Integrative analysis of homologous recombination repair patterns unveils prognostic signatures and immunotherapeutic insights in breast cancer.

Globally, breast cancer (BC) is the leading cause of female death and morbidity. Homologous recombination repair (HRR) is critical in BC. However, the prognostic role and immunotherapy response of HRR in BC remains to be clarified. Firstly, we identified HRR types in BC samples from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) dataset (GSE42568) based on 65 HRR genes (HRRGs). A differentially expressed gene (DEG) list for different HRR types was generated. Then, the influences of gene sets composed of these DEGs on biological pathways and BC prognosis were explored. Next, we identified gene clusters based on gene sets composed of DEGs. Genes associated with prognosis for DEGs were identified using univariate Cox regression. Finally, the HRR score was constructed based on genes associated with prognosis. We analyzed how HRR score correlates with tumor mutation burden (TMB), immune cell infiltration (ICI), and immunotherapy response. Three HRR clusters were discovered. HRR subtype A demonstrated decreased infiltration and a high number of immunosuppressive cells with a poor prognosis. DEGs among various HRR types were predominantly enriched in cell cycle and genomic stability-related pathways. The prognostic model based on sixteen DEGs accurately predicted BC prognosis. The HRRGs were differentially expressed in three DEG clusters. TMB, ICI, and immunotherapy responses differed significantly between the high and low HRR groups (HSG, LSG). The HSG was distinguished by a high degree of ICI and low TMB. LSG had a better response to anti-PD-1 or anti-PD-1 and anti-CTLA4 combination therapy. This work revealed that HRR patterns would contribute to predicting prognosis and immunotherapy response in BC, which may benefit patients.

XRCC5/6 polymorphisms and their interactions with smoking, alcohol consumption, and sleep satisfaction in breast cancer risk: A Chinese multi-center study.

BACKGROUND: X-ray repair cross-complementary 5 (XRCC5) and 6 (XRCC6) are critical for DNA repair. Few studies have assessed their association with breast cancer risk, and related gene-environment interactions remain poorly understood. This study aimed to determine the influence of XRCC5/6 polymorphisms on breast cancer risk, and their interactions with cigarette smoking, alcohol consumption, and sleep satisfaction. METHODS: The study included 1039 patients with breast cancer and 1040 controls. Four single-nucleotide polymorphisms of XRCC5 and two of XRCC6 were genotyped. Information about smoking, alcohol consumption, and sleep satisfaction was collected through questionnaires. Odds ratios (OR) and related 95% confidence intervals (95% CI) were assessed using unconditional logistic regression models. Gene-environment interactions were analyzed using logistic regression with multiplicative interaction models. RESULTS: XRCC5 rs16855458 was associated with increased breast cancer risk in the co-dominant (ptrend  = 0.003) and dominant (CA + AA vs. CC, OR = 1.29, 95% CI = 1.07-1.56, p = 0.008) genetic models after Bonferroni correction. The CG + GG genotype of XRCC6 rs2267437 was associated with an increased risk of estrogen receptor-negative/progesterone receptor-negative (ER-/PR-) breast cancer (CG + GG vs. CC: OR = 1.54, 95% CI = 1.12-2.13, p = 0.008) after Bonferroni correction. Moreover, an antagonistic interaction between XRCC5 rs16855458 and alcohol consumption (pinteraction  = 0.017), and a synergistic interaction between XRCC6 rs2267437 and sleep satisfaction were associated with breast cancer risk (pinteraction  = 0.0497). However, these interactions became insignificant after Bonferroni correction. CONCLUSION: XRCC5 rs16855458 was associated with breast cancer risk, and XRCC6 rs2267437 was associated with the risk of ER-/PR- breast cancer. Breast cancer risk associated with XRCC5 and XRCC6 polymorphisms might vary according to alcohol consumption and sleep satisfaction, respectively, and merit further investigation.

Relationship Between Lifestyle Habits and Health-Related Quality of Life of Recently Diagnosed Breast Cancer Patients: A Comparison Between Younger and Older Women in China.

Objective: The aim of this study was to evaluate the relationship between lifestyle habits and health-related quality of life (HRQoL) among different ages who were initially diagnosed with breast cancer (within the first 2 weeks) and to determine the contribution of lifestyle habits factors on HRQoL. Methods: Patients with breast cancer were recruited from 22 hospitals in 11 provinces or municipalities in northern and eastern China. The Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) was used to measure HRQoL. Chi-square test, ANOVA, and multivariable generalized linear models were conducted to identify the differences in HRQoL between two age groups (age <50 years and ≥50 years) and to evaluate the contribution of lifestyle habits factors on HRQoL of patients with breast cancer. Results: About 1,199 eligible patients with breast cancer were used for analysis. Younger women (aged <50 years) appeared to show lower scores than older women (aged ≥50 years) in HRQoL subscales, including emotional well-being (p = 0.003), functional well-being (p = 0.006), breast cancer subscale (p = 0.038), and FACT-B Total scores (p = 0.028). Tea and alcohol consumption and being very satisfied with sleep and current life were the strongest predictors of higher HRQoL in younger group. Meanwhile, no coffee consumption, frequent participation in physical activities, high sleep satisfaction, and current life satisfaction were the key predictors of higher HRQoL in older women with breast cancer. Conclusion: The relationship of the nine lifestyle habit items with HRQoL differed among younger and older women. The associated variable of low HRQoL can help clinicians take intervention early in order to improve the prognosis of patients with breast cancer.

Molecular fingerprint of precancerous lesions in breast atypical hyperplasia.

OBJECTIVE: To identify atypical hyperplasia (AH) of the breast by shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS), and to explore the molecular fingerprinting characteristics of breast AH. METHODS: Breast hyperplasia was studied in 11 hospitals across China from January 2015 to December 2016. All patients completed questionnaires on women's health. The differences between patients with and without breast AH were compared. AH breast lesions were detected by Raman spectroscopy followed by the SHINERS technique. RESULTS: There were no significant differences in clinical features and risk-related factors between patients with breast AH (n = 37) and the control group (n = 2576). Fifteen cases of breast AH lesions were detected by Raman spectroscopy. The main different Raman peaks in patients with AH appeared at 880, 1001, 1086, 1156, 1260, and 1610 cm-1, attributed to the different vibrational modes of nucleic acids, ß-carotene, and proteins. Shell-isolated nanoparticles had different enhancement effects on the nucleic acid, protein, and lipid components in AH. CONCLUSION: Raman spectroscopy can detect characteristic molecular changes in breast AH lesions, and may thus be useful for the non-invasive early diagnosis and for investigating the mechanism of tumorigenesis in patients with breast AH.

Accuracy for cytological evaluation in the detection of breast cancer among patients with pathologic nipple discharge: a PRISMA-compliant meta-analysis.

BACKGROUND: Nipple discharge cytology is a simple non-invasive method that may provide valuable information for detecting underlying malignancy. Several studies have investigated the diagnostic value of cytology in breast cancer patients with pathological nipple discharge, but the results have been highly variable. Herein we presented a systematic review and meta-analysis of published studies pertaining to the diagnostic capacity of nipple discharge cytology in patients with breast cancer. METHODS: A systematic literature search was performed (Medline/PubMed, Embase, Cochrane Library databases, and Google Scholar) to identify studies that investigated the diagnostic capacity of cytology with regard to breast cancer in patients with pathologic nipple discharge. Two independent researchers identified articles that assessed the sensitivity and specificity of cytological evaluation for breast cancer detection in patients with pathologic nipple discharge published between January 2000 and October 2018. Articles were only included in the meta-analysis if they met predetermined criteria. The characteristics of each study and the data they yielded were summarized. Quality assessment of all articles included was performed using the Methodological Index for Non-randomized Studies Criteria (MINORS) and the Quality Assessment of Diagnostic Accuracy Study 2 (QUADAS-2). Heterogeneity was tested via Cochran Q test and the I statistic using Stata 12.0 and Meta-DiSc 1.4 software, and meta-analysis was performed. RESULTS: A total of 286 articles were identified, of which 12 articles including a total of 1476 patients were deemed eligible for inclusion in the meta-analysis. A random-effects model assessing the capacity of nipple discharge cytology to predict breast cancer yielded pooled sensitivity 63% (95% confidence interval [CI]: 53%-72%), specificity 95% (95% CI: 87%-98%), positive likelihood ratio 12.35 (95% CI: 4.87-31.34), and negative likelihood ratio 0.39 (95% CI: 0.30-0.50). The diagnostic odds ratio was 31.88 (95% CI: 11.30-89.98). The area under the summary receiver operating characteristic curve was 0.79 (95% CI: 0.75-0.82). CONCLUSION: The current meta-analysis suggests that nipple discharge cytology is a useful diagnostic modality for detection of breast cancer in patients with pathological nipple discharge, with moderate sensitivity and high specificity.

Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer.

Multigene panel testing of breast cancer predisposition genes have been extensively conducted in Europe and America, which is relatively rare in Asia however. In this study, we assessed the frequency of germline mutations in 40 cancer predisposition genes, including BRCA1 and BRCA2, among a large cohort of Chinese patients with high hereditary risk of BC. From 2015 to 2016, consecutive BC patients from 26 centers of China with high hereditary risk were recruited (n = 937). Clinical information was collected and next-generation sequencing (NGS) was performed using blood samples of participants to identify germline mutations. In total, we acquired 223 patients with putative germline mutations, including 159 in BRCA1/2, 61 in 15 other BC susceptibility genes and 3 in both BRCA1/2 and non-BRCA1/2 gene. Major mutant non-BRCA1/2 genes were TP53 (n = 18), PALB2 (n = 11), CHEK2 (n = 6), ATM (n = 6) and BARD1 (n = 5). No factors predicted pathologic mutations in non-BRCA1/2 genes when treated as a whole. TP53 mutations were associated with HER-2 positive BC and younger age at diagnosis; and CHEK2 and PALB2 mutations were enriched in patients with luminal BC. Among high hereditary risk Chinese BC patients, 23.8% contained germline mutations, including 6.8% in non-BRCA1/2 genes. TP53 and PALB2 had a relatively high mutation rate (1.9 and 1.2%). Although no factors predicted for detrimental mutations in non-BRCA1/2 genes, some clinical features were associated with mutations of several particular genes.

A case-control study on risk factors of breast cancer in Han Chinese women.

This study aimed to investigate risk factors associated with breast cancer among Han Chinese women in northern and eastern China. A matched case-control study involving 1489 patients with breast cancer and 1489 controls was conducted across 21 hospitals in 11 provinces in China, from April 2012 to April 2013. We developed a structured questionnaire to record information from face-to-face interviews with participants. Student's t-tests, Pearson's chi-square tests, and univariate and multivariate conditional logistic regression analyses were used to identify variables with significant differences between the case and control groups. Ten variables were identified (P<0.05): location, economic status, waist-to-hip ratio, menopause, family history of breast cancer, present life satisfaction, sleep satisfaction, milk products, behavior prevention scores, and awareness of breast cancer. We identified a comprehensive range of factors related to breast cancer, among which several manageable factors may contribute to breast cancer prevention. Further prospective studies concerning psychological interventions, sleep regulation, health guidance, and physical exercise are required. A screening model for high-risk populations should be put on the agenda.

Circulating High-Molecular-Weight (HMW) Adiponectin Level Is Related with Breast Cancer Risk Better than Total Adiponectin: A Case-Control Study.

The level of total adiponectin, a mixture of different adiponectin forms, has been reported associated with breast cancer risk with inconsistent results. Whether the different forms play different roles in breast cancer risk prediction is unclear. To examine this, we measured total and high molecular weight (HMW) adiponectin in a case-control study (1167 sets). Higher circulating HMW adiponectin was negatively associated with breast cancer risk after adjusting for menopausal status and family history of breast cancer (P=0.024). We analyzed the relationship between adiponectin and breast cancer risk in 6 subgroups. Higher circulating HMW adiponectin was also negatively associated with breast cancer risk (P=0.020, 0.014, 0.035) in the subgroups of postmenopausal women, negative family history of breast cancer, BMI>=24.0. Total adiponectin was positively associated with breast cancer (P=0.028) in the subgroup of BMI<=24.0. Higher HMW/total adiponectin ratio was negatively associated with breast cancer (P=0.019) in the subgroup of postmenopausal women. Interestingly, in the subgroup of women with family history of breast cancer, higher circulating total and HMW adiponectin were positively associated with breast cancer risk (P=0.034, 0.0116). This study showed different forms of circulating adiponectin levels might play different roles in breast cancer risk. A higher circulating HMW adiponectin is associated with a decreased breast cancer risk, especially in postmenopausal, without family history of breast cancer or BMI>=24.0 subgroups, whereas higher circulating HMW adiponectin levels is a risk factor in women with a family history of breast cancer. Further investigation of different forms of adiponectin on breast cancer risk is needed.

A case-control study on risk factors of breast cancer in China.

INTRODUCTION: To screen the risk factors associated with breast cancer among Chinese women in order to evaluate the individual risk of developing breast cancer among women in China. MATERIAL AND METHODS: A case-control study on 416 breast cancer patients and 1156 matched controls was conducted in 14 hospitals in 8 provinces of China in 2008. Controls were age- and region-matched to the cases. Clinicians conducted in-person interviews with the subjects to collect information on demographics and suspected risk factors for breast cancer that are known worldwide. Conditional logistic regression was used to derive odds ratios (OR) and 95% confidence intervals (CI) for the associations between risk factors and breast cancer. RESULTS: Compared with matched controls, women with breast cancer were significantly more likely to have higher body mass index (BMI, OR = 4.07, 95% CI: 2.98-5.55), history of benign breast disease (BBD) biopsy (OR = 1.68, 95% CI: 1.19-2.38), older age of menarche (AOM) (OR = 1.41, 95% CI: 1.07-1.87), stress anticipation (SA), for grade 1-4, OR = 2.15, 95% CI: 1.26-3.66; for grade 5-9, OR = 3.48, 95% CI: 2.03-5.95) and menopause (OR = 2.22, 95% CI: 1.50-3.282) at the level of p < 0.05. Family history of breast cancer (FHBC) in first-degree relatives (OR = 1.66, 95% CI: 0.77-3.59) and use of oral contraceptives (OC) (OR = 1.59, 95% CI: 0.83-3.05) were associated with an increased risk of breast cancer at the level of p < 0.20. CONCLUSIONS: Our results showed that BMI, history of BBD biopsy, older AOM, SA and menopause were associated with increased risk of breast cancer among Chinese women. The findings derived from the study provided some suggestions for population-based prevention and control of breast cancer in China.

[Comparison of dynamic optical breast imaging (DOBI) and mammography in sensitivity, specificity and safety of breast cancer diagnosis: a prospective analysis of 62 patients in two centers].

OBJECTIVE: To assess the sensitivity, specificity and safety of dynamic optical breast imaging (DOBI) and mammography according to the pathological results. METHODS: From June 2005 to January 2006, 62 patients in Peking University People's Hospital and Capital Medical University Affiliated ChaoYang Hospital who received mammography and needed biopsy were enrolled prospectively, signed the consent form and recorded the comfortable level, acceptability and any complications during DOBI examination. Images obtained with DOBI and mammography were evaluated by 3 independent doctors who didn't know the pathological results to calculate the breast cancer diagnostic sensitivity and specificity. RESULTS: In this study the sensitivity and specificity of breast cancer diagnosis by mammography were 0.935 5±0.044 1 (95%CI 0.709 2-0.968 2)and 0.451 6±0.089 4 (95%CI 0.276 4-0.626 8)respectively. The sensitivity and specificity of DOBI were 0.838 7±0.066 1 (95%CI 0.709 2-0.968 2)and 0.612 9±0.087 5 (95%CI 0.441 4-0.784 4)respectively. In the DOBI examination there was no adverse reaction. The tolerability of DOBI was good. CONCLUSION: Dynamic optical breast imaging could provide the functional information about angiogenesis on the lesion and improve the breast cancer diagnostic specificity. It is a potential non-invasive breast functional imaging diagnostic tool and needs more large scale clinical trial to determine its indications and diagnostic criteria.

[Comparison of therapeutic effects of immediate implanting breast reconstruction after skin sparing mastectomy and modified radical mastectomy on breast cancer].

OBJECTIVE: To compare the therapy efficiency of immediate implanting breast reconstruction after skin sparing mastectomy and modified radical mastectomy in breast cancer. METHODS: This study retrospectively analyzed 530 female patients with early breast cancer operated in the department of General Surgery, Beijing Chaoyang Hospital, from Jan. 2004 to Dec. 2008, including 91 patients operated with skin sparing mastectomy and immediate implanting breast reconstruction and 439 patients with modified radical mastectomy. The follow up ended in Mar. 2010. By comparing complications, local recurrence, distant metastases and mortality rates between the two groups, the research was done to evaluate the therapy efficiency. RESULTS: In the group of immediate implanting reconstruction, 84 patients completed follow up with the median follow-up time of 35 months (14 - 72 months) while the local recurring rate was 2.4%, distant metastasis rate was 8.3% and mortality rate was 6.0%. In the group of modified radical mastectomy, 398 patients completed follow up with the median follow-up time of 36 months (12 - 74 months) while the local recurring rate was 3.3%, distant metastasis rate was 9.5% and mortality rate was 6.5%. Therefore there was no obvious statistic difference between the two groups in local recurring rate, distant metastasis rate and mortality rate (P > 0.05). Evaluation of aesthetic results was done in the 84 patients after immediate implanting reconstruction for 12 months which was 93% as good or excellent by surgeons while 87% by patients. Surgeons and patients were both satisfied with the breast appearance. CONCLUSION: For patients with early stage breast cancer, combining standard postoperative therapy, skin sparing mastectomy and immediate implanting reconstruction could achieve the same effect as the traditional modified radical mastectomy, while reconstruction would bring about better appearance and higher quality of life.

[Follow-up of benign gynecologic diseases in patients treated with tamoxifen for breast cancer].

OBJECTIVE: To explore the pattern of benign gynecologic diseases in patients treated with tamoxifen for breast cancer. METHODS: A total of 163 cases with breast cancer were followed up by gynecologists. The incidence rates of several benign gynecologic conditions were determined and were compared among women receiving tamoxifen and those not taking it. RESULTS: For a follow-up of 12-96 months, the incidence rates of leiomyomas requiring therapy was 9.20%. Compared with women not taking tamoxifen, the patients taking tamoxifen had a lower incidence rate of leiomyomas (17.59% vs 32.72%) (P < 0.05), the menopausal women taking tamoxifen had a greater incidence of endometrial lesions (P < 0.05) and the premenopausal women taking tamoxifen had a greater incidence of ovarian cysts (P < 0.05). CONCLUSION: Tamoxifen is a high risk factor for an increased risk of endometrial lesions for menopausal women and ovarian cysts for premenopausal women. But it acts as a protective factor for decreasing the incidence rate of leiomyomas.

Immediate breast reconstruction with implants after skin-sparing mastectomy: a report of 96 cases.

BACKGROUND: Skin-sparing mastectomy (SSM) with immediate breast reconstruction (IBR) has become increasingly popular as an effective treatment for patients with early-stage breast cancer requiring mastectomy. This study aimed to evaluate the clinical outcomes of IBR using permanent gel breast implants and Becker expandable breast implants after SSM. METHODS: A review of 96 patients undergoing IBR with Beck expandable or permanent gel breast implants after SSM from July 2002 to December 2006 was performed. Of the 96 patients, 30 had IBR after SSM with conservation of the nipple-areola complex (NAC). The mean patient age was 42 years (range, 29-57 years). Aesthetic outcomes were assessed according to the breast volume, shape, and symmetry with the opposite breasts after a mean follow-up period of 44 months. RESULTS: The aesthetic outcomes were graded as excellent for 29 patients, good for 47 patients, fair for 12 patients, and poor for 8 patients. The overall complication rate was 11.5% (11/96). The complications included prosthesis loss after skin flap necrosis subsequent to hematoma formation (n = 1), skin necrosis (n = 2), partial necrosis of preserved NAC (n = 1), capsular contracture (Baker 4, n = 2), wound infection not involving the prosthesis (n = 2), inversion of the injection port (n = 2), and seroma (n = 2). CONCLUSION: This study demonstrates that prosthetic breast reconstruction is a safe, reliable method with minimal complications and good to excellent aesthetic results for the majority of patients with early-stage breast cancer. For selected patients, NAC-sparing mastectomy can be performed without increasing the risk of local recurrences. Success depends on patient selection, proper incision for SSM, total coverage of the prostheses with muscles, and careful intra- and postoperative management.

[A selection of methods for immediate and delayed breast reconstruction].

OBJECTIVE: To investigate the surgical methods, indications and effects of postmastectomy breast reconstruction in 67 consecutive patients. METHODS: From July 2002 to October 2005, 67 patients received postmastectomy breast reconstructions. Immediate breast reconstructions were performed using full-size implants in 38 cases, Becker expandable implants in 16 cases, unilateral pedicled transverse rectus of abdominis musculocutaneous (TRAM) in 2 cases. Delayed breast reconstruction were carried out in 6 cases with unilateral pedicled TRAM flaps, 4 cases with extended latissimus dorsi musculocutaneous flap (ELDF), one case with Becker expandable implant. RESULTS: Of the patients, more than 90% were satisfied with the results. Minor complications were recorded in 5 patients, including small local skin necrosis, partial necrosis of nipple-areola complex preserved and seroma formation. CONCLUSIONS: Full-size implant breast reconstruction is ideal for slender, small-breast women undergoing immediate breast reconstruction after skin-sparing mastectomy, but not suitable for delayed breast reconstruction. Expandable implants can be used for immediate breast reconstruction in patients with large breast or those who received modified mastectomy and also can be used for delayed breast reconstruction in patients with well-preserved skin and muscle. TRAM or ELDF flap for breast reconstruction is a useful procedure with advantages of autologous tissue and excellent results, both are suitable for immediate and delayed breast reconstruction.

[Expandable implants in immediate breast reconstruction].

OBJECTIVE: To investigate the indications, surgical methods and esthetic results in patients undergoing immediate breast reconstruction with expandable implants. METHODS: From January 2002 to March 2006, immediate breast reconstructions were carried out with expandable implants following mastectomy in 30 breast cancer patients. Nipple-areola were preserved in 5 patients. RESULTS: Very satisfactory results were achieved. Minor complications were recorded in 3 patients, two with local skin necrosis, and another with partial necrosis of nipple-areola complex. CONCLUSIONS: The techniques provide better results for the patient who is not a candidate for simple implant reconstruction. These techniques also eliminate the need for a second major surgery to replace a temporary expander with a permanent implant in those patients needing soft tissue expansion. It is a simple procedure with advantages of no additional scarring, short time for convalescence.

[Classification and clinical study of plasma cell mastitis under breast duct endoscope].

OBJECTIVE: To evaluate the clinical significance of breast duct endoscope for plasma cell mastitis. METHODS: Breast duct endoscope was performed on 250 patients with nipple discharge. The characters of 95 cases of plasma cell mastitis under the breast duct endoscope were analyzed and studied. RESULTS: Among the 95 cases with plasma cell mastitis, 21 were in type I, 43 in type II, 18 in type III and 13 in type IV. Eighty-three cases were treated with no-operation treatment, and 45 completely released, 38 partly released. There were 5 cases with middle to serious atypical hyperplasia in 12 cases treated with operation, that were all confirmed by pathological examination. CONCLUSION: In patients with plasma cell mastitis, clear diagnosis can be made through breast duct endoscope, and the breast duct with lesions could be positioned. It is a necessary assistant method for patients to avoid biopsy or decrease the biopsy range.