Why are local recurrences after breast-conserving therapy more frequent in younger patients?

The influence of patient age on risk of recurrence in the breast was retrospectively studied in 496 stage I-II invasive ductal carcinomas treated by macroscopically complete primary tumor excision followed by radiotherapy. With a median follow-up of 71 months, local recurrence occurred in 13 of 62 (21%) patients younger than 40 years, compared with 48 of 434 (11%) older patients (P less than .025). Cox multivariate analysis of 18 parameters identified four that significantly determined risk: major lymphocytic stromal reaction (MCR), unsatisfactory resection margins, increasing histologic grade, and extensive intraductal cancer (DCIS) within the primary tumor. Compared with older patients, those younger than 40 years had tumors that more often exhibited MCR (36% v 20%, P less than .01), histologic grade 3 (42% v 28%, P less than .025), and very extensive DCIS (21% v 6%, P less than .001). The status of resection margins did not differ significantly between younger and older patients. Restriction of Cox analysis to patients younger than 40 indicated that risk was adequately described by MCR and percentage of DCIS, without consideration of grade or margins. For patients younger than 40, local failure occurred in four of five (80%) tumors with both MCR and more than 50% DCIS, in eight of 25 (32%) with either, and one of 32 (3.1%) with neither of these morphologic features. This study suggests that the higher local failure risk observed in patients younger than 40 years reflects the greater prevalence of certain morphologic characteristics in breast cancers in younger patients. Age itself does not appear to be an independent determinate of risk.

Is breast conservation after local recurrence feasible?

The feasibility of conservative salvage surgery was addressed in a clinicopathologic study of the results of wide excision for 50 selected parenchymal intramammary recurrences after standard breast conserving treatment. After median follow-up of 51 months, 16 (32%) second local failures were observed (5-year local control 62%). Cox multivariate analysis of 18 parameters indicated that only disease-free interval and resection margins significantly influenced local control. 5-year local control was 92% for recurrences occurring after 5 years vs. 49% for shorter intervals, and 73% for negative vs. 36% for positive or indeterminate margins. Local control appeared independent of morphologic features, initial tumour stage, patient age, recurrent tumour size and location. Median survival after second local failure was 33 months; tertiary therapy obtained ultimate local-regional control in 8 of 16 cases. The authors conclude that wide excision is a particularly satisfactory alternative to salvage mastectomy for late recurrences. Negative margins are essential. Further study will be required to establish additional guidelines allowing improved patient selection.

Mammary recurrences in women younger than forty.

The crude mammary recurrence rate was studied in 5-year age intervals for 1,382 Stage I and II breast cancer patients treated by conservative surgery and radiation therapy and followed for a median of 11 years. Patients younger than 40 had a significantly higher local recurrence rate (41/210, 19%) than did older patients (106/1172, 9%). The majority of excess recurrences in the younger patients occurred early, with recurrence rates between 5 and 10 years being equal for the 2 age groups. A comparison of the clinical characteristics of the patient groups yielded no obvious explanation for the higher local recurrence rate in the younger patients, and 15-year cancer-specific survival was identical. Within the younger age group, recurrence rate was independent of clinical tumor size, and was unaffected by adjuvant treatment. Young patients with positive axillary nodes or negative hormone receptors appear to be at particularly high risk for mammary failure. Despite this apparent correlation with biologic aggressiveness, the 41 patients with mammary recurrence experienced long-term survival from time of primary treatment which was not significantly worse than that of patients not having had local recurrence. For 37 patients with operable mammary recurrence, the 10-year survival from time of salvage surgery was 64%.

Contralateral breast cancer and other second malignancies in patients treated by breast-conserving therapy with radiation.

Metachronous contralateral breast cancers and other second malignancies were evaluated in 2,850 patients treated between 1960 and 1981 primarily with radiotherapy (RT) either alone or following breast-conserving surgery. One hundred eighty-four contralateral cancers were observed in 22,491 patient-years of observation (818 per 10(5) patient-years), with a cumulative probability of 4.5% at 5, 7.9% at 10, and 11% at 15 and 20 years. Compared to patients with unilateral tumors, those destined to develop contralateral cancers were younger (mean age 51.9 vs 56.6) and more often gave a family history of breast cancer. Contralateral breast cancers were more frequent for more extensive tumors (T3 10% vs T1-26%; with inflammatory signs 10.6% without 6%), and in patients with ipsilateral local recurrence (with 9.1%, without 5.6%). Patients with contralateral cancers had a significantly less favorable survival experience (15-year actuarial survival after primary therapy 42%) than patients without contralateral cancer (15-year survival 65.5%). In early stage patients treated with conservative surgery and RT, contralateral cancer was not prognostically more favorable than ipsilateral breast recurrence. Among 72 other second malignancies (320 per 10(5) patient-years) were 2 soft tissue sarcomas in the irradiated area. This corresponds to an incidence of 21 cases per 10(5) patient-years for survivors beyond the fifth year. The possible influence of RT on contralateral cancers and other second malignancies is discussed.

The prognostic significance of late local recurrence after breast-conserving therapy.

Of 178 local recurrences occurring in 1593 patients with clinical Stages I-II breast cancer treated by conservative surgery and megavoltage radiotherapy, 71 were diagnosed after the 5th year. Compared with recurrences occurring prior to 60 months, late recurrences were less frequently inoperable (1/71, 1.4%, versus 18/107, 17%, p less than 0.001), were more often located at a distance from the initial primary tumor (23/71, 32%, versus 15/106, 14%, p less than 0.005), and had a more favorable prognosis (5-year survival 84% versus 61% for late and early operable recurrences, respectively, p = 0.05). Five-year metastasis-free survival after late failure depended mainly on the anatomic extent of the recurrence (87% for recurrences apparently confined to the breast versus 34% for relapses involving the axilla, p less than 0.002). Prognosis of late recurrence appeared to be unaffected both by location of the recurrence within the breast and by the type of salvage operation used (mastectomy versus wide excision). Local-regional control after salvage surgery was satisfactory (89% at 5 years). Whereas recurrence in the breast prior to 5 years profoundly affected survival after initial diagnosis, patients with late failure had identical 15-year survival as other 5-year survivors who never failed locally. Late recurrences were more frequent in patients younger than 40 at initial treatment, and in patients who had inadequate radiotherapy. We conclude that late local recurrences after breast conservation do not represent a serious management problem.

How important is adequate radiotherapy for the long-term results of breast-conserving treatment?

The influence of radiotherapy dose parameters on longterm local control was studied in 134 clinical stage I-II breast cancer patients treated by tumorectomy and telecesium therapy during the 1960s. Recurrence in the breast was more frequent in patients receiving 75 Gy or less to the tumor bed (31% versus 15% for higher doses, p less than 0.05), and weekly dose rates of less than 8 Gy/week were associated with increased local-regional failure (30% versus 15% for higher weekly doses, p less than 0.01). The majority of local-regional failures were observed in the 53 patients having "inadequate" total or weekly radiotherapy doses (18/53, 34% versus 9/81, 11%, p less than 0.001). The importance of adequate radiotherapy applied to both older patients, as well as those younger than 40, who appear inherently to have a higher risk of local relapse. The mean interval to recurrence was markedly longer for inadequate radiotherapy (111 months, versus 75 months for adequate treatment), so that significant differences in local control became apparent only after 5 years. These results underscore the importance of radiotherapy technique in breast-conserving treatment, and suggest that an excessive reduction in the intensity of radiotherapy may result in an inordinate number of late local failures.

[Value of clinical tests in the diagnosis of breast cancer: report of 2,626 cases]. / Valeur de l'examen clinique dans le diagnostic du cancer du sein: à propos de l'étude de 2,626 observations.

The present study has assessed the value of clinical examination of breast cancers in a retrospective study of 2,626 cases of operated mammary lesions. Anatomopathology is used as basic reference. The fiability of the cancer diagnosis is 94%, its sensitivity is 90% and specificity 96%. The total error only amounts to 6%, with 2/3 false negatives and 1/3 false positives. The errors are for the most part due to the anatomopathologic nature of the tumor, its size, the area of the body it is situated in and also to the examiner and to the of the patient. Nevertheless clinical examination still remains the first diagnostic step, and is indispensable in all breast pathology.

[Cathepsin D: an independent prognostic factor in cancer of the breast]. / La cathepsine-D: un facteur pronostique indépendant dans le cancer du sein.

The total amount of cathepsin-D (mature forms and pro-enzyme especially) in the cytosol of 88 breast cancers including 85 primary cancers and 11 axillary lymph node metastasis was measured by way of immuno-radiometric assay. Maximum follow-up is 58 months. Cathepsin-D was found to be independent of clinical and biological parameters including axillary lymph node involvement and oestradiol receptors (RE). Univariate analysis has pointed out a significant linkage between overall survival and cathepsin-D, using a cut-off level of 30 pmol/mg protein which is the most discriminating value. Cathepsin-D appeared to be particularly useful in lymph-node-positive and RE-negative patients but it was not significant in the node-negative population. Multivariate analysis of the overall survival (Cox model) revealed that it was strongly related to oestradiol receptor, lymph node involvement and cathepsin-D.

[Reevaluation of indications for adjuvant hormone therapy in primary breast cancer with high metastatic risk]. / Réévaluation des indications d'une endocrino-hormonothérapie adjuvante dans les cancers primitifs du sein à haut risque métastatique.

This study concerns the correlation between ER and PR status, menopausal status and the effect of adjuvant hormonotherapy in high risk primary breast cancer patients. We have compared the results obtained in a randomized trial (Institut Paoli-Calmettes, Marseille) with those of a historic series (Centre René Huguenin, Saint-Cloud). The patients presented the same clinical and histological criteria and received identical therapeutic protocols (chemotherapy and/or hormonotherapy). Compared with patients receiving no adjuvant treatment, it appeared that: 1) in post-menopausal patients, a significant detrimental effect of tamoxifen was found in ER-negative patients, while in ER-positive patients hormonal treatment was well correlated with both the presence and level of steroid receptors; 2) in pre-menopausal patients, hormonal therapy (oophorectomy + tamoxifen) appeared to be mediated by a complex mechanism involving more than an ER-positive cell population. In the light of the published results, the present findings underline the importance of reevaluating the indications of hormonotherapy in terms of hormone receptors and menopausal status. They also indicate the importance of biological factors in the evaluation of response to therapy. They can identify, subsets of patients in whom a given therapeutic protocol is detrimental, even though it may be beneficial for the overall population. heterogeneity in response to therapy among patient subsets is one of the most important problems which confronts medical statisticians and clinical investigators.

[Curative radiotherapy with hope of saving the breast in operable breast cancers 403 cases with 5-year survival]. / Radiothérapie curative à espérance conservatrice des cancers du sein opérables. 403 cas de 5 ans

Between 1960 and 1975, 1 078 operable mammary carcinomas were treated by caesium therapy with the objective of conserving the breast. The authors analyse the indications for and results of this treatment in the 403 cases which have had more than 5 years follow up (241 cases were irradiated as primary treatment, 162 after having a simple tumorectomy). For the whole group 92 mastectomies were ultimately carried out: in 30 of them no tumour was found in the operative specimen. The tumorectomy cases, restricted to stage 1 of the UICC classification (pre 1962) -- PRV 0 IGR yielded the best results: 86 per cent 5 yeat cures with 9 out of 10 women retaining both breasts. The primary irradiation cases, all types considered, gave results comparable with those for primary radical surgery: 58 per cent 5 year cures-but 2 out of 3 women retained both breasts. By itself caesium therapy is capable of eradicating tumour in breast and axilla in half of the cases. It really amounts to a "double chance strategy"--an attempt at cure if possible with avoidance of mastectomy, this being in reserve in the event of failure.

[Prognostic value of thymidine kinase in cancer of the breast]. / Valeur pronostique de la thymidine kinase dans le cancer du sein.

We have measured by a radioenzymatic assay the thymidine kinase in the cytosol of 182 primary infiltrating breast cancers. Maximal follow-up is 95 months. Thymidine kinase was found to be related to SBR grade, tumour size and absence of oestradiol receptors (RE). Univariate analysis has pointed out a significant linkage between overall or metastase free survival and thymidine kinase, using a cut-off level of 80 mU/mg protein which is the most discriminating value. Thymidine kinase appeared to be particularly useful in lymph-node-positive, RE-negative and grade 3 patients. Multivariate analysis of the overall survival and of the metastase free survival (Cox model) revealed that they were strongly related to thymidine kinase status.

[Results of the conservative surgical and irradiation treatment of 132 nonpalpable ductal carcinomas in situ of the breast]. / Résultats du traitement par chirurgie conservatrice et irradiation de 132 carcinomes canalaires in situ non palpables du sein.

PURPOSE: Retrospective analysis of results of treatment of 132 subclinical ductal carcinomas in situ, non-palpable. MATERIAL AND METHODS: Patients were treated with limited surgery and 70 Gy radiation therapy (70 Gy). RESULTS: With a median follow-up of 7 years, the total recurrence rate was 6%, and the actuarial rate at 5 years 4% and at 10 years 13% at. These have no influence on recurrence on the specific actuarial survival rate which was 100% at 10 years. In spite of five infiltrating recurrences of seven, no metastasis appeared 48 months after the salvage surgery. The global rate of breast preservation was 92% at 7 years. DISCUSSION AND CONCLUSION: Therapeutic indications were developed taking into account the present analysis and a literature review (2,338 in situ ductal carcinomas, palpable or not, treated with conservative surgery, with or without adjuvant radio-therapy).

[Conservative treatment of sub-clinical noninfiltrating cancers of the breast (102 EOA in situ, TONO)]. / Le traitement conservateur des cancers du sein infra-cliniques canalaires non infiltrants (102 EOA in situ, TONO).

102 patients with sub-clinical intra ductal non invasive breast cancer (T0N0) treated by limited surgery and curative radiation therapy. Follow-up ranged from 2 to 10 years with a median follow-up of 59 months. The long term survival rate of this therapeutic approach, consisting of simple excision without any adjuvant treatment and radical mastectomy was close to 100%. The actuarial local recurrence rate was only 8.6% at 10 years (confidence interval: 4.6 to 12.6%), which strongly suggests that radiation therapy is active on multicentric foci. Salvage surgery could be performed in every case of local recurrence. The survival rate of in situ breast cancer (T0N0) treated by conservative radio-surgery is comparable to that of radical mastectomy, while cosmetic results and psychological impact appear to be better for the conservative technique (breast preservation rate = 91 to 96%).

[Breast cancer: prognostic factors. Apropos of 1000 conservative treatments]. / Cancer du sein: facteurs pronostiques. A propos de 1000 traitements conservateurs.

Prognosis was analyzed as a function of histologic grade, axillary gland spread and hormonal receptors in a consecutive series of 1000 patients with breast cancer (stages I and II) treated by conservative tumorectomy and axillary curettage, combined with radiotherapy, and followed up for between 3 and 12 years. The three factors analyzed are of major importance in that they constituted a veritable tumoral identity card. Grade I tumors, the absence of glandular spread and the presence of hormonal receptors are correlated with cancer of good prognosis, whereas grade III tumors, major axillary spread and absence of hormonal receptors are related to a poor prognosis. Their interactions are studied by comparing associations of good and poor prognostic factors, allowing determination of populations at low and high risk of therapeutic failure.

Results of salvage surgery for mammary recurrence following breast-conserving therapy.

A retrospective analysis was performed of 118 surgically treated mammary recurrences, occurring following primary conservative excision and radiation therapy for clinical Stages I and II breast cancer. Actuarial cancer-specific survival following salvage surgery was 72% at 5 years and 58% at 10 years. With a median followup of 7 years, further local-regional recurrences were observed in 20 of the 118 patients, many of whom could be treated by further surgery. Actuarial survival after recurrence was significantly influenced by initial clinical stage, as well as by the disease-free interval following primary therapy, but was similar for both premenopausal and postmenopausal patients and for patients treated by radical or breast-conserving salvage operations. For recurrences after the fifth year, actuarial survival following salvage surgery was 83% and 68% at 5 and 10 years, respectively. Survival for Stage I patients was favorable regardless of disease-free interval. It is concluded that recurrences in the breast following primary treatment with limited surgery and irradiation have a considerably more favorable prognosis than that of local failures after primary radical surgery. Suggestions for the management of these recurrences are presented.

Results of wide excision for mammary recurrence after breast-conserving therapy.

Of 1,245 patients treated with breast-conserving surgery and radiotherapy for Stage I and II breast cancers, 118 required a secondary operation subsequently for apparently isolated recurrence in the treated breast. Fifty-two of these 118 patients were selected for salvage treatment with wide excision, with or without axillary dissection, instead of resorting to mastectomy. With a median follow-up of 6 years, the actuarial cancer-specific survival (Kaplan-Meier) after treatment of recurrence was 79% at 5 years and 64% at 10 years. The probability of local control in the treated breast was 79% at 5 years after conservative salvage surgery. Of 12 patients in whom second local or regional recurrences developed, ten could be treated by further surgery. We concluded from this experience that wedge excision represents an adequate alternative to mastectomy in the salvage treatment of isolated breast recurrences that are mobile, 2 cm or smaller in diameter, and without signs of rapid growth.

An assessment of extensive intraductal component as a risk factor for local recurrence after breast-conserving therapy.

The influence of extensive intraductal component (EIC) on local recurrence risk was studied for 496 patients with stage I-II infiltrating ductal cancers treated by conservative surgery and irradiation. EIC was diagnosed in 65 of 231 (28%) premenopausal and 41 of 265 (15.5%) post-menopausal patients. Local recurrence risk was markedly increased in EIC+ patients (5-year actuarial risk 18% versus 8% without EIC, P less than 0.001), but this effect appeared limited to premenopausal patients. Local recurrence risk increased with increasing degree of EIC. EIC with more than 50% intraductal carcinoma was more prevalent in patients younger than 40, perhaps accounting to some degree for the higher local recurrence rates observed in younger patients. The presence of EIC had no influence on overall survival, on median time to local recurrence, or on short-term survival after local failure. The usefulness of EIC as a risk factor for local recurrence is discussed.