A novel nomogram for the preoperative prediction of sentinel lymph node metastasis in breast cancer.

BACKGROUND OR PURPOSE: A practical noninvasive method to identify sentinel lymph node (SLN) status in breast cancer patients, who had a suspicious axillary lymph node (ALN) at ultrasound (US), but a negative clinical physical examination is needed. To predict SLN metastasis using a nomogram based on US and biopsy-based pathological features, this retrospective study investigated associations between clinicopathological features and SLN status. METHODS: Patients treated with SLN dissection at four centers were apportioned to training, internal, or external validation sets (n = 472, 175, and 81). Lymph node ultrasound and pathological characteristics were compared using chi-squared and t-tests. A nomogram predicting SLN metastasis was constructed using multivariate logistic regression models. RESULTS: In the training set, statistically significant factors associated with SLN+ were as follows: histology type (p < 0.001); progesterone receptor (PR: p = 0.003); Her-2 status (p = 0.049); and ALN-US shape (p = 0.034), corticomedullary demarcation (CMD: p < 0.001), and blood flow (p = 0.001). With multivariate analysis, five independent variables (histological type, PR status, ALN-US shape, CMD, and blood flow) were integrated into the nomogram (C-statistic 0.714 [95% CI: 0.688-0.740]) and validated internally (0.816 [95% CI: 0.784-0.849]) and externally (0.942 [95% CI: 0.918-0.966]), with good predictive accuracy and clinical applicability. CONCLUSION: This nomogram could be a direct and reliable tool for individual preoperative evaluation of SLN status, and therefore aids decisions concerning ALN dissection and adjuvant treatment.

Mismatch Repair Deficiency and Microsatellite Instability in Triple-Negative Breast Cancer: A Retrospective Study of 440 Patients.

PURPOSE: To investigate the status of mismatch repair (MMR) and microsatellite instability (MSI) in triple-negative breast cancer (TNBC) and to examine correlations between MMR/MSI status and clinicopathological parameters. METHODS: We retrospectively collected tissue samples from 440 patients with TNBC and constructed tissue microarrays. Protein expression of MLH1, MSH2, MSH6, and PMS2 was detected by immunohistochemistry (IHC). We also analyzed 195 patient samples using MSI polymerase chain reaction (PCR) testing. Correlations between MSI status and clinicopathological parameters and prognosis were analyzed. RESULTS: The median age of the cohort was 49 years (range: 24-90 years) with a median follow-up period of 68 months (range: 1-170 months). All samples were positive for MLH1, MSH2, MSH6, and PMS2, except for one sample identified as MMR-deficient (dMMR) by IHC, with loss of MSH2 and intact MSH6 expression. MSI PCR revealed no case with high-frequency MSI (MSI-H), whereas 14 (7.2%) and 181 (92.8%) samples demonstrated low-frequency and absence of MSI events, respectively. The dMMR sample harbored low-frequency instability, as revealed by MSI PCR, and a possible EPCAM deletion in the tumor, as observed from next-generation sequencing. No correlations were detected between MMR or MSI status and clinicopathological parameters, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression, or survival. CONCLUSIONS: The incidence of dMMR/MSI-H is extremely low in TNBC, and rare discordant MSI PCR/MMR IHC results may be encountered. Moreover, MMR/MSI status may be of limited prognostic value. Further studies are warranted to explore other predictive immunotherapy biomarkers for TNBC.

MicroRNA-27b-3p Promotes Tumor Progression and Metastasis by Inhibiting Peroxisome Proliferator-Activated Receptor Gamma in Triple-Negative Breast Cancer.

Introduction: The role and underlying mechanisms of miR-27b-3p in triple-negative breast cancer (TNBC) remains unclear. Methods: miR-27b-3p expression level was evaluated in 99 TNBC patients with a median follow-up time of 133 months. The biological functions of miR-27b-3p by targeting PPARG were assessed by luciferase reporter assay, CCK-8 assay, Transwell assay, wound healing assay, western blot analysis and xenograft models. Results: High level of miR-27b-3p expression was found to confer poor prognosis in TNBC patients. MiR-27b-3p overexpression increased TNBC cell proliferation, migration, invasion, and metastasis. Our data suggested peroxisome proliferator-activated receptor gamma (PPARG) was a target of miR-27b-3p. The capacity of miR-27b-3p to induce TNBC progression and metastasis depended on its inhibition of the PPARG expression. Furthermore, restoring PPARG expression reversed the effect of miR-27b-3p overexpression. Mechanistically, miR-27b-3p regulated metastasis-related pathways through PPARG by promoting epithelial-mesenchymal transition. By suppressing PPARG, miR-27b-3p could also activate transcription factors Snail and NF-κB, thereby promoting metastasis. Conclusions: miR-27b-3p promotes TNBC progression and metastasis by inhibiting PPARG. MiR-27b-3p may be a potential prognostic marker of TNBC, and PPARG may be a potential molecular therapeutic target of TNBC.

The prognostic comparison among unilateral, bilateral, synchronous bilateral, and metachronous bilateral breast cancer: A meta-analysis of studies from recent decade (2008-2018).

BACKGROUND: The incidence of bilateral breast cancer (BBC) is increasing nowadays comprising 2%-11% of all breast cancer (BC). According to the interval time between the first and second cancer, BBC could be divided into synchronous (SBBC) and metachronous (MBBC). However, this interval time is quite different across studies. It remains controversial whether the survival of BBC, SBBC, and MBBC is similar or worse compared to that of unilateral breast cancer (UBC), and whether the survival of SBBC is similar or worse compared to MBBC. To better understand the survival of UBC, BBC, SBBC, and MBBC and how the interval time would influence the prognosis of SBBC and MBBC, we performed this meta-analysis on studies from recent 10 years (2008-2018). METHODS: Databases of PubMed, Embase, and Web of Science were searched for relevant studies within recent 10 years. Hazard ratio (HR) was adopted to evaluate the difference of overall survival (OS) of UBC, BBC, SBBC, and MBBC. HR of OS comparisons were performed between BBC vs UBC, SBBC vs UBC, MBBC vs UBC, and SBBC vs MBBC with 3, 6, 12 months as the interval time, respectively. RESULTS: There were 15 studies of 72 302 UBC and 2912 BBC included in the meta-analysis. The summary HR of OS comparison between BBC vs UBC was 1.68 (95% CI: 1.28-2.20), SBBC vs UBC was 2.01 (95% CI: 1.14-3.55), MBBC vs UBC was 3.22 (95% CI: 0.75-13.78). When 3, 6, 12 months were used as the interval time, the summary HR of the OS comparison between of SBBC vs MBBC were 0.64 (95% CI: 0.44-0.94), 1.17 (95% CI: 0.84-1.63) and 1.45 (95% CI: 1.10-1.92), respectively. CONCLUSION: BBC and SBBC showed worse prognosis in terms of OS compared to UBC while MBBC manifested similar or non-superior survival as UBC. The OS comparison between SBBC and MBBC changed with different interval time used. The longer the interval time used, the worse the survival of SBBC. SBBC with interval of 3-12 months between the two cancers had the worst prognosis. When 6 months was used to differentiate SBBC from MBBC, these two clinical entities showed similar OS.

Mammography-detected ultrasound-negative asymptomatic micro-calcifications in Chinese women: Would it be safe to watch and wait?

Although mammography (MG) has been widely used for breast cancer screening in the western world, over-diagnosis remains controversial. Milestone studies showed that ultrasound (US) was an effective primary screening test for breast cancer both in the western world and in China. US improves the sensitivity of screening in Chinese women who have denser breasts and develop breast cancer earlier than Caucasian counterparts, and is used as the primary imaging test in the hospital-based opportunistic screening among asymptomatic self-referred women. Our previous work showed that US result might further differentiate the MG-detected breast cancers into low risk (US+) and ultra-low risk (US-). Indeed, most of the MG+/US- breast cancers would be ultra-low risk cancers and almost always present as MG micro-calcifications. Furthermore, majority of the commonest MG+/US- abnormal finding of micro-calcification is usually benign. Biopsy of benign breast disease increases not only the risk of breast cancer, but the expenses of screening and healthcare. Our hypothesis proposes that mammography-positive ultrasound-negative (MG+/US-) asymptomatic micro-calcifications might not need immediate invasive procedures and be safe to observe until the micro-calcifications increase significantly or become US-positive. If this hypothesis is proved, US would serve as the primary imaging test for breast cancer screening in China, with MG as the selective screening test and diagnostic tool for surgical plan. Unnecessary biopsy or surgery might be avoided with screening expenses considerably decrease.

Tumor biology, clinicopathological characteristics and prognosis of screen detected T1 invasive non-palpable breast cancer in asymptomatic Chinese women (2001-2014).

BACKGROUND: Mammography screening usually detects low-risk breast cancer in the western world. However, little is known about the ultrasound and mammography screen-detected T1 invasive non-palpable breast cancer (NPBC) in asymptomatic Chinese women. RESULTS: With the increase of tumor size (T1a, b, c), lymph node positivity (8.7%, 18.3%, 26.0%, p = 0.018), pN (p = 0.028) and TNM stage (p = 0.035) increased accordingly. Tumor size (T1a, b, c) was correlated with high Ki-67 index (defined as ≥ 14%, 37.9%, 45.8%, 56.2%, p = 0.017), chemotherapy (20.4%, 35.2%, 57.3%, p < 0.001) and targeted therapy (2.9%, 9.9%, 15.1%, p = 0.008). T1a disease had higher chance of being luminal A and accompanied with ductal carcinoma in situ (DCIS), while T1c tumor being triple-negative and without DCIS. The 5-year disease free survival (DFS) of T1a, b, c NPBC were 99.0%, 96.9% and 92.9%, whereas the 5-year overall survival (OS) were 100.0%, 100.0% and 97.9% respectively. There was no significant difference in 5-year DFS or OS among the T1 NPBC subgroups or subtypes/immunophenotypes. PATIENTS AND METHODS: From 2001 to 2014, 4,574 screening positive women received biopsies in Peking Union Medical College (PUMC) Hospital, and 729 NPBC including 437 T1 unilateral invasive NPBC were diagnosed. With a median follow-up time of 32 months (6-163 months), the clinicopathological characteristics, treatment choice, 5-year DFS and OS were compared between T1a, T1b and T1c NPBC. The DFS and OS prognostic factors were identified. CONCLUSION: Screen-detected T1 invasive NPBC could be regarded as low-risk cancer in Chinese women. TNM stage and LN metastasis instead of molecular subtype was identified as the DFS prognostic factors while radiotherapy as the OS predictor.

Clinicopathological characteristics and long-term prognosis of screening detected non-palpable breast cancer by ultrasound in hospital-based Chinese population (2001-2014).

PURPOSE: The mainstay modality of breast cancer screening in China is the hospital-based opportunistic screening among asymptomatic self-referred women. There is little data about the ultrasound (US) detected non-palpable breast cancer (NPBC) in Chinese population. METHODS: We analyzed 699 consecutive NPBC from 1.8-2.3 million asymptomatic women from 2001 to 2014, including 572 US-detected NPBC from 3,786 US-positive women and 127 mammography (MG) detected NPBC from 788 MG-positive women. The clinicopathological features, disease-free survival (DFS) and overall survival (OS) were compared between the US- and MG-detected NPBC. Prognostic factors of NPBC were identified. RESULTS: Compared to MG, US could detect more invasive NPBC (83.6% vs 54.3%, p<0.001), lymph node positive NPBC (19.1% vs 10.2%, p=0.018), lower grade (24.8% vs 16.5%, p<0.001), multifocal (19.2% vs 6.3%, p<0.001), PR positive (71.4% vs 66.9%, p=0.041), Her2 negative (74.3% vs 54.3%, p<0.001), Ki67 high (defined as >14%, 46.3% vs 37.0%, p=0.031) cancers and more NPBC who received chemotherapy (40.7% vs 21.3%, p<0.001). There was no significant difference in 10-year DFS and OS between US-detected vs MG-detected NPBC, DCIS and invasive NPBC. For all NPBC and the US-detected NPBC, the common DFS-predictors included pT, pN, p53 and bilateral cancers. CONCLUSION: US could detect more invasive, node-positive, multifocal NPBC in hospital-based asymptomatic Chinese female, who could achieve comparable 10-year DFS and OS as MG-detected NPBC. US would not delay early detection of NPBC with improved cost-effectiveness, thus could serve as the feasible initial imaging modality in hospital-based opportunistic screening among Chinese women.

HER2 amplification level is not a prognostic factor for HER2-positive breast cancer with trastuzumab-based adjuvant treatment: a systematic review and meta-analysis.

BACKGROUND: Trastuzumab-based therapy is a standard, targeted treatment for HER2-positive breast cancer in the adjuvant setting. However, patients do not benefit equally from it and the association between HER2 amplification level and patients' survival remains controversial. A systematic review and meta-analysis was conducted by incorporating all available evidence to evaluate the association between disease free survival (DFS) and HER2 amplification level. RESULTS: Three cohort studies involving 1360 HER2-positive breast cancer patients stratified by HER2 amplification magnitude were eligible for meta-analysis. The combined HRs for DFS were 1.05 (95% CI: 0.80-1.36, p = 0.74) and 0.97 (95% CI: 0.73-1.29, p = 0.83) for HER2 gene copy number (GCN) and HER2/CEP 17 ratio. No evidence of heterogeneity or public bias was found. METHODS: Databases including PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL), were searched for eligible literature. HER2 amplification level was evaluated by fluorescence in situ hybridization (FISH) in terms of gene copy number (GCN) and HER2/CEP17 ratio. Hazard ratios (HRs) for DFS with 95% confidence interval (CI) according to the amplification level of HER2 were extracted. The outcomes were synthesized based on a fixed-effects model. CONCLUSIONS: HER2 amplification level is not a prognostic factor for HER2-positive breast cancer with trastuzumab-based targeted therapy in the clinical adjuvant setting.

Prognosis of subtypes of the mucinous breast carcinoma in Chinese women: a population-based study of 32-year experience (1983-2014).

PURPOSE: The heterogeneous nature of the mucinous breast cancer (MBC), with its pure (PMBC) and mixed subtypes (MMBC), calls for precise prognosis assessment. METHODS: We analyzed 197 consecutive MBC patients, including 117 PMBC and 80 MMBC, who were treated from 1983 to 2014. The clinicopathological features, treatment choice, disease-free survival (DFS) and overall survival (OS) were compared among PMBC, MMBC and MMBC subgroups. Prognostic factors of PMBC and MMBC were identified. RESULTS: Compared to PMBC, MMBC had more lymph node metastasis (p = 0.043), Her2 positivity (p = 0.036), high Ki-67 index (defined as>20%, p = 0.026) and anti-Her2 targeted therapy (p = 0.016). The 5-year DFS of PMBC and MMBC were 90.4% and 86.2%, whereas the 5-year OS were 99.0% and 98.7%. No significant difference was found in DFS or OS among all MBC subtypes. High Ki-67 (p = 0.020) appeared as DFS factor in PMBC, while anti-Her2 targeted therapy (p = 0.047) as the DFS predictors in MMBC. CONCLUSION: MMBC manifested similar 5-year survival to PMBC in Chinese woman, suggesting that intra-tumoral heterogeneity might not interfere with MBC short-term prognosis.

[Analysis of prognostic factors related to triple-negative breast cancer].

OBJECTIVE: To investigate the prognostic factors related to triple-negative breast cancer (TNBC) by analyzing clinicopathologic characteristics, treatment and prognosis. METHODS: Three hundred and five TNBC patients treated between January 2004 and December 2011 were enrolled and retrospectively reviewed with Kaplan-Meier and Cox proportional hazards models. All patients were females and the age onset were 24-82 years old (the median were 50 years old). RESULTS: The follow-up period was 1 to 114 months, with median 38 months. The 5-year disease free survival (DFS) rate was 68% and overall survival (OS) rate 75%. The peak risk of recurrence occurs within the first 2-3 years after initial treatment of the disease, but distant relapse after this time is much less common. Survival analysis showed that surgery type (χ(2) = 4.030, P = 0.045), tumor grade (χ(2) = 8.000, P = 0.046), lymph-vascular invasion (χ(2) = 10.386, P = 0.001) and lymph node stage (χ(2) = 119.36, P = 0.000), TNM stage (χ(2) = 65.961, P = 0.000) and treatment plan (χ(2) = 28.371, 21.874, 32.163, all P = 0.000) were statistically related to DFS; while age (χ(2) = 10.226, P = 0.006), lymph-vascular invasion (χ(2) = 18.881, P = 0.000), lymph node stage (χ(2) = 98.958, P = 0.000), TNM stage (χ(2) = 65.342, P = 0.000) and type of treatment (χ(2) = 17.862, 18.708, 31.921, all P = 0.000) were related to OS. The lymph nodes stage was prognostic factor related to both DFS and OS. CONCLUSIONS: TNBC was characterized by poor prognosis and rapid progression. The lymph nodes metastatic status was the most important prognostic factor of TNBC.

[Expression of mitogen activated protein kinase phosphatase-1 in pancreatic cancer].

OBJECTIVE: To evaluate the expression of mitogen activated protein kinase phosphatase-1(MKP-1)in pancreatic cancer. METHODS: Totally 60 cases of normal pancreas, chronic pancreatitis(CP), and pancreatic cancer tissues were collected by operation in our hospital. Pancreatic tissues were analyzed by Northern blot analysis and Western blot analysis. Meanwhile, MKP-1 expression was detected in 6 pancreatic cancer cell lines by Western blot analysis. RESULTS: Northern blot analysis of total RNA revealed relatively low MKP-1 mRNA expression in 7 of 20(35%)normal pancreatic samples. In the remaining 13 samples, the MKP-1 mRNA was absent to faint detectable. In 7 of the 20 CP samples, MKP-1 was demonstrated moderate to high expression. In contrast, 12 of 20(60%)pancreatic cancer samples MKP-1 mRNA was expressed at high levels, whereas in the remaining 8 cancer tissues this mRNA moiety was present at low to moderate levels. Densitometric analysis with normalization to 7S revealed that the median level of MKP-1 mRNA in CP and cancerous tissues was increased by 6.2 folds(P=0.035)and 8.1 folds(P=0.016)in comparison with the median level in the normal pancreatic samples, respectively. Overexpression of MKP-1 was also found in 6 pancreatic cancer cell lines, in which the expression of MKP-1 was slightly lower in one pancreatic cancer cell line but high in the remaining 5 cell lines. CONCLUSIONS: MKP-1 is over-expressed in pancreatic cancer, CP tissues, and pancreatic cell lines. It is speculated that MKP-1 may play an important role in tumorigenesis of pancreatic cancer.

[Comparative analysis of early diagnostic tools for breast cancer].

OBJECTIVE: Mammography is the principle imaging modality used for early diagnosis of breast cancer in Western countries. It has not been well-established whether this Western diagnostic modality is adoptable for Chinese women. The aim of this study was to evaluate the respective accuracy of the common diagnostic tools for breast cancer including history-taking, physical examination, ultrasound and mammography. METHODS: Clinical presentation and investigations for consecutive patients undergoing history-taking, physical examination, ultrasound, mammography and pathological assessment at Peking Union Medical College Hospital were prospectively recorded between April 2010 and September 2011. Breast cancer high-risk factors acquired by history-taking were input into the risk assessment model established previously by Eleventh Five Year Key Programs for Science and Technology Development of China (Grant No. 2006BAI02A09) and classified into low-, medium-, high- and extremely high-risk groups. The low- and medium-risk groups were defined as test negative, while the high- and extremely high-risk groups were defined as test positive. Each mammogram and ultrasound was reported prospectively using a five-point reporting scale of the American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS). Clinical data were compared with pathological findings. Sensitivity, specificity, positive predictive value (PRV), negative predictive value (NPV) and accuracy of respective diagnostic methods were calculated and compared. The patients were divided into two groups, above and below 50 years of age for subgroup analysis. RESULTS: A total of 1468 patients (1475 breast lesions) constituted the study population. The median age was 44 (range 13 - 92) years. Five hundred and fifty-one patients were diagnosed as breast cancer. The median age at diagnosis was 51 years and breast cancer peaked in the age group of 40 - 60 years. The sensitivity of risk assessment model, physical examination, ultrasound and mammogram was 47.5%, 86.2%, 89.8% and 79.3%, respectively; specificity was 68.8%, 83.3%, 81.0% and 88.7%, respectively; PRV was 47.6%, 75.5%, 73.8% and 80.8%, respectively; NPV was 68.8%, 91.0%, 93.0% and 87.8%, respectively; and accuracy was 60.9%, 84.4%, 84.3% and 85.2%, respectively. Further subgroup analysis demonstrated that age is an important factor influencing the sensitivity and specificity of physical examination, ultrasound and mammography. CONCLUSIONS: Ultrasound is more sensitive than mammography for early diagnosis of breast cancer in Chinese women and should be routinely used as a first-line diagnostic tool. Only a single diagnostic method is not enough sometimes and combined examination is needed for some high-risk populations.