We determined the prevalence and characteristics of BRCA1/2 germline mutations in a large cohort of Chinese women with breast cancer. A total of 5931 unselected Chinese women with breast cancer were enrolled in this study and underwent testing for BRCA1/2 mutations. Of these, 543 patients were familial breast cancer, 1033 were early-onset disease (≤40 years) without family history of breast cancer, and 4355 were sporadic breast cancer. In total, 232 patients (3.9 %) carried a BRCA1 or BRCA2 mutation (110 in BRCA1and 122 in BRCA2) in this cohort of 5931 patients. BRCA1/2 mutation rate was 16.9 % (92/543) in familial breast cancers, 5.2 % (54/1033) in early-onset breast cancers (≤40 years), and 2.0 % in sporadic breast cancers (>40 years), respectively. The BRCA1/2 mutation rate was 27.0 % in 111 familial breast cancers diagnosed at and before the age of 40. 41.4 % of mutations in this cohort were specific for Chinese population. Recurrent mutations accounted for 44.8 % of the entire mutations in 2382 cases that BRCA1 and BRCA2 genes were fully sequenced in this study. Both BRCA1 and BRCA2 mutation carriers were significantly more likely to be early-onset and bilateral breast cancers, high-grade cancer, and to have a family history of breast cancer compared with non-carriers. BRCA1 mutation carriers were more likely to be triple-negative cancer than BRCA2 mutation carriers and non-carriers. Our data provide guidelines for Chinese women with breast cancer who should undergo BRCA1/2 genetic testing; additionally, recurrent mutations account for nearly half of the mutations and some of them are specific for Chinese women.

The role of TP53 mutations in predicting response to neoadjuvant chemotherapy in breast cancer remains controversial. The aims of this study were to investigate whether TP53 mutations were associated with response and survival in breast cancer patients who received neoadjuvant chemotherapy. Therefore, we identified TP53 mutations in the core-needle biopsy tumor samples obtained before the neoadjuvant chemotherapy from 351 operable primary breast cancer patients who either received anthracycline/cyclophosphamide-based (n 5 252) or paclitaxel (n 5 99) neoadjuvant chemotherapy. We found that 41.0% (144 of 351) of patients harbored TP53 mutations, and 14.8% of patients achieved a pCR (pathologic complete response) after neoadjuvant chemotherapy. Among patients treated with anthracycline/cyclophosphamide (n 5 252), patients with TP53 mutations had a significantly higher pCR rate than those with wild-type (28.6 vs.7.1%; p < 0.001), and TP53 mutation was an independent favorable predictor of pCR [odds ratio (OR) 5 3.41; 95% confidence interval (CI) 1.50-7.77; p 5 0.003] in this group; moreover, patients with TP53 mutation had a better distant recurrence-free survival (DRFS) than those with wild-type [unadjusted hazard ratio (HR) 5 0.43; 95% CI 0.20-0.94; p 5 0.030] in this group. Among patients treated with paclitaxel (n 5 99), no significant difference in pCR rates was observed between patients with or without TP53 mutations (15.2 vs. 11.3%; p 5 0.57). Our results suggested that patients with TP53 mutations are more likely to respond to anthracycline/ cyclophosphamide-based neoadjuvant chemotherapy and have a favorable survival.Although anthracycline or taxane is one of the most active agents to date and is widely used in breast cancer in the neoadjuvant settings, only a minority of patients achieve a pathologic complete response (pCR) when the patients receive anthracycline or taxane neoadjuvant chemotherapy. 1,2 Thus, it is very useful to identify the patients who are more likely to respond to neoadjuvant chemotherapy and spare them from the unnecessary regimens in clinical practice.TP53 encodes a transcription factor that modulates response to cellular stress through transcriptional regulation of genes involved in DNA repair, cell-cycle arrest, apoptosis and senescence. 3,4 Moreover, TP53 is one of the most mutated genes in human cancers, 5 with a mutation rate of 30-40% in breast cancers. 6,7 TP53 mutations affect the transcriptional activity of TP53 protein 7 or even acquire new functions. [8][9][10] The fundamental functions and the high mutation rate of the TP53 gene make it a potential predictive and/or prognostic marker.Previous studies suggested that TP53 mutations were associated with poor survival in breast cancers. 11,12 On the other hand, the associations between TP53 mutations and response to neoadjuvant chemotherapy in breast cancer are controversial. [13][14][15][16][17][18][19][20][21] Some studies indicated that patients with TP53 mutation are less likely to respond to anthracycline-based neoadjuvan...

PURPOSE The absolute cumulative risk of contralateral breast cancer (CBC) for patients with BRCA1/ 2 variants is unknown. The purpose of this study was to develop a CBC risk prediction model for assessing CBC risk for BRCA1/ 2 carriers. METHODS The primary cohort of 491 patients with BRCA1/ 2 variants was derived from a large series of unselected patients with breast cancer. A nomogram was established on the basis of the results of a multivariate Cox regression analysis from this cohort. This model, named BRCA-CRisk, was further validated by an independent cohort of 205 patients with BRCA1/ 2 variants. Discrimination and calibration of the model were assessed. RESULTS In the primary cohort of 491 patients, 66 developed contralateral breast cancer after a median follow-up of 7.0 years. Four variables were significantly associated with risk of CBC and were incorporated in the establishment of the BRCA-CRisk prediction model: younger age at first breast cancer (with continuous variable, P = .002), positive first-degree family history of breast and/or ovarian cancer (hazard ratio [HR], 1.89; 95% CI, 1.16 to 3.08; P = .011), variant located near the 3′ region of BRCA (HR, 2.01; 95% CI, 1.23 to 3.30; P = .006), and endocrine therapy (HR, 0.54; 95% CI, 0.33 to 0.88; P = .013). The area under the time-dependent curves for the 5- and 10-year cumulative risks of CBC were 0.775 and 0.702, respectively. The model was well validated in the independent cohort of 205 BRCA1/ 2 carriers, with area under the curves of 0.750 and 0.691 for 5 and 10 years, respectively. CONCLUSION BRCA-CRisk model provides a useful tool for assessing the absolute cumulative risk of CBC for BRCA1/ 2 carriers and may help carriers and clinicians optimally select risk-reducing strategies on the basis of individual CBC risk.

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The demand for genetic testing for breast cancer susceptibility genes is increasing for both breast cancer patients and healthy individuals. Here we established a novel high-throughput assay to detect germline pathogenic variants in breast cancer susceptibility genes. In general, up 10 to 50 individual genomic DNA samples were mixed together to create a mixed DNA sample and the mixed DNA sample was subjected to a next-generation multigene panel. Germline pathogenic variants in breast cancer susceptibility genes could be found in the mixed DNA sample; next, site-specific Sanger sequencing was performed to identify individuals who carried he pathogenic variant in the mixed samples. We found that the recall and precision rates were 89.9% and 92.9% when twenty individual genomic samples were mixed. Therefore, our new assay can increase an approximately 20-fold of efficacy to identify the pathogenic variants in breast cancer susceptibility genes in individuals when compared with current assay.