Does the Dose of Standard Adjuvant Chemotherapy Affect the Triple-negative Breast Cancer Benefit from Extended Capecitabine Metronomic Therapy? An Exploratory Analysis of the SYSUCC-001 Trial.

Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.

Analysis of Breast Cancer Screening Results and Influencing Factors of Breast Cancer in Guangdong Province from 2017 to 2021.

BACKGROUNDS: Breast cancer screening plays an important role in the early detection, diagnosis and treatment of breast cancer. The aim of this study was to evaluate the screening results and explore the influencing factors of breast cancer detection rate in Guangdong. METHODS: This cross-sectional study was conducted among 2,024,960 women aged 35-64 in Guangdong Province during 2017-2021. The data about breast cancer screening information were collected from the Guangdong maternal and child health information system. Descriptive statistical analysis was used to explain demographic characteristics and results of breast cancer screening. The generalized linear regression model was applied to analyze the related influencing factors of breast cancer detection rate. RESULTS: The estimated detection rate of breast cancer in Guangdong Province is 70.32/105, with an early diagnosis rate of 82.06%. After adjusting covariates, those women with older age (45-55 [OR (95% CI) 2.174 (1.872, 2.526)], 55-65 [OR (95% CI) 2.162 (1.760, 2.657)]), education for high school ([OR (95% CI) 1.491 (1.254, 1.773)]) and older age at first birth ([OR (95% CI) 1.632 (1.445, 1.844)]) were more likely to have higher detection rate of breast cancer. No history of surgery or biopsy ([OR (95% CI) 0.527 (0.387, 0.718)]), no history of breast cancer check ([OR (95% CI) 0.873 (0.774, 0.985)]) and no family history of breast cancer ([OR (95% CI) 0.255 (0.151, 0.432)]) women were more likely to screen negative for breast cancer (P < 0.05). CONCLUSION: The detection rate of breast cancer in screening showed an increasing trend year by year in Guangdong Province. Older age, education for high school and older age at first birth were risk factors for breast cancer detection rate, while no surgery or biopsy history, no family history of breast cancer and no history of breast cancer check were protective factors.

Effect of Capecitabine Maintenance Therapy Using Lower Dosage and Higher Frequency vs Observation on Disease-Free Survival Among Patients With Early-Stage Triple-Negative Breast Cancer Who Had Received Standard Treatment: The SYSUCC-001 Randomized Clinical Trial.

Importance: Among all subtypes of breast cancer, triple-negative breast cancer has a relatively high relapse rate and poor outcome after standard treatment. Effective strategies to reduce the risk of relapse and death are needed. Objective: To evaluate the efficacy and adverse effects of low-dose capecitabine maintenance after standard adjuvant chemotherapy in early-stage triple-negative breast cancer. Design, Setting, and Participants: Randomized clinical trial conducted at 13 academic centers and clinical sites in China from April 2010 to December 2016 and final date of follow-up was April 30, 2020. Patients (n = 443) had early-stage triple-negative breast cancer and had completed standard adjuvant chemotherapy. Interventions: Eligible patients were randomized 1:1 to receive capecitabine (n = 222) at a dose of 650 mg/m2 twice a day by mouth for 1 year without interruption or to observation (n = 221) after completion of standard adjuvant chemotherapy. Main Outcomes and Measures: The primary end point was disease-free survival. Secondary end points included distant disease-free survival, overall survival, locoregional recurrence-free survival, and adverse events. Results: Among 443 women who were randomized, 434 were included in the full analysis set (mean [SD] age, 46 [9.9] years; T1/T2 stage, 93.1%; node-negative, 61.8%) (98.0% completed the trial). After a median follow-up of 61 months (interquartile range, 44-82), 94 events were observed, including 38 events (37 recurrences and 32 deaths) in the capecitabine group and 56 events (56 recurrences and 40 deaths) in the observation group. The estimated 5-year disease-free survival was 82.8% in the capecitabine group and 73.0% in the observation group (hazard ratio [HR] for risk of recurrence or death, 0.64 [95% CI, 0.42-0.95]; P = .03). In the capecitabine group vs the observation group, the estimated 5-year distant disease-free survival was 85.8% vs 75.8% (HR for risk of distant metastasis or death, 0.60 [95% CI, 0.38-0.92]; P = .02), the estimated 5-year overall survival was 85.5% vs 81.3% (HR for risk of death, 0.75 [95% CI, 0.47-1.19]; P = .22), and the estimated 5-year locoregional recurrence-free survival was 85.0% vs 80.8% (HR for risk of locoregional recurrence or death, 0.72 [95% CI, 0.46-1.13]; P = .15). The most common capecitabine-related adverse event was hand-foot syndrome (45.2%), with 7.7% of patients experiencing a grade 3 event. Conclusions and Relevance: Among women with early-stage triple-negative breast cancer who received standard adjuvant treatment, low-dose capecitabine maintenance therapy for 1 year, compared with observation, resulted in significantly improved 5-year disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01112826.

Use of urinary balloon catheter to prevent postoperative bleeding after ultrasound-guided vacuum-assisted breast biopsy.

Postoperative bleeding is the most frequent serious complications after vacuum-assisted breast biopsy (VABB). The aim of this study was to evaluate the clinical effect of using urinary balloon catheter to prevent postoperative bleeding after ultrasound-guided VABB. From May 2016 to June 2018, 324 patients who underwent ultrasound-guided VABB were randomized into the study group and control group. In the study group, an urinary balloon catheter was inserted into the excision cavity to prevent bleeding and hematoma. In the control group, compression with thorax pressure bandage was used for hemostasis. Postoperative subcutaneous ecchymosis and hematoma were recorded and compared between the two groups. The rates of postoperative ecchymosis and hematoma in the study group were significantly lower than that in the control group (5.6% vs 13.0%, P < .05; 8.0% vs 20.4%, P < .05). Among patients with lesions ≤1.5 cm, the rates of postoperative ecchymosis and hematoma were 2.9% and 4.3% in the study group, 6.5% and 11.7% in the control group, but there was no statistically significant difference between the two groups (P > .05). Among patients with lesions >1.5 cm, the rates of postoperative ecchymosis and hematoma in the study group were significantly lower than that in the control group (7.6% vs 18.8%, P < .05; 10.9% vs 28.2%, P < .05). Hemostasis with balloon urinary catheter is a safe and effective method to prevent postoperative bleeding after VABB.

Expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67 in ductal carcinoma in situ (DCIS) and DCIS with microinvasion.

Ductal carcinoma in situ (DCIS) represents a heterogeneous disease in its histologic appearance and biological potential. Some women treated for DCIS subsequently develop invasive breast cancer. DCIS with microinvasion is considered as the interim stage in the progression from DCIS to invasive breast cancer. Analysis of the differences between DCIS and DCIS with microinvasion may aid in understanding the characteristic of DCIS with microinvasion and identifying biological factors determining progression of DCIS to invasive disease.Retrospective analysis of 219 cases between 2012 and 2018 was performed in our institution. The pathological results and axillary lymph nodes status were collected. Analysis of the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 in pure DCIS (164 cases), and DCIS with microinvasion (55 cases) using immunohistochemistry.DCIS with microinvasion had a higher nuclear grade (P < .001) and was more likely to have sentinel lymph node biopsy (SLNB) positivity (P = .039) than DCIS. Expression of ER, PR were significantly higher in DCIS compared with DCIS with microinvasion (P < .001, P < .001). While the expression of HER-2 in DCIS with microinvasion (56.4%) was significantly higher than in DCIS (36.6%, P = .01). Furthermore, DCIS with microinvasion was significantly more likely to have aggressive subtype (Triple-negative and HER2-enriched tumors, P = .005).Our results indicated that DCIS with microinvasion was different from pure DCIS in clinicopathologic characteristics and molecular alterations. It displayed a more aggressive biological nature than pure DCIS. It may be a distinct entity.

An obligatory anaerobic Salmonella typhimurium strain redirects M2 macrophages to the M1 phenotype.

A genetically engineered Salmonella typhimurium strain that may be applied in the medically useful therapeutic strategy of using bacterial agents to target breast cancer in a tumor-bearing nude mouse model has been previously reported. Furthermore, immune cell accumulation in breast tumor types has been observed, particularly distributed in regions surrounding the bacteria. M2 macrophages are associated with breast cancer aggressiveness, whereas M1 macrophages are prone to devouring bacteria and killing cancer cells. Therefore, this engineered tumor-targeting salmonella strain was used in an attempt to reverse the phenotype of M2 macrophages into the M1 phenotype. Subsequent to the co-culture of M2 macrophages with the bacteria for a short time, >50% of the M2 macrophages were invaded by bacteria. These M2 macrophages exhibited a decreased expression of mannose receptor (an M2 phenotypic marker) and increased expression of human leukocyte antigen-antigen D related (an M1 phenotypic marker). The results of the present study indicated that differentiated M2 macrophages may be redirected into the M1 phenotype following exposure to the engineered bacteria stimulus. This effect may be a potential mechanism by which bacteria retard tumor growth. Thus, this engineered bacterium may be a useful candidate for targeting and redirecting M2 macrophages into the M1 phenotype.

A hyposensitive anticancer drug induces higher surface expression and release of heat shock proteins in a human hepatocellular carcinoma cell line.

Heat shock proteins (HSPs) respond to multiple stresses and have been implicated as essential immune chaperones that regulate innate and adaptive immunity. The exposure of HSPs containing tumour peptide complex to immune surveillance elements may elicit a specific anti-tumour response. The present study examined the potential of anticancer drugs to induce apoptosis of HepG2 cells and elicit the expression of HSP proteins, including HSP70 and gp96, on the membrane or their release to the extracellular environment, leading to HSP exposure. In the present study, etoposide and carboplatin were classified by an adenosine triphosphate assay as representatives of hypersensitive and hyposensitive anticancer drugs, respectively. Flow cytometry, immunofluorescence, ELIZA and reverse transcription quantitative polymerase chain reaction were all used to detect changes in the HSPs. The results demonstrated that etoposide and carboplatin induced apoptosis of HepG2 cells. In addition, following treatment with etoposide or carboplatin, HSP70/gp96 expression increased, demonstrating a 'transfer expression' pattern: The cytosol expression decreased while the surface expression increased. These alterations progressed steadily with notable alterations following treatment with etoposide for 24 h or carboplatin for 72 h. Additionally, at the end of treatment, release of HSP70/gp96 to the extracellular environment increased. Notably, following treatment with the hyposensitive anticancer drug carboplatin for 72 h, the surface expression of gp96 in HepG2 cells was significantly increased. These results suggest that when combined with cancer cell apoptosis, anticancer drugs induce the membrane expression and release of HSP70/gp96 in hepatocellular carcinoma (HCC) cells, which may represent a crucial event in the immune anti-tumour response. Notably, treatment with the hyposensitive anticancer drug for a longer time period resulted in greater surface expression and release of gp96, which suggests a potential use for hyposensitive anticancer drugs in HSP-based dendritic cell vaccine preparation and chemoimmunotherapy for HCC patients.

A nomogram based on mammary ductoscopic indicators for evaluating the risk of breast cancer in intraductal neoplasms with nipple discharge.

Mammary ductoscopy (MD) is commonly used to detect intraductal lesions associated with nipple discharge. This study investigated the relationships between ductoscopic image-based indicators and breast cancer risk, and developed a nomogram for evaluating breast cancer risk in intraductal neoplasms with nipple discharge. A total of 879 consecutive inpatients (916 breasts) with nipple discharge who underwent selective duct excision for intraductal neoplasms detected by MD from June 2008 to April 2014 were analyzed retrospectively. A nomogram was developed using a multivariate logistic regression model based on data from a training set (687 cases) and validated in an independent validation set (229 cases). A Youden-derived cut-off value was assigned to the nomogram for the diagnosis of breast cancer. Color of discharge, location, appearance, and surface of neoplasm, and morphology of ductal wall were independent predictors for breast cancer in multivariate logistic regression analysis. A nomogram based on these predictors performed well. The P value of the Hosmer-Lemeshow test for the prediction model was 0.36. Area under the curve values of 0.812 (95 % confidence interval (CI) 0.763-0.860) and 0.738 (95 % CI 0.635-0.841) was obtained in the training and validation sets, respectively. The accuracies of the nomogram for breast cancer diagnosis were 71.2 % in the training set and 75.5 % in the validation set. We developed a nomogram for evaluating breast cancer risk in intraductal neoplasms with nipple discharge based on MD image findings. This model may aid individual risk assessment and guide treatment in clinical practice.

Screening of significantly hypermethylated genes in breast cancer using microarray-based methylated-CpG island recovery assay and identification of their expression levels.

To screen candidate methylation markers for early detection of breast cancer and to explore the relationship between methylation and gene expression, we performed methylated-CpG island recovery assay (MIRA) combined with CpG island array on 61982 CpG sites across 4162 genes in 10 cancerous and 10 non-cancerous breast tissues. Direct bisulfite sequencing and combined bisulfite restriction analysis (COBRA) were carried out in independent cancerous and non-cancerous samples. Gene expression was analyzed by microarrays and validated using RT-PCR. We detected 70 significantly hypermethylated genes in breast cancer tissues, including many novel hypermethylated genes such as ITGA4, NFIX, OTX2 and FGF12. Direct bisulfite sequencing showed widespread methylation occurring in intragenic regions of the WT1, PAX6 and ITGA4 genes and in the promoter region of the OTX2 gene in breast cancer tissues. COBRA assay confirmed that the WT1, OTX2 and PAX6 genes were hypermethylated in breast cancer tissues. Clustering analysis of the gene expression of 70 significantly hypermethylated genes revealed that most hypermethylated genes in breast cancer were not expressed in breast tissues. RT-PCR assay confirmed that WT1 and PITX2 were only weakly expressed in the breast cancer tissues and were not expressed in most non-cancerous breast tissues. OTX2 and PAX6 were not expressed in either breast cancer or non-cancerous tissues. In conclusion, these results will expand our knowledge of hypermethylated genes and methylation sites for early detection of breast cancer and deepen our understanding of the relationship between methylation and gene expression. The MIRA approach can screen candidate methylated genes for further clinical validation more effectively than gene expression microarray-based strategy.

[Anti-mycobacteria drugs therapy for periductal mastitis with fistula].

OBJECTIVES: To study the etiology, clinical and pathologic characteristics of periductal mastitis with fistula and estimate the effect of anti-mycobacterial agents for periductal mastitis with fistula. METHODS: Totally 27 patients of periductal mastitis with fistula received anti-mycobacteria drugs therapy from December 2008 to September 2011 were analyzed retrospectively. All of the patients were female. The mean age at onset was 28 years (range 15 to 40 years old). The main clinical manifestation of the 27 patients was breast fistula, including 21 patients with single fistula and 6 patients with multiple fistula. Three patients manifested with pure fistula, 14 patients with both fistula and lump, 10 patients with fistula, lump and abscess. The samples including pus or tissues of all patients were underwent bacteria culture and all patients core needle biopsy. All patients were given primary anti-mycobacteria drugs therapy, parts of patients received surgery based on the evaluation of medical treatment. RESULTS: The common bacteria culture of all patients failed to demonstrate any causative microorganism. Four cases were selected randomly to undergo PCR of mycobacteria, only one case was identified as Massiliense in bacteria culture of mycobacteria. Twenty-seven patients with periductal mastitis with fistula were treated with anti-mycobacterial agents (isoniazid, rifampicin and ethambutol or pyrazinamide of triple oral drugs) for 1 to 3 months, the fistula of all 27 patients were closed well. Sixteen patients were treated with the agents only and cured. Eleven patients received surgical treatment after treated with the medical agents. None of the patients were given mastectomy. All patients had no reccurence until now. CONCLUSIONS: The periductal mastitis with fistula has a closely relationship with the infection of nontuberculosis mycobacteria. Those patients could be treated with triple anti-mycobacterial agents and could also avoided mastectomy.

[The clinical study of high-frequency ultrasound-guided vacuum-assisted biopsy for breast microcalcifications].

OBJECTIVE: To evaluate the clinical application of high-frequency ultrasound-guided vacuum-assisted biopsy for breast microcalcifications. METHODS: Sixty-six patients with 70 lesions of microcalcifications detected at mammography underwent high-frequency ultrasound-guided vacuum-assisted biopsy from July 2009 to October 2010. All patients were female, aged 24 to 61 years (median age 40 years). Among 70 lesions of microcalcifications, unilateral lesions were 62 cases and bilateral lesions were 4 cases. The clinical factors that affected the success of biopsy were investigated by χ(2) test and Logistic regression analysis. RESULTS: Among 70 lesions of microcalcifications, the successful rate of biopsy was 72.9% (51/70). The biopsy successful rate of microcalcifications without and with masses were 65.2% (30/46) and 87.5% (21/34) respectively (χ(2) = 3.960, P = 0.047). The biopsy successful rate of microcalcifications of maximal diameter more than 5 mm was higher than that of maximal diameter less than 5 mm (88.9% vs. 55.9%, χ(2) = 9.633, P = 0.002). The Logistic regression analysis showed that the types and maximal diameter of microcalcifications were the main factors that affected the success of biopsy. CONCLUSION: The clinical application of high-frequency ultrasound-guided vacuum-assisted biopsy was an effective option for the diagnosis of breast microcalcifications, especially for the type of microcalcifications with masses and the maximal diameter more than 5 mm.

[Risk factors of breast cancer in women in Guangdong and the countermeasures].

OBJECTIVE: To screen high-risk population of breast cancer by analyzing the risk factors of breast cancer in Guangdong Province. METHODS: A case-control study was performed to identify the risk factors of breast cancer between premenopausal women and postmenopausal women. Chi-square test and unconditional logistic regression were used to analyze the data. RESULTS: In premenopausal women, prophylactic, family history of breast cancer, bad mood, bad life incidence and work load were the risk factors, and breast hyperplasia history, breast tissue examination history, regular exercise and sleeping without bra were the protective factors. In postmenopausal women, family history of breast cancer was the risk factor, and breast hyperplasia history and mood adjustment were the protective factors. CONCLUSION: The risk and protective factors of breast cancer differ between premenopausal and postmenopausal women, which highlights the importance of using different risk models to screen the high-risk populations.