The modified shrinkage classification modes could help to guide breast conserving surgery after neoadjuvant therapy in breast cancer.

Purpose: The traditional shrinkage classification modes might not suitable for guiding breast conserving surgery (BCS) after neoadjuvant therapy (NAT). Aim was to explore the modified shrinkage classification modes to guide BCS after NAT. Methods: From April 2010 to 2018, 104 patients were included. All patients underwent MRI examinations before and after NAT. Residual tumors were removed and divided into more than 30 tissue blocks at 5-mm intervals. After performing routine procedures for paraffin-embedded histology, we made semiserial sections (6-µm thick). The MRI and pathology 3D models were reconstructed with 3D-DOCTOR software. Combined with traditional shrinkage modes and efficacy of NAT, we derived modified shrinkage classification modes which oriented by BCS purpose: modified concentric shrinkage modes (MCSM) and modified non concentric shrinkage modes (MNCSM). The MCSM means the longest diameter of residual tumor was less than 50% and ≤2cm in comparison with the primary tumor before NAT. Other shrinkage modes were classified as MNCSM. Results: According to traditional shrinkage modes, 50 (48.1%) cases were suitable for BCS;while 70 (67.3%) cases were suitable for BCS according to the modified shrinkage modes (p=0.007). The consistency of MRI 3D reconstruction in assessing modified shrinkage classification modes was 93.2%, while it was 61.5% when assessing traditional shrinkage modes. Multivariate analysis showed that primary tumor stage, mammographic malignant calcification, molecular subtypes and nodal down-staging after NAT were independent predictors of modified shrinkage modes (all p<0.05). A nomogram was created based on these four predictors. With a median follow-up time of 77 months, the recurrence/metastasis rate in the MCSM and MNCSM group was 7.1% and 29.4%, respectively. Conclusion: Modified shrinkage classification modes could help to guide the individualized selection of BCS candidates and scope of resection after NAT. MRI 3D reconstruction after NAT could accurately predict modified shrinkage modes and extent of residual tumor.

Mutant Allele Frequency-Based Intra-Tumoral Genetic Heterogeneity Related to the Tumor Shrinkage Mode After Neoadjuvant Chemotherapy in Breast Cancer Patients.

The shrinkage mode of tumor extent after neoadjuvant chemotherapy (NAC) is an important index to evaluate the odds of breast-conserving surgery. However, there is no sufficient measurement to predict the shrinkage mode after NAC. In this study, we analyzed 24 patients' formalin-fixed, paraffin-embedded samples before and after treatment and analyzed 456 cancer-related genes panel by using target next-generation sequencing. Meanwhile, the pathological shrinkage mode was reconstructed in three dimensions after surgery, and the genetic heterogeneity level was estimated by mutant-allele tumor heterogeneity (MATH). We measured the genetic intra-tumor heterogeneity and explored its correlation with the shrinkage mode after NAC. A total of 17 matched pair samples of primary tumor tissue and residual tumor tissue were successfully accessed. It was found that the most common mutated genes were TP53 and PIK3CA in both samples before and after NAC, and no recurrent mutations were significantly associated with the shrinkage mode. Besides, the MATH value of formalin-fixed, paraffin-embedded samples before and after NAC was analyzed by the area under the curve of the receiver operating characteristic, and it is feasible to classify patients into concentric shrinkage mode and non-concentric shrinkage mode in NAC based on the MATH threshold of 58. Our findings indicate that the MATH value was associated with the shrinkage mode of breast cancer in a non-linear model. Patients with the MATH value below the threshold of 58 before and after NAC displayed a concentric shrinkage mode. The area under the curve was 0.89, with a sensitivity of 0.69 and specificity of 1. Our study might provide a promising application of intra-tumor heterogeneity that is measured by MATH to make a choice of surgery.

Laboratory indicators predict axillary nodal pathologic complete response after neoadjuvant therapy in breast cancer.

The purpose was to integrate clinicopathological and laboratory indicators to predict axillary nodal pathologic complete response (apCR) after neoadjuvant therapy (NAT). The pretreatment clinicopathological and laboratory indicators of 416 clinical nodal-positive breast cancer patients who underwent surgery after NAT were analyzed from April 2015 to 2020. Predictive factors of apCR were examined by logistic analysis. A nomogram was built according to logistic analysis. Among the 416 patients, 37.3% achieved apCR. Multivariate analysis showed that age, pathological grading, molecular subtype and neutrophil-to-lymphocyte ratio were independent predictors of apCR. A nomogram was established based on these four factors. The area under the curve (AUC) was 0.758 in the training set. The validation set showed good discrimination, with AUC of 0.732. In subtype analysis, apCR was 23.8, 47.1 and 50.8% in hormone receptor-positive/HER2-, HER2+ and triple-negative subgroups, respectively. According to the results of the multivariate analysis, pathological grade and fibrinogen level were independent predictors of apCR after NAT in HER2+ patients. Except for traditional clinicopathological factors, laboratory indicators could also be identified as predictive factors of apCR after NAT. The nomogram integrating pretreatment indicators demonstrated its distinguishing capability, with a high AUC, and could help to guide individualized treatment options.

Lay abstract The purpose of this study was to integrate more pretreatment indicators, including clinicopathological factors and simple laboratory indicators, to predict axillary nodal pathologic complete response (apCR) after neoadjuvant therapy for breast cancer. The authors collected the pretreatment clinicopathological factors and laboratory indexes of 416 nodal-positive patients with breast cancer. The authors then built a nomogram to predict the therapeutic effect in axillary lymph nodes. Among 416 patients, 37.3% (155 of 416) achieved apCR. The results showed that age, pathological grading, molecular subtype and neutrophil-to-lymphocyte ratio were independent predictors of apCR. Based on these four factors, a nomogram was then built. This nomogram helped to predict apCR. In addition to traditional clinicopathological factors, laboratory indicators were also identified as predictive factors of apCR after neoadjuvant therapy. Integrating pretreatment indicators might help to predict apCR and guide individualized treatment options.

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.

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.

Sentinel lymph node biopsy in patients with breast ductal carcinoma in situ: Chinese experiences.

The axillary treatment of patients with ductal carcinoma in situ (DCIS) remains controversial. The aim of the present study was to evaluate the roles of sentinel lymph node biopsy (SLNB) in patients with breast DCIS. A database containing the data from 262 patients diagnosed with breast DCIS and 100 patients diagnosed with DCIS with microinvasion (DCISM) who received SLNB between January 2002 and July 2014 was retrospectively analyzed. Of the 262 patients with DCIS, 9 presented with SLN metastases (3 macrometastases and 6 micrometastases). Patients with large tumors diagnosed by ultrasound or with tumors of high histological grade had a higher positive rate of SLNs than those without (P=0.037 and P<0.0001, respectively). Of the 100 patients with DCISM, 11 presented with metastases. Younger patients had a higher positive rate of SLNs (P=0.028). According to the results of this study and the systematic review of recent studies, the indications of SLNB for patients with DCIS are as follows: SLNB should be performed in all DCISM patients and in those DCIS patients who received mastectomy, and could be avoided in those who received breast-conserving surgery. However, SLNB should be recommended to patients who have high risks of harboring invasive components. The risk factors include a large, palpable tumor, a mammographic mass or a high histological grade.

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.

Risk factors for sentinel lymph node metastasis and validation study of the MSKCC nomogram in breast cancer patients.

OBJECTIVE: To evaluate the risk factors for sentinel lymph node metastasis and validate the value of the Memorial Sloan-Kettering Cancer Center nomogram for the prediction of sentinel lymph node metastasis in breast cancer patients. METHODS: A sentinel lymph node biopsy database containing 1227 consecutive breast cancer patients (416 patients with at least one positive sentinel lymph node) was retrospectively analyzed. The predictive value of the Memorial Sloan-Kettering Cancer Center nomogram was calculated by the trend line and the area under the receiver-operator characteristic curve. Meanwhile, predictors for sentinel lymph node metastasis were also evaluated. RESULTS: Tumor size, histological grade, lymphovascular invasion, mulifocality, estrogen receptor and progesterone receptor status were significant independent predictors for sentinel lymph node metastasis (all P<0.01). The Memorial Sloan-Kettering Cancer Center nomogram presented an area under the receiver-operator characteristic curve value of 0.730. Patients with predictive value<16% had a frequency of sentinel lymph node metastasis of 0.9%. Those with values larger than 70% had a frequency of 96.2%. CONCLUSIONS: The risk factors for sentinel lymph node metastasis in our study were consistent with those in the Memorial Sloan-Kettering Cancer Center nomogram. The Memorial Sloan-Kettering Cancer Center nomogram is a useful tool that could accurately predict the probability of sentinel lymph node metastasis in our breast cancer patients. Axillary surgical staging might be avoided in patients with a predictive value of <16% and axillary lymph node dissection might be done directly in those with a predictive value >70%, while other patients should still accept sentinel lymph node biopsy.