Marieke E. Straver

Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial

BACKGROUND If treatment of the axilla is indicated in patients with breast cancer who have a positive sentinel node, axillary lymph node dissection is the present standard. Although axillary lymph node dissection provides excellent regional control, it is associated with harmful side-effects. We aimed to assess whether axillary radiotherapy provides comparable regional control with fewer side-effects. METHODS Patients with T1-2 primary breast cancer and no palpable lymphadenopathy were enrolled in the randomised, multicentre, open-label, phase 3 non-inferiority EORTC 10981-22023 AMAROS trial. Patients were randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node, stratified by institution. The primary endpoint was non-inferiority of 5-year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group. Analyses were by intention to treat and per protocol. The AMAROS trial is registered with ClinicalTrials.gov, number NCT00014612. FINDINGS Between Feb 19, 2001, and April 29, 2010, 4823 patients were enrolled at 34 centres from nine European countries, of whom 4806 were eligible for randomisation. 2402 patients were randomly assigned to receive axillary lymph node dissection and 2404 to receive axillary radiotherapy. Of the 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy; these patients constituted the intention-to-treat population. Median follow-up was 6·1 years (IQR 4·1-8·0) for the patients with positive sentinel lymph nodes. In the axillary lymph node dissection group, 220 (33%) of 672 patients who underwent axillary lymph node dissection had additional positive nodes. Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group. 5-year axillary recurrence was 0·43% (95% CI 0·00-0·92) after axillary lymph node dissection versus 1·19% (0·31-2·08) after axillary radiotherapy. The planned non-inferiority test was underpowered because of the low number of events. The one-sided 95% CI for the underpowered non-inferiority test on the hazard ratio was 0·00-5·27, with a non-inferiority margin of 2. Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years. INTERPRETATION Axillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1-2 primary breast cancer and no palpable lymphadenopathy. Axillary radiotherapy results in significantly less morbidity. FUNDING EORTC Charitable Trust.

Magnetic Resonance Imaging Response Monitoring of Breast Cancer During Neoadjuvant Chemotherapy: Relevance of Breast Cancer Subtype

PURPOSE To evaluate the relevance of breast cancer subtypes for magnetic resonance imaging (MRI) markers for monitoring of therapy response during neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS MRI examinations were performed in 188 women before and during NAC. MRI interpretation included lesion morphology at baseline, changes in morphology, size, and contrast uptake kinetics (initial and late enhancement). By using immunohistochemistry, tumors were divided into three subtypes: triple negative, human epidermal growth factor receptor 2 (HER2) positive, and estrogen receptor (ER) positive/HER2 negative. Tumor response was assessed dichotomously (ie, presence or absence of residual tumor in the surgical specimen). Complementary, a continuous scale assessment was used (the breast response index [BRI], representing the relative change in tumor stage). Multivariate regression analysis and receiver operating characteristic analysis were employed to establish significant associations. RESULTS Residual tumor at pathology was present in 31 (66%) of 47 triple-negative tumors, 23 (61%) of 38 HER2-positive tumors, and 96 (93%) of 103 ER-positive/HER2-negative tumors. Multivariate analysis of residual disease showed significant associations between breast cancer subtype and MRI (area under the curve [AUC], 0.84; P < .001). BRI also showed significant correlation among breast cancer subtype, MRI, and age (Pearsons r = 0.465; P < .001). In subset analysis, this was only significant for triple-negative tumors (P < .001) and HER2-positive tumors (P < .05). Residual tumor after NAC in the triple-negative and HER2-positive group is significantly associated with the change in largest diameter of late enhancement during NAC (AUC, 0.76; P < .001). No associations were found for ER-positive/HER2-negative tumors. CONCLUSION MRI during NAC to monitor response is effective in triple-negative or HER2-positive disease but is inaccurate in ER-positive/HER2-negative breast cancer.

Concordance of clinical and molecular breast cancer subtyping in the context of preoperative chemotherapy response

ER, PR and HER2 status in breast cancer are important markers for the selection of drug therapy. By immunohistochemistry (IHC), three major breast cancer subtypes can be distinguished: Triple negative (TNIHC), HER2+IHC and LuminalIHC (ER+IHC/HER2−IHC). By using the intrinsic gene set defined by Hu et al. five molecular subtypes (BasalmRNA, HER2+mRNA, Luminal AmRNA, Luminal BmRNA and Normal-likemRNA) can be defined. We studied the concordance between analogous subtypes and their prediction of response to neoadjuvant chemotherapy. We classified 195 breast tumors by both IHC and mRNA expression analysis of patients who received neoadjuvant treatment at the Netherlands Cancer institute for Stage II–III breast cancer between 2000 and 2007. The pathological complete remission (pCR) rate was used to assess chemotherapy response. The IHC and molecular subtypes showed high concordance with the exception of the HER2+IHC group. 60% of the HER2+IHC tumors were not classified as HER2+mRNA. The HER2+IHC/Luminal A or BmRNA group had a low response rate to a trastuzumab-chemotherapy combination with a pCR rate of 8%, while the HER2+mRNA group had a pCR rate of 54%. The Luminal AmRNA and Luminal BmRNA groups showed similar degrees of response to chemotherapy. Neither the PR status nor the endocrine responsiveness index subdivided the ER+IHC tumors accurately into Luminal AmRNA and Luminal BmRNA groups. Molecular subtyping suggests the existence of a HER2+IHC/LuminalmRNA group that responds poorly to trastuzumab-based chemotherapy. For LuminalIHC and triple negativeIHC tumors, further subdivision into molecular subgroups does not offer a clear advantage in treatment selection.

Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients: Final analysis of the EORTC AMAROS trial (10981/22023).

LBA1001 Background: Sentinel node biopsy (SNB) is standard in assessing axillary lymph node status for cN0 breast cancer patients. In case of a positive SNB, if treatment is advised, axillary lymph node dissection (ALND) is the current standard. Although ALND provides excellent regional control, it may give harmful side effects. Axillary radiotherapy (ART) instead of ALND was hypothesized to provide comparable regional control and less side effects. METHODS From 2001 to 2010, patients with cT1E2N0 primary breast cancer were enrolled in the EORTC phase III non-inferiority AMAROS trial. Patients were randomized between ALND and ART in case of a positive SNB. Primary endpoint was 5-year axillary recurrence rate. Secondary endpoints were overall survival (OS), disease-free survival (DFS), quality of life (QOL), shoulder movement and lymphedema at 1 and 5 years. RESULTS Of the 4,806 patients entered in the trial, 744 in the ALND-arm and 681 in the ART-arm had a positive SNB, 60% with a macrometastasis. The two treatment-arms were comparable regarding age, tumor size, grade, tumor type, and adjuvant systemic treatment. With a median follow up of 6.1 years, the 5-year axillary recurrence rate after a positive SNB was 0.54% (4/744) after ALND versus 1.03% (7/681) after ART. The planned non-inferiority test was underpowered because of the unexpectedly low number of events. The axillary recurrence rate after a negative SNB was 0.8% (25/3131). There were no significant differences between treatment arms regarding OS (5 yr estimates: 93.27% ALND, 92.52% ART, p=0.3386) and DFS (5 yr estimates: 86.90% ALND, 82.65% ART, p=0.1788). Lymphedema was found significantly more often after ALND (1yr: 40% ALND, 22% ART, p<0.0001 and 5yr: 28% ALND, 14% ART, p<0.0001). There was a nonsignificant trend toward more early shoulder movement impairment after ART. These findings were compatible with a trend in two QOL items in the arm symptom scale: swelling (ART better) and movement (ALND better). There were no other differences in QOL. CONCLUSION ALND and ART after a positive SNB provide excellent and comparable regional control. ART reduces the risk of short-term and long-term lymphedema compared to ALND. CLINICAL TRIAL INFORMATION NCT00014612.

Detection of extra-axillary lymph node involvement with FDG PET/CT in patients with stage II-III breast cancer.

PURPOSE The aim of this prospective study was to assess the incidence of extra-axillary lymph node involvement on baseline FDG PET/CT in patients with stage II-III breast cancer scheduled for neo-adjuvant chemotherapy. METHODS Patients with invasive breast cancer of >3 cm and/or proven axillary lymph node metastasis were included for before neo-adjuvant chemotherapy. Baseline ultrasound of the infra- and supraclavicular regions was performed with fine-needle biopsy as needed. Subsequently FDG PET/CT was performed. All visually FDG-positive nodes were regarded as metastatic based on the previously reported high specificity of the technique. RESULTS Sixty patients were included. In 17 patients (28%) extra-axillary lymph nodes were detected by FDG PET/CT, localised in an intra-mammary node (1 lymph node in 1 patient), mediastinal (2 lymph nodes in 2 patients), internal mammary chain (9 lymph nodes in 8 patients), intra- and interpectoral (6 lymph nodes in 4 patients), infraclavicular (5 lymph nodes in 4 patients) and in the contralateral axilla (3 lymph nodes in 2 patients). Ultrasound-guided cytology had detected extra-axillary lymph node involvement in seven of these patients, but was unable to detect extra-axillary nodes in the other 10 patients with positive extra-axillary lymph nodes on FDG PET/CT. Radiotherapy treatment was altered in 7 patients with extra-axillary involvement (12% of the total group). CONCLUSIONS FDG PET/CT detected extra-axillary lymph node involvement in almost one-third of the patients with stage II-III breast cancer, including regions not evaluable with ultrasound. FDG PET/CT may be useful as an additional imaging tool to assess extra-axillary lymph node metastasis, with an impact on the adjuvant radiotherapy management.

Marking the axilla with radioactive iodine seeds (MARI procedure) may reduce the need for axillary dissection after neoadjuvant chemotherapy for breast cancer

An important benefit of neoadjuvant chemotherapy is the increased potential for breast‐conserving surgery. At present the response of axillary lymph node metastases to chemotherapy is not easily assessed, rendering axilla‐conserving treatment difficult. The aim was to assess a new surgical method for evaluating the axillary response to chemotherapy.

Towards rational axillary treatment in relation to neoadjuvant therapy in breast cancer

AIMS The purpose of this study is to analyse nodal staging and axillary response in breast cancer patients treated with neoadjuvant chemotherapy (NAC) to explore venues to safely spare patients axillary clearance whenever it could be avoided. METHODS In 327 patients we determined the nodal status before NAC by ultrasound-guided cytology and if indicated by sentinel node biopsy (SNB). In patients with proven metastasis we analysed the axillary response after NAC. RESULTS Before NAC, the ultrasound-guided cytology was positive in 252 patients. In the remaining 75 patients SNB was performed prior to NAC. The SNB was negative in 53 patients, thus in these patients axillary clearance could be avoided. All 274 patients with proven axillary metastases at diagnosis underwent axillary clearance after NAC. Twenty percent of the cytology-positive patients (50/252) had an axillary pathological complete remission (pCR) and 68% of the SNB-positive patients (15/22) had no lymph node (LN) metastasis after NAC. Subgroups with a high axillary pCR rate were patients with triple-negative tumours (57%) and human epidermal growth-factor receptor 2 (HER2)-positive tumours (68%) who had a pCR of the primary tumour. CONCLUSIONS Twenty percent of the patients with proven metastasis by cytology prior to NAC have an axillary pCR. The axillary pCR rate is very high in certain subgroups. Identification of these patients, could result in more axilla-conserving therapies.

Comparison of the sentinel node procedure between patients with multifocal and unifocal breast cancer in the EORTC 10981-22023 AMAROS Trial: Identification rate and nodal outcome

INTRODUCTION Multifocal breast cancer is associated with a higher risk of nodal involvement compared to unifocal breast cancer and the drainage pattern from multifocal localisations may be different. For this reason, the value of the sentinel node biopsy (SNB) procedure for this indication is debated. The aim of the current analysis was to evaluate the sentinel node identification rate and nodal involvement in patients with a multifocal tumour in the EORTC 10981-22023 AMAROS trial. PATIENTS AND METHODS From the first 4000 registered patients, 342 were identified with a multifocal tumour on histological examination and compared to a randomly selected control group of 684 patients with a unifocal tumour. The outcome of the SNB was assessed. RESULTS The sentinel node was identified in 96% of the patients with a multifocal tumour and in 98% of those with unifocal disease. In the multifocal group, 51% had a metastasis in the sentinel node compared to 28% in the unifocal group; and further nodal involvement after a positive sentinel node was found in 40% (38/95) and 39% (39/101) respectively. CONCLUSION In this prospective international multicentre study, the 96% detection rate indicates that the SNB procedure can be highly effective in patients with a multifocal tumour. Though the tumour-positive rate of the sentinel node was twice as high in the multifocal group compared to the unifocal group, further nodal involvement after a positive sentinel node was similar in both groups. This suggests that the SNB procedure is safe in patients with multifocal breast cancer.

Accurate axillary lymph node dissection is feasible after neoadjuvant chemotherapy

BACKGROUND Recently, lower axillary lymph node retrieval after neoadjuvant chemotherapy was reported. We did not have this experience, and retrospectively analyzed our axillary lymph node dissections (ALNDs). METHODS One hundred ninety-one patients who had ALND after neoadjuvant chemotherapy were compared with 192 patients with primary ALND after a positive sentinel node biopsy. RESULTS There were no differences in the mean number of nodes retrieved between the neoadjuvant group and the primary surgery group: 16.3 (range 4-38) and 15.8 (range 6-33), respectively (P = .4); or in the retrieval of fewer than 10 lymph nodes: 13/191 (7%) and 11/192 (6%) (P = .7). The number of cases with retrieval of more than 20 lymph nodes was higher in the neoadjuvant group: 42/191 (22%) versus 26/192 (13%) (P = .03). In the neoadjuvant group, 150/191 (79%) patients had residual lymph node metastasis after neoadjuvant chemotherapy. CONCLUSION Our results show the feasibility and need to remove enough lymph nodes to provide precise prognostic information and adequate local control.

Radioguided occult lesion localisation (ROLL) in breast-conserving surgery after neoadjuvant chemotherapy

BACKGROUND An important benefit of neoadjuvant chemotherapy, as compared to adjuvant chemotherapy, in breast cancer patients is down staging of the primary tumour, which allows for more breast-conserving surgery. When a tumour becomes non-palpable after this down staging, precise localisation of the original tumour bed is crucial to be able to perform breast-conserving surgery. Radioguided Occult Lesion Localisation with (99m)Technetium (ROLL-(99m)Tc) is commonly used to perform breast-conserving surgery in patients with non-palpable breast tumours. We modified this technique to use it in the neoadjuvant setting. The present analysis was performed to assess its feasibility and analyse the number of patients in which a mastectomy was correctly withheld using this technique. METHODS A retrospective analysis was performed for all patients who were treated with neoadjuvant chemotherapy between 2007 and 2010 in our institute and underwent breast-conserving surgery with the ROLL-(99m)Tc technique afterwards. The status of the margins and the weight of the resected specimen were assessed. RESULTS The median weight of the resected specimen in these 83 patients was 53 g (range: 11-204 g). Eleven of the 58 patients with residual disease revealed positive margins at pathological examination. However, in only 5 of those 11 patients a secondary mastectomy was indicated. This means that in 94% of all included patients a mastectomy was correctly withheld. CONCLUSION The ROLL-(99m)Tc technique is a feasible technique that can be used to perform breast-conserving surgery after neoadjuvant chemotherapy in a carefully selected group of patients.