The AMAROS Trial: After Mapping of the Axilla Radiotherapy or Surgery of the Axilla
The AMAROS trial is a phase III study comparing axillary lymph node dissection (ALND) with axillary radiation therapy in patients with proven axillary metastasis by sentinel node biopsy (SNB). The main objective is to prove equivalent locoregional control and reduced morbidity for axillary radiation therapy. Additional aims of the study are to analyze technical results of the SNB procedure and to analyze the influence of the different treatment arms on adjuvant treatment decisions.
Patients with operable, unifocal invasive breast cancer (5 to 50 mm) and clinically negative lymph nodes are randomized between ALND and axillary radiation therapy. SNB is performed using the combined technique: radioactive tracer and blue dye. Before a participating institution was allowed to enter patients, it must have performed at least 30 SNB procedures followed by a complete ALND, and it must have been site visited as part of the surgical quality assurance. The identification rate had to be >90% and no more than 1 false-negative result should have been encountered. Quality of life and arm and shoulder function are evaluated yearly. In the ALND arm, at least a level 1 and 2 dissection is performed. The target area for the radiotherapy consists of all 3 levels and the medial supraclavicular fossa. The prescribed dose is 50 Gy in 25 fractions. Adjuvant systemic therapy and radiotherapy are given according to the institutional guidelines. The primary end point is axillary recurrence rate. Assuming a SNB-positive rate of 30%, 4766 patients need to be registered, which is expected to be realized by the end of 2009. Interim analysis of the first 2000 patients showed that the sentinel node identification rate was 97% (range per institute: 89% to 99%), 33% (n = 658) of the patients were SNB positive, 62% (n = 1245) were SNB negative, and 2% (n = 32) had other outcomes (nonaxillary, missing data). In the SNB-positive group of 658 patients, the treatment noncompliance was 12%, 314 patients were correctly treated with ALND, and 277 patients were correctly treated with axillary radiation therapy. In the sentinel node positive group, 71% had 1 positive sentinel node. In the ALND arm, nodal involvement was seen in 1 to 3 lymph nodes in 83%, in 4 to 9 lymph nodes in 12%, and more than 9 lymph nodes in 5%. There were no significant differences between the ALND and axillary radiation therapy arm in the administration of adjuvant chemotherapy (both 58%) or adjuvant hormonal therapy (76% vs 71%, respectively). Of the patients treated with ALND, 6% received adjuvant axillary radiation therapy because more than 3 positive lymph nodes were found.
These interim results indicate that with a 97% detection rate in this prospective international multicenter study using the combination of radioactive tracer and blue dye, the sentinel node procedure is highly effective. Furthermore, this analysis shows that there are no major differences in prescribing adjuvant systemic therapy between the two treatment arms and assumes that the administration of adjuvant systemic therapy is mainly based on tumor and patient characteristics and SNB status alone.
Radiation Dose Intensity Study in Breast Cancer in Young Women: A Randomized Phase III Trial of Additional Dose to the Tumor Bed
The previously mentioned boost versus no boost trial showed that young age is an independent factor of LR after BCT. In patients less than 51 years of age, the rate of breast recurrence is decreased by 50% after a dose of 66 Gy to the tumor bed, compared with 50 Gy (no boost). The effect of increased radiation dose seems independent from the delivery of adjuvant systemic treatment. Because the LR for young patients is still quite high (>1% per year), a consecutive trial has been initiated in the Netherlands to investigate whether a higher boost dose will decrease the LR further. This trial will compare the effect of a low boost (16 Gy) versus a high boost (26 Gy) on LR and cosmesis, in patients less than 51 years of age. The second aim of this study is to investigate whether genetic and/or protein profiles can be determined that correlate with LR rate, lymph node metastases, distant metastases and survival, radiosensitivity, and age. Therefore, fresh-frozen tumor tissue and blood samples will be collected for designing mRNA and miRNA profiles. This trial plans to accrue 2400 patients, and it is expected that it will be completed in 2010.
The MINDACT Trial: Microarray in Node-Negative Disease May Avoid Chemotherapy
By using gene-expression profiling, the Netherlands Cancer Institute developed a 70-gene prognostic signature for node-negative breast cancer. The signature was developed as a dichotomous risk classification for the end point of distant metastasis within 5 years. The same group performed a first validation of this gene signature on 295 patients and confirmed that it outperforms all the traditional clinical prognostic factors and clearly separates patients to a group with an excellent prognosis at 10 years and to a group with a high risk of recurrence before 5 years. Furthermore, when compared with current commonly used risk classifications (ie, the St. Gallen guidelines and the National Institutes of Health [NIH] consensus), the 70-gene signature not only predicted those women who would have needed chemotherapy (as demonstrated by the onset of distant metastases within 5 years), but also women who could have been spared adjuvant chemotherapy, as seen from their excellent long-term outcome.9-11
The goal of the MINDACT trial is to prospectively validate the 70-gene prognosis signature providing the level 1 evidence of its utility. This study aims to give us a definitive answer regarding the clinical relevance of the 70-gene signature, its performance compared with traditional prognostic factors, and, as a secondary aim, its ability to predict response to commonly prescribed adjuvant treatments. Using this new tool, MINDACT aims to better define patient prognosis and therefore to better select patients who need adjuvant chemotherapy; by doing so, it is expected that 10% to 20% of women who would normally receive adjuvant chemotherapy based on their clinicopathologic factors will be spared the inconvenience and morbidity of this therapy, without having any negative impact on their survival.
The primary objective of the trial is to confirm that the number of patients that can be safely spared adjuvant chemotherapy is significantly increased when the decision is based on the 70-gene signature rather than on clinicopathologic methods, and the critical group of patients who have a high risk of recurrence according to the clinicopathologic criteria but a low risk according to the 70-gene prognosis signature is not undertreated. Because the 70-gene prognosis signature also outperforms traditional prognostic factors in predicting disease outcome in patients with 1 to 3 positive nodes, both patients with node-negative disease and those with 1 to 3 nodes positive are eligible for this trial.
All patients with operable breast cancer 0.5 to 5.0 cm in size 0 to 3 positive nodes are eligible. Before surgery, patients first consent that a part of their cancer is kept for research and microarray analysis. This is the registration phase of the trial. If, after surgery the patient is eligible for the study, consent is asked for the first randomization. Enrolled patients receive their clinical risk classification on the basis of Adjuvant Online! (high versus low clinical risk) and on the basis of the 70-gene signature (genomic high versus low risk). Patients who are concordant to clinical and genomic low-risk prognosis (and who have usually hormone-responsive tumors) are eligible for the hormonal therapy randomization: 7 years letrozole, 2.5 mg daily, versus 2 years tamoxifen, 20 mg daily, followed by 5 years of letrozole. Those patients who have concordant high-risk prognostic estimates will receive chemotherapy (and endocrine treatment if hormone receptor positive) and are eligible for the randomization between: anthracycline-based chemotherapy (including taxanes for node-positive patients) versus a non-anthracycline-containing regimen (docetaxel plus capecitabine). Primary end point is the breast cancer specific disease-free survival at 5 years in the discordant group clinically high/genomic low without chemotherapy (>93%).
The study started early 2007 and by September 2008, 1400 patients are registered and 550 enrolled. After enrollment of the first 800 patients, expected in December 2008, a thorough analysis will be performed on compliance, success of micro-array analysis, and so on.
Notably, from all patients, complex 44 K gene arrays and RNA samples are available, allowing for research on predictive factors.
Power Trial: Positive Sentinel Node: Wait and See, Excision, or Radiotherapy
With the introduction of the SNB technique, the pathologic assessment of the sentinel node has increased. Immuno-histochemical staining and multistep sectioning of lymph nodes have resulted in the detection of micrometastasis (0.2 to 2 mm) and (sub) micrometastasis (<0.2 mm). The prognostic impact of these sub-micrometastases and the appropriate treatment of these patients remain uncertain. Further nodal involvement in patients with micrometastases is seen in around 20%.12 The overall false-negative rate of the SNB procedure is a median of 7%, and the axillary recurrence rate is 0.3% (67 of 14,959) after a median follow-up of 34 months.13,14 These results assume that only 5% of the false-negative lymph node metastasis becomes clinically apparent. So, of the 100 patients with micrometastasis, 20 will have further nodal involvement and 1 will have an axillary recurrence. Because of this limited risk on clinically apparent recurrences, we hypothesized that patients with micrometastases in the sentinel node may be candidates for no further axillary treatment. The morbidity will be reduced by omitting unnecessary treatment and keeping sufficient regional control. The main objective of the trial is to prove less than 2% axillary recurrences at 3 years for patients with proven sub-micrometastases by SNB if axillary treatment is omitted. After finishing patient accrual in the AMAROS trial, this will become the new EORTC sentinel node trial.