Mattia Intra

Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23–01): a phase 3 randomised controlled trial

BACKGROUND For patients with breast cancer and metastases in the sentinel nodes, axillary dissection has been standard treatment. However, for patients with limited sentinel-node involvement, axillary dissection might be overtreatment. We designed IBCSG trial 23-01 to determine whether no axillary dissection was non-inferior to axillary dissection in patients with one or more micrometastatic (≤2 mm) sentinel nodes and tumour of maximum 5 cm. METHODS In this multicentre, randomised, non-inferiority, phase 3 trial, patients were eligible if they had clinically non-palpable axillary lymph node(s) and a primary tumour of 5 cm or less and who, after sentinel-node biopsy, had one or more micrometastatic (≤2 mm) sentinel lymph nodes with no extracapsular extension. Patients were randomly assigned (in a 1:1 ratio) to either undergo axillary dissection or not to undergo axillary dissection. Randomisation was stratified by centre and menopausal status. Treatment assignment was not masked. The primary endpoint was disease-free survival. Non-inferiority was defined as a hazard ratio (HR) of less than 1·25 for no axillary dissection versus axillary dissection. The analysis was by intention to treat. Per protocol, disease and survival information continues to be collected yearly. This trial is registered with ClinicalTrials.gov, NCT00072293. FINDINGS Between April 1, 2001, and Feb 28, 2010, 465 patients were randomly assigned to axillary dissection and 469 to no axillary dissection. After the exclusion of three patients, 464 patients were in the axillary dissection group and 467 patients were in the no axillary dissection group. After a median follow-up of 5·0 (IQR 3·6-7·3) years, we recorded 69 disease-free survival events in the axillary dissection group and 55 events in the no axillary dissection group. Breast-cancer-related events were recorded in 48 patients in the axillary dissection group and 47 in the no axillary dissection group (ten local recurrences in the axillary dissection group and eight in the no axillary dissection group; three and nine contralateral breast cancers; one and five [corrected] regional recurrences; and 34 and 25 distant relapses). Other non-breast cancer events were recorded in 21 patients in the axillary dissection group and eight in the no axillary dissection group (20 and six second non-breast malignancies; and one and two deaths not due to a cancer event). 5-year disease-free survival was 87·8% (95% CI 84·4-91·2) in the group without axillary dissection and 84·4% (80·7-88·1) in the group with axillary dissection (log-rank p=0·16; HR for no axillary dissection vs axillary dissection was 0·78, 95% CI 0·55-1·11, non-inferiority p=0·0042). Patients with reported long-term surgical events (grade 3-4) included one sensory neuropathy (grade 3), three lymphoedema (two grade 3 and one grade 4), and three motor neuropathy (grade 3), all in the group that underwent axillary dissection, and one grade 3 motor neuropathy in the group without axillary dissection. One serious adverse event was reported, a postoperative infection in the axilla in the group with axillary dissection. INTERPRETATION Axillary dissection could be avoided in patients with early breast cancer and limited sentinel-node involvement, thus eliminating complications of axillary surgery with no adverse effect on survival. FUNDING None.

Sentinel-lymph-node biopsy as a staging procedure in breast cancer: update of a randomised controlled study

BACKGROUND In women with breast cancer, sentinel-lymph-node biopsy (SLNB) provides information that allows surgeons to avoid axillary-lymph-node dissection (ALND) if the SLN does not have metastasis, and has a favourable effect on quality of life. Results of our previous trial showed that SLNB accurately screens the ALN for metastasis in breast cancers of diameter 2 mm or less. We aimed to update this trial with results from longer follow-up. METHODS Women with breast tumours of diameter 2 cm or less were randomly assigned after breast-conserving surgery either to SLNB and total ALND (ALND group), or to SLNB followed by ALND only if the SLN was involved (SLN group). Analysis was restricted to patients whose tumour characteristics met eligibility criteria after treatment. The main endpoints were the number of axillary metastases in women in the SLN group with negative SLNs, staging power of SLNB, and disease-free and overall survival. FINDINGS Of the 257 patients in the ALND group, 83 (32%) had a positive SLN and 174 (68%) had a negative SLN; eight of those with negative SLNs were found to have false-negative SLNs. Of the 259 patients in the SLN group, 92 (36%) had a positive SLN, and 167 (65%) had a negative SLN. One case of overt clinical axillary metastasis was seen in the follow-up of the 167 women in the SLN group who did not receive ALND (ie, one false-negative). After a median follow-up of 79 months (range 15-97), 34 events associated with breast cancer occurred: 18 in the ALND group, and 16 in the SLN group (log-rank p=0.6). The overall 5-year survival of all patients was 96.4% (95% CI 94.1-98.7) in the ALND group and 98.4% (96.9-100) in the SLN group (log-rank p=0.1). INTERPRETATION SLNB can allow total ALND to be avoided in patients with negative SLNs, while reducing postoperative morbidity and the costs of hospital stay. The finding that only one overt axillary metastasis occurred during follow-up of patients who did not receive ALND (whereas eight cases were expected) could be explained by various hypotheses, including those from cancer-stem-cell research.

Sentinel lymph node biopsy in breast cancer: ten-year results of a randomized controlled study.

Objective:Sentinel node biopsy (SNB) is widely used to stage the axilla in breast cancer. We present 10-year follow-up of our single-institute trial designed to compare outcomes in patients who received no axillary dissection if the sentinel node was negative, with patients who received complete axillary dissection. Methods:From March 1998 to December 1999, 516 patients with primary breast cancer up to 2 cm in pathologic diameter were randomized either to SNB plus complete axillary dissection (AD arm) or to SNB with axillary dissection only if the sentinel node contained metastases (SN arm). Results:The 2 arms were well-balanced for number of sentinel nodes found, proportion of positive sentinel nodes, and all other tumor and patient characteristics. About 8 patients in the AD arm had false-negative SNs on histologic analysis: a similar number (8, 95% CI: 3–15) of patients with axillary involvement was expected in SN arm patients who did not receive axillary dissection; but only 2 cases of overt axillary metastasis occurred. There were 23 breast cancer-related events in the SN arm and 26 in the AD arm (log-rank, P = 0.52), while overall survival was greater in the SN arm (log-rank, P = 0.15). Conclusions:Preservation of healthy lymph nodes may have beneficial consequences. Axillary dissection should not be performed in breast cancer patients without first examining the sentinel node.

Chemotherapy Is More Effective in Patients with Breast Cancer Not Expressing Steroid Hormone Receptors A Study of Preoperative Treatment

Purpose: The purpose of this research was to identify factors predicting response to preoperative chemotherapy. Experimental Design: In a large volume laboratory using standard immunohistochemical methods, we reviewed the pretreatment biopsies and histologic specimens at final surgery of 399 patients with large or locally advanced breast cancer (cT2-T4, N0–2, M0) who were treated with preoperative chemotherapy. The incidence of pathological complete remission and the incidence of node-negative status at final surgery were assessed with respect to initial pathological and clinical findings. Menopausal status, estrogen receptor status, progesterone receptor status [absent (0% of the cells positive) versus expressed], clinical tumor size, histologic grade, Ki-67, Her-2/neu expression, and type and route of chemotherapy were considered. Results: High rates of pathological complete remission were associated with absence of estrogen receptor and progesterone receptor expression (P < 0.0001), and grade 3 (P = 0.001). Significant predictors of node-negative status at surgery were absence of estrogen receptor and progesterone receptor expression (P < 0.0001), clinical tumor size <5 cm (P < 0.001), and use of infusional regimens (P = 0.003). The chance of obtaining pathological complete remission or node-negative status for patients with endocrine nonresponsive tumors compared with those having some estrogen receptor or progesterone receptor expression was 4.22 (95% confidence interval, 2.20–8.09, 33.3% versus 7.5%) and 3.47 (95% confidence interval, 2.09–5.76, 42.9% versus 21.7%), respectively. Despite the significantly higher incidence of pathological complete remission and node-negative status achieved by preoperative chemotherapy for patients with estrogen receptor and progesterone receptor absent disease, the disease-free survival was significantly worse for this cohort compared with the low/positive expression cohort (4-year disease-free survival %: 41% versus 74%; hazard ratio 3.22; 95% confidence interval, 2.28–4.54; P < 0.0001). Conclusions: Response to preoperative chemotherapy is significantly higher for patients with endocrine nonresponsive tumors. New chemotherapy regimens or combinations should be explored in this cohort of patients with poor outcome. For patients with endocrine responsive disease, the role of preoperative endocrine therapies should be studied.

Size of Breast Cancer Metastases in Axillary Lymph Nodes: Clinical Relevance of Minimal Lymph Node Involvement

BACKGROUND Overt ipsilateral axillary lymph node metastases of breast cancer are the most significant prognostic indicators for women who have undergone surgery, yet the clinical relevance of minimal involvement (isolated tumor cells and micrometastases) of these nodes is uncertain. PATIENTS AND METHODS We evaluated biologic features, adjuvant treatment recommendations, and prognosis for 1,959 consecutive patients with pT1-3, pN0, minimal lymph node involvement (pN1mi or pN0i+), or pN1a (single positive node) and M0, who were operated on and counseled for medical therapy from April 1997 to December 2000. RESULTS Patients with pN1a and pN1mi/pN0i+, when compared with patients with pN0 disease, were more often prescribed anthracycline-containing chemotherapy (39.1% v 33.2% v 6.1%, respectively; P < .0001) and were less likely to receive endocrine therapy alone (9.8% v 19.4% v 41.9%, respectively; P < .0001). At the multivariate analysis, a statistically significant difference in disease-free survival (DFS) and in the risk of distant metastases was observed for patients with pN1a versus pN0 disease (hazard ratio [HR] = 2.04; 95% CI, 1.46 to 2.86; P < .0001 for DFS; HR = 2.32; 95% CI, 1.42 to 3.80; P = .0007 for distant metastases) and for patients with pN1mi/pN0i+ versus pN0 disease (HR = 1.58; 95% CI, 1.01 to 2.47; P = .047 for DFS; HR = 1.94; 95% CI, 1.04 to 3.64; P = .037 for distant metastases). CONCLUSION Even minimal involvement of a single axillary node in breast cancer significantly correlates with worse prognosis compared with no axillary node involvement. Further studies are required before widespread modification of clinical practice.

Breast carcinoma in elderly women: Features of disease presentation, choice of local and systemic treatments compared with younger postmenopausal patients

Aging remains one of the single greatest risk factors for the development of new breast carcinoma. The aim of the study was to evaluate the relation between biologic features at first diagnosis of breast carcinoma and treatment choice for postmenopausal women ≥ 50 years to optimize treatment in the elderly.

Prognosis and adjuvant treatment effects in selected breast cancer subtypes of very young women (<35 years) with operable breast cancer

BACKGROUND There is limited knowledge about prognosis of selected breast cancer subtypes among very young women. PATIENTS AND METHODS We explored patterns of recurrence by age according to four immunohistochemically defined tumor subtypes: Luminal A and Luminal B (estrogen receptor positive and/or progesterone receptor positive and either human epidermal growth factor receptor 2 (HER2) positive and/or high Ki-67), HER2-positive (and) endocrine receptor absent and Triple Negative, in 2970 premenopausal patients with pT1-3, pN0-3 and M0 breast cancer. RESULTS Patients <35 years of age (315, 11%) presented a significantly increased risk of recurrence and death [hazards ratio (HR) = 1.65, 95% confidence interval (CI) 1.30-2.10 and HR = 1.78, 95% CI 1.12-2.85, respectively] when compared with older patients (2655, 89%) with similar characteristics of disease. This was true considering patients with Luminal B [HR = 1.62, 95% CI 1.21-2.18 for disease-free survival (DFS) and HR = 2.09, 95% CI 0.96-4.53 for overall survival (OS)] and with Triple Negative (HR = 2.04, 95% CI 1.11-3.72 for DFS and HR = 2.20, 95% CI 1.10-4.41 for OS) breast cancer, observing the highest risk of recurrence in the younger patients with HER2-positive breast cancer (HR = 2.37, 95% CI 1.12-5.02) when compared with older patients. CONCLUSIONS Very young patients with Triple Negative, Luminal B or HER2-positive breast cancer have a worse prognosis when compared with older patients with similar characteristics of disease.

Full-Dose Intraoperative Radiotherapy With Electrons During Breast-Conserving Surgery: Experience With 590 Cases

Background:Previous studies show that local recurrences after breast-conserving treatment occur in the site of the primary tumor. The need for postoperative radiotherapy on the whole breast is challenged in favor of radiotherapy limited to the area of the breast at high risk of recurrence. The new mobile linear accelerators easily moved close to the operating table to allow the full-dose irradiation during surgery. Patients and Methods:From July 1999 to December 2003, 590 patients affected by unifocal breast carcinoma up to a diameter of 2.5 cm received wide resection of the breast followed by intraoperative radiotherapy with electrons (ELIOT). Most patients received 21 Gy intraoperatively, biologically equivalent to 58 to 60 Gy in standard fractionation. Patients were evaluated 1, 3, 6, and 12 months after surgery, and thereafter every 6 months, to look for early, intermediate, late complications, and other events. Results:After a follow-up from 4 to 57 months (mean, 24 months; median, 20 months), 19 patients (3.2%) developed breast fibrosis, mild in 18, severe in 1, which resolved within 24 months. Three patients (0.5%) developed local recurrences, 3 patients ipsilateral carcinomas in other quadrants and other 5 patients contralateral breast carcinoma. One patient (0.2%) died of distant metastases. Conclusions:ELIOT is a safe method for treating conservatively operated breasts, avoids the long period of postoperative radiotherapy, and reduces drastically the cost of radiotherapy. ELIOT reduces radiation to normal tissues and organs. Results on short-term and middle-term toxicity up to 5 years of follow-up are good. Data on local control are encouraging.

Sentinel node biopsy is not a standard procedure in ductal carcinoma in situ of the breast: The experience of the European institute of oncology on 854 patients in 10 years

Objective:The aim of this study is to assess the role of sentinel lymph node (SLN) biopsy in patients with pure ductal carcinoma in situ of the breast (DCIS) as a rationale for recommending the best managing option for the treatment of such patients in daily practice. Summary Background Data:DCIS cannot give rise to axillary metastases by definition. Axillary dissection is therefore not indicated. The role of SLN biopsy in the management of DCIS has not yet been established. Methods:From March 1996 to September 2006, 854 patients with pure DCIS underwent SLN biopsy at the European Institute of Oncology. Clinical and pathologic data were prospectively collected. When previous surgery or stereotactic biopsy had been performed elsewhere, all the histopathological preparations were reviewed. Patients with microinvasion were excluded from this investigation. Lymphatic mapping was performed using a radiocolloid technique. Results:SLN metastases were detected in 12 (1.4%) DCIS patients. In 7 cases, only micrometastases (<2 mm) were diagnosed and in 5 cases macrometastases. In addition, isolated tumoral cells (ITC) (<0.2 mm) were identified in 4 additional patients. Eleven patients underwent complete axillary dissection. None of these patients had additional positive axillary lymph nodes. Conclusions:Because of the low prevalence of metastatic involvement, SLN biopsy should not be considered a standard procedure in the treatment of all patients with DCIS. The sole criteria for proposing SLN biopsy in DCIS should be when there exists any uncertainty regarding the presence of invasive foci at definitive histology.

Response to primary chemotherapy in breast cancer patients with tumors not expressing estrogen and progesterone receptors

BACKGROUND We recently demonstrated that in premenopausal patients with estrogen receptors (ER)-absent tumors, early initiation of systemic chemotherapy after primary surgery might improve outcome. These data indicate a different responsiveness to chemotherapy for tumors not expressing hormone receptors. To test this hypothesis we evaluated the responsiveness to preoperative chemotherapy in patients with ER and progesterone receptors (PgR)-absent tumors. PATIENTS AND METHODS Patients with biopsy-proven T2-T3, N0-2 breast cancer treated at a single institution from January 1995 to August 1999 with preoperative chemotherapy were retrospectively evaluated. ER and PgR were determined immunohistochemically and classified for this purpose as absent (0% of the cells positive) or positive (> or = 1% of the cells). RESULTS On 117 evaluable patients 72 had an objective response (61%). A significant difference in response was observed for patients with ER and PgR absent compared with those with ER and/or PgR-positive tumors (82% vs. 57%, P = 0.03 Fisherss exact test). Pathological complete remission rates were also significantly different in the two groups (23% vs. 7%, respectively; P = 0.04). CONCLUSIONS The different degree of response according to hormone receptors expression supports the hypothesis that tumors not expressing both ER and PgR might represent a different clinical entity in terms of chemotherapy responsiveness.