© 2004 European Society for Medical Oncology
Minimal and small size invasive breast cancer with no axillary lymph node involvement: the need for tailored adjuvant therapies
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
* Correspondence to: Dr M. Colleoni, Division of Medical Oncology, Department of Medicine, Istituto Europeo di Oncologia, Via Ripamonti 435, 20141 Milan, Italy. Tel: +39-02-5748-9439; Fax: +39-02-5748-9212; Email: marco.colleoni{at}ieo.it
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Abstract |
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Background: Prognosis of patients 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 patients 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 patients was 43 months.
Results: No local or distant relapse was observed for patients 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 patients with high Ki-67 was 12.9 (95% CI 1.5–112.0, 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. 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
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Introduction |
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TopAbstractIntroductionPatients and methodsTherapy receivedResultsDiscussionReferences |
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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 patients [3–5]. In fact, a significant reduction in the odds of mortality 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 patients that might benefit from systemic chemotherapy, thus avoiding unnecessary therapy in very low risk patients, 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 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.
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Patients and methods |
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TopAbstractIntroductionPatients and methodsTherapy receivedResultsDiscussionReferences |
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We collected information on all consecutive breast cancer patients operated on at the European Institute of Oncology between April 1997 and December 2001. 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 110–200 µm 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 400x 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 Access® once weekly on 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 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 |
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TopAbstractIntroductionPatients and methodsTherapy receivedResultsDiscussionReferences |
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All patients 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 patients that received breast-conserving surgery, excluding only elderly patients for whom radiation was considered inappropriate because of co-morbid conditions. Systemic adjuvant therapy was recommended for patients with node-negative tumors 1 cm in size according to 1995–2001 St Gallen Consensus Conference guidelines [14–16]. Several changes, in particular for low-risk patients, occurred during the three guidelines used. In fact, in 1995 the Consensus panel agreed that a population of patients 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 patients who should not be offered adjuvant systemic therapy.
Due to the absence of clear indications in the literature, patients 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.
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Results |
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TopAbstractIntroductionPatients and methodsTherapy receivedResultsDiscussionReferences |
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From April 1997 to December 2001, a total of 6068 patients with breast cancer were referred to the interdisciplinary evaluation and their data were included in the database. We pre-selected 869 (14.3%) patients with node-negative disease and size
1 cm. We subsequently excluded patients that presented with recurrent tumors, non-invasive breast cancers, bilateral tumors and males. A total of 425 patients 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 patients assessable per biological feature is given in Table 1. In the ‘microinvasive’ group, when compared with pT1a and pT1b, there were significantly higher 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).
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Local treatment received by the patients 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 patients 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 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 patients 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%) patients with pT1a and pT1b disease, respectively.
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Median follow-up was 43 months (range 1.5–82.4 months). No local or distant relapse was observed for patients 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 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 patients with pT1a or pT1b tumors, the hazard ratio (HR) for patients with high Ki-67 was 12.9 [95% confidence interval (CI) 1.49–112; P=0.02). When Ki-67 was evaluated according to the median value, patients with higher Ki-67 (>12%) still had a significantly poorer DFS at univariate analysis if compared with patients with lower Ki-67 (12%, P=0.013). Younger patients (<35 years) also had a tendency to increased risk for relapse although not statistically significant (HR 4.76, 95% CI 0.93–24.3, P=0.06). Table 6 shows the characteristics of relapsing patients. 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, included, respectively, one ipsilateral breast tumor recurrence and one chest wall relapse.
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Discussion |
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TopAbstractIntroductionPatients and methodsTherapy receivedResultsDiscussionReferences |
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Treatment of small tumors represents an area of controversy. According to the St Gallen adjuvant treatment guidelines, treatment of patients with node-negative disease varies substantially according to the baseline prognosis [6
–8]. For patients 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 patients 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 patients 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 patients whose tumors expressed high Ki-67 (20%) was 12.9 (95% CI 1.5–112; P=0.02) with a 4-year DFS of only 93.3%. Similar results in terms of poor outcome for patients 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 patients with node-negative disease and small size was uncommonly reported in the past. In a small study on 68 assessable patients, the value of Ki-67 significantly correlated with DFS [23]. In particular, a DFS of 100% was observed for patients 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 patients. 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 patients 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 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 patients with microinvasive disease. Patients with pT1a or pT1b demonstrated a different pattern of relapse, especially in selected subgroups of patients 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 patients 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 patients 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 patients. Susan et al. [8] reported on 38 lesions with microinvasion or probable microinvasion, diagnosed during the period 1980–1996, with nodes negative for metastasis. None of 33 patients, followed for a mean of 7.5 years (range, 1.0–14.4 years), developed local recurrence or metastasis. Mann et al. [17] reported on 18 patients 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 patients (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 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 patients 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 patients are indicated to assess adequately the prognostic significance of this lesion.
Patients with pT1a and pT1b disease, in particular if their tumors overexpress Ki-67, have a limited but substantial risk of recurrence, and therefore adjuvant therapy according to endocrine responsiveness of the tumor and patient preference represents a reasonable option.
Received for publication April 26, 2004. Revision received June 24, 2004. Accepted for publication June 25, 2004.
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