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© 1999 American Society for Clinical Oncology Breast-Conserving Therapy: Proteases as Risk Factors in Relation to Survival After Local RelapseFrom the Division of Endocrine Oncology, Department of Medical Oncology, Rotterdam Cancer Institute, Dr. Daniel den Hoed Kliniek/Academic Hospital Rotterdam, Rotterdam, the Netherlands. Address reprint requests to Marion E. Meijer-van Gelder, MD, Josephine Nefkens Institute, Room Be428, Dr Molewaterplein 50, 3015 GE Rotterdam, the Netherlands.
PURPOSE: To evaluate whether cathepsin D, urokinase-type plasminogen activator (uPA), its inhibitor, plasminogen activator inhibitor-1 (PAI-1), or clinical factors can predict which patients are at risk for developing distant metastases after local recurrence (LR). PATIENTS AND METHODS: Of 1,630 patients treated with breast-conserving surgery and radiotherapy of the breast between 1980 and 1992, LR developed in 171 as a first event. From the available primary tumor tissues, we determined the cytosolic levels of cathepsin D, uPA and PAI-1.
RESULTS: In patients with LR, a short ( CONCLUSION: In patients treated with breast-conserving therapy who had LR as a first event, a short DFI and skin involvement were strong indicators for poor PR-DMFS and PR-OS. The proteases studied did not contribute significantly to the final multivariate model.
BREAST-CONSERVING SURGERY for invasive breast cancer is an appropriate method of primary therapy for stage I and II breast cancer. Several retrospective studies and randomized trials have shown that there is no significant difference in distant disease-free and overall survival between various kinds of local treatment for primary breast cancer, including breast-conserving therapy (BCT) and total mastectomy.1-8 One of the major concerns in BCT is the development of local recurrence (LR). Differences in surgical procedures and radiotherapeutic techniques, as well as the application of various kinds of systemic adjuvant therapy,9-11 might be responsible for the reported variation in the incidence of LR. In the literature, the LR rate after lumpectomy and irradiation varies from 3% to 12% at 5 years. The number of LRs increases slowly but continuously with longer follow-up, up to 10% to 20% after 10 years.3,8,12-23 Veronesi et al12 reported an estimated yearly conditional event probability for LR of about 1%. Breast cancer recurrence by itself seems to be an independent factor to predict poor distant disease-free and overall survival.12,24-27 Because there are no differences in prognosis between patients treated with BCT or mastectomy, this indicates that the LR may be considered as a marker for aggressiveness of the primary tumor, ie, its ability to cause distant metastasis (DMet). However, not all patients with LR are at high risk. An extensive intraductal component, strongly predicting residual disease and LR, does not correlate with distant disease-free or overall survival.17,28-32 For the treatment of LR, it is important to differentiate between LR with or without the higher risk of developing distant disease. The biochemical processes that ultimately lead to tumor cell invasion and metastasis require degradation of the basement membrane and surrounding extracellular matrix. Different proteases are important in the processes of cell invasion, adhesion, migration, arrest at the metastatic site, growth, and neoangiogenesis at the primary and metastatic site. Accumulated data from preclinical and clinical studies strongly suggest that the urokinase system of plasminogen activation plays a central role in the processes leading to metastasis formation.33-36 In 1988, Duffy et al37 showed that a high tumor activity of the serine protease urokinase-type plasminogen activator (uPA) was associated with a poor prognosis in patients with primary breast cancer. Shortly thereafter, it was shown that patients with primary breast cancer had a poor prognosis if the primary tumor expressed high levels of the lysosomal aspartyl protease cathepsin D.38,39 A variety of studies have shown that high tumor levels of uPA, its inhibitor, plasminogen activator inhibitor-1 (PAI-1),36,40 and cathepsin D41,42 are associated with a poor prognosis in primary breast cancer. Therefore, it is of interest to study whether the expression levels of cathepsin D, uPA, and/or PAI-1 in the primary tumor or LR tissues can be used to predict which patients with LR will be at high risk for developing DMets. In the present study, we determined the levels of cathepsin D, uPA, PAI-1, estrogen receptor (ER), and progesterone receptor (PgR) in primary tumors and available LR tissues of 1,630 patients who were treated with BCT. Their levels have been correlated with the clinical outcome after their first presentation of LR.
Patients and Tissues The study group comprised 1,630 Dutch patients with operable primary breast cancer between 1980 and 1992 who had no signs of distant disease within 3 months after surgery. Patients who had a history of malignancy before they developed breast cancer were excluded. All patients underwent breast-conserving surgery (lumpectomy) followed by radiotherapy (RT) on the breast (mostly external RT, 45 Gy plus a 20-Gy boost). An axillary dissection was performed in 99% (1,617 of 1,630) of the patients. Patients with positive axillary nodes (n = 542) were treated with adjuvant RT (n = 218, 40%) and/or systemic therapy. Adjuvant chemotherapy (mainly cyclophosphamide, methotrexate, and fluorouracil) was given to 255 patients, while 92 patients received adjuvant hormonal therapy, either alone (78 patients) or in combination with chemotherapy (14 patients). The median age of the patients at the time of primary surgery was 50 years (range, 22 to 84 years). All patients underwent primary surgery in our center or were referred for RT while surgery took place in regional community hospitals. All patients were routinely examined every 3 to 6 months during the first 5 years of follow-up and once a year thereafter. A computerized database contained age, menopausal status, tumor status, treatment, and updated clinical information on each patient. Pathologic values were extracted from the original pathology reports. The median follow-up of surviving patients was 88 months (range, 12 to 197 months). Four hundred seventy-three patients (29%) died, 42 of them with no evidence of disease. These patients were censored at last follow-up in the analysis for disease-free survival (DFS). Patient and tumor characteristics are listed in Table 1.
Every renewed tumor growth in the treated breast that occurred as first event at least 3 months after surgery for the primary tumor was considered LR. Because patients with local-regional recurrence (LRR) or DMet at the same time as or within 1 month after developing LR are treated differently (mainly systemic) from patients with LR only (mainly surgery), they were not defined as having LR in our study and were not analyzed further in postrelapse survival analyses. An extensive intraductal component was determined to be present when more than 25% of the tumor area consisted of ductal carcinoma in situ or at least 10 ductulobular units were involved. Multifocality was defined as more than one tumor location in the lumpectomy specimen, with the largest focus representing the tumor size.
Assay of uPA, PAI-1, Cathepsin D, ER, and PgR uPA and PAI-1 levels were determined in breast tumor cytosols using enzyme-linked immunosorbent assays45,46 with reagents that are now commercially available in assay kits (American Diagnostica, Greenwich, CT). Cathepsin D levels were determined in breast tumor cytosols using a radiometric immunoassay (ELSA-CATH-D; CIS Bio International, Gif-sur-Yvette, France).47 The cut points used to classify tumors as high and low were 1.15 ng/mg protein for uPA,45 17 ng/mg protein for PAI-1,46 and 45 pmol/mg protein for cathepsin D.42
Statistics For survival analyses, we used the following definitions. Disease-free interval (DFI) was defined as the time between primary surgery and the first recurrence of breast cancer. The group with no evidence of disease during follow-up was named NED. The first recurrence of breast cancer, at least 3 months after primary surgery, was further subdivided into LR, every renewed tumor growth in the treated breast, LRR, (ipsilateral axillary, infraclavicular, supraclavicular, or internal mammary nodes), contralateral breast carcinoma (CBC), and DMet. When different kinds of recurrences were diagnosed at the same time, or within 1 month, the recurrence with the worst prognosis was chosen. The end point breast cancer–related death and the time elapsed from primary surgery to death was used for survival analyses. In the group of patients with LR associated with postrelapse distant metastasis-free survival (PR-DMFS), we used as an end point all second recurrences except LR. The start date was therefore the date of the LR and the end date was the date of LRR or DMet. For postrelapse overall survival (PR-OS), the time interval between LR and death was used, with death from any cause as the end point. Survival probabilities were calculated by the actuarial method of Kaplan and Meier,48 using the log-rank test to test for differences. Both uni- and multivariate analyses were performed using the Cox proportional hazards model. Logistic regression was used for dichotomous outcome variables. The likelihood ratio test was used to test for differences between models with variables included and excluded. All P values were two-sided and relate to all available follow-up data.
Sites of Recurrence After Lumpectomy We classified the 1,630 patients who underwent breast-conserving surgery and RT at the end of the follow-up period as NED (945 patients, 58%) or by their first site of relapse. One hundred seventy-one patients (10%) developed LR, 81 (5%) CBC, 70 (4%) LRR, and 363 (22%) DMet as the first event. Notably, in the patients in whom CBC developed as the first event, the frequency of LR was twice as high (19 of 81, or 23%) as compared with that observed in all patients (10%). Furthermore, of the 171 patients in whom LR developed as the first event, 18 (11%) subsequently developed CBC, also approximately twice the frequency observed in all 1,630 patients (5%). Table 1 shows the relative distribution of patient and tumor characteristics for groups of patients stratified by the site of first event. Figure 1 shows the disease-specific survival of the 685 relapsing patients as a function of the site of first event. The groups of patients with LR and CBC had a survival rate of 61% ± 4% and 67% ± 6%, respectively, at 10-year follow-up. These patients had a significantly better prognosis than those in whom LRR or DMet developed as the first event (10-year DSS, 21% ± 6% and 14% ± 2%, respectively) (Fig 1).
Disease-Free Survival as a Function of uPA, PAI-1, and Cathepsin D Status
Characteristics of Patients With LR In 124 patients (73%), the LR developed in the same quadrant or in the vicinity of the primary tumor, in 39 patients (23%) it developed in a different quadrant, and for eight patients (4%) the site of the LR was unknown. The location of the LR was not significantly related to the length of PR-DMFS or PR-OS (both, P = .8). After developing LR as the first event, 53% (92 of 171) of the patients developed DMet, with nine of them developing LRR before DMet. Of the remaining 79 patients who showed NED at their last follow-up date, 12 patients had one or more LRs that were adequately treated. All 171 patients with LR had a 5-year PR-DMFS of 43% ± 4%. The levels of cathepsin D, uPA, and PAI-1 were determined in available primary tumor tissues (ranging from 108 to 110 samples, depending on the variable analyzed) of the 171 LR patients. Only a small number of the 167 patients treated with salvage surgery had LR tissue available for determination of the levels of cathepsin D (n = 66), uPA (n = 65), and PAI-1 (n = 65). Among the limited number of patients for whom the cathepsin D (n = 41), uPA (n = 40), and PAI-1 levels (n = 41) were determined in both the primary tumor and the corresponding LR tissue, there were no statistically significant differences between the levels.
DFI and Skin Involvement
Using DFI as an end point, logistic regression analyses of the levels of ER, PgR, cathepsin D, uPA, and PAI-1 in the primary tumors showed that in patients with a DFI of more than 2 years, the primary tumor levels of ER were higher; in contrast, the primary tumor levels of uPA and PAI-1 were significantly lower when compared with levels in tumors of patients with a DFI of Of the 171 LRs, 31 of the tumors had skin involvement. Skin recurrence alone was observed in 15 patients, and 16 patients had skin as well as parenchyma involvement of their LR. There was no significant difference in PR-DMFS or PR-OS between the 16 patients with and the 15 patients without parenchymal disease. In further analyses, therefore, these 31 patients were considered as one group. These patients had a significantly worse PR-DMFS (Fig 2C) and PR-OS (Fig 2D), as compared with patients with only parenchyma involvement of their LR. Logistic regression analyses of the levels of ER, PgR, cathepsin D, uPA, and PAI-1 in the primary tumors in relation to the type of relapse (skin v no skin) did not reveal any significant relationship between the levels of the biologic factors and skin involvement of LR.
Cox Uni- and Multivariate Analyses
In Cox multivariate regression analyses, after including age, menopausal status, nodal status, and size of the primary tumor, of the clinical variables only type of LR (skin involvement v no skin involvement) and DFI (
The pathogenesis of LR after BCT is not fully understood. Compared with patients who do not experience LR, those who do have a poor DMet-free and overall survival. Several studies show that patients who experience LR as the first event have a two- to four-fold increased risk of developing DMet.15,25,26,49 In our study, among the 171 patients with LR as the first event, the 5-year PR-DMFS was only 43%. It is presumed that LR is not the cause of DMet but rather an indicator of aggressive biologic characteristics of the primary tumor.12,26 It is important to distinguish LR caused by inadequate local treatment from LR as an indicator of developing DMet due to unfavorable tumor characteristics. The latter patients might benefit from a more aggressive therapy. Young age at the time of surgery, extensive intraductal component, and multifocality were strong prognostic factors for the development of LR in our study, which is in agreement with several other studies.12,17,28-32,49-53 In the present study, the levels of biologic factors (ER, PgR, cathepsin D, uPA, and PAI-1) in the primary tumors were not related to the occurrence of LR. This is in agreement with Silvestrini et al,53 who studied ER and PgR in 110 node-negative patients who developed LR as first site of relapse, and with Knoop et al,54 who studied uPA and PAI-1 in a total group of 47 LR patients. We observed a relationship between higher levels of cathepsin D, uPA, and PAI-1 in the primary tumor and the occurrence of DMet as first event. The association of these factors with a poor prognosis for patients with primary breast cancer has been well documented.36-42
The time interval from surgery of the primary tumor to detection of LR as first event is an important prognostic indicator. The risk of developing DMet is inversely related to the time from surgery to LR.12,15,24,26-28,55-57 Veronesi et al12 reported a 6.6-fold higher risk of developing DMet for patients who developed a LR within the first year after surgery compared with patients who developed a LR more than 3 years after surgery. For patients who developed a LR in the second and third year after surgery, these risks were 2.2-fold and 1.2-fold higher, respectively. For time intervals of 5 or more years between primary surgery and development of LR, no difference in overall survival could be demonstrated in most studies.12,15,28,56 Compared with patients with a DFI of more than 5 years, we found that patients who experienced LR in the first year after surgery had a relative risk of 3.7 for developing DMet; the relative risk was 3.0 and 1.7 for patients who experienced LR in the second and third years after surgery, respectively. As a consequence, the PR-OS was considerably decreased for patients with a DFI of
In general, LR in the skin is rare. However, skin involvement predicts a poor outcome and there is a high risk that DMet will develop.15,29,55,58,59 In our study involving 171 patients, 15 (9%) had LR in the skin only which is comparable with the 8% reported by Gage et al,59 and 16 (9%) had skin and parenchyma recurrence. These 31 patients (18%) with skin involvement of their relapse had a substantially decreased PR-OS (P < .001). In contrast to what we observed in the group with a DFI of In Cox univariate analyses for PR-DMFS and PR-OS, nodal status, time interval to LR, and skin involvement were strong prognostic factors. Of the biologic factors, high levels of uPA and PAI-1 in the primary tumor were significantly associated with a poor PR-OS. However, such relationships were not found in the analysis for PR-DMFS. This might be the result of a relationship of these factors with a poor response to systemic therapy for DMet. In this respect, previous studies have shown a relationship between a poor response on systemic therapy and high levels of uPA,60,61 PAI-160 and cathepsin D.62,63 In Cox multivariate analyses for PR-DMFS and PR-OS, a short DFI and skin involvement were independent factors of poor prognosis. In conclusion, patients who were treated with BCT for primary breast cancer and experienced a LR within 2 years and/or showed skin involvement of their LR have a poor clinical outcome. These patients might benefit from a more aggressive treatment of their LR. However, the impact of the proteases in relation to survival after LR is not clear yet.
Supported by grant no. DDHK 96-1234 from the Dutch Cancer Society, Amsterdam, the Netherlands We thank Drs M. Schmitt (Munich, Germany) and M.D. Kramer (Heidelberg, Germany), and American Diagnostica Inc (Greenwich, CT) for reagents and enzyme-linked immunosorbent assay kits for the measurement of uPA and PAI-1. We gratefully express our thanks to the community hospitals in the region, especially the surgeons and internists of the St Clara Hospital, Ikazia Hospital, and St Franciscus Gasthuis at Rotterdam, for their assistance in collecting the patients' clinical follow-up data.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 years) disease-free interval (DFI) and skin involvement of LR were associated with poor postrelapse distant metastasis-free survival (PR-DMFS, P = .001, both) and postrelapse overall survival (PR-OS; P < .0001 and P < .0002, respectively). The primary tumor levels of uPA and PAI-1 were elevated for patients with a short DFI (P < .01), but such a relation was not observed for patients with skin involvement. In univariate analyses, high levels of uPA and PAI-1 in the primary tumor were associated with poor PR-OS (P = .038 and P = .040, respectively) but not PR-DMFS. In Cox multivariate analyses for PR-DMFS and PR-OS, only a short DFI and skin involvement of the LR were independently associated with a poor clinical outcome. 
