could be the result of the early initiation of chemotherapy, but we cannot exclude that this difference might be attributable to a slightly more aggressive treatment. So far, the trend in favour of decreased metastases was not statistically significant. The local control appeared similar in both subgroups.

Value of axillary dissection in addition to lumpectomy and radiotherapy in early breast cancer

Axillary dissection in early breast cancer remains controversial because of its substantial side-effects and because its value with respect to recurrence or survival has not been unequivocally proven. Between 1982 and 1987, 658 patients were included in a prospective randomised comparison of lumpectomy alone with lumpectomy plus axillary dissection. All patients had a unilateral breast tumour not exceeding 3 cm in diameter and lymph-node involvement or metastases. Radiation therapy was given to both groups. The two groups of patients were similar with respect to mean age, TNM stage, and presence of hormonal receptors. Median follow-up was 54 months. 5-year survival of the patients was 94.2% (95% Cl: 92.1-96.4). There was a significant advantage in survival in the axillary dissection group (p = 0.014). Recurrence of tumour in the breast was similar in the two groups but visceral metastases, supraclavicular metastases, and lymph-node recurrences were less frequent in the axillary dissection group. Survival was related to the age of the patients (p = 0.005), the presence of positive nodes (p = 0.006), the histological grading (p less than 0.0001), and the presence of hormonal receptors (progesterone p = 0.0008, oestrogen p less than 0.0001). Treatment-adjusted relative risk was 2.4 (95% Cl: 1.3-4.2). The findings show that axillary dissection is justified for treatment of small breast cancers, although whether the better survival is due to axillary clearance itself or to adjuvant treatment for lymph-node involvement is unclear.

Contralateral breast cancer: annual incidence and risk parameters.

PURPOSE To screen for factors that might predict the risk of developing metachronous contralateral breast cancer (CBC), taking into account the influence of local or distant recurrence, and to assess the annual incidence of CBC. PATIENTS AND METHODS Of 4,748 women with invasive unilateral breast cancer, clinical stage I to IIIa, treated between 1981 and 1987, 282 metachronous CBCs were diagnosed. Due to competing risks between the occurrence of CBC and other events, several options for multivariate analysis were considered. RESULTS The median follow-up time was 80 months (range, 1 to 158). The cumulative rate of CBC was 4.1% +/- 0.3% at 5 years, and the annual incidence rate of CBC increased slowly, while the risk of local recurrence and metastases decreased after the fourth year. Whichever model we chose, age less than 55 years (relative risk [RR] = 1.40) at the time of diagnosis of the first breast cancer, as well as the presence of lobular type carcinoma (RR = 1.50), was associated with an increased risk of developing a tumor in the contralateral breast. Adjuvant chemotherapy significantly decreased (RR = 0.54) the risk of CBC. CONCLUSION Lobular histology and age less than 55 years are found to increase the risk of CBC, while adjuvant chemotherapy significantly decreased the risk of CBC. The progressive rise in the annual incidence rates of CBC, together with the absence of a link between clinical prognostic factors of the first cancer and CBC, suggested that CBC can be considered as a second primary breast cancer.

BREAST TUMOUR RESPONSE TO PRIMARY CHEMOTHERAPY PREDICTS LOCAL AND DISTANT CONTROL AS WELL AS SURVIVAL

The purpose of the present paper was to evaluate correlations between clinical response to chemotherapy and outcome in a subgroup analysis of premenopausal patients with tumours considered too large for breast conserving surgery, treated with primary chemotherapy (n = 200) from a previously published trial (Scholl S.M., Fourquet A., Asselain B, et al. Eur J Cancer 1994, 30A, 645-652). Objective response rates amounted to 65% following four courses. In a multivariate Cox regression analysis, comparing seven parameters, the following variables were associated with poor survival: clinically involved nodes [N1b:RR: 2.7 (95% CI 1.3-5.3)], the failure to respond to chemotherapy [D:RR: 2.62 (95% CI 1.3-5)] and a raised S phase fraction [SPF > 5%: RR: 2.4 (95% CI 1.2-5)]. Parameters associated with increased metastatic recurrence rates, by order of entry in the model, were: young age [< 35: RR: 2.46 (95% CI 1.2-5)], large clinical tumour size [T3: RR: 2.02 (95% CI 1.2-3.4)], poor histological grade (SBR III: RR: 1.93 (95% CI 1.1-3.3)] and the failure to respond to chemotherapy [D: RR: 1.91 (95% CI 1-3.4)]. The assessment of both tumour cell proliferation rates as well as possibly drug resistance markers (although not available in the present study) should be helpful in selecting patients likely to benefit from intensified chemotherapy regimens. The most accurate predictor of response in the present study appeared to be the response to chemotherapy treatment itself.

Neoadjuvant chemotherapy in operable breast cancer

Primary chemotherapy in localised breast cancer may prevent tumour spread during surgical treatment and reduce proliferation of micrometastases. A randomised clinical trial, in 196 premenopausal and postmenopausal patients with operable (T2-3, N0-1b) breast cancer, was started in November 1983 at the Institut Curie to compare neoadjuvant and adjuvant regimens of chemotherapy with radiotherapy with or without surgery. The patients have been followed up for 35-70 months (median 54). A neoadjuvant group received two monthly cycles of intravenous doxorubicin/cyclophosphamide/5-fluorouracil before locoregional therapy and four cycles subsequently. Six monthly cycles following locoregional therapy were administered to the adjuvant group. Because of inclusion of postmenopausal and/or node-negative patients, compliance was less than optimal in 39 patients who were analysed separately according to actual dose received. Tumour response, evaluated after two cycles of neoadjuvant chemotherapy, was significantly associated with dose (P = 0.003). Survival showed a slight non-significant advantage for the neoadjuvant group. Survival plotted by actual dose was also similar. Neoadjuvant chemotherapy was safe and at least as effective as the adjuvant regimen. Patients have been accrued to a subsequent larger trial of chemotherapy as first-line treatment.

Conservative treatment of early breast cancer: prognostic value of the ductal in situ component and other pathological variables on local control and survival. Long-term results.

Four hundred and thirty-four patients with infiltrative ductal carcinoma were treated by limited surgery and irradiation between January 1960 and December 1980. The median follow-up was 103 months. Retrospective pathological analysis of the primary tumor identified a subset of pathological parameters which were predictors of local breast failure and survival. Pathological predictors of local breast recurrence were: incomplete surgical excision (P less than 0.0001), lymphatic invasion (P less than 0.02) and presence of an extensive in situ component (EDISC) (P less than 0.03). Pathological predictors of survival were: incomplete surgery (P less than 0.007), size of the primary tumour (P less than 0.03), high histologic grade (P less than 0.005), lymphatic invasion (P less than 0.0001) and absence of associated in situ component (P less than 0.008). This study emphasizes the role of the in situ component in the prognosis of breast carcinoma treated with conservative management.

Simultaneous bilateral breast carcinomas: A retrospective review of 149 cases☆

PURPOSE To evaluate clinical and biological characteristics as well as treatment outcome in simultaneous bilateral breast carcinomas. METHODS AND MATERIALS Between 1981 and 1990, 149 patients were diagnosed to have simultaneous bilateral breast carcinoma, defined as tumor arising in both breasts within a maximum of a 6-month interval, in the absence of distant metastases. The median age was 58. Out of a total of 298 tumors, the clinical tumor size was T0-T1 in 40%, T2 in 45%, and T3-T4 in 15% of tumors. The majority of patients (83%) were clinically node negative. Seventy-eight percent of all tumors were classified ductal invasive; 6% were invasive lobular carcinomas; in situ tumors were present in 9%. More than two-thirds of all tumors were well or moderately well differentiated. Tumors were estrogen positive in 86% and progesterone positive in 69% of 62% of patients for whom this information was available in both tumors. Treatment had been by bilateral mastectomy in 43%, by exclusive irradiation in 16%, and by combined surgery and radiation in 41%. RESULTS Median follow-up was 68 months (11-141). A number of positive correlations existed between the tumors in both breasts more often than by chance alone: These were the presence of lobular carcinomas in both breasts (p = 0.06), the same histological grade (p = 0.002), similar ER (p = 0.03) and PR (p = 0.01) status. Five-year rates for survival and disease-free interval were 86% (80-92) and 70% (62-78), respectively. For each patient the stage of the largest tumor at diagnosis was defined as maximum stage. When survival figures were compared between each maximum stage and matched stages of a group of unilateral breast cancer patients treated during the same time interval in our institute, bilateral breast cancer fared not worse than unilateral breast tumors. Treatment related complications occurred in eight patients (5%). CONCLUSION Simultaneous bilateral breast carcinomas have similar biological, but not clinical, features more frequently than would be predicted by chance alone. So far, the number of patients is too small, and the follow-up is too short to determine whether or not the prognosis is equivalent to that of unilateral breast cancer patients of equal stage. Bilateral conservative treatment is feasible with acceptable cosmetic results and toxicity by using carefully designed radiotherapy techniques.

Isolated axillary recurrences after conservative treatment of breast cancer

This retrospective study presents the diagnostic, prognostic and therapeutic problems raised by axillary recurrences (AR). 1589 cases of breast cancer measuring less than 3 cm, treated at the Institut Curie between 1981 and 1987, were studied by a combination of surgery and radiotherapy. Treatment of the breast always included wide local excision associated with irradiation. The axilla was treated either by dissection (865 cases) or by irradiation (724 cases) and 159 patients received chemotherapy. 26 patients (2%) developed AR, confirmed by fine needle aspiration cytology in 92% of cases. None of these 26 patients had initially received chemotherapy. The treatment of the AR was variable, adapted to the initial treatment. 22 patients retained their breast during treatment of the AR and none subsequently developed a local recurrence. 4 mastectomies were performed and histological examination revealed a subclinical local recurrence in 2 cases. The TNM classification, menopausal status, size of the tumour and hormonal receptor status were not risk factors for AR. Young age (P = 0.01) and high histological grade (P = 0.03) were significant risk factors for AR. The AR rate was similar whether axillary dissection or axillary irradiation had been performed. The overall 5-year survival after initial treatment was 85% for AR and 95% for the reference population. The overall 4-year survival after recurrence was 69% and the incidence of metastasis was markedly increased (P = 0.002). 2 of the 26 patients developed lymphoedema of the arm after treatment of AR. We confirm that AR worsens the prognosis, but not significantly more than local recurrence. Young age and the modified histological grading of Scarff Bloom and Richardson were risk factors for AR. Although excision of the AR is necessary to ensure local control, mastectomy is unnecessary when clinical examination and mammography are normal.