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Clinical Cancer Research 14, 25, January 1, 2008. doi: 10.1158/1078-0432.CCR-07-0450
© 2008 American Association for Cancer Research
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Human Cancer Biology

Two Distinct Local Relapse Subtypes in Invasive Breast Cancer: Effect on their Prognostic Impact

Patrizia Casalini1, Maria Luisa Carcangiu2, Raija Tammi6, Päivi Auvinen7, Veli-Matti Kosma7,8, Pinuccia Valagussa3, Marco Greco4, Andrea Balsari5, Sylvie Ménard1 and Elda Tagliabue1

Authors' Affiliations: 1 Experimental Oncology, 2 Pathology, 3 Ufficio Operativo, and 4 Department of Surgery, Fondazione IRCCS "Istituto Nazionale dei Tumori", and 5 Institute of Pathology, University of Milan, Milan, Italy, 6 Departments of Biomedicine and Anatomy, University of Kuopio, 7 Department of Oncology and Pathology, Kuopio University Hospital, and 8 Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Kuopio, Kuopio, Finland

Requests for reprints: Sylvie Ménard, Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy. Phone: 39-2239-2571; Fax: 39-2236-2692; E-mail: sylvie.menard{at}istitutotumori.mi.it.


   Abstract
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 Abstract
Materials and Methods
 Results
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Purpose: Local relapse (LR) remains an important concern in breast cancer surveillance. Given the unique opportunity to study local recurrences in the breast in the absence of irradiation, we tested the possibility of identifying a particular tumor feature that might account for LR.

Experimental Design: Archival specimens from 235 patients belonging to the control arm (no radiotherapy) of the Milan 3 Trial were retrieved and included in this study. H&E-stained histologic slides were reviewed for diagnostic reassessment. A panel of biological variables was assessed by immunohistochemical/cytochemical staining.

Results: Onset of LR was significantly linked only to patient's age, with a hazard ratio (HR) to relapse reduced by 60% in patients >50 years of age (P = 0.002). Univariate and multivariate Cox analyses in women ≤50 years of age indicated that only expression of hyaluronan in tumor cells was associated with LR risk (HR, 2.48; P = 0.0364 and HR, 2.34; P = 0.0580, respectively). In patients >50 years of age, lymph node and estrogen receptor status were significantly predictive of LR (HR, 3.34; P = 0.0113 and HR, 0.39; P = 0.0424, respectively). Multivariate analysis indicated that apart from lymph node positivity (HR, 3.48; P = 0.0120), none of the variables associated with LR in univariate analysis displayed an independent LR-predictive power. LR had a strong prognostic impact on distant metastasis in patients >50 years of age, whereas in younger women, LR did not affect the risk of metastasis.

Conclusions: These results support the notion that LR arises from two distinct mechanisms, one that is more frequent in young patients, associated with host characteristics, and is not linked with prognosis, and another that is less frequent, but is associated with tumor aggressiveness which represents a peculiar and distinct marker of breast tumor malignancy.

Local relapse (LR) represents an important concern for patients with breast cancer because local tumor recurrence after breast-conserving therapy has been associated with the risk of distant spread and shorter survival (1–3). Although the risk for LR after breast-conserving surgery can be reduced significantly by radiotherapy (1) and by chemo-hormonal treatments (4), LR remains a major clinical problem because patients with a short interval from primary resection to LR are at an especially high risk for distant metastasis (5). Many studies have sought to identify the factors associated with an increased risk of recurrence, and the presence of an extensive intraductal component and the patient's age have been reported to be important predictors of LR (6–9). Although the yearly incidence for LR is low, the cumulative risk may be very high among younger patients who may live years, even decades, with their operated breast. Thus, molecular markers that predict the risk for LR would represent an extremely useful tool in planning appropriate treatment.

Recently, hyaluronan, an ubiquitous extracellular matrix molecule which is involved in various cellular functions (10), has been proposed to play a role in tumor growth and dissemination (11). Overexpression of hyaluronan in breast cancer cells and in the surrounding stroma is strongly associated with lymph node positivity, high tumor grade, and poor survival, thereby identifying high-risk groups and further pointing to a role for hyaluronan in invasion and metastasis (12). Its expression is increased during active tissue remodeling, e.g., during morphogenesis and wound healing (13). Hyaluronan may support tumor growth by regulating cell proliferation or by enhancing tumor neovascularization through fragmentation into angiogenic oligosaccharides (14). By virtue of its large size, the hyaluronan molecule can render the cancer cell microenvironment favorable to cell movement, and thus, breast cancer growth. In addition, hyaluronan may enhance tumor development by providing a molecular bridge that facilitates the attachment of hyaluronan receptor–bearing tumor cells to extracellular matrix components. Hyaluronan has been reported to modulate cell behavior by activating the signaling functions of its cognate cell surface receptors (10). Hyaluronan receptors also immobilize hyaluronan on the cell surface and contribute to hyaluronan endocytosis for lysosomal catabolism (15).

The Milan 3 Trial (16) provided a unique opportunity to study LR among 235 patients with breast cancer, none of whom received radiotherapy after the breast-conserving surgery. In this study, we tested established tumor variables as well as more recently described biological variables for their potential relationship to LR, with particular focus on hyaluronan levels in breast cancer cells or in the tumor stroma with respect to LR development and to other conventional prognostic factors.


   Materials and Methods
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Patients. The Milan 3 Trial studied the efficacy of radiation therapy after breast-conserving surgery in women with localized breast cancer; patients with tumor tissue containing resectioned margins were excluded from the study (16). A total of 579 patients in that study were treated with quadrantectomy and axillary dissection; 235 randomly allocated patients did not receive radiotherapy and represent the population studied here. The median age of the 235 patients was 53 years (range, 24-70); 101 (43%) of the patients were ≤50 years of age, and 134 (57%) were >50 years of age. Of the 84 node-positive patients, 52% received adjuvant chemotherapy, 44% received hormonal therapy, and 2% declined adjuvant treatment. Specifically, both premenopausal and postmenopausal patients negative for estrogen receptors (ER) received cyclophosphamide, methotrexate, and fluorouracile, whereas postmenopausal patients positive for ERs received tamoxifen. The follow-up median time of the patients was 10 years. Institutional approval from our Ethics Committee was obtained for the conduct of the study. Patients had agreed to the use of samples from their tumors for future investigation, although they did not provide written permission for the present study, which was done many years after the initial diagnosis.

H&E-stained histologic sections from each patient were reviewed for diagnostic reassessment. Histologic grading was assigned, according to Elston and Ellis (17), based on tubule formation, nuclear morphology, and number of mitoses. Desmoplasia was considered present when the proliferation of fibroblasts was detected in a myxoid fibrous stroma with dense eosinophilic collagen fibers around the tumor. Inflammation was scored positive when a dense or moderate infiltration of inflammatory cells was present, and negative when only occasional inflammatory cells were found.

Biological variables. At the same time of the retrospective pathologic review, a panel of immunocytochemical stains was done on paraffin-embedded tissue. Immunohistochemical stainings were carried out on formalin-fixed, paraffin-embedded tissue using heat-induced epitope retrieval in 10 mmol/L of citrate buffer (pH 6.0) and the following panel of monoclonal antibodies (mAb): anti-p53 mAb DO7 (Novocastra), anti-Ki67 mAb MIB1, anti-BCL2 mAb clone 124, and anti-ER mAb 1D5 (Dako). HER2 oncoprotein overexpression was analyzed using the HercepTest kit according to the manufacturer's instructions (Dako). Immunoreactions were developed using the streptavidin-biotin-peroxidase technique, followed by counterstaining with Carazzi hematoxylin. Immunostaining was done using an automated immunostainer (TechMate 1000; Dako). Appropriate cases with known reactivity for each antibody applied were used as positive controls. The evaluation of the immunohistochemical staining was done in a blinded fashion by M.L. Carcangiu and E. Tagliabue; the variability was <5%.

Sections were scored positive for p53, BCL2, and ER when about >10% of all tumor cells were labeled. Cases with >1% MIB1-positive tumor cells in the section were scored as positive. HER2 was considered positive when 2+ and 3+ (according to the HercepTest score) membrane labeling was observed.

Detection of hyaluronan. Hyaluronan staining was done on formalin-fixed, paraffin-embedded tissue sections from 199 breast carcinomas using the biotinylated hyaluronan binding region of aggrecan and a link protein (bHABC) as previously described (18). The specificity of the staining was controlled by digesting some sections with Streptomyces hyaluronidase in the presence of protease inhibitors before staining or by preincubating the bHABC probe with hyaluronan oligosaccharides. Staining in stroma was graded as "weak", "moderate", or "strong" when intense hyaluronan signals were found in <1/3, 1/3 to 2/3, or >2/3, respectively, of the areas evaluated. The expression of hyaluronan in breast tumor cells was considered negative when hyaluronan was not detected, or detected in a very small proportion of cells (<5%) and positive when hyaluronan was detected in >5% of the cells. In most positive cases, hyaluronan was located both on the plasma membrane and in the cytoplasm of the tumor cells.

Statistical analysis. Overall survival was defined as the time elapsed from the date of surgery and the date of death from any cause or the date of last follow-up. Distant metastasis-free survival and LR cumulative incidence were defined as the time elapsed from the date of surgery and the date of the first event, respectively. Distant metastasis-free survival or LR cumulative incidence curves were drawn by the life-table method and the statistical significance tested by the log-rank test. In contrast with the original Milan 3 Trial (16, 19), the cutoff age was fixed at 50 years according to the majority of recently published studies. Univariate and multivariate analyses were carried out by PHREG procedure using a Cox regression model (20), and statistical significance was tested by {chi}2. After univariate investigation, all variables with P ≤ 0.15 were retained for the multivariate analysis. All analyses were conducted using SAS software (SAS Institute, Inc.). Two-sided P values below the conventional 5% thresholds were considered statistically significant.


   Results
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Discussion
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Table 1 summarizes the clinicopathologic and biological characteristics of the tumors in the present study. Lymph node–positive patients represent 36% of the patients, 84% had a tumor size of <2 cm (24% had tumors ≤1 cm, and 60% ranged between 1.1 and 2.0 cm), ductal carcinoma in situ was present in 64% of the cases, and desmoplasia and inflammation in 36% and 38%, respectively, whereas 21% of the tumors were poorly differentiated (grade 3). About half of the tumors were ER-positive, whereas HER2-positive patients comprised 15% of the cases. High cell proliferative activity (based on MIB1) and accumulated p53 were detected in ~20% of cases, whereas the apoptosis marker BCL2 was positive in about half of the cases. Cancer cell–associated hyaluronan was detected in 47% of the cases. Stromal hyaluronan staining was strong in 65% of cases, and moderate or weak in 26% and 9%, respectively.


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  		Table 1. Tumor characteristics

 
LR was observed in 52 of 235 (22%) of the patients, with a significantly higher incidence among the patients ≤50 years of age (32 of 101, 32%) as compared with patients >50 years of age (20 of 134, 15%; P = 0.0022). The other variables associated with age were ductal carcinoma in situ, more frequent in patients ≤50 years of age than in older patients (73% versus 57%), and ER, which was more frequently expressed in women >50 years of age (64% versus 37%).

The prognostic role of LR was then analyzed according to age in this series of 235 patients. Log-rank analysis showed that cumulative incidence of distant metastasis was significantly influenced by LR in older (P = 0.009; Fig. 1B ) but not in younger patients (P = 0.7889; Fig. 1A). Indeed, the hazard ratio (HR) of distant metastasis indicated that LR increased the risk of distant metastasis by 2.85-fold [95% confidence interval (95% CI), 1.39-5.85; P = 0.0043] in patients >50 years of age, but did not significantly affect the risk of metastasis in patients ≤50 years of age (HR, 1.45; 95% CI, 0.65-3.22; P = 0.3597). LR also significantly affected overall survival in older (HR, 2.89; 95% CI, 1.37-6.08; P = 0.0052) but not in younger patients (HR, 1.54; 95% CI, 0.86-2.77; P = 0.1458).


Figure 1
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  		Fig. 1. Distant metastasis-free survival according to LR; solid line, LR negative; dotted line, LR positive. A, 101 patients ≤50 y of age; B, 134 patients >50 y of age.

 
The different prognostic effects of LR in the two age groups suggests that biological differences in LR occur in younger patients versus older patients. We therefore analyzed several factors known to be associated with tumor progression in the two subsets of patients. Cox univariate analysis (Table 2 ) revealed that only hyaluronan in tumor cells was significantly associated with risk of LR (HR, 2.48; P = 0.0364) in women ≤50 years of age. In patients >50 years old, only lymph nodes and ER status (HR, 3.34; P = 0.0113 and HR, 0.39; P = 0.0424, respectively) were significantly predictive of LR; whereas HER2 positivity showed a high HR of 2.29, but was not statistically significant.


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  		Table 2. Univariate analysis for local relapses in patients according to age

 
The association between hyaluronan staining in tumor cells and in the tumor stroma was highly statistically significant (P < 0.0001; Table 3 ). Positive hyaluronan staining in tumor cells, detected in 47% of the tumors, was associated with strong stromal staining in 84% of the cases as compared with 49% in tumors with negative hyaluronan staining in the tumor cells. The few cases showing weak hyaluronan staining in the stroma were all negative for tumor cell staining; moderate stroma staining was present in only 16% of cases with hyaluronan-positive cells. Hyaluronan cellular positivity was also associated with several unfavorable prognostic factors, such as grade 3 disease (P = 0.004), high cell proliferation status evaluated as positivity for MIB1 (P = 0.006), and accumulation of p53 (P = 0.017). This pattern of relationships did not vary when correlations were analyzed according to the two patient age groups (data not shown). The intensity of hyaluronan stromal staining did not correlate with the other biological markers evaluated in the present study, with the exception of an inverse correlation with desmoplasia; in the presence of desmoplasia, stromal staining was weak in 11 of 17 cases (65%), moderate in 19 of 52 cases (37%), and strong in 43 of 130 cases (33%; P = 0.0392).


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  		Table 3. Frequency of tumor characteristics according to hyaluronan expression in tumor cells

 
Log-rank analysis (Fig. 2 ) revealed a significant correlation between the presence of hyaluronan in tumor cells and the probability of LR in the patient subgroup aged ≤50 years. Thus, although hyaluronan staining was not significantly associated with LR incidence among the total number of patients (Fig. 2A) or in the subgroup of patients aged >50 years (Fig. 2C), LR incidence was significantly higher (P = 0.0302) when tumor cells exhibited hyaluronan staining in patients ≤50 years of age (Fig. 2B).


Figure 2
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  		Fig. 2. Cumulative incidence of local recurrences according to hyaluronan expression in tumor cells. Solid line, hyaluronan negative; dotted line, hyaluronan positive. A, 199 total patients; B, 85 patients ≤50 y of age; C, 114 patients >50 y of age.

 
Multivariate analysis was carried out with covariates displaying P < 0.15, i.e., tumor cells positive for hyaluronan and MIB1 were both associated with an increased probability of LR (HR, 1.94) in patients ≤50 years of age. The results indicated that the hyaluronan in tumor cells remained associated with LR with the same HR (2.349; 95% CI, 0.970-5.690; P = 0.0585), whereas the HR associated with MIB1 positivity decreased to 1.258 (95% CI, 0.503-3.143; P = 0.6235). In patients >50 years of age, multivariate analysis indicated that apart from lymph node positivity with a HR of 3.48 (95% CI, 1.31-8.92; P = 0.0120), none of the variables associated with LR in univariate analysis displayed an independent LR predictive power, with the HR decreasing to 1.87 for HER2-positive cases (95% CI, 0.60-5.84; P = 0.2814) and increasing to 0.41 (95% CI, 0.16-1.07; P = 0.686) for ER.

Univariate analysis of factors predictive of distant metastasis (Table 4 ) indicated some differences from factors predictive of LR. Indeed, hyaluronan in tumor cells or in the stroma was not associated with distant metastasis in either of the two age subgroups. Instead, conventional prognostic factors such as lymph nodes (HR, 3.35; P = 0.0009), which were found to be associated with LR in patients >50 years of age, as well as tumor size (HR, 4.01; P = 0.0219), MIB1 (HR, 2.64; P = 0.0075), and BCL2 (HR, 0.44; P = 0.0188) were predictive of distant metastasis. In younger patients, only lymph node–positivity was found to predict distant events (HR, 2.35; P = 0.0362). Multivariate analysis in patients ≤50 years of age, carried out with lymph nodes, inflammation, and ER, revealed that ER was borderline significant (HR, 0.34; 95% CI, 0.11-1.02; P = 0.0552) and the presence of inflammation, although borderline significant, reduced the probability of distant events to a ratio of 0.35 (95% CI, 0.12-1.08; P = 0.0680). In patients >50 years old, lymph nodes (HR, 2.47; 95% CI, 1.22-4.97; P = 0.0116), LR (HR, 2.75; 95% CI, 1.30-5.82; P = 0.0081), and MIB1 (HR, 2.62; 95% CI, 1.26-5.44; P = 0.0098) showed significant independent predictive power after backward elimination, whereas BCL2 (P = 0.1447) and tumor size (P = 0.0833) were removed from the model.


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  		Table 4. Univariate analysis for distant metastasis in patients according to age

 

   Discussion
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 Discussion
References
 
Our results indicate that LR after conservative breast tumor surgery has a strong prognostic effect on distant metastases in patients older than 50 years, but not in patients 50 years or younger. This new finding assumes particular significance in light of the data set considered, i.e., 235 cases not irradiated after quadrantectomy. Based on these results, we postulate the existence of two distinct types of LR: one that is more frequent in younger patients but is not associated with poor prognosis, and one that is less frequent but is associated with aggressiveness. The putative difference in the mechanisms that generate the two LR subtypes seems to lie in the host's characteristics.

The only independent risk factor for LR among the younger patients was the positive expression of hyaluronan in breast carcinoma cells, an association that has, to our knowledge, never been previously reported. Because the frequency of hyaluronan expression was similar in both age groups and, consistent with previous studies (11, 18), hyaluronan in tumor cells correlated with poor tumor differentiation (grade 3, MIB1, and p53 positivity), we speculate that the host environment is a major player in this type of recurrence. Thus, despite protection from apoptosis or attachment/detachment of neighboring cells through the action of hyaluronan (10) which occurs independently of age, the prevailing hormonal and metabolic conditions of younger patients only (e.g., high levels of estrogen and serum growth factors), as well as the remodeling potential of mammary stroma upon interaction with tumor cells might promote the proliferation of residual tumor cells independent of their aggressiveness. The higher proportion of ER-positive tumors evidenced in older patients, together with the significant protective role of hormone receptor expression in LR occurrence only in this age group, strongly support the possibility that low hormone levels in postmenopausal women contribute considerably in slowing the growth rate of tumor cells still present after surgery. In the present data set, the frequency of lymph node–positive patients was similar in the two age groups. Because only lymph node–positive patients received chemotherapy adjuvant treatment, the influence of the treatment on LR onset can be excluded. Consistent with this speculation is the lack of effect of lymph node involvement in LR in younger patients; the presence of LR in younger patients also did not correlate with the risk of distant metastases.

In elderly women, the conventional prognostic factors displayed an independent predictive power for LR. The lymph node–positive cases had significantly higher risk for LR than lymph node–negative cases. In addition, ER positivity protected significantly from LRs. Thus, the relapsed cases are mainly lymph node–positive and hormone receptor–negative. Accordingly, in this age group, lymph node positivity, tumor size, and LR status significantly affected the risk for distant metastases and overall survival. These results are in agreement with the previously published data (21). The limited number of LRs in this patient subset prevented a multivariate analysis of the putative effect of hormonal treatment on the risk of this event. Nevertheless, multivariate analysis on the interaction between hormonal therapy and LR did not significantly influence the risk of distant metastasis (data not shown), indicating no confounding effect of this therapy in older patient groups.

In a univariate analysis of the younger group, lymph node status was the unique significant variable in predicting distant metastases; however, in a multivariate setting, receptor status and inflammation together seemed to supplant nodal status in controlling distant events. Concerning the variable of inflammation, the reduced risk of distant events might be related to the more robust immunologic system in younger compared with older patients. Indeed, moderate or marked diffuse inflammation in breast cancer has been associated with better prognosis (22), suggesting that the immunoprotective effects of inflammation outweigh the protumorigenic effects.

The results of this study cannot be generalized to the patient population with locally more advanced cases (i.e., more lymph node–positive cases, or to patients who relapse after local radiotherapy) because those cases may be biologically totally different. However, this study shows that a number of local relapses following conservative surgery might be rather benign without distant metastases even if it could be argued that in node-positive patients, locoregional and systemic treatments following LR could have influenced the effect of LR on tumor aggressiveness. The most important notion from a clinical point of view is that those benign cases can be among young women. The role of conservative surgery has been especially problematic among young women because they might live many years with the operated breast, and thus, with the risk of LR. This study shows that the conservative surgery can be safe, despite the occasional local relapses among a number of young breast cancer patients with favorable prognosis, whereas it warrants the reconsideration of excluding older women with early breast cancer from radiation therapy (23). Another relevant item underscored by our findings is the need for defining whether local radiotherapy, which significantly reduces LR, is principally useful for eliminating cells which grow locally without the capacity for distant metastases, or whether it could also affect the development of aggressive LR.


   Acknowledgments
 
We thank Matteo Marcuzzo and Piera Aiello for technical assistance and Daniela Silva for manuscript preparation.


   Footnotes
 
Grant support: Associazione Italiana per la Ricerca sul Cancro.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 2/23/07; revised 6/29/07; accepted 9/24/07.


   References
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 References
 

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