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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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 1.5112.0, 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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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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Therapy received |
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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 19952001 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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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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Discussion |
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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 1.5112; 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 [2427]. 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 19801996, with nodes negative for metastasis. None of 33 patients, followed for a mean of 7.5 years (range, 1.014.4 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 (542) but with axillary positive nodes in the range of 420%. 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 [3032
]. 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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References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Silvestrini R, Daidone MG, Luisi A et al. Biologic and clinicopathologic factors as indicators of specific relapse types in node-negative breast cancer. J Clin Oncol 1995; 13: 697704.[Abstract]
3. Early Breast Cancer Trialists' Collaborative Groups. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351: 14511467.[CrossRef][ISI][Medline]
4. Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352: 930942.[CrossRef][ISI][Medline]
5. Early Breast Cancer Trialists' Collaborative Group. Ovarian ablation in early breast cancer: overview of the randomised trials. Lancet 1996; 348: 11891196.[CrossRef][ISI][Medline]
6. Goldhirsch A, Wood WC, Gelber RD et al. Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol 2003; 21: 33573365.
7. American Joint Committee on Cancer. Cancer Staging Manual, 5th edition. Philadelphia, PA: Lippincott-Raven Publishers 1997; 171178.
8. Susan A, Silver MD, Fattaneh A, Tavassoli MD. Mammary ductal carcinoma in situ with microinvasion. Cancer 1998; 82: 23822390.[CrossRef][ISI][Medline]
9. Werling RW, Hwang H, Yaziji H, Gown AM. Immunohistochemical distinction of invasive from noninvasive breast lesions: a comparative study of p63 versus calponin and smooth muscle myosin heavy chain. Am J Surg Pathol 2003; 27: 8290.[CrossRef][ISI][Medline]
10. Rosen PP, Oberman H. Tumors of the Mammary Gland. Washington, DC: Armed Forces Institute of Pathology 1993.
11. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer, I: the value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 2002; 41: 151.[CrossRef][Medline]
12. Colleoni M, Orvieto E, Nolè F et al. Prediction of response to primary chemotherapy for operable breast cancer. Eur J Cancer 1999; 35: 574579.[CrossRef][ISI][Medline]
13. Veronesi U, Paganelli G, Viale G. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 2003; 349: 546553.
14. Goldhirsch A, Wood WC, Senn HJ et al. Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. J Natl Cancer Inst 1995; 87: 14411445.[ISI][Medline]
15. Goldhirsch A, Glick JH, Gelber RD, Senn HJ. Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. J Natl Cancer Inst 1998; 90: 16011608.
16. Goldhirsch A, Glick JH, Gelber RD et al. Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. Seventh International Conference on Adjuvant Therapy of Primary Breast Cancer. J Clin Oncol 2001; 19: 38173827.
17. Mann GB, Port ER, Rizza C et al. Six-year follow-up of patients with microinvasive, T1a, and T1b breast carcinoma. Ann Surg Oncol 1999; 6: 591598.
18. Quiet CA, Ferguson DJ, Weichselbaum RR, Hellman S. Natural history of node-negative breast cancer: a study of 826 patients with long-term follow-up. J Clin Oncol 1995; 13: 11441151.[Abstract]
19. Rosner D, Lane W. Predicting recurrence in axillary-node negative breast cancer patients. Breast Cancer Res Treat 1993; 25: 127139.[ISI][Medline]
20. Hery M, Delozier T, Ramaioli A et al. Natural history of node-negative breast cancer: are conventional prognostic factors predictors of time to relapse? Breast 2002; 11: 442448.[CrossRef][ISI][Medline]
21. McGuire WL, Clark GM. Prognostic factors for recurrence and survival in axillary node-negative breast cancer. J Steroid Biochem 1989; 34: 145148.[CrossRef][ISI][Medline]
22. Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 1999; 17: 14741481.
23. Lee AKC. Lymph node negative invasive breast carcinoma1 centimeter or less in size (T1a,bN0M0). Cancer 1997; 79: 761771.[CrossRef][ISI][Medline]
24. Rosner D, Lane WW, Penetrante R. Ductal carcinoma in situ with microinvasion: a curable entity using surgery alone without need for adjuvant therapy. Cancer 1991; 67: 14981503.[ISI][Medline]
25. Bedwani R, Vana J, Rosner D et al. Management and survival of female patients with "minimal" breast cancer: as observed in the long-term and short-term surveys of the American College of Surgeons. Cancer 1981; 47: 27692778.[ISI][Medline]
26. Jotti GS, Petit JY, Contesso G. Minimal breast cancer: a clinically meaningful term? Semin Oncol 1986; 13: 384392.[ISI][Medline]
27. Nevin JE, Pinzon G, Moran TJ, Baggerly JT. Minimal breast carcinoma. Am J Surg 1980; 139: 357359.[ISI][Medline]
28. Wong JH, Kopald KH, Morton DL. The impact of microinvasion on axillary node metastases and survival in patients with intraductal breast cancer. Arch Surg 1990; 125: 12981302.[Abstract]
29. Solin LJ, Fowble BL, Yeh I-T et al. Microinvasive ductal carcinoma of the breast treated with breast-conserving surgery and definitive irradiation. Int J Radiat Oncol Biol Phys 1992; 23: 961968.[ISI][Medline]
30. Boland GP, Chan KC, Knox WF et al. Value of the Van Nuys Prognostic Index in prediction of recurrence of ductal carcinoma in situ after breast-conserving surgery. Br J Surg 2003; 90: 426432.[CrossRef][ISI][Medline]
31. Rodrigues N, Carter D, Dillon D et al. Correlation of clinical and pathologic features with outcome in patients with ductal carcinoma in situ of the breast treated with breast-conserving surgery and radiotherapy. Int J Radiat Oncol Biol Phys 2002; 54: 13311335.[CrossRef][ISI][Medline]
32. Fisher B, Bryant J, Dignam JJ et al. National Surgical Adjuvant Breast and Bowel Project. Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol 2002; 20: 41414149.