Annals of Oncology Advance Access originally published online on August 22, 2007
Annals of Oncology 2007 18(10):1632-1640; doi:10.1093/annonc/mdm268
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© 2007 European Society for Medical Oncology
breast cancer |
Prognostic role of the extent of peritumoral vascular invasion in operable breast cancer
1 Research Unit in Medical Senology at the Department of Medicine
2 Unit of Quality Control
3 Division of Epidemiology and Biostatistics
4 Division of Pathology and Laboratory Medicine
5 Division of Senology, European Institute of Oncology
6 University of Milan School of Medicine, Milan, Italy
* Correspondence to: Marco Colleoni MD, Research Unit in Medical Senology at the Department of Medicine, Istituto Europeo di Oncologia, Via Ripamonti 435, 20141, Milan, Italy. Tel: +39–02–57489439; Fax: +39–02–574829212; E-mail address: marco.colleoni{at}ieo.it
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Abstract |
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Background: The clinical relevance of the degree of peritumoral vascular invasion (PVI) in patients with no or limited involvement of the axillary nodes is unknown.
Materials and methods: 2606 consecutive patients with pT1-3, pN0 (1586)-1a (1020) and M0, operated and counseled for medical therapy from 1/2000 to 12/2002, were prospectively classified according to the degree of PVI: absent (2017, 77.4%), focal (368, 14.1%), moderate (51, 2.0%) and extensive (170, 6.5%).
Results: Patients with extensive PVI were more likely to be younger, to have larger tumors, high tumor grade, axillary-positive nodes, high Ki-67 expression and HER2/neu over-expression compared with patients having less PVI (P for trend, <0.0001). In patients with node-negative disease a statistically significant difference in disease-free survival (DFS), risk of distant metastases and overall survival (OS) was observed at the multivariate analysis for extensive PVI versus no PVI (hazard ratios: 2.11, 95% CI, 1.02 to 4.34, P = 0.04 for DFS; 4.51, 95% CI, 1.96 to 10.4, P< 0.001 for distant metastases; 3.55, 95% CI, 1.24 to 10.1, P = 0.02 for OS).
Conclusions: The extent of vascular invasion should be considered in the therapeutic algorithm in order to properly select targeted adjuvant treatment.
Key words: peritumoral vascular invasion, breast cancer, prognostic factor
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Despite the efforts to identify prognostic and predictive factors, optimal tailoring of adjuvant therapies is still a matter of debate. Appropriate identification of prognostic factors and predictive parameters of responsiveness to specific treatment programs continues to represent a major research issue.
A series of guidelines and recommendations for the selection of adjuvant systemic treatments was recently proposed at the 9th International Conference on Adjuvant Therapy of Primary Breast Cancer [1]. Significant changes in estimation of risk were made and allocation to risk group departed from the traditional node-positive/node-negative boundary. It was recognized that some patients with node-negative, low grade disease should be considered at intermediate risk of relapse if, for example, they had peritumoral vascular invasion (PVI), since they have a similar risk of relapse as patients with one to three involved axillary lymph nodes. Accordingly, for patients with PVI, treatment choice follows an algorithm similar to that for node-positive disease.
Controversies, however, still exist on the role of PVI in the risk assessment of patients with operable breast cancer. Several previous studies, performed with small series of patients and using heterogeneous methodologies, failed to confirm any prognostic role of vascular invasion [2–3] and its value in patients with one or few positive axillary lymph nodes is considered uncertain [1,4]. No consistent assessment of vascular invasion was performed in the past [5] and current methodology of PVI quantification is still characterized by high intra- and interobserver variability. In particular, the extent of PVI was never taken into account in the prognostic evaluation.
Moreover, current knowledge on the prognostic value of PVI is largely dependent upon old retrospective series, collected during several years [6–11]. We therefore, prospectively analyzed the prognostic role of PVI extent in terms of both DFS and OS in a large group of patients with surgery, pathological evaluation and treatment recommendations performed by the same team of physicians. The distribution of biological features investigated according to the most recently available technical details and adjuvant treatment recommendations were also evaluated.
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patients and methods |
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We collected information on all consecutive breast cancer patients operated at the European Institute of Oncology between January 2000 and December 2002. Data on the patient's medical history, concurrent diseases, surgery, pathological evaluation and results of staging procedures (blood chemistry, hematological values, bone scan, chest film and upper abdominal ultrasound examination) were evaluated. Pathological assessment included assessment of the primary tumor size, histological type and grade, and of axillary lymph nodes status including a sentinel node biopsy (SNB) [12], when applicable. PVI was assessed according to Rosen et al. [13] on hematoxylin and eosin-stained slides, without attempting any distinction between blood and lymphatic vessels. Primary tumors were extensively sampled for histopathological examination, with at least two blocks being taken from tumors less than 1 cm, and three to four blocks from larger tumors. PVI was prospectively scored as absent (no evidence of PVI), focal (one focus of PVI in one tumor block only), moderate (more than one focus of PVI in one tumor block only), and extensive (one or more foci of PVI in more than one tumor block). Tumor grade was evaluated according to Elston and Ellis [14]. Estrogen (ER) and progesterone receptor (PgR) status, Ki-67 labeling index (LI), as assessed with the MIB1 monoclonal antibody, and HER2/neu over-expression were evaluated immunocytochemically as previously reported [15]. The threshold for ER and PgR positivity was 1% and for Ki-67 LI 20%, as previously reported [15]. Data were entered into a "user-friendly" database designed with Microsoft Access® once weekly from a mean number of 25 patients per week, and checked by a data manager. The database was then used for an interdisciplinary discussion (among surgeons, medical and radiation oncologists and pathologists) resulting in the proposal for an adjuvant treatment program.
statistical analysis
The Fisher exact test and the Mantel–Haenszel chi-square test for trend were used to assess the association between categorical or ordinal variables and the presence of PVI. Multivariate logistic regression was used to assess the predictive value of baseline tumor and/or patient characteristics for nodal status. The primary endpoints were disease-free survival (DFS) and overall survival (OS). DFS was defined as the length of time from the date of surgery to any relapse (including ipsilateral breast recurrence), the appearance of a second primary cancer (including contralateral breast cancer), death or the date of last follow-up visit, whichever occurred first. OS was determined as the time from surgery until the date of death (from any cause) or the date of last contact. Plots of the survival according to age were drawn using the Kaplan–Meier method. The log-rank test was used to assess the survival difference between strata. Multivariate Cox proportional hazard regression analysis was used to assess the independent prognostic significance of various clinical and histopathological characteristics of the tumor on survival. Factors included in multiple regression analyses included age, tumor diameter, ER and PgR expression, Ki-67 expression, Her2/Neu over-expression, vascular invasion, grade and treatment. All analyses were performed with the SAS software version 8.02 (Cary, NC). All P-values were two-sided.
treatment received
All patients received adequate local treatment (breast conserving surgery or total mastectomy) plus sentinel node biopsy or complete axillary dissection. The Sentinel lymph node (SLN) was identified and isolated using a gamma probe as a guide, as previously published [16].
Postoperative breast irradiation (RT) was proposed to all patients that received breast-conserving surgery, excluding only elderly patients for whom radiation therapy was considered inappropriate [17]. Systemic adjuvant therapy was recommended according to St. Gallen's treatment guidelines [18,19]. In particular, the selection of adjuvant systemic treatment was based upon indicators of responsiveness to treatment (endocrine responsiveness of the tumor) and of risk of relapse. For patients with node-negative and endocrine-responsive disease, adjuvant endocrine therapy alone according to menopausal status was indicated (tamoxifen for a duration of 5 years in postmenopausal patients and the combination of tamoxifen for 5 years plus gonadotropin-releasing hormone analogues for at least 2 years in premenopausal patients) [18]. In patients at higher risk (e.g. due to PVI or pN1a disease) and/or with indicators of uncertain endocrine responsiveness, chemotherapy was added to the endocrine treatment program. Anthracycline-containing chemotherapy was considered as the first option in patients with higher risk (e.g. AC, adriamycin and cyclophoshamide, for four courses [20]); in cases of comorbidities, patients preferences and limited risk (e.g. pN0-1mi disease) classical CMF (oral cyclophosphamide, methotrexate and fluorouracil) for a duration of three to six courses was considered [21]. In cases of endocrine non-responsive disease, 6 months of chemotherapy was indicated. Regimens used were classical CMF for six courses in node-negative disease and AC for four courses followed by classical CMF for three courses [21] or intensive Oral cyclophosphamide, epirubicin and fluorouracil for six courses [22] in node-positive disease, according to the degree of the patient's risk.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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A total of 5004 consecutive patients with invasive breast cancer were referred for interdisciplinary evaluation between 1/2000 and 12/2002 and their data were included in the database. All patients (n = 2709) with previously untreated, primary invasive breast cancer, without lymph node metastases (pN0) or with one to three involved axillary lymph nodes (pN1a disease) were available for the current analysis. We subsequently excluded patients with metastatic disease at presentation (n = 7), males (n = 10), other previous tumor (n = 51) and bilateral tumors (n = 35).
The characteristics of the 2606 patients considered for the analysis are shown in Table 1. A total of 1586 patients were classified pN0 (or pN0 [sn]), whereas 1020 patients had one to three metastatic lymph nodes. The distribution of PVI was as follows: absent 2017, focal 368, moderate 51 and extensive 170. Patients with extensive PVI were more likely to be younger, to have larger or higher grade tumor, elevated Ki-67 LI, positive axillary lymph nodes and HER2/neu over-expression compared with patients with less extensive PVI (P for trend <0.0001).
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PVI was associated with the presence of lymph node involvement in the multivariate analysis. In particular, patients with extensive PVI had an OR of 9.05 (95% CI, 5.99 to 13.7) for nodal involvement (P < 0.0001) (Table 2).
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treatment
Four hundred and thirteen patients had a mastectomy as the primary treatment, 2193 had quadrantectomy; 1838 patients underwent SNB. In 560 of the latter patients, the SNB was positive and completion axillary dissection was therefore performed. Patients with extensive PVI were at larger chance of being candidate to anthracycline-containing chemotherapy (62.4 % vs. 40% vs. 39% vs. 17.9 % respectively) and less likely to receive endocrine therapy alone (13.5% vs. 32% vs. 38.7% vs. 60.4% respectively) (P < 0.0001) (Table 3).
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events
The median follow-up for DFS was 3.8 years and for OS was 4.3 years. Overall 4-year DFS for patients with no, focal, moderate and extensive PVI were 89%, 89%, 90% and 83%, respectively (log-rank P = 0.34), and 4-year OS was 97%, 98%, 98% and 97%, respectively (log-rank P = 0.47). In patients with node-negative disease, 4-year DFS for patients with no, focal, moderate and extensive PVI was 90%, 86%, 94% and 74%, respectively (log-rank P = 0.06), and 4-year OS was 98%, 96%, 94% and 93% respectively (log-rank P = 0.01). The Kaplan–Meier curves for DFS and OS according to nodal status are displayed in Figure 1. Of 1303 patients with a negative SNB, 4-year DFS for patients with no, focal, moderate and extensive PVI was 91%, 84%, 100% and 74%, respectively (log-rank P = 0.013), and 4-year OS was 98%, 95%, 100% and 91%, respectively (log-rank P < 0.0001). The Kaplan–Meier curves for DFS and OS accordingly to PVI in patients with a negative SNB are displayed in Figure 2.
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multivariate analysis
We investigated the independent association of nodal status, biological features and probability of relapse using the Cox proportional hazards regression analysis. As shown in Table 4, a prognostic value for extensive PVI (vs. absent) on OS and DFS was observed for the population of patients with node-negative disease. In these patients a statistically significant difference in DFS, risk of distant metastases and OS was observed at the multivariate analysis for extensive PVI versus no PVI (HR: 2.11, 95% CI, 1.02 to 4.34, P = 0.04 for DFS; 4.51, 95% CI, 1.96 to 10.4, P<0.001 for distant metastases; 3.55, 95% CI, 1.24 to 10.1, P = 0.02 for OS) (Table 5). In patients with negative SNB, the HR for extensive PVI (vs. absent) was 2.13 (0.97–4.67), P = 0.059 for DFS and 4.11 (1.36–12.5), P = 0.013 for OS. No significant difference in terms of DFS, risk of distant metastases and OS was observed for patients with both focal and moderate PVI versus no PVI.
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In the multivariate analysis, size of the tumor >2 cm was significantly associated with increased risk of distant metastasis (HR 2.13, P = 0.006), loco-regional relapse (HR 1.88, P = 0.04), poorer DFS (HR 1.88, P = 0.0002) and OS (HR 2.40, P = 0.005) in the population of patients with node-negative disease. Similarly, Ki-67 LI (
20%) significantly correlated with an increased risk of loco-regional relapse (HR 3.32, P = 0.005), distant metastasis (HR 2.21, P = 0.05), poorer DFS (HR 2.36, P < 0.0001) and OS (HR 4.33, P = 0.003). Young age (<35 years) significantly correlated with increased risk of loco-regional relapse (HR 3.06, P = 0.04), poorer DFS (HR 2.34, P = 0.01) and OS (HR 3.77, P = 0.009). Lack of expression of steroid hormone receptors was associated to an increased risk of death (HR 2.75, P = 0.005) (Table 5). |
discussion |
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The occurrence of axillary lymph node metastasis is the most powerful, independent prognostic parameter in women with newly diagnosed breast cancer. As reported in the most recent St. Gallen Consensus Conference, the number of involved axillary lymph nodes is pivotal in the risk evaluation [1]. Emerging data on the clinical significance of PVI has prompted the introduction of this factor in the therapeutic algorithm of candidate patients to adjuvant treatment. Early studies suggested that the occurrence of PVI may provide additional prognostic information, and that PVI is associated with a particularly unfavorable outcome among patients with node-negative disease [6–11].
The extent of PVI, however, was not taken into account for clinical decision-making [5]. Despite the acceptance of PVI as prognostic feature, there is no information on the clinical implication of the extent of PVI (whether focal, moderate or extensive) and whether such an evaluation might accurately identify patients at higher risk, thus sparing unnecessary treatments to a large group of patients.
Data from past series include information on several aspects of the disease collected in the earlier period, when neither systemic treatments nor various prognostic and predictive factors were available, as they are today [1]. Adjuvant systemic therapies and precise determination of the biological characteristics of primary tumors likely are the most relevant innovations of the current assessments of patients with early-stage breast carcinoma.
This study provides useful insights into the prognosis of breast cancer because it is based on a large number of patients, collected in a relatively short time, thus allowing the adoption of modern procedures. The pathologists, surgeons and medical oncologists used consistent approaches during the years of reference. As reported in Table 2, the occurrence of PVI was significantly correlated with other prognostic features such as younger age, larger tumors, high histological grade, high Ki-67 LI, and HER2/neu over-expression. Most importantly, a significant correlation between PVI and extent of nodal involvement was found. Others have already reported the correlation between PVI and nodal involvement [23,24]. In fact, PVI is considered as a mirror of tumor cell dissemination to axillary lymph nodes and spread to distant sites [5]. Viale et al. [23] evaluated 4351 consecutive patients surgically treated for breast carcinoma who also underwent SLNB. Tumor size and PVI emerged as the most powerful, independent predictors of SLN metastases. In particular, PVI was associated with a 5.3-fold greater risk for SLN involvement, thus reinforcing that it is the most powerful predictor of axillary lymph node metastases. It is therefore reasonable to focus on the prognostic role of PVI in patients with limited or no axillary node involvement.
In the present study, extensive PVI was found at the multivariate analysis to be an independent prognostic factor for DFS, OS and risk of distant metastases in patients with axillary node-negative disease. The value of PVI has been already documented in node-negative breast cancer with respect to both DFS [6–10] and OS [4,9–11]. Rosen et al. demonstrated that the prognosis of patients with node-negative disease and PVI was worse than that of patients with node-positive disease [4]. Lauria et al. also found that the relative risk of death in patients with node-negative breast carcinoma with lymph vessel invasion was sufficiently high to warrant adjuvant treatment [11].
In the trials described above, analyses were performed based on a so-called "lymphovascular invasion grouping," which combines limited and more extensive PVI. In the present study, which represents the largest available, prospective analysis conducted by the same team of pathologists on the extent of PVI, we demonstrated different prognostic implications for extensive PVI (defined as the presence of multiple foci of PVI in more than 1 tumor block) compared with a less extensive vascular invasion. Some clinical studies that failed to show any prognostic value for PVI provided empirical data that the quantitative assessment of PVI might be important, and that extensive PVI is a distinct entity from less extensive PVI [2–3]. In the present study only 29% of patients with PVI presented with extensive PVI. Therefore, the use of the extent of PVI in the therapeutic algorithm might spare unnecessary treatments to a large number of patients (i.e. those who presented with only focal or moderate PVI) that presented a similar degree of risk compared with patients presenting without PVI.
The results of the present study indicated a prognostic role of extensive PVI in patients with negative SNB. In fact, in these patients the HRs for extensive PVI (vs. absent) were 2.13 (0.97–4.67), P = 0.059 for DFS and 4.11 (1.36–12.5), P = 0.013 for OS. Since extensive PVI is the strongest predictor of lymph node metastasis, the occurrence of extensive PVI in patients with negative SNB could identify cases of false-negative SNB. However, it should also be stressed that in our study only one patient developed axillary nodal metastases together with relapse at distant sites whereas all the other patients had relapses at distant sites only.
The finding that extensive PVI is an important prognostic factor significantly associated with increased risk of relapse and death in patients with node-negative disease when compared with less extensive amounts of PVI was derived from the study of a population of patients undergoing an adjuvant therapy program which might have interfered with the clinical outcome. A shown in Table 3, 62.4% of patients with extensive PVI were candidated to anthracycline-containing regimens, as compared with 40%, 39% and 17.9% of the patients with moderate, focal or absent PVI, respectively. Similarly, endocrine therapy alone was prescribed to only 13.5 % of patients with extensive PVI, as compared to 32%, 38.7% and 60.4 % of patients with moderate, focal or absent PVI, respectively.
In the multivariate analysis other known prognostic factors were found to be significantly associated with the clinical outcome. As shown in Table 5, young age (<35 years) was found to significantly correlate with DFS and OS. Moreover, size of the tumor and elevated Ki-67 LI significantly correlated with DFS, risk of distant metastases and OS. The degree of expression of Ki-67 antigen is a measure of tumor proliferation that has been correlated with outcome in several studies [25–27]. The present study extends the evidence that the level of Ki-67 LI is a valuable prognostic factor in early breast cancer. Additional studies using database analyses or prospective trials are required to confirm these results. If confirmed, future risk assessment for the selection of should include Ki-67 LI.
Endocrine non-responsive breast cancer (no expression of any ER or PgR) is characterized by a high risk of early relapse, decreasing risk of relapse over time (relapse-free survival curves appear to plateau) and significant response to chemotherapy irrespective of patient age [1]. These tumors are biologically distinct from endocrine-responsive breast cancer, which accounts for the majority of cases in unselected series. As showed in Table 5, the absence of both estrogen and progesterone receptors significantly correlated with worse survival in the present study in the node-negative cohort (HR 2.75, 95% CI, 1.35–5.60, P = 0.005). Moreover, the poorer DFS for patients with extensive PVI was significantly greater for patients with the so called "triple negative" (lack of expression of ER, PgR and HER-2/Neu receptor) tumor phenotype (HR 6.73, 95% CI, 1.50–30.3, P = 0.03). The recent identification of different biologic and clinical behavior for this tumor subtype has led to the development of tailored research and therapies [28, 29]. The poor outcome observed in the present study in a population of patients with triple-negative tumor and extensive PVI undergoing an adjuvant therapy program indicates that new, targeted treatment options should be explored in this cohort of patients.
In conclusion, we demonstrated that in patients with operable breast cancer and node-negative disease, only extensive PVI significantly correlates with worse prognosis. Conversely, no significant prognostic value was observed for focal or moderate PVI in both the cohorts of patients with axillary node-negative or pN1a axillary disease. The assessment of PVI extent should therefore be added to the list of features which must be taken into account while making tailored therapeutic choices in the adjuvant setting.
Received for publication January 19, 2007. Revision received March 9, 2007. Accepted for publication April 30, 2007.
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