The SOAPET study is the first prospective trial to investigate the accuracy of LymphPET in evaluating axillary status in cN0 patients detected by clinical examination. Its primary endpoint of an NPV of 87.8% for LymphPET was met. According to our results, in patients with a negative axillary physical examination, approximately 21% will have LN-macro after SLNB, even when combined with preoperative ultrasound, 13.7% of patients with no lymph nodes detected by preoperative ultrasound, still had LN-macro. Importantly, after combining ultrasound and LymphPET, we were able to screen potential patients who may avoid axillary evaluation with an NPV >90%.
Currently, in primary cN0 breast cancer, SLNB is the gold standard for regional axillary staging, with better physical function of the upper limb when compared with AD; however, it can also lead to specific axillary morbidity in both the early and late postoperative periods. In patients treated with SLNB alone, the rate of wound infections, axillary seromas, and paresthesia was 25% in Z0011 [11], and long-term postsurgical complications were recorded as 4% lymphoedema, 13% sensory neuropathy, and 13% motor neuropathy in IBCSG 23-01 [12]. Higher rates of lymphedema and an arm circumference increase of >10% were recorded after SLNB followed by axillary radiotherapy in AMAROS [13]. Therefore, screening cN0 patients to avoid surgical evaluation is an essential focus of current research. Several ongoing prospective randomized trials, such as SOUND trial and BOOG 2013-08 trial, are comparing SLNB with observation in cN0 patients treated with breast-conserving therapy [4, 14]. The key technical indicators for such trials are the NPV of preoperative assessment, as a higher number of FN means LN-macro remain in the axillary, which may lead to a higher local failure rate.
Initial data of the SOUND trial showed that 13.4% of patients in the SLNB group had LN-macro [15], the NPV of preoperative axillary assessment by physical examination and ultrasound was approximately 87%. It is still unclear whether 13% of FN with no lymph node surgical evaluation will influence outcomes. Our study had a similar finding, among patients with a negative axillary physical examination and no lymph nodes detected by preoperative ultrasound, 13.7% still had LN-macro. Therefore, it is essential to determine the omission of SLNB with increasing the NPV of preoperative axillary assessment.
Several studies have investigated axillary ultrasound in patients with early breast cancer. Retrospective data of 577 axillary ultrasounds demonstrated that a negative axillary ultrasound generally excludes the presence of pN2–3 disease, whereas ultrasound cannot accurately differentiate between pN1 and pN2-3 disease [16]. FN is relatively high, as in 118 patients with no node detected by ultrasound, 21% were ultimately found to be node-positive [17]; although these FN results did not significantly impact adjuvant medical decision-making, as patients with FN had recurrence-free survival equivalent to patients with pathological N0 disease [18].
Other studies have further evaluated whether metabolic imaging technology may increase accuracy in evaluating axillary status in early breast cancer. In 349 T1 patients who were preoperatively examined using ultrasound, MRI, and 18F-FDG PET/CT, the NVP was around 81.7–82.6%, suggesting that there are no definitive modalities for detecting node metastasis in T1 breast cancer to replace SLNB [8]. After combining 18F-FDG PET/CT and ultrasound, in 138 ultrasound-negative and 18F-FDG uptake-negative patients, 15% were found to have lymph node involvement [9]. Therefore, even with high specificity, 18F-FDG PET/CT demonstrated poor sensitivity in the detection of axillary metastases [19].
A possible explanation for this is that, currently, the whole-body 18F-FDG PET/CT system typically yields reconstructed images with a resolution of 5–15mm, depending on the injected dose, imaging time, post-reconstruction filtering, and intrinsic resolution of the scanner. This reduces the system’s ability to detect small lesions (<1 cm) and/or lesions with low tracer uptake [20]. According to our previous study, the spatial resolution of LymphPET is much higher than whole-body PET/CT, with 88% sensitivity and 79% specificity [10].
In the current study, we found that the diagnostic accuracy of LymphPET was nearly equal to ultrasound. The sensitivity, specificity, and NPV for LymphPET were 60%, 77.2%, and 87.8%, respectively, and those for US-neg were 57.5%, 71.8%, and 86.3%. When combined LymphPET in the preoperative assessment, in the physical exam-negative and ultrasound-negative patients, we were able to further screen 80% of patients (100/124) with a 91% NPV for axillary lymph node macrometastases, and providing technical support for future studies looking at the omission of axillary evaluation.
Usually, FN rate of 10% for SLNB is acceptable. In Z0011, patients who underwent AD had 27% non-SLN positive, assuming patients with SLNB only still had around 30% with positive node remain in axillary, with the additional local treatment of radiotherapy, the local regional recurrence is less than 1% [11]. Similarly, in the AD group in AMAROS, 33% of patients had additional positive nodes; 5-year axillary lymph node recurrence was found to be 1.19% in SLNB group after axillary radiotherapy [13]. Therefore, we believe that LymphPET could be a reliable preoperative evaluation method, and axillary surgical evaluation can be omitted if both ultrasound and LymphPET are negative.
Limitations
Our study has several limitations. Firstly, isolated tumor cells (<0.2mm) and micrometastases (0.2–2 mm) were not calculated in the analysis. Currently, such small metastases are hard to detect by any imaging technique. Patients with micrometastatic tumor deposits, pN0(i+) or pN1mi, do not appear to have a worse 8-year disease-free survivalor overall survival compared with SLN-negative patients [21]. Whether treatment recommendations for systemic therapy should consider the presence of a single micrometastatic lymph node identified during complete serial sectioning of sentinel node(s) is still controversial [22].Axillary radiotherapy might reduce axillary lymph node recurrence, especially in patients following breast-conserving therapy with no axillary surgical intervention [23]. Secondly, in patients with FN detected by ultrasound and LymphPET, adjuvant systemic therapy may be inadequate without knowing the definitive node status. In our study, three patients who were HER2 positive and/or triple-negative would receive system adjuvant therapy in any case. For 5 patients with Luminal type N1 diseases, genomic signatures now represent an important progress in optimal selection of high risk patients that might benefit from the addition of chemotherapy to adjuvant endocrine therapy [24, 25]. One patient with invasive lobular carcinoma N2 disease (ID 128) might receive inadequate adjuvant treatment if the axillary node status is unknown. Due to these limitations, in the second stage of the SOAPET, we will select patients ready for breast-conserving therapy who are both ultrasound and LymphPET negative, and genomic signatures will be recommended to patients with Luminal type, to assess the safety of omitting surgical axillary evaluation in such population.
In conclusion, the results of our study indicate that LymphPET can be used to identify cN0 patients, reducing the FN rate by <10%. The second stage of the SOAPET trial is ongoing to confirm the safety of omitting SLNB according to preoperational axillary evaluation when integrating LymphPET.