Annals of Oncology Advance Access published online on June 10, 2008
Annals of Oncology, doi:10.1093/annonc/mdn393
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Axillary recurrence in sentinel lymph node-negative breast cancer patients
1 Department of Medical Oncology
2 Breast Unit
3 Department of Nuclear Medicine
4 Department of Pathology, Ospedali Riuniti di Bergamo, Bergamo, Italy
* Correspondence to: Dr P. Poletti, Unità Operativa di Oncologia medica, Ospedali Riuniti di Bergamo, Largo Barozzi 1, 24128 Bergamo, Italy. Tel: +39-035-269724; Fax: +39-035-266173; E-mail: ppoletti{at}ospedaliriuniti.bergamo.it
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionReferences |
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Background: Sentinel lymph node biopsy (SLNB) was developed to axillary lymph node dissection (ALND) in the treatment of breast cancer. SLNB is predictive of axillary node status. Major concern is the occurrence of a false-negative SLN. Purpose of this study is to determine the rate of axillary recurrence in our series of unselected patients.
Patients and methods: All patients with a negative SLNB from November 1999 to December 2006 have been treated and followed at our unit. Information on patients’ characteristics, treatment and follow-up has been collected.
Results: Eight-hundred and four patients with negative SLNB did not receive ALND. After a median follow-up of 38.8 months, 21 patients had distant metastases, four had axillary relapse, nine had an in-breast recurrence and two had both. All patients with axillary recurrence received axillary dissection and systemic adjuvant therapy. They are all presently alive and free from disease.
Conclusion: Data from this series, the largest from a general hospital, showed that isolated axillary node recurrence after negative SLNB is rare (<1%) and comparable with those reported from referral cancer institutions. We confirm that SLNB for the treatment of early breast cancer patients of a community-based hospital is safe and reliable.
axillary lymph node recurrence, breast cancer, sentinel lymph node biopsy
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Axillary lymph node dissection (ALND) has recently been recommended in the management of early breast cancer for staging and planning of adjuvant systemic therapy [1, 2]. Sentinel lymph node biopsy (SLNB) was developed with the purpose to avoid unnecessary extended axillary dissection in pathologically negative lymph node patients and, when carried out by trained surgeons, SLNB is highly predictive of axillary node status [3, 4]. In our experience, derived from a population-based Breast Cancer Unit, it has been calculated that
50% of all incoming patients can avoid axillary dissection because of a negative SLNB [5]. Several studies have shown accuracy and safety of the procedure, and SLNB has been accepted by a consensus conference of 2001 as a routine alternative to ALND in clinically negative lymph node breast cancer patients [6]. Major concern with the practice of SLNB is the occurrence of a false-negative sentinel lymph, and although large multicenter randomized trials are in progress in the United States and Europe, limited data are available on the rate of axillary recurrence after SLNB not followed by ALND, mostly from single-institutions series. The main purpose of this study is to report on the rate of axillary recurrence in our series of consecutive unselected early breast cancer patients with a negative SLNB from a community-based Breast Cancer Unit. |
patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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patients and follow-up
From 1999, data of women with early breast cancer treated at the Breast Unit of Ospedali Riuniti in Bergamo, Italy, have been prospectively collected into an Outcome Research in Oncology database with information on demographics, previous medical history, diagnosis, surgical procedures, pathologic features, systemic therapies and follow-up. We reviewed the data on all 804 patients with invasive breast cancer who underwent SLNB without ALND from November 1999 (when routine use of SLNB was started) to December 2006, and all axillary lymph node recurrences in this patient population were studied. Follow-up visits, including physical examination of the breast and axilla and blood analyses, were carried out at 6-month intervals. Mammography, ultrasound and X-rays were carried out annually or on the basis of symptoms and physical findings. Informations analyzed for each patients were demographics, pathologic features of the tumor, type of surgery, systemic and locoregional adjuvant therapies and follow-up.
sentinel node biopsy procedure
Since November 1999 radioactive SLNB has been routinely carried out at our Breast Unit and described elsewhere [5].
In the study period, sentinel node pathologic examination was carried out in two ways. In the first period (2000–2005), SLN was divided in two and 20 consecutive sections were carried out on the frozen half, while for permanent sections the paraffin block was completely sectioned at 0.1-mm intervals. In the second period (from 2006 onward), the SLN was completely frozen and sectioned, the first 15 sections at 50-µm intervals and the remaining sections at 100-µm intervals. The technique used was hematoxylin–eosin staining.
treatment of the primary carcinoma
The vast majority of patients with conservative breast surgery underwent conventional external beam radiotherapy on the whole breast through tangential fields (50 + 10 Gy as a boost on the tumor bed), while 74 of these patients were enrolled in a multicenter trial investigating the role of adjuvant radiotherapy after conservative surgery. No radiotherapy was delivered to the axilla. Since January 2006 postmenopausal patients with unifocal disease <2.5 cm in diameter have been treated with intraoperative radiotherapy (21 Gy on the tumor bed in a unique dose) [7] within a prospective cohort study ongoing at our center. Systemic adjuvant treatment was prescribed according to Saint Gallen Conference recommendations [8].
statistical analysis
The purpose of the study was to review the data on the development of axillary recurrence, any breast cancer-related event and overall survival (OS). Event-free survival was calculated from the date of surgery to the date of the event or last follow-up visit. OS was calculated from the date of surgery to the date of death or last follow-up visit. Curves of OS and disease-free survival were calculated by Kaplan–Meier method.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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From November 1999 to December 2006, 804 patients with invasive breast carcinoma underwent only SLNB for axillary sampling. The patients’ demographics and tumor characteristics are listed in Table 1. Median age of the cohort was 63 years (range 31–97 years). The median tumor size was 1.4 cm (range 0.03–6), with only 20% being T2–3 lesions. Six hundred seventy-five patients had invasive ductal carcinoma. Seven hundred forty-two patients (92%) underwent breast-conserving surgery. The median and mean numbers of SLNs found per patients were 1 (range 1–18) and 1.6 ± 1, respectively. Five hundred sixty-six patients (70%) received radiotherapy on the operated mammary gland, 68 patients of them were give intraoperative radiotherapy on the tumor bed. Seventy-four patients were randomized in a multicenter two-arm trial investigating the role of adjuvant radiotherapy after conservative surgery, 39 patients received postoperative radiotherapy and 35 only surgery (Table 2). The types of adjuvant systemic therapies are listed in Table 3.
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The median follow-up time was 38.8 months (range 4.1–96.7 months). During this period, 56 unfavorable events occurred and 27 patients died (Table 4). Overall, there were seven axillary recurrences, including four cases of isolated axillary recurrence, two cases of both in-breast and axillary recurrence and one case of axillary recurrence and distant metastases. Overall, 21 patients developed distant metastases (including the patient with concomitant axillary recurrence), nine patients had an in-breast recurrence only and 20 had a new primary (five new contralateral breast primary and 15 other cancers). The median time to axillary recurrence was 18 months (range 5–20) and the median time to distant recurrence was 40 months (range 5–72), but this difference is not statistically significant with the continuity-corrected Pearson
2 test. Of the 27 deaths during the study period, five were due to metastatic breast cancer and 22 were related to other causes. OS and event-free survival are shown in Figures 1 and 2, respectively.
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The first patient with isolated axillary recurrence had an estrogen receptor-negative and progesterone receptor-positive 2.2-cm G3 ductal invasive carcinoma. She had received adjuvant chemotherapy cyclophosphamide, methotrexate, fluorouracil (CMF) followed by endocrine therapy within an IBCSG trial (BIG1-98: tamoxifen versus letrozole). She developed axillary relapse 22 months after surgery. At the time of axillary salvage clearance, 2 of 17 axillary lymph showed localization of an estrogen and progesterone receptor-negative metastatic breast cancer.
The second patient had a 1.3-cm G3 endocrine receptor-positive ductal invasive carcinoma. She had received six cycles of adjuvant CMF followed by tamoxifen. She developed axillary recurrence 11 months after surgery, while on tamoxifen. At the time of axillary salvage clearance, 4 of 15 axillary lymph showed localization of an estrogen and progesterone receptor-negative metastatic breast cancer.
The third patient had a 1.6-cm G2 estrogen and progesterone receptor-positive ductal invasive carcinoma. The adjuvant treatment was tamoxifen. Nineteen months later she developed axillary metastases (four of seven lymph nodes isolated) that still were estrogen- and progesterone positive.
The fourth patient had received conservative surgery and sentinel node biopsy for a 1.9-cm G2 ductal invasive carcinoma that was estrogen and progesterone receptor positive. The patient refused further surgery because of a focal involvement of excision margins by in situ disease. She was started on adjuvant treatment with tamoxifen. Four months later she changed her mind and asked for radical surgery. When carried out, no carcinoma was found in the mammary gland, but five lymph nodes were isolated along the axilla extension, one of them was positive for metastases.
At relapse, all four patients received total axillary dissection followed by an anthracycline-based chemotherapy and eventually an endocrine therapy. They are currently alive and free of disease.
Two patients had in-breast and axillary recurrence; the first patient had a 2-cm G3 estrogen receptor-positive, progesterone receptor-negative ductal invasive carcinoma. She had received adjuvant endocrine therapy (tamoxifen) and was randomized not to perform radiotherapy in a trial investigating its role after conservative surgery. Eighteen months later she developed an in-breast and axillary relapse. A quadrantectomy with axillary dissection was carried out showing a 1.9-cm G3 estrogen receptor-positive, progesterone receptor-negative ductal invasive carcinoma; 8 of 18 axillary lymph were metastatic. The second patient had a 2.5-cm G2 endocrine receptor-positive ductal invasive carcinoma. She had received adjuvant ovarian ablation and tamoxifen. She developed an in-breast and axillary relapse after 72 months. At that time she had received mastectomy and total axillary dissection; she had a 1.6-cm G2 endocrine receptor-positive ductal invasive carcinoma with 6 of 17 lymphs involved.
The two patients received adjuvant chemotherapy followed by aromatase inhibitor-based endocrine therapy; they are currently alive and free of disease.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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SLNB in early breast cancer aims at identifying axillary lymph node-negative patients in order to spare them unnecessary axillary dissection [9] and its related discomfort [10]. Although the procedure has been proven to be accurate and safe, a rate of false-negative SLN of 3%–5% has been reported [4, 11, 12]. Currently, the impact of inaccuracy of SLNB on regional control and ultimately on survival is unknown. A way to analyze this issue is to look at the rate of axillary recurrence after a negative SLNB not followed by ALND. Large randomized trials are ongoing to compare disease-free survival and OS between patients treated with ALND and those treated with SLNB alone [13]. In the meanwhile, the procedure has acquired widespread worldwide application and it is now routinely in use even in small centers. Data from observational studies are available, but they are mostly from single specialized referral institutions. Our study shows that in a large series of unselected early breast cancer patients treated in a community-based hospital with a dedicated surgeon team, axillary recurrence is low and comparable with published experience. At a median follow-up of 38.8 months, only four (0.5%) isolated axillary recurrences occurred in 804 SLN-negative patients, after 22, 11, 19 and 4 months from surgery. All four patients received total axillary dissection and further systemic adjuvant therapies, and they are currently alive and free from disease. Our data are consistent with those reported in similar observational studies (Table 5), either from single referral institutions or from a multicenter experience, with axillary recurrence rates ranging from 0% to 1% (median 0.6). [7, 9, 14–34] The very low rate of axillary recurrence in all these studies support the idea that SLNB without ALND can be safely offered to SLN-negative breast cancer patients. It can be argued that the follow-up is still relatively short, but in the NSABP B-04 study the majority of the axillary relapses in patients treated without axillary dissection occurred within the first 2 years [35]. On the other hand, it is known from trials in neo-adjuvant setting that chemotherapy can be able to sterilize metastatic axillary lymph nodes. Therefore, the widespread use of systemic adjuvant therapy could partially explain the low rate of axillary relapse. In our study, we decided to report separately axillary relapse which occurred together with in-breast recurrence and with distant relapse. In our experience, two women showed a new breast cancer together with axillary involvement and a woman showed systemic dissemination of the disease together with axillary involvement: we think these cases of axillary relapse can be caused either by propagation from the new breast cancer or within the context of systemic dissemination of the disease, rather than from disease persistence at the time of primary surgery, and therefore should not account for axillary failure of SLNB.
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In conclusion, this is the largest series of unselected breast cancer patients treated only with SLNB from a single community-based hospital reported so far. Our results confirm previous data and encourage the use of SLNB without ALND even in community-based Breast Cancer Unit where a team of adequately trained breast surgeons is present.
Received for publication May 6, 2008. Accepted for publication May 19, 2008.
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