Genomic Signature of the Standardized Uptake Value in 18F-Fluorodeoxyglucose Positron Emission Tomography in Breast Cancer

The standardized uptake value (SUV), an indicator of the degree of glucose uptake in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), has been used for predicting the clinical behavior of malignant tumors. However, its characteristics have been insufficiently explored at the genomics level. Here, we aim to identify genomic signatures reflecting prognostic SUV characteristics in breast cancer (BRC). Through integrative genomic profiling of 3710 BRC patients, including 254 patients who underwent preoperative FDG-PET, we identified an SUV signature, which showed independent clinical utility for predicting BRC prognosis (hazard ratio [HR] 1.27, 95% confidence interval [CI] = 1.12 to 1.45, p = 2.23 × 10-4). The risk subgroups classified by the signature exhibited mutually exclusive mutation patterns of TP53 and PIK3CA and showed significantly different responsiveness to immunotherapy. Experimental assays revealed that a signaling axis defined by TP53-FOXM1 and its downstream effectors in glycolysis-gluconeogenesis, including LDHA, might be important mediators in the FDG-PET process. Our molecular characterizations support an understanding of glucose metabolism and poor prognosis in BRC with a high SUV, utilizable in clinical practice to assist other diagnostic tools.ope

A nomogram constructed using intraoperative ex vivo shear-wave elastography precisely predicts metastasis of sentinel lymph nodes in breast cancer

OBJECTIVE: To develop a nomogram and validate its use for the intraoperative evaluation of nodal metastasis using shear-wave elastography (SWE) elasticity values and nodal size METHODS: We constructed a nomogram to predict metastasis using ex vivo SWE values and ultrasound features of 228 axillary LNs from fifty-five patients. We validated its use in an independent cohort comprising 80 patients. In the validation cohort, a total of 217 sentinel LNs were included. RESULTS: We developed the nomogram using the nodal size and elasticity values of the development cohort to predict LN metastasis; the area under the curve (AUC) was 0.856 (95% confidence interval (CI), 0.783-0.929). In the validation cohort, 15 (7%) LNs were metastatic, and 202 (93%) were non-metastatic. The mean stiffness (23.54 and 10.41 kPa, p = 0.005) and elasticity ratio (3.24 and 1.49, p = 0.028) were significantly higher in the metastatic LNs than those in the non-metastatic LNs. However, the mean size of the metastatic LNs was not significantly larger than that of the non-metastatic LNs (8.70 mm vs 7.20 mm, respectively; p = 0.123). The AUC was 0.791 (95% CI, 0.668-0.915) in the validation cohort, and the calibration plots of the nomogram showed good agreement. CONCLUSIONS: We developed a well-validated nomogram to predict LN metastasis. This nomogram, mainly based on ex vivo SWE values, can help evaluate nodal metastasis during surgery. KEY POINTS: • A nomogram was developed based on axillary LN size and ex vivo SWE values such as mean stiffness and elasticity ratio to easily predict axillary LN metastasis during breast cancer surgery. • The constructed nomogram presented high predictive performance of sentinel LN metastasis with an independent cohort. • This nomogram can reduce unnecessary intraoperative frozen section which increases the surgical time and costs in breast cancer patients.ope

Clinical Features of Breast Cancer in South Korean Patients with Germline TP53 Gene Mutations

Purpose: Li-Fraumeni syndrome (LFS) is a rare autosomal cancer syndrome caused by a germline mutation in the TP53 gene. Breast cancer in LFS patients is of various subtypes; however, limited data are available on the clinicopathological features of these subtypes and their appropriate treatments. This study aimed to review the clinical features and treatments for breast cancer in South Korean patients with germline TP53 mutations. Methods: Data on the clinicopathological features and treatment of all breast cancer patients with LFS were collected retrospectively from the available database of 4 tertiary hospitals in the Republic of Korea. Results: Twenty-one breast cancer cases in 12 unrelated women with confirmed germline TP53 mutations were included in the study. The median age at diagnosis was 33.5 years. The histopathological diagnosis included invasive ductal carcinoma (n = 16), ductal carcinoma in situ (n = 3), and malignant phyllodes tumor (n = 2). While 42% and 31% of the cases were positive for estrogen and progesterone receptors, respectively, 52.6% were human epidermal growth factor receptor 2 (HER2) positive, and 21% were triple-negative. The treatments included mastectomy (52%) and breast-conserving surgery (38%). Five patients underwent radiotherapy (RT). The median follow-up period was 87.5 (8-222) months. There were 3 ipsilateral and 4 contralateral breast recurrences during the follow-up, and 8 patients developed new primary cancers. In the post-RT subgroup, there were 2 ipsilateral and 2 contralateral breast recurrences in 1 patient, and 4 patients had a new primary cancer. Conclusion: As reported in other countries, breast cancer in LFS patients in South Korea had an early onset and were predominantly but not exclusively positive for HER2. A multidisciplinary approach with adherence to the treatment guidelines, considering mastectomy, and avoiding RT is encouraged to prevent RT-associated sequelae in LFS patients.ope

Metastasis Risk Assessment Using BAG2 Expression by Cancer-Associated Fibroblast and Tumor Cells in Patients with Breast Cancer

Few studies have examined the role of BAG2 in malignancies. We investigated the prognostic value of BAG2-expression in cancer-associated fibroblasts (CAFs) and tumor cells in predicting metastasis-free survival in patients with breast cancer. Tissue-microarray was constructed using human breast cancer tissues obtained by surgical resection between 1992 and 2015. BAG2 expression was evaluated by immunohistochemistry in CAFs or the tumor cells. BAG2 expression in the CAFs and cytoplasm of tumor cells was classified as positive and negative, and low and high, respectively. BAG2-CAF was evaluated in 310 patients and was positive in 67 (21.6%) patients. Kaplan-Meier plots showed that distant metastasis-free survival (DMFS) was lesser in patients with BAG2(+) CAF than in patients with BAG2(-) CAF (p = 0.039). Additionally, we classified the 310 patients into two groups: 109 in either BAG2-high or BAG2(+) CAF and 201 in BAG2-low and BAG2(-) CAF. DMFS was significantly reduced in patients with either BAG2-high or BAG2(+) CAF than in the patients of the other group (p = 0.005). Multivariable analysis demonstrated that DMFS was prolonged in patients with BAG2(-) CAF or BAG2-low. Evaluation of BAG2 expression on both CAFs and tumor cells could help in determining the risk of metastasis in breast cancer.ope

Comparison of patients with small (≤2 cm) breast cancer according to adherence to breast screening program.

BACKGROUND: We investigated whether adherence to breast screening would yield a clinical benefit even among patients with small breast cancer (≤2 cm) by comparing differences between those who did and did not adhere to breast screening. METHODS: Patients who were diagnosed with invasive T1 breast cancer and treated at Gangnam Severance Hospital from January 2006 to June 2014 were included. Of the 632 study patients, 450 and 182 were classified as screen-adherent and non-adherent. Adherence to the breast screening program was defined as the completion of breast screening examinations within 3 years before cancer diagnosis. Recurrence-free survival (RFS) and metastasis-free survival (MFS) were compared between the groups. Propensity score matching were applied to compare survival outcome. RESULTS: Adherent patients were more likely to have a lower histologic grade (P < 0.001), high estrogen receptor expression (P = 0.040), and lower HER2-positivity (P = 0.026). The adherent group had more favorable subtypes compared to the non-adherent group, with a greater percentage of Luminal/HER2-negative subtype (66.7% vs. 56.5%) and a lower percentage of HER2 subtype (8.3% vs. 16.7%). The RFS and MFS were significantly better in the adherent group (P = 0.003, 0.010, respectively). In the case-matched cohort, superior survival of the adherent group was maintained. CONCLUSIONS: Adherence to breast screening in patients with small breast tumors was associated with more favorable tumor biology and better prognosis. Our findings suggest that adherence to breast screening might offer clinical benefits in terms of tumor biology as well as early detection.ope

PD-L1 expression evaluated by 22C3 antibody is a better prognostic marker than SP142/SP263 antibodies in breast cancer patients after resection

Immune checkpoint inhibitors (ICI) have demonstrated efficacy in the treatment of solid cancers. However, there is no unified predictive biomarker available for ICIs. We aimed to compare the prognostic impact of using three PD-L1 antibodies (SP142, SP263, and 22C3) for immunohistochemical (IHC) analysis. We retrospectively investigated tumor tissues derived from 316 breast cancer cases, by constructing tissue microarrays and by performing IHC staining. The immune-cell expression rate (for SP142 and SP263) and combined proportional score (for 22C3) were evaluated, and survival outcomes were analyzed. Prediction models were developed, and values of Harrel's c-index and areas under curves were calculated to compare the discriminatory power. Negative PD-L1 expression based on the 22C3-IHC assay was determined to be an independent prognostic marker for recurrence-free survival (RFS, P = 0.0337) and distant metastasis-free survival (DMFS, P = 0.0131). However, PD-L1 expression based on SP142- and SP263-IHC assays did not reveal a prognostic impact. Among the three antibodies, adding PD-L1 expression data obtained via 22C3-IHC assay to the null model led to a significant improvement in the discriminatory power of RFS and DMFS. We suggest that PD-L1 expression based on the 22C3-IHC assay is a superior prognostic marker than that based on SP142- and SP263-IHC assays.ope

Association of Body Mass Index With 21-Gene Recurrence Score Among Women With Estrogen Receptor-Positive, ERBB2-Negative Breast Cancer

Importance: Body mass index (BMI) may affect the 21-gene recurrence score (RS) in patients with ER-positive, ERBB2-negative breast cancer. If high BMI increases genomic risk in ER-positive, ERBB2-negative breast cancer, weight control will become more important. Objective: To assess the association between RS and BMI according to age groups and address BMI as a factor associated with high RS. Design, setting, and participants: This cohort study included 2295 patients with ER-positive, ERBB2-negative breast cancer who had undergone a multigene assay between March 29, 2010, and December 31, 2020, in 2 hospitals. All of the study patients were Korean women, and the median follow-up period was 45 months (range, 1-40 months). The correlations between continuous RS and BMI were investigated. A high BMI was defined as a body mass index greater than or equal to 25. In the younger age group (age ≤45 years), a high RS was defined as an RS of greater than 20. Exposures: Body mass index. Main outcomes and measures: The Pearson correlation coefficient was used to estimate the association between RS and BMI. A multivariable binary logistic model was used to identify high RS. Results: Among the 2295 women included (mean [SD] age, 49.8 [4.00] years; range, 22-81 years), 776 were aged 45 years or younger; RS and BMI were weakly correlated (correlation coefficient, 0.119; P < .001) in this younger group. Among them, the proportion of patients with an RS greater than 20 was significantly higher in the high BMI group than in the normal BMI group (45.5% [46 of 101] vs 27.3% [184 of 675]; P < .001). In the multivariable analysis, high BMI was an associated factor for high RS (odds ratio, 2.06; 95% CI, 1.28-3.32; P = .003). The 21-gene multigene assay-guided chemotherapy rate was significantly higher in patients with high BMI (30.7% [31 of 101] vs 20.2% [136 of 674]; P = .02). Conclusions and relevance: In this cohort study of women aged 45 years or younger, high BMI was associated with higher RS in those with ER-positive, ERBB2-negative breast cancer; further studies are necessary to examine the underlying mechanisms.ope

Application of the 21-Gene Recurrence Score in Patients with Early HR-Positive/HER2-Negative Breast Cancer: Chemotherapy and Survival Rate According to Clinical Risk

We assessed the impact of 21-gene Recurrence Score (RS) assay on chemotherapy decision-making according to binary clinical risk stratification in patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. We included patients with tumors measuring 1-5 cm, N0-1, and HR+/HER2- breast cancer who underwent surgery followed by adjuvant treatment. The clinical risk was determined by a modified version of Adjuvant! Online. We performed propensity score matching (PSM) according to the application of 21-gene RS separately in the low and high clinical risk groups. Before PSM, 342 (39.0%) of 878 patients were classified as having high clinical risk. In the high clinical risk group, 21-gene RS showed a significantly reduced chemotherapy rate of 39.3%, without increasing the recurrence. After PSM, the 21-gene RS application significantly reduced chemotherapy rate by 34.0% in 200 patients with high clinical risk (21-gene RS application, 32.0% vs. no 21-gene RS application, 66.0%, p < 0.001). There was also no significant difference in RFS according to 21-gene RS status in the high clinical risk group (log-rank test, p = 0.467). These results support the usefulness of the 21-gene RS to reduce the chemotherapy rate without adversely affecting prognosis in a high clinical risk group.ope

The Role of Bile Duct Probe for Bile Duct Division during Donor Right Hemihepatectomy

Background: To prevent bile duct related complications, exact division of donor bile duct is essential, not only for the recipient, but also for the donor during living donor liver transplantation. Cholangiography has been used for bile duct division during living donor right hemihepatectomy. This study was conducted to determine if bile duct probe could be used to replace cholangiography for bile duct division during living donor right hemihepatectomy. Methods: Surgical outcomes of 234 donors with right hemihepatectomy and duct to duct biliary anastomosis in living donor liver transplantation between January 2009 and December 2014 were retrospectively analyzed. A total of 85 donors used the bile duct probe for bile duct division during the right hemihepatectomy, whereas 149 donors used cholangiography. All donors underwent preoperative magnetic resonance cholangiopancreatography (MRCP). Results: The expected number of bile duct orifices based on MRCP did not differ significantly from the observed number of bile duct orifices after bile duct division (10 donors and five donors in each group were mismatched, P=0.238). The operation time was 384.7 minutes in the probe group, which was significantly shorter than that of the cholangiography group (400.4 minutes, P=0.041). Conclusions: Bile duct probing without intraoperative cholangiography might be a feasible procedure for bile duct division during living donor hemihepatectomy.ope

Prognostic Value of Neutrophil-to-Lymphocyte Ratio and Early Standardized Uptake Value Reduction in Patients With Breast Cancer Receiving Neoadjuvant Chemotherapy

Purpose: We investigated the treatment response and prognosis using the neutrophil-to-lymphocyte ratio (NLR) and standardized uptake value (SUV) of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in neoadjuvant settings. Methods: Baseline NLR and maximum SUV (SUVmax) were retrospectively analyzed in 273 females with breast cancer who received neoadjuvant chemotherapy followed by surgery. Of these, 101 patients underwent 18F-FDG PET after 3-4 neoadjuvant chemotherapy cycles, which allowed the measurement of ΔSUVmax, an early reduction in SUVmax. NLR and early SUVmax reduction (ΔSUVmax) were classified as low and high, respectively, relative to the median values. Results: The mean NLR was lower, and the mean ΔSUVmax was higher in patients with pathologic complete response (pCR) than in those with residual tumors. The ΔSUVmax was an independent variable associated with pCR. Furthermore, the high NLR group had poor recurrence-free survival (RFS) and overall survival. Among patients with ΔSUVmax data, high NLR (adjusted hazard ratio, 2.82; 95% confidence intervals [CI], 1.26-6.28; P = 0.016) and low ΔSUVmax (adjusted hazard ratio, 2.39; 95% CI, 1.07-5.34; P = 0.037) were independent prognostic factors for poor RFS. The categorization of the patients into four groups according to the combination of NLR and ΔSUVmax showed that patients with high NLR and low ΔSUVmax had significantly poorer RFS. Conclusion: Baseline NLR and ΔSUVmax were significantly associated with the prognosis of patients with breast cancer who received neoadjuvant chemotherapy. These results suggest that metabolic non-responders with defective immune systems have worse survival outcomes.ope