An ultrasound-based nomogram for predicting axillary node pathologic complete response after neoadjuvant chemotherapy in breast cancer: Modeling and external validation.

INTRODUCTION: The staging and treatment of axillary nodes in breast cancer have become a focus of research. For breast cancer patients with fine-needle aspiration-or core needle biopsy-confirmed positive nodes, axillary lymph node dissection (ALND) after neoadjuvant chemotherapy (NAC) is still a standard treatment. However, some patients achieve an axillary pathologic complete response (pCR) after NAC. In this study, the authors sought to construct a model to predict axillary pCR in patients with positive axillary lymph nodes (cN+) breast cancer. METHODS: Data from patients with pathologically proven cN+ breast cancer treated with NAC followed by ALND between January 2010 and April 2019 at the Peking University Cancer Hospital were reviewed. Axillary lymph node status was assessed using ultrasonography before and after NAC. The patient cohort was assigned to the construction and internal validation cohorts according to admission time. A nomogram was constructed based on the significant factors associated with axillary pCR. The predictive performance of the model was externally validated using data from Peking University First Hospital. RESULTS: This study included 953 and 267 patients from Peking University Cancer Hospital and Peking University First Hospital, respectively. In the construction cohort, 39.7% (238 of 600) of patients achieved axillary pCR after NAC. The result of multivariate logistic regression analysis showed that tumor grade, clinical nodal response, NAC regimen, tumor pCR, lymphovascular invasion, and tumor biologic subtype were significant independent predictors of ypN0 (p < 0.05). The areas under the receiver operating characteristic curves for the construction, validation, and independent testing cohorts were 0.87 (95% confidence interval [CI], 0.84-0.90), 0.83 (95% CI, 0.79-0.87), and 0.84 (0.79-0.89), respectively. CONCLUSIONS: A nomogram was constructed to predict the pCR of axillary lymph nodes after NAC for breast cancer. Validation of both the internal and external cohorts achieved good predictive performance, indicating that the model has preliminary clinical application prospects.

CT Radiomics for Predicting Pathological Complete Response of Axillary Lymph Nodes in Breast Cancer After Neoadjuvant Chemotherapy: A Prospective Study.

BACKGROUND: The diagnostic effectiveness of traditional imaging techniques is insufficient to assess the response of lymph nodes (LNs) to neoadjuvant chemotherapy (NAC), especially for pathological complete response (pCR). A radiomics model based on computed tomography (CT) could be helpful. PATIENTS AND METHODS: Prospective consecutive breast cancer patients with positive axillary LNs initially were enrolled, who received NAC prior to surgery. Chest contrast-enhanced thin-slice CT scan was performed both before and after the NAC (recorded as the first and the second CT respectively), and on both of them, the target metastatic axillary LN was identified and demarcated layer by layer. Using pyradiomics-based software that was independently created, radiomics features were retrieved. A pairwise machine learning workflow based on Sklearn (https://scikit-learn.org/) and FeAture Explorer was created to increase diagnostic effectiveness. An effective pairwise auto encoder model was developed by the improvement of data normalization, dimensionality reduction, and features screening scheme as well as the comparison of the prediction effectiveness of the various classifiers. RESULTS: A total of 138 patients were enrolled, and 77 (58.7%) in the overall group achieved pCR of LN after NAC. Nine radiomics features were finally chosen for modeling. The AUCs of the training group, validation group, and test group were 0.944 (0.919-0.965), 0.962 (0.937-0.985), and 1.000 (1.000-1.000), respectively, and the corresponding accuracies were 0.891, 0.912, and 1.000. CONCLUSION: The pCR of axillary LNs in breast cancer following NAC can be precisely predicted using thin-sliced enhanced chest CT-based radiomics.

Neoadjuvant endocrine therapy for strongly hormone receptor-positive and HER2-negative early breast cancer: results of a prospective multi-center study.

PURPOSE: For estrogen receptor (ER)-positive breast cancer, neoadjuvant endocrine therapy (NET) has been shown to be as effective as neoadjuvant chemotherapy (NACT). We evaluated the prognostic significance of Preoperative Endocrine Prognostic Index (PEPI). METHODS: We conducted a prospective, multi-center, non-randomized, controlled trial that enrolled postmenopausal early-stage strongly ER-positive (≥ 50%) and HER2-negative breast cancer patients. All patients were given 4-month NET before surgery. The primary objective was to investigate the 5-year recurrence-free survival (RFS) in patients who had PEPI 0-1 or pathological complete response (pCR) without chemotherapy. Patients who had PEPI 0-1 or pCR were recommended to receive adjuvant endocrine therapy only and patients had PEPI ≥ 2 may receive adjuvant chemotherapy at the discretion of the treating physician. RESULTS: A total of 410 patients were included and 352 patients constituted the per-protocol population. Overall, 9 patients (2.5%) had pCR (ypT0/is ypN0), 128 patients (36.4%) had PEPI = 0, and 56 patients (15.9%) had PEPI = 1. After a median follow-up of 60 months (4-104 months), patients who had PEPI 0-1 or pCR showed an improved 5-year RFS [99.5% (95% CI 98.5-99.9%) for PEPI 0-1 or pCR group vs. 93.7% (95% CI 89.6-97.8%) for PEPI ≥ 2 group, P = 0.028]. No survival difference was detected between patients received adjuvant chemotherapy vs. no chemotherapy among PEPI ≥ 2 cases. CONCLUSION: PEPI 0-1 or pCR may be used to define a group of ER-positive and HER2-negative postmenopausal early breast cancer patients with low relapse risk for whom adjuvant chemotherapy can be safely withheld. Studies on the identification and alternative treatment options for endocrine-resistant tumors are warranted. CLINICAL TRIAL REGISTRATION: NCT01613560.

Effect of Local Versus General Anesthesia in Breast-Conserving Surgery on Cancer Recurrence and Cost.

BACKGROUND: The association between the type of anesthesia used and the recurrence of cancer remains controversial. This study aimed to compare the effects of local vs general anesthesia on recurrence-free survival and cost after breast-conserving surgery. MATERIALS AND METHODS: We reviewed the data of 2778 patients who underwent breast-conserving surgery followed by radiation at our center between 1999 and 2014. We analyzed the data of 994 patients with hormone receptor-positive and Her2-negative tumors who underwent breast-conserving surgery without axillary lymph node dissection under local or general anesthesia. Patients were grouped according to whether local or general anesthesia was used for the surgery. RESULTS: Of the 994 patients enrolled in this study, 367 received local anesthesia and 627 patients received general anesthesia. The median follow-up duration for all patients was 93 months. The Kaplan-Meier survival curves did not reveal significant differences between the recurrence-free survival of the two groups, with 5-year recurrence-free survival rates of 96.3% (95% CI, 94.3-98.3%) in the local anesthesia group and 97.3% (95% CI, 95.9-98.7%) in the general anesthesia group. The total cost of hospitalization in the local anesthesia group was significantly lower than that in the general anesthesia group (P <.001). The difference in the cost between the two groups remained significant, irrespective of the type of hospitalization, after excluding 165 patients receiving chemotherapy during their hospitalization. CONCLUSIONS: Our analysis indicated no association between the type of anesthesia used during breast-conserving surgery and the long-term prognosis of breast cancer. However, breast-conserving surgery under local anesthesia may be a less expensive option than that under general anesthesia.

Impact of the addition of carboplatin to anthracycline-taxane-based neoadjuvant chemotherapy on survival in BRCA1/2-mutated triple-negative breast cancer.

Whether adding carboplatin to standard neoadjuvant chemotherapy improves survival in BRCA1/2-mutated triple-negative breast cancer (TNBC) is unknown. In this retrospective study, we aimed to explore the efficacy of anthracycline-taxane (A-T)-based or anthracycline-taxane/carboplatin (A-TP)-based neoadjuvant chemotherapy in BRCA1/2-mutated TNBC. A total of 1585 operable primary breast cancer patients were treated with either neoadjuvant A-T (n = 886) or A-TP regimen (n = 699). BRCA1 and BRCA2 germline mutations were determined in all subjects. Pathological complete response (pCR), recurrence-free survival (RFS), distant recurrence-free survival (DRFS) and overall survival (OS) were estimated. Of the entire cohort, 102 patients (6.4%) carried a pathogenic BRCA1/2 germline mutation. After a median follow-up of 81 months, no significant differences in survival between the A-T and A-TP arms were found in the entire cohort. However, among 288 TNBC patients, BRCA1/2 mutation carriers had significantly better survival when treated with the A-TP regimen than with the A-T regimen (5-year RFS: 82.6% vs 47.9%; P = .024; 5-year DRFS: 88.5% vs 46.9%; P = .010; 5-year OS: 88.2% vs 49.9%; P = .036). Multivariate analyses revealed that the A-TP regimen was a significantly favourable factor for RFS and DRFS and showed a trend towards better OS when compared with the A-T regimen in BRCA1/2-mutated TNBC (RFS: adjusted hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.06-0.91, P = .035; DRFS: HR, 0.17; 95% CI, 0.03-0.80; P = .025; OS: HR, 0.29; 95% CI, 0.06-1.49; P = .14). Our study suggested that BRCA1/2-mutated TNBC patients gain a survival benefit when carboplatin is added to standard A-T-based neoadjuvant chemotherapy.

Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers in a large cohort of unselected Chinese breast cancer patients.

To estimate the cumulative risk of contralateral breast cancer (CBC) in BRCA1/2 carriers in a large cohort of unselected Chinese breast cancer patients. Our study comprised 9,401 unselected Chinese breast cancer patients and BRCA1/2 germline mutations were determined in all patients. After a median follow-up of 5.7 years, 181 patients developed CBC in this cohort. Compared to noncarriers, BRCA1 and BRCA2 carriers had a 4.52-fold (95% CI, 2.63-7.76) and 5.54-fold (95% CI, 3.51-8.74) increased risk of CBC, respectively. The 10-year cumulative risk of CBC was 15.5% (95% CI, 9.9-24.2) for BRCA1 carriers, 17.5% (95% CI, 10.9-28.0) for BRCA2 carriers and 3.2% (95% CI, 2.5-4.1) for noncarriers. Younger age at first breast cancer diagnosis was significantly associated with an increased 10-year risk of CBC for BRCA1 carriers (≤40 years vs. >40 years: 21.5% vs. 11.9%, unadjusted hazard ratio [HR] = 2.51, 95% CI, 1.03-6.15, p = 0.044), but not for BRCA2 carriers and noncarriers. The 10-year cumulative CBC risk was significantly higher in both BRCA1 and BRCA2 carriers who had a family history of breast cancer than in those who did not (BRCA1: 27.5% vs. 9.4%, adjusted HR = 2.64, 95% CI, 1.01-6.97, p = 0.049; BRCA2: 27.1% vs. 12.8%, adjusted HR = 2.29, 95% CI, 1.04-5.06, p = 0.040). In conclusion, the risk of CBC was a substantial high in BRCA1/2 carriers in unselected Chinese breast cancer patients, and CBC risk is much more remarkable in both BRCA1 and BRCA2 carriers who had a family history of breast cancer. Younger age at first breast cancer diagnosis also enhanced CBC risk in BRCA1 carriers.

BRCA1 c.5470_5477del, a founder mutation in Chinese Han breast cancer patients.

The spectrum and frequency of BRCA1/2 pathogenic variants may be ethnicity-specific. Whether high-frequency founder mutations are present in Chinese women remains largely unknown. In the current study, germline pathogenic variants in the BRCA1/2 genes were determined in 9,505 unselected Chinese Han breast cancer (BC) patients by next-generation and/ or Sanger sequencing. Four hundred and seventy-one (5.0%) BC patients carried BRCA1/2 pathogenic variants in this cohort. A total of 25 recurrent pathogenic variants (at least found in four unrelated patients) were identified in this cohort (8 BRCA1 and 17 BRCA2 recurrent pathogenic variants), 161 patients carried one of these recurrent pathogenic variants in this cohort of 9,505 patients. All of these 25 recurrent pathogenic variants were further explored whether they had founder effect through haplotype analysis. The most common pathogenic variant, BRCA1 c.5470_5477del, was found in 30 BC patients from 29 unrelated families. Twenty-seven of these 29 unrelated patients who carried this BRCA1 c.5470_5477del mutation shared an identical haplotype, indicating that BRCA1 c.5470_5477del was a founder mutation in the Chinese Han population. Furthermore, BRCA1 c.5470_5477del mutation carriers had a significantly worse survival than noncarriers (disease-free survival, p = 0.049; overall survival, p = 0.029). Taken together, our data suggested that BRCA1 c.5470_5477del is a founder mutation in the Chinese Han population and BRCA1 c.5470_5477del mutation carriers have a poor survival.

Prevalence and clinical impact of TP53 germline mutations in Chinese women with breast cancer.

The prevalence and clinical relevance of TP53 germline mutations in a large unselected breast cancer series are largely unknown. Here, we determined TP53 germline mutations in a large cohort of 10,053 unselected breast cancer patients through multigene panel-based next-generation and/or Sanger sequencing assays. We found that 0.5% of patients (50 cases) carried a pathogenic TP53 germline mutation in this large series of 10,053 unselected breast cancer patients, and the prevalence of TP53 germline mutation was 3.8% in very early onset breast cancer (age ≤30 years) in this large cohort. TP53 mutation carriers were significantly more likely to have early onset cancer (p < 0.001) and bilateral breast cancer (p = 0.03), they and were significantly more likely to respond to carboplatin-based neoadjuvant chemotherapy compared to anthracycline- or taxane-based regimen in terms of pathologic complete response (50% vs. 0%, p = 0.006). At the median follow-up of 54 months, TP53 mutation was an independent unfavorable factor for recurrence-free survival (RFS), distant recurrence-free survival (DRFS), and overall survival (OS) (RFS, adjusted hazard ratio [HR]: 2.24, 95% confidence interval [CI]: 1.15-4.33, p = 0.02; DRFS, adjusted HR: 2.73, 95% CI: 1.41-5.30, p = 0.003; OS, adjusted HR: 4.60, 95% CI: 2.26-9.41, p < 0.001) in multivariate analyses. Our study suggested that TP53 germline mutations occur more frequently in very early onset unselected breast cancer patients; and TP53 germline mutation carriers have a very poor survival and may benefit from carboplatin-based neoadjuvant chemotherapy in unselected breast cancer patients.

Comparisons of breast conserving therapy versus mastectomy in young and old women with early-stage breast cancer: long-term results using propensity score adjustment method.

PURPOSE: This study aimed to compare the effect of BCT versus mastectomy on the recurrence and survival of different-aged patients, and to investigate whether effects of BCT versus mastectomy on survival of young patients were consistent with those of old patients. METHODS: Data on women with primary invasive breast cancer between 2007 and 2011 were extracted from the institutional database of Breast Center. Disparities in hormone receptor, tumor size, lymph node status, and Her-2 status between BCT and mastectomy groups were adjusted using the propensity score (PS) adjustment method. Patients were divided by age into two groups (≤ 40 years and > 40 years). We assessed proportions of local recurrence (LR), distant disease-free survival (DDFS), disease-free survival (DFS), and breast cancer-specific survival (BCSS) in different-aged groups; this assessment was further stratified by surgical treatment. RESULTS: A total of 2964 patients were included; 565 (19%) were aged ≤ 40 years. In the entire cohort, hazard ratios (HR) of BCT versus mastectomy for DDFS and DFS were 0.56 (P = 0.029) and 0.55 (P = 0.008), respectively. After PS adjustment, there was no significant difference between BCT and mastectomy in LR, DDFS, DFS and BCSS in the young age group. In the old age group, women who underwent BCT exhibited improved DDFS (HR 0.57, 95% CI 0.39-0.84, P = 0.004). CONCLUSIONS: BCT did not significantly affect survival outcomes of young patients with breast cancer. Superior survival of BCT compared to mastectomy was observed only in old patients.

Spectrum and clinical relevance of PALB2 germline mutations in 7657 Chinese BRCA1/2-negative breast cancer patients.

PURPOSE: To investigate the prevalence and clinical relevance of PALB2 germline mutations in BRCA1/2-negative breast cancer patients. METHODS: The exons and intron-exon boundaries of the PALB2 gene were sequenced by multigene panel testing in a cohort of 7657 Chinese BRCA1/2-negative breast cancer patients. RESULTS: Of the 7657 patients, 54 (0.71%) carried pathogenic PALB2 germline mutations, all of which were nonsense or frameshift mutations leading to a truncated protein. The 54 patients carried 42 distinct pathogenic mutations, of which 17 (40.5%) were novel and 8 were recurrent mutations. Compared with non-carriers, PALB2 pathogenic mutation carriers developed breast cancer at a younger age (47.52 years vs. 51.35 years, p = 0.016) and were more likely to have triple-negative (24.1% vs. 13.4%, p = 0.022) or HER2 negative (87.0% vs. 74.2%, p = 0.031) breast cancer and large breast tumors (> 2 cm) at diagnosis (72.2% vs. 57.0%, p = 0.024). PALB2 mutation carriers were also more likely to have family histories of breast and/or ovarian cancer (27.8% vs. 8.4%, p < 0.001) and any types of cancer (57.4% vs. 31.6%, p < 0.001) when compared with non-carriers. CONCLUSIONS: PALB2 germline mutations are present at 0.71% in Chinese BRCA1/2-negative breast cancer patients and are more frequent in patients with triple-negative breast cancer and family histories of breast and/or ovarian cancer.

Germline mutation in DNA-repair genes is associated with poor survival in BRCA1/2-negative breast cancer patients.

BRCA1/2 genes are the most frequently germline mutated DNA-repair genes, and the survival of BRCA1/2 carriers has been extensively explored in breast cancer. However, the prevalence of germline mutations in non-BRCA1/2 DNA-repair genes and the survival of carriers are largely unknown in a large cohort of unselected breast cancer patients. Germline mutations in 16 DNA-repair genes were determined using a multigene panel in 7657 BRCA1/2-negative breast cancer patients who were unselected for family history of cancer or age at diagnosis. Among the 7657 BRCA1/2-negative breast cancer patients, 257 (3.4%) carried at least 1 pathogenic germline mutation in the 16 DNA-repair genes. The prevalence of DNA-repair gene mutations was significantly higher in familial breast cancers (5.2%, P = 0.002) and early-onset breast cancers (diagnosed at and before the age of 40) (4.5%, P = 0.003) than that of sporadic breast cancers (2.9%) (diagnosed above age of 40), respectively. The DNA-repair gene mutation carriers were significantly more likely to have a larger tumor (P = 0.04) and axillary lymph node metastasis (P = 0.03). Moreover, DNA-repair gene mutation was an independent unfavorable factor for recurrence-free survival (adjusted hazard ratio [HR] = 1.38, 95% CI: 1.00-1.91, P = 0.05) and disease-specific survival (adjusted HR=1.63, 95% CI: 1.04-2.57, P = 0.03) in this cohort. Overall, 3.4% of BRCA1/2-negative breast cancer patients carried germline mutations in the 16 DNA-repair genes, and the DNA-repair gene mutation carriers exhibited an aggressive phenotype and had poor survival compared with noncarriers.

Risk of ipsilateral breast tumor recurrence in primary invasive breast cancer following breast-conserving surgery with BRCA1 and BRCA2 mutation in China.

PURPOSE: BRCA1/2 germline mutations are associated with a high risk of breast cancer, which may preclude mutation carriers from breast-conserving surgery (BCS). This study retrospectively examined whether mutation status influenced the rate of ipsilateral breast tumor recurrence (IBTR) after BCS  in Chinese women. METHODS: Patients who underwent BCS were enrolled in carriers group and non-carriers group according to their BRCA1/2 mutation status in the study. The correlations were analyzed between IBTR incidence and BRCA1/2 mutation. The IBTR cases were further separated into new primary tumor (NP) and true local recurrences (TR). The risk factors of NP were studied in multivariate analysis. RESULTS: 1947 consecutive Chinese women with primary invasive breast cancer were selected. 103 patients were identified as BRCA1/2 mutation carriers and 1844 were non-carriers. BRCA1/2 mutation carriers were younger (P < 0.001) with more often negative HER-2 expression (P = 0.01) and tumor size over 2 cm (P = 0.04) than non-carriers. The median follow-up for all patients was 80 months. The rate of IBTR was 3.9% in mutated carriers and 2.0% in non-carriers, respectively (P = 0.16). In IBTR cases, NP incidence was 3.9% in carrier group and 0.6% in non-carrier group, respectively (P < 0.01). After adjustment of all clinical-pathological factors, BRCA1/2 mutation was the only statistical risk factor of NP incidence (HR = 6.29, P = 0.002), while positive lymph node was nearly statistically significant (HR = 2.70, P = 0.06). CONCLUSIONS: BCS may be a rational option for Chinese BRCA1/2 mutation carriers. High NP incidence in mutation carriers should be paid close attention in the future.

Prevalence and characterization of ATM germline mutations in Chinese BRCA1/2-negative breast cancer patients.

PURPOSE: The ataxia telangiectasia-mutated (ATM) gene is a moderate susceptibility gene for breast cancer. However, little is known about the breast cancer phenotypes associated with ATM mutation. We therefore investigated the spectrum and clinical characteristics of ATM germline mutations in Chinese breast cancer patients. METHODS: A multi-gene panel was performed to screen for ATM germline mutations in 7657 BRCA1/2-negative breast cancer patients. All deleterious mutations were validated by independent polymerase chain reaction (PCR)-Sanger sequencing. RESULTS: A total of 31 pathogenic mutations in the ATM gene across 30 carriers were identified, and the ATM mutation rate was 0.4% (30/7,657) in this cohort. The majority of the mutations (90.3%, 28/31) were nonsense or frameshift mutations. Of the total ATM mutations, 61.3% (19/31) were novel mutations and 13 recurrent mutations were found. ATM mutations carriers were significantly more likely to have a family history of breast and/or ovarian cancer (26.7% in carriers vs. 8.6% in non-carriers, p < 0.001), as well as a family history of any cancer (60.0% in carriers vs. 31.5% in non-carriers, p = 0.001). In addition, ATM mutations carriers were significantly more likely to have oestrogen receptor (ER)-positive (p = 0.011), progesterone receptor (PR)-positive (p = 0.040), and lymph node-positive breast cancer (p = 0.034). CONCLUSIONS: The prevalence of the ATM mutation is approximately 0.4% in Chinese BRCA1/2-negative breast cancer. ATM mutation carriers are significantly more likely to have a family history of cancer and to develop ER- and/or PR-positive breast cancer or lymph node-positive breast cancer.

Efficacy of pegfilgrastim to support neoadjuvant dose-dense epirubicin and cyclophosphamide chemotherapy in breast cancer.

PURPOSE: The role of long-acting hematopoietic growth factor in supporting dose-dense chemotherapy and minimizing hematologic toxicity has not been established. We investigated the efficacy and safety of once-per-cycle pegfilgrastim in breast cancer patients receiving neoadjuvant dose-dense epirubicin and cyclophosphamide (ddEC). METHODS: Newly diagnosed stage I to III breast cancer patients received four cycles of ddEC (E, 100 mg/m2 and C, 600 mg/m2 every 2 weeks) and 6 mg of subcutaneous pegfilgrastim on day 2 of each cycle. The primary endpoint was to evaluate the incidence of chemotherapy delay. Secondary endpoints include the incidences of febrile neutropenia (FN) and grade 3/4 neutropenia during the four ddEC cycles. RESULTS: A total of 240 patients were enrolled and 913 ddEC cycles were administered in the study. Chemotherapy delay occurred in 15 patients (6.3% of patients, 95% CI 3.2-9.4%) for 17 cycles (1.9% of cycles, 95% CI 1.0-2.8%). The most frequent cause of chemotherapy delay was transaminase elevation (10 patients, 12 cycles). A total of 12 patients (5.0%, 95% CI 2.2-7.8%) developed 13 episodes of FN. Of the 221 patients that completed four ddEC cycles with pegfilgrastim support, 209 patients (94.6%, 95% CI 91.6-97.6%) had a 100% relative dose intensity (RDI). A RDI ≥ 85% was achieved in 217 of 221 patients (98.2%, 95% CI 96.5-99.9%). Bone pain of any grade was recorded in 85 of 220 evaluable patients (38.6%, 95% CI 32.2-45.0%). CONCLUSIONS: Pegfilgrastim is effective and safe in facilitating four cycles of neoadjuvant ddEC, with low incidences of chemotherapy delay and febrile neutropenia.

RAD50 germline mutations are associated with poor survival in BRCA1/2-negative breast cancer patients.

RAD50 is a highly conserved DNA double-strand break (DSB) repair gene. However, the associations between RAD50 germline mutations and the survival and risk of breast cancer have not been fully elucidated. Here, we aimed to investigate the clinical impact of RAD50 germline mutations in a large cohort of unselected breast cancer patients. In our study, RAD50 germline mutations were determined using next-generation sequencing in 7657 consecutive unselected breast cancer patients without BRCA1/2 mutations. We also screened for RAD50 recurrent mutations (L719fs, K994fs, and H1269fs) in 5000 healthy controls using Sanger sequencing. We found that 26 out of 7,657 (0.34%) patients had RAD50 pathogenic mutations, and 16 patients carried one of the three recurrent mutations (L719fs, n = 6 cases; K994fs, n = 5 cases; and H1269fs, n = 5 cases); the recurrent mutation rate was 0.21%. The frequency of the three recurrent mutations in the 5,000 healthy controls was 0.18% (9/5,000). These mutations did not confer an increased risk of breast cancer in the studied patients [odds ratios (OR), 1.16; 95% confidence interval (CI), 0.51-2.63; p = 0.72]. Nevertheless, multivariate analysis revealed that RAD50 pathogenic mutations were an independent unfavourable predictor of recurrence-free survival (RFS) [adjusted hazard ratio (HR) 2.66; 95% CI, 1.18-5.98; p = 0.018] and disease-specific survival (DSS; adjusted HR 4.36; 95% CI, 1.58-12.03; p = 0.004) in the entire study cohort. Our study suggested that RAD50 germline mutations are not associated with an increased risk of breast cancer, but patients with RAD50 germline mutations have unfavourable survival compared to patients without these mutations.

Predictive value of BRCA1/2 mRNA expression for response to neoadjuvant chemotherapy in BRCA-negative breast cancers.

It is well known that BRCA1 and BRCA2 play a central role in DNA repair, but the relationship between BRCA1 and BRCA2 mRNA expression and response to neoadjuvant chemotherapy in sporadic breast cancer patients has not been well established. Here, we investigate the association between BRCA1 or BRCA2 mRNA expression levels and pathological response in 674 BRCA1/2 mutation-negative breast cancer patients who received neoadjuvant chemotherapy. BRCA1 and BRCA2 mRNA expression were assessed using quantitative real-time polymerase chain reaction in core biopsy breast cancer tissue obtained prior to the initiation of neoadjuvant chemotherapy. A total 129 patients (19.1%) achieved pathological complete response (pCR) after neoadjuvant chemotherapy. Among patients treated with anthracycline-based chemotherapy (n = 531), BRCA1 mRNA low expression patients had a significantly higher pCR rate than intermediate or high BRCA1 mRNA expression groups (24.6% vs 16.8% or 14.0%, P = .031) and retained borderline significance (OR = 1.54, 95% CI = 0.93-2.56, P = .094) in multivariate analysis. Among the 129 patients who received a taxane-based regimen, pCR rate showed no differences in BRCA1 low, intermediate, and high mRNA level subgroups (19.6%, 26.8% and 21.4%, respectively; P = .71). BRCA2 mRNA level was not associated with pCR rate in the anthracyline-based treated subgroup (P = .60) or the taxane-based regimen subgroup (P = .82). Taken together, our findings suggested that BRCA1 mRNA expression could be used as a predictive marker in BRCA1/2 mutation-negative breast cancer patients who received neoadjuvant anthracycline-based treatment.

Identification and analysis of CHEK2 germline mutations in Chinese BRCA1/2-negative breast cancer patients.

PURPOSE: Cell-cycle-checkpoint kinase 2 (CHEK2) is an important moderate-penetrance breast cancer predisposition gene; however, recurrent CHEK2 mutations found in Caucasian women are very rare in Chinese population. We investigated the mutation spectrum and clinical relevance of CHEK2 germline mutations in Chinese breast cancer patients. METHODS: The entire coding regions and splicing sites of CHEK2 were screened in 7657 Chinese BRCA1/2-negative breast cancer patients, using 62-gene panel-based sequencing. RESULTS: Out of 7657 BRCA1/2-negative breast cancer patients, 26 (0.34%) carried CHEK2 pathogenic germline mutations. Most of these mutations (92.3%, 24/26) were nonsense or frameshift mutations; 84.6% (22/26) of them were in forkhead-associated (FHA) or kinase domains. Of the 18 types of CHEK2 mutations we found, 61.1% (11/18) of were novel mutations and two recurrent mutations (Y139X and R137X) were found in this cohort. Patients with CHEK2 mutations were significantly more likely to have family histories of breast and/or ovarian cancer (23.1% vs. 8.6%, p = 0.022) and family histories of any cancer (50.0% vs. 31.6%, p = 0.044); and were significantly more likely to have lymph node-positive (53.8% vs. 27.3%, p = 0.002) and progesterone receptor (PR)-positive (88.5% vs. 64.5%, p = 0.011) breast cancers. CONCLUSIONS: Among Chinese breast cancer patients, the CHEK2 germline mutation rate is approximately 0.34% and two specific mutations (Y139X and R137X) are recurrent. Patients with CHEK2 mutations are significantly more likely to have family histories of cancer, and to develop lymph node-positive and/or PR-positive breast cancers.

99mTc-rituximab as a tracer for sentinel lymph node biopsy in breast cancer patients: a single-center analysis.

PURPOSE: This study aimed to determine the long-term prognosis of breast cancer patients with 99mTc-rituximab for sentinel lymph node biopsy (SLNB). METHODS: A total of 2947 patients with negative sentinel lymph nodes (SLNs) omitting axillary lymph node dissection (ALND), treated between June 2005 and December 2013, were retrospectively analyzed. SLNB was performed prior to adjuvant therapy. RESULTS: After a median follow-up of 62 months, 22 cases of axillary recurrence (AR) were observed. The 5-year AR rate (ARR) was 0.7% [95% confidence interval (CI) 0.3-1.1%] and the 5-year relapse-free survival (RFS) was 95.2% (95% CI 94.4-96.0%). Multivariate analysis showed that abnormal axillary ultrasound with negative fine-needle aspiration (FNA) [hazard ratio (HR) 3.79, 95% CI 1.55-9.28; P = 0.004], not receiving radiotherapy (HR 4.38, 95% CI 1.47-13.05; P = 0.008), and age ≤ 40 years (HR 2.93, 95% CI 1.19-7.20; P = 0.020) were independent risk factors for AR. CONCLUSIONS: ARR of SLNB-negative patients with 99mTc-rituximab is low. Abnormal axillary ultrasound with negative FNA, not receiving radiotherapy, and age ≤ 40 years were prognostic factors for higher ARRs.

Low expression of RECQL is associated with poor prognosis in Chinese breast cancer patients.

BACKGROUND: RECQL is a number of the RecQ DNA helicase family and plays an important role in maintaining genome stability. Although several studies have reported that RECQL mutations were correlated with the susceptibility to breast cancer, the effect on prognosis in breast cancer was not yet clarified. Here, we explored the association between RECQL expression level and survival in patients with breast cancer. METHODS: In the first cohort, the RECQL mRNA expression level was evaluated in 774 primary breast cancer patients using a quantitative real-time PCR assay. Then, in the second independent cohort, the level of RECQL protein expression was detected in 322 patients with breast cancer using immunohistochemistry assay. Survival curves of patients with RECQL expression were compared using the Kaplan-Meier method with log-rank test. RESULTS: In the first cohort of 774 breast cancer patients, the low expression level of RECQL mRNA was significantly correlated with aggressive clinicopathological characteristics, including the positive lymph node status (P = 0.026), HER2 overexpression (P < 0.001), ER negative status (P = 0.047) and high tumor grade (P = 0.041). Moreover, the low expression level of RECQL mRNA was significantly associated with poor distant recurrence-free survival (DRFS, unadjusted hazard ratio (HR): 2.77, 95% confidence interval (CI): 1.88-4.09, P < 0.001) and disease-specific survival (DSS, unadjusted HR: 3.10, 95% CI: 1.84-5.20,P < 0.001), and it remained an independent unfavorable factor for DRFS and DSS (DRFS: adjusted HR: 3.04, 95% CI: 1.89-4.87, P < 0.001; DSS: adjusted HR: 4.25, 95% CI: 2.12-8.46, P < 0.001). In the second cohort of 322 breast cancer patients, low expression of RECQL protein was also subject to poor survival in breast cancer, and it was an independent prognosis factor of poor DRFS by multivariate analysis (DRFS: adjusted HR: 2.12, 95% CI: 1.16-3.88, P = 0.015). CONCLUSIONS: Breast cancer patients with low RECQL expression had a worse survival. The expression level of RECQL may be a potential prognosis factor for breast cancer.

A new model to predict risk of nonsentinel lymph node status in Chinese sentinel lymph node-positive patients after neoadjuvant chemotherapy.

There is no previous predictive model to assess risk of nonsentinel lymph node metastases (NSLN) in sentinel lymph node (SLN)-positive breast cancer patients after neoadjuvant chemotherapy (NAT). Our goal was to develop a new predictive model for SLN-positive patients after NAT, and validate this new model. A series of 513 patients with metastases in SLN who received NAT were used to evaluate factors affecting NSLN status. Logistic regression analysis was performed to develop a predictive model, which was validated by a subsequent prospective 138 patients. There were 115 (22.4%) patients with metastases in NSLN followed by axillary lymph node dissection (ALND). Multivariate analysis indicated that tumor (T) stage, number of positive SLN,micrometastases, extracapsular extension (ECE), and clinical response of primary tumor after NAT were significant independent predictors for the NSLN metastases. Area under the curve (AUC) of the model was 0.795 (95% CI, 0.734-0.861). When applied to the prospective series, the model accurately predicted the risk of NSLN disease, AUC was 0.772 (95% CI, 0.653-0.845). We present a new predictive model to assess the risk of NSLN status in Chinese SLN-positive breast cancer patients after NAT. The predictive model performed well in prospective validation but needs to be further studied in external center patients before application to clinical use.