Minimal and small size invasive breast cancer with no axillary lymph node involvement: the need for tailored adjuvant therapies

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1 Original article Annals of Oncology 15: , 2004 doi: /annonc/mdh434 Minimal and small size invasive breast cancer with no axillary lymph node involvement: the need for tailored adjuvant therapies M. Colleoni 1 *, N. Rotmensz 2, G. Peruzzotti 1, P. Maisonneuve 2, G. Viale 3, G. Renne 3, C. Casadio 3, P. Veronesi 4, M. Intra 4, R. Torrisi 1 & A. Goldhirsch 1 1 Division of Medical Oncology, Department of Medicine, 2 Division of Epidemiology and Biostatistics, 3 Division of Pathology and University of Milan School of Medicine, 4 Division of Senology, European Institute of Oncology, Milan, Italy Received 26 April 2004; revised 24 June 2004; accepted 25 June 2004 Introduction Background: Prognosis of with node-negative disease and tumor size <1 cm is a matter of controversy. While data exist to clearly correlate small tumor size to better prognosis, the fact that very small breast cancers may express biological markers of dire prognosis leads many to ignore small tumor size during treatment decision-making. Patients and methods: Data from 425 classified as having node-negative pt1mic, pt1a or pt1b after surgery (from April 1997 to December 2001) at the European Institute of Oncology, were analyzed to be described as disease-free according to prognostic variables including: Ki-67 (<20% versus >_20% of the cells), ER (absent versus positive >_1% of the cells), PgR (absent versus positive >_ 1% of the cells), grade, overexpression or amplification of HER2/neu, presence of peritumoral vascular invasion and age (by decade). The median follow-up for this cohort of was 43 months. Results: No local or distant relapse was observed for with pt1mic breast cancer; 4-year disease-free survival for pt1a and pt1b was 97.0% and 97.6%, respectively. In both univariate and multivariate analyses the most relevant prognostic factor for this low-risk population was Ki-67 labeling. The 4-year disease-free survival was 99.2% for tumors with low Ki-67 and 93.3% for tumors with high Ki-67 (>_20%) labeling. The hazard ratio (HR) for with high Ki-67 was 12.9 (95% CI , P = 0.02). Conclusions: Within the first 4 years, microinvasive breast cancer parallels ductal carcinoma in situ (DCIS) rather than invasive carcinoma. Costs and benefits of adjuvant therapy should be accurately weighted in these. Patients with pt1a and pt1b, node-negative disease have a limited but substantial risk of recurrence and therefore adjuvant therapy, according to endocrine responsiveness of the tumor and patient preference, should continue to be offered as a reasonable treatment option. Key words: adjuvant therapy, breast cancer, tumor size Patients with node-negative breast carcinoma have a good prognosis; however 20 30% of these individuals will experience a recurrence and die of systemic disease [1, 2]. The findings from the overview publication reporting results on ovarian ablation, tamoxifen and chemotherapy effects demonstrated a significant advantage from these adjuvant therapies and justify adjuvant treatment of a wide spectrum of indications, including node-negative [3 5]. In fact, a significant reduction in the odds of mortality *Correspondence to: Dr M. Colleoni, Division of Medical Oncology, Department of Medicine, Istituto Europeo di Oncologia, Via Ripamonti 435, Milan, Italy. Tel: ; Fax: ; marco.colleoni@ieo.it with chemotherapy [3] or tamoxifen [4] was observed in the node-negative population. A series of guidelines and recommendations for selection of adjuvant systemic treatments in the specific patient population of node-negative was recently proposed at the 8th International Conference on Adjuvant Therapy of Primary Breast Cancer [6]. Tumor size, grade, steroid hormone receptor status and age are factors considered to define differential prognosis for treatment selection. Proper identification of that might benefit from systemic chemotherapy, thus avoiding unnecessary therapy in very low risk, still requires further investigation. Treatment of small tumors, and in particular of microinvasive (pt1mic) breast cancer, received little attention in the past. A wide range of diagnostic criteria has been used q 2004 European Society for Medical Oncology

2 1634 in published studies for the evaluation of microinvasion. In 1997, the American Joint Committee on Cancer defined microinvasive breast carcinoma as the extension of cancer cells beyond the basement membrane into the adjacent tissues, with no single focus >1 mm in greatest dimension [7]. This system refers only to the largest invasive component and ignores the size of the ductal carcinoma in situ (DCIS) and the number of invasive foci. Susan and co-workers, in 1997, defined microinvasion as a single focus of invasive carcinoma <_2 mm or up to three foci of invasion, each <_1 mm in greatest dimension [8]. It has recently been demonstrated that the highlighting of myoepithelial cells using antibodies to cytoskeletal proteins, or to the nuclear protein p63, a member of the p53 gene family, can play an important role in distinguishing invasive carcinoma from its histologic mimics. The use of this technique might result in improved selection and identification of this uncommon disease presentation [9]. The aim of this study was to investigate the prognostic role of size of the tumor. In particular, we evaluated if microinvasive breast cancer, where the indication for adjuvant therapy is unclear, represents a different clinical entity and therefore should be considered separately in the therapeutic algorithm. Patients and methods We collected information on all consecutive breast cancer operated on at the European Institute of Oncology between April 1997 and December 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 retrieved. The surgically removed breast lesions were thoroughly sampled for pathological examination. In case of microcalcifications, the specimens were sliced and subjected to X-ray examination to ensure complete sampling of all the microcalcification-containing tissue. Specimens without calcifications were extensively sampled, taking at least one block/cm of the lesion. Samples from the surrounding tissue were also examined and in the case of mastectomy, the areola nipple complex was also evaluated histologically. Tissue sections from all previous needle biopsies (at least three sections/core, cut at mm intervals) and from all surgical resections performed elsewhere were reviewed. Tumors were classified histologically according to the World Health Organization Histological Classification of Breast Tumors, as modified by Rosen and Obermann [10]. Tumor grading was assessed according to Elston and Ellis [11]. We looked for peritumoral vascular invasion as recommended by Rosen and Obermann [10]. Microinvasive breast cancer was diagnosed according to the TNM classification and following the criteria of Rosen and Obermann [10]. Estrogen receptor (ER) and progesterone receptor (PgR) status, Ki-67 labeling index determined with the MIB1 monoclonal antibody, and HER2/neu overexpression were evaluated immunocytochemically as previously reported [12]. In particular, HER2/neu overexpression was evaluated using a 1/100 dilution of a polyclonal antiserum (Dako, Glostrup, Denmark) and considering only complete and intense membrane staining of at least 10% neoplastic cells as evidence of overexpression (3+). For evaluation of ER and PgR status and Ki-67 labeling index, the percentage of cells exhibiting definite nuclear staining over up to 2000 neoplastic cells examined at 400 magnification was recorded. The stained slides were evaluated independently by two of the authors. Only nuclear immunoreactivity was evaluated for ER, PgR and MIB1. The threshold for ER and PgR positivity was 1% and for MIB1 positivity 20%, as previously published [12]. Histological grade and biological features were evaluated on the invasive component of the tumor. Data were entered by surgeons into a user-friendly database designed with Microsoft Accessw once weekly on a mean number of 25 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 a proposal for an adjuvant treatment program. Typically, a medical oncologist (and a radiation oncologist, if applicable) discussed the proposed treatment with the patient and verified the accuracy of the items entered into the database (internal quality control). Therapy received All received adequate local treatment (breast-conserving surgery or total mastectomy) plus sentinel node biopsy or complete axillary dissection. Patients with primary breast cancer were assigned to undergo sentinel node biopsy in case of cytologically or histologically verified breast carcinoma <_3 cm in size (measured clinically and/or by imaging techniques) and clinically uninvolved axillary lymph nodes. Patients received sentinel-node biopsy followed by axillary dissection only if the sentinel node contained metastatic or micrometastatic breast cancer. Immunohistochemistry was used in case of doubtful or atypical cell-detection with hematoxylin and eosin. In case of neoplastic cells identified with immunohistochemistry the sentinel node was considered as positive. The sentinel node was identified and isolated using the probe as a guide as previously published [13]. Postoperative breast irradiation (RT) was proposed to all the that received breast-conserving surgery, excluding only elderly for whom radiation was considered inappropriate because of co-morbid conditions. Systemic adjuvant therapy was recommended for with nodenegative tumors <_ 1 cm in size according to St Gallen Consensus Conference guidelines [14 16]. Several changes, in particular for low-risk, occurred during the three guidelines used. In fact, in 1995 the Consensus panel agreed that a population of who have a 10-year mortality of <_ 10% would not be candidates for receiving routine adjuvant systemic therapy, whereas in the 1998 Consensus Conference only the population with <10% chance of relapse was not considered for adjuvant therapy. In the 2001 Consensus Conference, the panel no longer defined a group of who should not be offered adjuvant systemic therapy. Due to the absence of clear indications in the literature, with pt1mic disease were not candidates for chemotherapy. Endocrine therapy was proposed in case of endocrine-responsive pt1mic (defined as ER and/or PgR expression >_ 1% of the cells), and included tamoxifen 20 mg/day for a duration of 5 years. Results From April 1997 to December 2001, a total of 6068 with breast cancer were referred to the interdisciplinary evaluation and their data were included in the database.

3 1635 We pre-selected 869 (14.3%) with node-negative disease and size <_ 1 cm. We subsequently excluded that presented with recurrent tumors, non-invasive breast cancers, bilateral tumors and males. A total of 425 were thus included in the analysis, 325 classified as pt1b, 76 as pt1a and 24 as pt1mic. DCIS was present in all the cases of pt1mic evaluated. In all cases the histological grade of DCIS was the same grade as the corresponding invasive component (pt1mic). The number of assessable per biological feature is given in Table 1. In the microinvasive group, when compared with pt1a and pt1b, there were significantly higher Table 1. Patient characteristics Strata No. percentages of tumours classified as ER negative (37.5% versus 24.0% and 12.6%, respectively; P = 0.001), PgR negative (56.5% versus 37.3% and 23.1%, respectively; P <0.0001), and classified as grade 3 (50.0% versus 13.2% and 11.4%, respectively; P = < 0.001). Local treatment received by the is summarized in Table 2 and proposal of an adjuvant treatment program is indicated in Tables 3 and 4. Patients with microinvasive disease (compared with with pt1a and pt1b disease) were generally not given cytotoxic therapy, thus being more likely to be candidates for observation (63.6% versus 21.6% versus 11.4%, respectively; P <0.001) and were given less endocrine pt1mic pt1a pt1b P value for trend N % N % N % All Age < Grade G G G pn Negative Sentinel neg ER Absent Present PgR Absent Present < ER/PgR ER PgR ER+PgR /ER PgR ER+PgR < HER2/neu 0/+/ Ki-67 <20% >_ 20% VI Absent Present N, nodes; ER, estrogen receptor; PgR, progesterone receptor; VI, vascular invasion.

4 1636 Table 2. Local treatment: surgery and radiotherapy No. of assessable Quadrantectomy without RT Quadrantectomy + RT Mastectomy No. % No. % No. % Total pt1mic pt1a pt1b RT, radiotherapy. Table 3. Treatment proposed according to size of tumor No. of assessable therapy (31.8% versus 60.8% versus 68.9%, respectively; P <0.001) or chemotherapy (4.5% versus 17.6% versus 19.7%, respectively, P <0.001). In endocrine unresponsive disease chemotherapy was given in only one patient with pt1mic disease (12.5%) compared with nine (50%) and 25 (73.5%) of with pt1a and pt1b disease, respectively (Table 4). Moreover chemoendocrine therapy was not given in pt1mic disease compared with four (7.3%) and 39 (13.4%) with pt1a and pt1b disease, respectively. Median follow-up was 43 months (range months). No local or distant relapse was observed for with pt1mic breast cancer. The 4-year disease-free survival (DFS) for pt1a and pt1b was 97.0% and 97.6%, respectively (Figure 1). Using the Cox proportional hazards regression analysis we investigated the independent association between biological features and probability of relapse. In both univariate (Table 5) and multivariate analyses (Table 6) the most No treatment ET Non-anthracycline containing CT Anthracycline containing CT No. % No. % No. % No. % Total pt1mic pt1a pt1b ET, endocrine therapy; CT, chemotherapy. Table 4. Treatment proposed and events according to size and endocrine responsiveness of the tumor Endocrine responsive No. No treatment ET CT + ET No. Endocrine non-responsive a No treatment n (%) Events n (%) Events n (%) Events n (%) Events n (%) Events Total (11.2) (76.8) 5 43 (12.1) (40.0) 0 36 (60.0) 3 pt1mic 13 6 (46.2) 0 7 (53.8) 0 0 (0.0) (87.5) 0 1 (12.5) 0 pt1a 55 6 (10.9) 1 45 (81.8) 0 4 (7.3) (50.0) 0 9 (50.0) 1 pt1b (9.7) (76.9) 5 39 b (13.4) (26.5) 0 25 (73.5) 2 a Defined as ER and PgR absent. b Four of the 39 did not receive ET. ET, endocrine therapy; CT, chemotherapy; ER, estrogen receptor; PgR, progesterone receptor. significant prognostic factor for this low-risk population was Ki-67. The 4-year DFS was 99.2% for tumors with low Ki-67, and 93.3% for tumors with high Ki-67 (>_ 20%) (Figure 2). Among with pt1a or pt1b tumors, the hazard ratio (HR) for with high Ki-67 was 12.9 [95% confidence interval (CI) ; P = 0.02). When Ki-67 was evaluated according to the median value, with higher Ki-67 (>12%) still had a significantly poorer DFS at univariate analysis if compared with with lower Ki-67 (<_ 12%, P = 0.013). Younger (<35 years) also had a tendency to increased risk for relapse although not statistically significant (HR 4.76, 95% CI , P = 0.06). Table 6 shows the characteristics of relapsing. Nodal metastases included one patient with supraclavicular lymph node metastasis after axillary dissection, and one patient with axillary lymph node metastasis after sentinel node biopsy Table 7. Local relapses registered 4.4 and 8.4 months after surgery, CT

5 1637 Figure 1. Kaplan Meier plots of disease-free survival comparing pt1mic versus pt1a versus pt1b for with node-negative breast cancer. included, respectively, one ipsilateral breast tumor recurrence and one chest wall relapse. Discussion Treatment of small tumors represents an area of controversy. According to the St Gallen adjuvant treatment guidelines, treatment of with node-negative disease varies substantially according to the baseline prognosis [6 8]. For with small tumors but considered at average risk (e.g. endocrine-unresponsive disease, or endocrine-responsive disease but with unfavorable prognostic features such as young age or histological grade classified as 2 3), the treatment choice follows an algorithm similar to that for node-positive disease. For those with minimal risk disease, the question of whether to treat with endocrine therapy or not depends on a risk benefit analysis, in which the low relapse rate within the first 10 years, the potential reduction of reappearance of breast cancer in the conserved breast and in the contralateral breast should be taken into account and weighed against risks of endocrine treatment. Controversy regarding the clinical algorithm for with small tumors is related to the limited information available on their prognosis [17]. Studies published reported a long-term DFS ranging between 79% and 98% [18 21]. Factors related to good prognosis were low grade [19, 20], old age [21, 22] and ER-negative disease [18, 21]. However, these studies suffered from small sample size and information on biological features based on old methodologies such as hormone steroid receptor evaluation. In fact, a recently reported study indicated that endocrine responsiveness obtained by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer [22]. In this study, performed on a group of submitted to surgery in the recent years and with biological features evaluated with new techniques and by the same team of pathologists, a limited but not negligible risk of recurrence was detected. The elevated expression of Ki-67 was found to be a significant predictor of poor outcome. The HR for Table 5. Univariate analysis on 393 with pt1a and pt1b disease Strata No. of All 393 pt No. of events Log-rank test 1a 75 2 (2.7%) 1b (2.2%) Age < (28.6%) (2.3%) (2.2%) (0.8%) < Tumor grade G (0.6%) G (2.9%) G (4.3%) Nodal status Negative (3.1%) Sentinel neg (1.9%) ER Absent 56 3 (5.4%) Present (1.8%) PgR Absent 99 6 (6.1%) Present (1.0%) ER/PgR ER PgR 49 3 (6.1%) ER+PgR /ER PgR (5.3%) ER+PgR (1.1%) Cerb-B (1.1%) (6.3%) Ki-67 <20% (0.4%) >_ 20% (7.3%) < VI Absent (2.4%) Present 24 0 (0.0%) ER, estrogen receptor; PgR, progesterone receptor; VI, vascular invasion. Table 6. Multivariate analysis in 390 with pt1a/ pt1b tumors Variables HR (95% CI) a P PgR (absent versus present) 2.36 ( ) Ki-67 (>_ 20% versus <20%) 12.9 ( ) Age (<35 versus 35+) 4.76 ( ) a Hazard ratio (HR) and 95% confidence intervals (CI) obtained from a multivariate Cox proportional hazard regression model with all terms fitted simultaneously. PgR, progesterone receptor.

6 1638 Figure 2. Kaplan Meier plots of disease-free survival comparing elevated Ki-67 (>_ 20%) versus low Ki-67 (<20%) for pt1mic, pt1a, pt1b node-negative breast cancer. whose tumors expressed high Ki-67 (>_ 20%) was 12.9 (95% CI ; P = 0.02) with a 4-year DFS of only 93.3%. Similar results in terms of poor outcome for overexpressing Ki-67 were also registered when the median value of Ki-67 (12%) was considered as cut-off. The role of Ki-67 in with node-negative disease and small size was uncommonly reported in the past. In a small study on 68 assessable, the value of Ki-67 significantly correlated with DFS [23]. In particular, a DFS of 100% was observed for with low Ki-67 expression (<_ 5%). Although a multivariate analysis was not conducted, as in this study, these results indicate a possible role for Ki-67 in the identification of high-risk. Further investigations in order to confirm the prognostic role and proper cut-off of Ki-67 are required in larger studies with prolonged follow-up. Controversies are much higher in the subgroup of with microinvasive disease where information on outcome and especially on treatment recommendation are lacking, due to the low frequency of this presentation and the differences in terminology used [24 27]. Interpretation of data from the literature relating to clinical outcome is likely to be inconclusive if meticulous attention is not paid to the diagnostic criteria Table 7. Characteristics of who developed breast related events and methodologies used in the evaluation of microinvasion. In this study microinvasive disease was classified according to the American Joint Committee on Cancer, which defined pt1mic breast carcinoma as the extension of cancer cells beyond the basement membrane into the adjacent tissues, with no single focus >1 mm in greatest dimension. Evaluation was performed by the same team of pathologists with p63 evaluation in doubtful cases. Using a stringent and reproducible definition of microinvasive carcinoma, we have demonstrated that pt1mic disease had a different clinical behavior if compared with pt1a or pt1b disease. No evidence of disease relapse was observed in the cohort of with microinvasive disease. Patients with pt1a or pt1b demonstrated a different pattern of relapse, especially in selected subgroups of like those presenting elevated Ki-67 expression. It is noteworthy that, despite the higher incidence of poor prognostic features such as high grade and absence of ER and PgR, in the present series with pt1mic breast cancer were frequently candidate to observation (63.6% versus 21.6% versus 11.4%; P <0.001) and were given less endocrine therapy (31.8% versus 60.8% versus 68.9%; P <0.001), if compared with larger size tumors. Moreover, adjuvant chemotherapy was proposed only for one patient in the microinvasive group. The study presented here is unique since we selected a group of with node-negative disease. Very few studies that have used a definition of microinvasion roughly comparable to ours have also provided follow-up data and information on treatment received by the. Susan et al. [8] reported on 38 lesions with microinvasion or probable microinvasion, diagnosed during the period , with nodes negative for metastasis. None of 33, followed for a mean of 7.5 years (range, years), developed local recurrence or metastasis. Mann et al. [17] reported on 18 with microinvasive disease and node-negative disease. After a median follow-up of 6 years none had a local or distant relapse. Other authors reported on small groups of (5 42) but with axillary positive nodes in the range of 4 20%. DFS rates ranged between 100% and 91%, but interpretation of these results is difficult due to different Age G Menopause pt Diameter (cm) ER PgR Ki-67 (%) Her/Neu Adjuvant therapy Event DFS (months) 34 3 Pre 1a 0.13 Neg Neg 35 CMF6 Local relapse Post 1b 0.60 Pos Pos Anastrozole Local relapse Post 1b 1.00 Pos Neg 25 Tamoxifen Local relapse Pre 1b 1.00 Pos Pos 45 GnRH analogue and tamoxifen Lymph nodes Pre 1a 0.20 Pos Neg Nil Distant metastases Post 1b 0.80 Neg Neg 24 CMF6! tamoxifen Lymph nodes Pre 1b 0.80 Neg Neg 38 CMF6 Distant metastases Pre 1b 0.90 Pos Pos 3 Nil Controlateral Post 1b 0.90 Pos Neg CMF3! tamoxifen Controlateral 11.7 G, grade; ER, estrogen receptor; PgR, progesterone receptor; GnRH, gonadotrophin-releasing hormone; CMF, cyclophosphamide, methotrexate, 5-fluorouracil.

7 methodology in the assessment of microinvasion and the presence of nodal metastases. Based on the results of this study, it appears that the natural history of microinvasive breast cancer, within the first 4 years, more closely parallels DCIS than invasive carcinoma. In fact, after median follow-up ranging between 4 and 8 years studies on DCIS reported, an ipsilateral breast tumor recurrence rate between 3% and 17%, a controlateral breast cancer rate between 2% and 6%, whereas distant treatment failures were infrequent [30 32]. Considering the absence of clear evidence of benefits for adjuvant therapy in with microinvasive breast cancer and node-negative disease, costs and benefits of adjuvant therapy should be accurately weighed, thus avoiding widespread use of aggressive treatments. Further studies with prolonged follow-up of large series of are indicated to assess adequately the prognostic significance of this lesion. 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