Neoadjuvant therapy and sentinel lymph node biopsy in HER2-positive breast cancer patients: results from the PEONY trial.

OBJECTIVE: The aim of the study is to evaluate the optimal timing of sentinel lymph node biopsy (SLNB) in patients with clinical negative axillary lymph nodes (ALNs) before neoadjuvant therapy (NAT) and the feasibility of SLNB substituting for ALN dissection in patients with positive ALNs who convert to node negative, for HER2-positive disease. METHODS: Patients receiving SLNB with dual tracer mapping in the PEONY trial were analyzed. RESULTS: For 80 patients with clinical negative ALNs, the node negative rate by pathology after NAT was 83.8%. SLNB was performed after NAT in 71 patients. The identification rate of sentinel lymph nodes (SLNs) was 100%. For patients with positive ALNs before NAT, the axillary pathologic complete response rate in the dual HER2 blockade arm was significantly higher than that in the single blockade arm (p = 0.002). SLNB was performed in 71 patients. The identification rate was 100% and the false-negative rate was 17.2%. The false-negative rates were 33.3%, 14.3%, and 0 when 1, 2, and more than 2 SLNs were detected. There was no false-negative case when more than 1 SLN and the clipped nodes were removed simultaneously. CONCLUSIONS: For clinical ALN negative patients, HER2-positive subtype is found to have high node negative rate by pathology and it is recommended to undergo SLNB after NAT. For patients with positive ALNs who convert to negative, the false-negative rate is high. Dual tracer mapping, more than 2 SLNs detected, more than 1 SLN identified plus the clips placed are the guarantees for lower false-negative rate.

Neo-adjuvant chemotherapy and axillary de-escalation management for patients with clinically node-negative breast cancer.

This study aimed to explore the optimal time of sentinel lymph node biopsy (SLNB) and neo-adjuvant chemotherapy (NAC) and to assess the feasibility of selective elimination of axillary surgery after NAC in clinically node-negative (cN0) patients. From April 2010 to August 2018, 845 patients undergoing surgery after NAC were included in this retrospective study to analyze the correlation between different clinicopathological characteristics of cN0 patients and negative axillary lymph node after NAC (ypN0). Among the 148 cN0 patients, 83.1% (123/148) were ypN0. The rates of ypN0 in patients with hormone receptor positive (HR+)/HER2-, HR+/HER2+, HR-/HER2+, and triple-negative (TN) breast cancer were 75.4% (46/61), 82.6% (19/23), 85.2% (23/27), and 94.6% (35/37), respectively (P < 0.001). The rates of ypN0 in TN and HER2+ patients were 94.6% and 95.5%, which were significantly higher than that in HR+/HER2- patients (P < 0.05). Molecular subtypes, clinical stage, radiologic complete response, and pathologic complete response (bpCR) of the breast tumor correlated with ypN0 after full-course NAC (P < 0.05). Molecular subtypes (OR = 2.374, P = 0.033), clinical stage (OR = 0.320, P = 0.029), and bpCR (OR = 0.454, P = 0.012) were independent predictors for ypN0. The optimal time of SLNB and NAC in cN0 patients might be different among different molecular subtypes: it would be preferable to perform SLNB prior to NAC for HR+/HER2- patients, and SLNB after NAC for TN and HER2+ patients to reduce the risk of axillary lymph node dissection. In view of the high ypN0 rate in cN0 patients, axillary surgical staging might be selectively eliminated, especially for HER2+ and TN patients.

The feasibility of targeted axillary dissection for breast cancer axillary surgery de-escalation after neoadjuvant therapy: A prospective cohort study.

PURPOSE: Targeted axillary dissection (TAD) after neoadjuvant therapy (NAT) includes removing of marked and sentinel lymph nodes (SLNs). The aim was to investigate the optimization of TAD localization techniques after NAT among breast cancer patients. METHODS: From November 2020 to 2022, we prospectively enrolled 107 lymph node-positive breast cancer patients in XX Hospital and received complete cycles of NAT. Patients were randomly divided into the following 3 groups before treatment: group A, marked node with clip (n=34); group B, marked node with 125I seed (n=32); and group C, marked node with clip and 125I seed (n=41). Dual tracers were used to search for SLNs after NAT. The main endpoint was the detection rate of marked nodes and false-negative rate (FNR). RESULTS: The detection rates using the TAD localization technique were 82.6% (28/34), 100% (32/32), and 100% (41/41) for groups A, B, and C, respectively (P>0.05). The FNR rates were 15.8%, 5.9%, and 5.6% among group A, B, and C, respectively (P>0.05). The FNR rates in cN1 patients were 5.1%, 2.7%, and 2.6%, among these three groups, respectively (P>0.05). The change in distance between 125I seeds and clips in axillary lymph nodes was <3 mm. The FNR rates of TAD guided by dye tracer, radiolabeled tracer, and dual tracers were 5.4%, 5.2%, and 3.4%, respectively (P>0.05). The negative predictive values were 93.0%, 93.0%, and 95.2%, respectively (P>0.05). CONCLUSION: Considering inexpensive and detect rate of 125I seeds, it is recommended that placement of 125I seeds to localize metastatic nodes in neoadjuvant setting. The TAD guided by dye tracer is also feasible for axillary de-escalation surgery after NAT in countries or regions without radiolabeled colloid.

Controversial Opinion of "All pCRs are the Same" in St. Gallen International Consensus Guidelines 2021.

The opinion of "all pCRs are the same" in St. Gallen International Consensus Guidelines 2021 attracted the attention from clinical doctors. But this opinion is not consistent with the current clinical practice guidelines. The evidence-based medical evidence supported that the survival benefit of pCR was associated with treatment regimes, initial staging, and tumor biomarkers. To compare with the different status, the survival prognosis of pCRs is not the same. Furthermore, the pretreatment clinical stage, pathological stage, tissue grade, and subtype still influence on the survival prognosis of pCR. The pCR should be stratified according to histological factors and to guide the identification of individualized treatment after neoadjuvant therapy. In the future, a de-escalation treatment might be detected by the clinical trials of neoadjuvant therapy which would approach "all pCRs are the same".

Axillary management still needed for patients with sentinel node micrometastases.

More attention has been paid to the axillary management over the past 50 years, and clinical practice has been changed as results of the random controlled trials. The American College of Surgeons Oncology Group Z0011 and International Breast Cancer Study Group (IBCSG) 23-01 trials provided high-level evidence to support the omission of axillary lymph nodes dissection (ALND) in sentinel lymph node (SLN)-positive patients receiving breast-conserving surgery (BCS) and adjuvant systemic treatment. In patients treated with BCS, whole breast irradiation (WBI) with tangential fields could lead to substantial axillary irradiation and control the residual tumor burden in axilla, whereas (intraoperative) partial breast irradiation has no therapeutic effect on these residual axillary metastases. In the observation group of the IBCSG 23-01 trial, 425 patients received BCS and 80 (18.8%) of them just underwent intra-operative radiotherapy. While the 10-year axillary recurrence rate was acceptable low (1.7%, 8/467) in the no ALND group, it was 4.5% (6/134) in patients without axillary management, which was significantly higher than that of 0.6% (2/333) in patients with axillary management (P=0.0024). Should we accept an axillary recurrence rate as high as 4.5% in patients with only SLNs micrometastases? What is the best way to control the residual tumor burden in the axilla and decrease the recurrence rate if there is no ALND? The evidence showed that both WBI after BCS (Z0011, AATRM [Agència d'Avaluació de Tecnologia i Recerca Mèdiques]) and axillary regional nodal irradiation after mastectomy/BCS OTOASOR (Optimal Treatment Of the Axilla - Surgery Or Radiotherapy), AMAROS (After Mapping of the Axilla: Radiotherapy Or Surgery) could control the regional residual tumor burden when the SLN is positive and an ALND is omitted. In the modern era, systemic therapy could further decrease the risk of local/regional recurrences. After the subanalysis of the POSNOC (POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy), SERC (Sentinelle Envahiet Randomisation du Curage), and Dutch BOOG (BOrstkanker Onderzoek Groep) trials, a prediction model might be established to identify those patients who could beneft from no axillary management as a guide to clinical practice. At present, axillary management should still be required for patients with SLN micrometastases.

The Lymphatic Drainage Pattern of Internal Mammary Sentinel Lymph Node Identified by Small Particle Radiotracer (99mTc-Dextran 40) in Breast.

PURPOSE: The purpose of this study was to detect the lymphatic drainage pattern of internal mammary area and verify the concept of internal mammary sentinel lymph node (IM-SLN) in breast. MATERIALS AND METHODS: A small particle radiotracer (99mTc-Dextran 40) was prepared and tested. 99mTc-Dextran 40 was injected into intraparenchyma at the sound breast by a modified radiotracer injection technique. Subsequently, dynamic single-photon emission computed tomography (SPECT), computed tomography (CT), and SPECT/CT combination images were performed to identify the radioactive lymph vessels and internal mammary lymph nodes (IMLNs). The direction of lymph drainage and the location of the IMLNs were identified in the SPECT/CT imaging. RESULTS: The radiochemical purity of 99mTc-Dextran 40 was > 95%. 99mTc-Dextran 40 could drainage into first, second, and third lymph node and the radioactive lymph node could be detected by the γ detector in the animal experiment. After 99mTc-Dextran 40 injecting into intraparenchyma, 50.0% cases (15/30) were identified the drainage lymphatic vessels and radioactive IMLNs by SPECT. The drainage lymphatic vessel was found from injection point to the first IMLN (IM-SLN) after 10.5±0.35 minutes radiotracer injection, and then 99mTc-Dextran 40 was accumulated into the IM-SLN. The combination imaging of SPECT/CT showed the second IMLN received the lymph drainage from the IM-SLN. The lymphatic drainage was step by step in the internal mammary area. CONCLUSION: The lymph was identified to drain from different regions of the breast to IM-SLN, and then outward from IM-SLN to other IMLN consecutively. It demonstrated the concept of the IM-SLN and provided more evidences for the application of internal mammary sentinel lymph node biopsy.

Parotid gland metastasis from carcinoma of the breast detected by PET/CT: Case report and review.

RATIONALE: The parotid gland is an unusual site for metastatic disease from breast cancer, and it usually has a poor prognosis. PATIENT CONCERNS: A 36-year-old woman presented to our department with a swelling in her left parotid gland. The patient did not receive any other treatment after breast conserving surgery. DIAGNOSES: Multifocal metastases in the bones, lymph nodes, left parotid and contralateral mammary gland were proved by PET/CT. INTERVENTIONS: Eight cycles of first-line rescue chemotherapy, combining with zoledronic acid in treatment of bone metastasis, followed by the combination of endocrine therapy and ovarian function suppression after chemotherapy. OUTCOMES: The patient obtained clinical complete response in the metastasis tumor of parotid gland, lymph nodes, and bones. LESSONS: It is necessary for patient to receive comprehensive treatment after receiving surgery. Through this case, we present the appropriate management of advanced breast cancer accompanying with the parotid gland metastasis. PET/CT is a useful method to diagnose and evaluate the metastasis lesions.

Internal mammary lymph nodes radiotherapy of breast cancer in the era of individualized medicine.

Inclusion internal mammary lymph nodes as a part of regional nodal irradiation have a potential to reduce local recurrence, distant recurrence, and improve survival in breast cancer. However, the increased risk of cardiac toxicity and lungs injure associated with internal mammary lymph nodes irradiation has drew more and more attention. Estimating risk of metastasis in internal mammary lymph nodes based on axillary lymph nodes metastasis status is not always reliable: low-risk do not always mean negative in internal mammary lymph nodes and high-risk do not always indicate positive in internal mammary lymph nodes. Inaccurate prediction of in internal mammary lymph nodes metastasis might lead to over- or under-treatment of in internal mammary lymph node. Internal mammary sentinel lymph node biopsy is a minimally invasive technique which has a high potential to accurately evaluate the metastasis status in in internal mammary lymph nodes and improve accuracy of nodal staging. This technique might be a useful tool to guide individualized internal mammary lymph nodes irradiation.

Axillary and internal mammary sentinel lymph node biopsy in breast cancer after neoadjuvant chemotherapy.

With the improvement of neoadjuvant chemotherapy (NAC), the proportion of pathological complete response (pCR) in the breast and axillary lymph node (ALN) is increasing. The evaluation of pCR does not include the status of internal mammary lymph node (IMLN). This study is to evaluate the roles of both axillary sentinel lymph node biopsy (ASLNB) and internal mammary sentinel lymph node biopsy (IM-SLNB) in breast cancer patients after NAC. There were 74 patients enrolled into this study. IM-SLNB was performed on patients with radioactive internal mammary sentinel lymph node (IM-SLN). Patients (n = 8) with cN0 and ycN0 received ASLNB, and axillary lymph node dissection (ALND) in cases of positive axillary sentinel lymph node (ASLN). Patients (n = 48) with cN+ but ycN0 received ASLNB and ALND. Patients (n = 18) with ycN+ received ALND without ASLNB. The visualization rate of IM-SLN was 56.8% (42/74). The success rate of IM-SLNB was 97.6% (41/42) and the metastasis rate of IM-SLN was 7.3% (3/41). The success rate of ASLNB was 100% (56/56). The false negative rate (FNR) of ASLNB was 17.2% (5/29). The FNR in patients with 1, 2 and ≥ 3ASLNs examined was 27.3% (3/11), 20.0% (2/10) and 0% (0/8) respectively. ASLNB could be performed on ycN0 after NAC, and ALND should be performed on initially ALN-positive patients. IM-SLNB should be considered after NAC, especially for patients with clinically positive axillary nodes before NAC, which might help make clear of the pathological nodal staging of both ALN and IMLN, improve the definition of nodal pCR, and guide the individual adjuvant regional and systemic therapy.

Preparation study of indocyanine green-rituximab: A new receptor-targeted tracer for sentinel lymph node in breast cancer.

An appropriate receptor-targeted tracer for sentinel lymph node biopsy (SLNB) was prepared. We combined the fluorescence tracer (Indocyanine green, ICG) with Rituximab (a chimeric human/murine monoclonal antibody targeting the CD20 antigen on the surface of lymphocyte) directly to produce a new tracer (ICG-Rituximab). When the new tracer drains to the lymph node, Rituximab will combine with CD20 receptor on the B-cell surface in the lymph node. If the statue of antibody-receptor connection does not reach saturation, the number of Rituximab is less than CD20. With this appropriate injection dose, the new tracer could only stay in sentinel lymph node (SLN) and make it imaging. Positive fluorescence SLN was detected 12 minutes after injection with no other organs imaging. The imaging of SLN was stable and clear for 20-24 hours. Due to SLN stained with more ICG than the lymphatic vessel, the fluorescence situation of SLN would be brighter than the vessel. The surgeon can detect the positive fluorescence SLN easily without following the fluorescence imaging lymphatic vessel. The results of our preliminary study showed that the new tracer might be useful for improving SLN imaging and worth further clinical study. SLNB with the new tracer could be a convenient method for detecting SLN and would become a standard performance in clinical practice.

Validation study for the hypothesis of internal mammary sentinel lymph node lymphatic drainage in breast cancer.

According to axilla sentinel lymph node lymphatic drainage pattern, we hypothesized that internal mammary sentinel lymph node (IM-SLN) receives lymphatic drainage from not only the primary tumor area, but also the entire breast parenchyma. Based on the hypothesis a modified radiotracer injection technique was established and could increase the visualization rate of the IM-SLN significantly. To verify the hypothesis, two kinds of tracers were injected at different sites of breast. The radiotracer was injected with the modified technique, and the fluorescence tracer was injected in the peritumoral intra-parenchyma. The location of IM-SLN was identified by preoperative lymphoscintigraphy and intraoperative gamma probe. Then, internal mammary sentinel lymph node biopsy (IM-SLNB) was performed. The fluorescence status of IM-SLN was identified by the fluorescence imaging system. A total of 216 patients were enrolled from September 2013 to July 2015. The overall visualization rate of IM-SLN was 71.8% (155/216). The success rate of IM-SLNB was 97.3% (145/149). The radiotracer and the fluorescence tracer were identified in the same IM-SLN in 127 cases, the correlation and the agreement is significant (Case-base, rs=0.836, P<0.001; Kappa=0.823, P<0.001). Different tracers injected into the different sites of the intra-parenchyma reached the same IM-SLN, which demonstrates the hypothesis that IM-SLN receives the lymphatic drainage from not only the primary tumor area but also the entire breast parenchyma.

Internal Mammary Sentinel Lymph Node Biopsy With Modified Injection Technique: High Visualization Rate and Accurate Staging.

Although the 2009 American Joint Committee on Cancer incorporated the internal mammary sentinel lymph node biopsy (IM-SLNB) concept, there has been little change in surgical practice patterns because of the low visualization rate of internal mammary sentinel lymph nodes (IMSLN) with the traditional radiotracer injection technique. In this study, various injection techniques were evaluated in term of the IMSLN visualization rate, and the impact of IM-SLNB on the diagnostic and prognostic value were analyzed.Clinically, axillary lymph nodes (ALN) negative patients (n = 407) were divided into group A (traditional peritumoral intraparenchymal injection) and group B (modified periareolar intraparenchymal injection). Group B was then separated into group B1 (low volume) and group B2 (high volume) according to the injection volume. Clinically, ALN-positive patients (n = 63) were managed as group B2. Internal mammary sentinel lymph node biopsy was performed for patients with IMSLN visualized.The IMSLN visualization rate was significantly higher in group B than that in group A (71.1% versus 15.5%, P < 0.001), whereas the axillary sentinel lymph nodes were reliably identified in both groups (98.9% versus 98.3%, P = 0.712). With high injection volume, group B2 was found to have higher IMSLN visualization rate than group B1 (75.1% versus 45.8%, P < 0.001). The IMSLN metastasis rate was only 8.1% (12/149) in clinically ALN-negative patients with successful IM-SLNB, and adjuvant treatment was altered in a small proportion. The IMSLN visualization rate was 69.8% (44/63) in clinically ALN-positive patients with the IMSLN metastasis rate up to 20.5% (9/44), and individual radiotherapy strategy could be guided with the IM-SLNB results.The modified injection technique (periareolar intraparenchymal, high volume, and ultrasound guidance) significantly improved the IMSLN visualization rate, making the routine IM-SLNB possible in daily practice. Internal mammary sentinel lymph node biopsy could provide individual minimally invasive staging, prognosis, and decision making of the internal mammary radiotherapy, especially for clinically ALN-positive patients.

Validation study of the modified injection technique for internal mammary sentinel lymph node biopsy in breast cancer.

According to the hypothesis of internal mammary sentinel lymph node (IM-SLN) lymphatic drainage pattern, a modified radiotracer injection technique (periareolar intraparenchyma, high volume, and ultrasonographic guidance) was established. To verify the accuracy of the hypothesis and validate the modified radiotracer injection technique and to observe whether the lymphatic drainage of the whole breast parenchyma could reach to the same IM-SLN, different tracers were injected into different locations of the breast. The validation study results showed that the correlation and the agreement of the radiotracer and the fluorescence tracer are significant (case-base, r s =0.808, P<0.001; Kappa =0.79, P<0.001). It proved that the lymphatic drainage from different location of the breast (the primary tumor, the subareolar plexus) reached the same IM-SLNs and the hypothesis of IM-SLN lymphatic drainage pattern (ie, IM-SLN receives lymphatic drainage from not only the primary tumor area, but also the entire breast parenchyma). In other words, it validated the accuracy of our modified radiotracer injection technique.