Treatment of Hyperlipidemia With Alirocumab in a Liver Transplant Recipient With Poor Blood Lipid Control: Case Report.

The use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, such as alirocumab, to treat drug-resistant hypercholesterolemia is increasing; however, to date there have been no studies on the use of alirocumab to treat the hyperlipidemia that follows liver transplantation. Here we report a case of successful management of hyperlipidemia, albeit without total reversal of elevated serum triglycerides, with alirocumab monotherapy in a liver transplantation patient who was resistant to rosuvastatin and fenofibrate. In terms of safety, only transient palpitations following the first few alirocumab injections were recorded. This case illustrates that alirocumab can be a viable option for patients who experience poor lipid control after liver transplantation.

Postoperative blood glucose increase is associated with futile recanalization in patients with successful thrombectomy: a retrospective study.

BACKGROUND: Timely recognition of futile recanalization might enable a prompt response and an improved outcome in post-thrombectomy patients. This study aims to evaluate whether postoperative blood glucose increase (BGI) could act as an indicator of futile recanalization in patients receiving a successful thrombectomy. METHODS: This is a single-center, retrospective analysis of patients with anterior circulation large-vessel occlusion and successful thrombectomy between February 2019 and June 2022. BGI was defined as a higher level of blood glucose at the first postoperative morning than at admission. Futile recanalization was defined as patients with a modified Rankin Scale score of 3-6 at 90 days after onset. Multivariable binary logistic regression was used to assess the association of BGI with futile recanalization. RESULTS: A total of 276 patients were enrolled, amongst which 120 patients (43.5%) had BGI. Futile recanalization was more prevalent among patients with BGI compared to those without (70.0 vs. 49.4%, P = 0.001). After adjusting for potential confounders, BGI was associated with a higher likelihood of futile recanalization (adjusted OR: 2.97, 95%CI: 1.50-5.86, P = 0.002). This association was consistently observed regardless of diabetes history, occlusion site, time from symptom onset to groin puncture, or reperfusion status. CONCLUSION: Our findings support BGI serving as an indicator of futile recanalization in patients with anterior circulation large-vessel occlusion and successful thrombectomy.

Postoperative fibrinogen-to-albumin ratio acting as an indicator of futile recanalization in patients with successful thrombectomy.

BACKGROUND: Timely recognition of futile recanalization might enable a prompter response and thus improve outcomes in patients receiving successful thrombectomy. This study aims to evaluate whether postoperative fibrinogen-to-albumin ratio (FAR) could act as an indicator of futile recanalization. METHODS: This is a single-center, retrospective analysis of patients with acute anterior circulation large-vessel occlusion and successful thrombectomy between May 2019 and June 2022. FAR was defined as postoperative blood levels of fibrinogen divided by those of albumin, and dichotomized into high and low levels based on the Youden index. Futile recanalization was defined as patients achieving a successful recanalization with a modified Rankin Scale score of 3-6 at 90 days. Multivariable logistic regression was used to assess the association of FAR with futile recanalization. RESULTS: A total of 255 patients were enrolled, amongst which 87 patients (34.1%) had high postoperative FAR. Futile recanalization was more prevalent among patients with high FAR compared to those with low FAR (74.7% vs. 53.0%, p = .001). After adjusting for potential confounders, high postoperative FAR was found to independently correspond with the occurrence of futile recanalization (adjusted OR 2.40, 95%CI 1.18-4.87, p = .015). This association was consistently observed regardless of prior antithrombotic therapy, treatment of intravenous thrombolysis, occlusion site, time from symptom onset to groin puncture, and reperfusion status. CONCLUSION: Our findings support high postoperative FAR serving as an indicator of futile recanalization in patients with anterior circulation large-vessel occlusion and successful thrombectomy.

Impact of volemia at admission on the effect of collateral status on functional outcomes in patients undergoing endovascular thrombectomy.

BACKGROUND AND PURPOSE: Having good collaterals is associated with better clinical outcomes in patients undergoing endovascular thrombectomy. This study aims to evaluate whether the effect of collateral status on functional outcomes is modified by volemia at admission. METHODS: This is a single-center, retrospective analysis of patients who had acute proximal anterior circulation occlusion and underwent endovascular thrombectomy between January 2019 and June 2022. Volemia at admission, evaluated by blood urea nitrogen-to-creatinine ratio, was used to dichotomize patients into dehydrated and hydrated groups. The primary outcome was functional independence (90-day modified Rankin Scale score = 0-2). Secondary outcomes were the rates of successful reperfusion, 24-h symptomatic intracranial hemorrhage, and 90-day all-cause mortality. Multivariable logistic regression analysis was used to assess the interaction between collateral status and volemia at admission on outcomes. RESULTS: A total of 290 patients were enrolled, among whom having good collaterals was associated with functional independence (adjusted odds ratio [OR] = 2.71, 95% confidence interval [CI] = 1.41-5.22, p = 0.003). Having good collaterals benefited dehydrated patients (adjusted OR = 3.33, 95% CI = 1.45-7.63, p = 0.004) but not hydrated patients (adjusted OR = 2.21, 95% CI = 0.73-6.68, p = 0.161). However, an interaction between collaterals and volemia at admission on functional independence was not observed (p = 0.319). The rates of successful reperfusion, symptomatic intracerebral hemorrhage, and all-cause mortality were similar between those with good and poor collaterals in both dehydrated and hydrated patients. CONCLUSIONS: The effect of collateral status on the functional independence of patients undergoing thrombectomy is not modified by volemia at admission.

The effect of intravenous thrombolysis on patients with successful thrombectomy depends on final reperfusion grade: A retrospective study.

AIMS: Although intravenous thrombolysis (IVT) has not shown confirmative effects on the outcomes of patients receiving successful thrombectomy, it might influence the outcomes of a subset of these patients. This study aims to evaluate whether the effects of IVT depend on final reperfusion grade in patients with successful thrombectomy. METHODS: This is a single-center, retrospective analysis of patients with an acute anterior circulation large-vessel occlusion and a successful thrombectomy between January 2020 and June 2022. Final reperfusion grade was evaluated by the modified Thrombolysis in Cerebral Infarction (mTICI) score, which was dichotomized into incomplete (mTICI 2b) and complete (mTICI 3) reperfusion. The primary outcome was functional independence (90-day modified Rankin Scale score 0-2). Safety outcomes were 24-h symptomatic intracranial hemorrhage and 90-day all-cause mortality. Multivariable logistic regression analyses were used to assess the interactions between IVT treatment and final reperfusion grade on outcomes. RESULTS: When comparing all 167 patients enrolled in the study, IVT did not influence the extent of functional independence (adjusted OR: 1.38; 95% CI: 0.65-2.95; p = 0.397). The effect of IVT on functional independence depended on final reperfusion grade (p = 0.016). IVT benefited patients with incomplete reperfusion (adjusted OR: 3.70; 95% CI 1.21-11.30; p = 0.022), but not those with complete reperfusion (adjusted OR: 0.48, 95% CI: 0.14-1.59; p = 0.229). IVT was not associated with 24-h symptomatic intracerebral hemorrhage (p = 0.190) or 90-day all-cause mortality (p = 0.545). CONCLUSIONS: The effect of IVT on functional independence depended on final reperfusion grade in patients with successful thrombectomy. IVT appeared to benefit patients with incomplete reperfusion, but not those with complete reperfusion. Because reperfusion grade cannot be determined prior to endovascular treatment, this study argues against withholding IVT in IVT-eligible patients.

Impact of Sentinel Lymph Node Biopsy on Treatment Decision and Survival in Patients Aged ≥70 Years with Breast Cancer: A Retrospective Study.

Background: Whether sentinel lymph node biopsy should be performed in patients ≥70 years old with early-stage invasive breast cancer is controversial. We examined the effect of sentinel lymph node biopsy on the treatment and outcomes in this population. Materials and Methods: In this retrospective study, patients aged ≥70 years who were treated for invasive breast cancer with sentinel lymph node biopsy followed by mastectomy or lumpectomy between 2010 and 2019 were identified from our database. Patients were compared according to sentinel lymph node status. Outcomes were analyzed using the Kaplan-Meier method and Cox multivariate analysis. Results: Of the 376 patients enrolled in this study, 311 (82.7%) were sentinel lymph node-negative and 65 (17.3%) were sentinel lymph node-positive. The median follow-up duration for all patients was 70 months. Systemic treatment and radiation were similar between sentinel lymph node-negative and -positive groups. Disease-free survival, distant disease-free survival, breast cancer-specific survival, overall survival were not significantly different between groups (88.2% vs 87.6%, 96.7% vs 94.8%, 96.2% vs 93.6%, and 93.5% vs 90.0%, respectively). Sentinel lymph node status, tumor size, chemotherapy, endocrine therapy, and adjuvant radiation were included in Cox multivariate analysis. None of the variables were found to significantly affect disease-free survival, distant disease-free survival, breast cancer-specific survival, and overall survival. Conclusions: Our analysis indicated that sentinel lymph node status may not affect systemic treatment decisions or survival in patients aged ≥70 years with breast cancer.

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.

Comparison of Survival After Breast-Conserving Therapy vs Mastectomy Among Patients With or Without the BRCA1/2 Variant in a Large Series of Unselected Chinese Patients With Breast Cancer.

Importance: Whether patients with breast cancer who carry a BRCA1/2 variant can safely undergo breast-conserving therapy (BCT) remains controversial. Objective: To compare survival rates after BCT vs mastectomy in BRCA1/2 variant carriers and noncarriers in a large series of unselected patients with breast cancer. Design, Setting, and Participants: In this cohort study, a large consecutive series of 8396 unselected patients with primary breast cancer underwent either BCT, mastectomy with radiotherapy, or mastectomy alone from October 1, 2003, to May 31, 2015, at the Breast Center of Peking University Cancer Hospital in China. All patients were assessed for BRCA1/2 germline variant status. Statistical analysis was performed from May 1 to September 30, 2020. Main Outcomes and Measures: The primary outcomes were breast cancer-specific survival (BCSS) and overall survival (OS); secondary outcomes included recurrence-free survival, distant recurrence-free survival, and ipsilateral breast tumor recurrence. Results: Of these 8396 Chinese patients (8378 women [99.8% women]; mean [SD] age, 50.8 [11.4] years; 187 BRCA1 carriers, 304 BRCA2 carriers, and 7905 noncarriers), 3135 (37.3%) received BCT, 1511 (18.0%) received mastectomy with radiotherapy, and 3750 (44.7%) received mastectomy alone. After a median follow-up of 7.5 years (range, 0.3-16.6 years), both BRCA1 and BRCA2 variant carriers treated with BCT had similar rates of survival compared with those treated with mastectomy with radiotherapy (BCSS: hazard ratio [HR] for BRCA1, 0.58 [95% CI, 0.16-2.10]; P = .41; HR for BRCA2, 0.46 [95% CI, 0.15-1.41]; P = .17; OS: HR for BRCA1, 0.61 [95% CI, 0.18-2.12]; P = .44; HR for BRCA2, 0.72 [95% CI, 0.26-1.96]; P = .52) or mastectomy alone (BCSS: HR for BRCA1, 0.70 [95% CI, 0.22-2.20]; P = .54; HR for BRCA2, 0.59 [95% CI, 0.18-1.93]; P = .39; OS: HR for BRCA1, 0.77 [95% CI, 0.27-2.21]; P = .63; HR for BRCA2, 0.62 [95% CI, 0.22-1.73]; P = .37) after adjusting for clinicopathologic factors and adjuvant therapy. For noncarriers, patients receiving BCT had significantly better survival than those receiving mastectomy with radiotherapy (BCSS: HR, 0.45 [95% CI, 0.36-0.57]; P < .001; OS: HR, 0.46 [95% CI, 0.37-0.58]; P < .001) or mastectomy alone (BCSS: HR, 0.71 [95% CI, 0.57-0.89]; P = .003; OS: HR, 0.71 [95% CI, 0.58-0.87]; P < .001) in multivariable analyses. Conclusions and Relevance: This study suggests that BRCA1/2 variant carriers treated with BCT have survival rates at least comparable to those treated with mastectomy with radiotherapy or mastectomy alone and that BCT could be an option for BRCA1/2 variant carriers when the tumor is clinically appropriate for BCT.

Single-Cell RNA Sequencing Reveals the Cellular Origin and Evolution of Breast Cancer in BRCA1 Mutation Carriers.

The cell of origin and the development of breast cancer are not fully elucidated in BRCA1 mutation carriers, especially for estrogen receptor (ER)-positive breast cancers. Here, we performed single-cell RNA sequencing (RNA-seq) on 82,122 cells isolated from the breast cancer tissues and adjacent or prophylactic normal breast tissues from four BRCA1 mutation carriers and three noncarriers. Whole-exome sequencing was performed on breast tumors from the four BRCA1 mutation carriers; for validation, bulk RNA-seq was performed on adjacent normal breast tissues from eight additional BRCA1 mutation carriers and 14 noncarriers. Correlation analyses suggested that breast cancers in BRCA1 mutation carriers might originate from luminal cells. The aberrant luminal progenitor cells with impaired differentiation were significantly increased in normal breast tissues in BRCA1 mutation carriers compared with noncarriers. These observations were further validated by the bulk RNA-seq data from additional BRCA1 mutation carriers. These data suggest that the cell of origin of basal-like breast tumors (ERneg) in BRCA1 mutation carriers might be luminal progenitor cells. The expression of TP53 and BRCA1 was decreased in luminal progenitor cells from normal breast tissue in BRCA1 mutation carriers, which might trigger the basal/mesenchymal transition of luminal progenitors and might result in basal-like tumor development. Furthermore, ERhigh luminal tumors might originate from mature luminal cells. Our study provides in-depth evidence regarding the cells of origin of different breast cancer subtypes in BRCA1 mutation carriers. SIGNIFICANCE: Single-cell RNA-seq data indicate that basal-like breast cancer (ERneg) might originate from luminal progenitors, and ERhigh luminal breast cancer might originate from mature luminal cells in BRCA1 mutation carriers.

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.

Clinical phenotypes combined with saturation genome editing identifying the pathogenicity of BRCA1 variants of uncertain significance in breast cancer.

Characterizing the pathogenicity of BRCA1 variants of uncertain significance (VUSs) is a major bottleneck in clinical management of BRCA1-associated breast cancer. Saturation genome editing (SGE) was recently reported as an innovative laboratory-based approach to assess the pathogenicity of BRCA1 variants. We combined clinical phenotypes and SGE score to identify the pathogenicity of BRCA1 VUSs detected in a cohort of 8,085 breast cancer patients. According to SGE function score, 33 out of 144 BRCA1 VUSs detected were classified into "loss of function" (n = 13), "intermediate" (n = 2), and "functional" (n = 18) groups. Compared with non-carriers, "loss of function" VUS carriers (n = 19) presented significantly worse clinicopathological characteristics. These included younger age at breast cancer diagnosis (44.4 years vs. 51.2 years, P = 0.01), stronger family history of any cancer (57.9% vs. 32.3%, P = 0.017) especially breast or ovarian cancer (47.4% vs. 9.3%, P < 0.001), more bilateral breast cancer (31.6% vs. 3.4%, P < 0.001), and triple-negative breast cancer (47.4% vs. 12.8%, P < 0.001), which were comparable to those of pathogenic variant carriers. In contrast, the clinical phenotypes of "functional" VUS carriers were similar to those of non-carriers. These results indicated that SGE was a reliable method in BRCA1 variant classification. Combining SGE function score and the available evidence, twelve out of 33 BRCA1 VUSs were reclassified as pathogenic or likely pathogenic variants and one was benign.

Glycine Improves Ischemic Stroke Through miR-19a-3p/AMPK/GSK-3ß/HO-1 Pathway.

PURPOSE: To explore the molecular mechanism of glycine in improving ischemic stroke. PATIENTS AND METHODS: The serum samples of patients with ischemic stroke and healthy people were compared. The ischemic stroke model of PC12 cells was established by oxygen-glucose deprivation (OGD). qPCR quantified miR-19a-3p and AMPK mRNA, and protein expression was detected by Western blot. MTT was used to detect cell activity. Flow cytometry was used to detect cells. Glucose metabolism kit was used to detect glucose intake and formation amount of lactic acid. RESULTS: Compared with the control group, OGD group (OGDG) showed lower cell activity and increased cell apoptosis. TNF-α, IL-1ßI, L-6, Caspase 3, Caspase 9 and Bax were up-regulated, and Glut1, HK2, LDHA, PDK1, PKM2 and Bcl2 were down-regulated. At the same time, glucose intake, formation amount of lactic acid and cell apoptosis rate were reduced, and AMPK/GSK-3ß/HO-1 pathway activity was down-regulated. Glycine could counteract the above phenomena in OGDG. miR-19a-3p and AMPK decreased and increased, respectively, during glycine therapy. AMPK was the target gene of miR-19a-3p. Rescue experiments demonstrated that glycine improved cell apoptosis, inflammatory response and glucose metabolism disorder of ischemic stroke through miR-19a-3p/AMPK/GSK-3ß/HO-1 pathway. CONCLUSION: Glycine improves ischemic stroke through miR-19a-3p/AMPK/GSK-3ß/HO-1 pathway.

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.

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.

Co-mutation of TP53 and PIK3CA in residual disease after neoadjuvant chemotherapy is associated with poor survival in breast cancer.

PURPOSE: The prevalence and clinical relevance of TP53 and PIK3CA mutations in pretreatment breast cancer have been previously reported. However, little is known regarding these mutations in residual tumor tissues after neoadjuvant chemotherapy. Here, we investigated the association between TP53 and PIK3CA mutations in residual disease and survival of breast cancers. METHODS: TP53 and PIK3CA somatic mutations were examined in 353 post-neoadjuvant chemotherapy residual tumor tissues by Sanger sequencing. Survival curves of patients with TP53 and PIK3CA mutations were compared using the Kaplan-Meier method. RESULTS: Fifty-six (15.9%) of the 353 patients carried a TP53 somatic mutation and 79 patients (22.4%) carried a PIK3CA somatic mutation. A total of 18 patients carried co-mutation of TP53 and PIK3CA. Patients with somatic co-mutation were more likely to have high-grade tumors (35.3% vs. 10.6%, P = 0.010), estrogen receptor-negative tumors (55.6% vs. 26.7%, P = 0.009), progesterone receptor-negative tumors (61.1% vs. 30.5%, P = 0.008) and triple-negative tumors (35.3% vs. 13.3%, P = 0.025) compared with non-carriers. More importantly, co-mutation of TP53 and PIK3CA carriers had a significantly worse disease-free survival (DFS) and distant disease-free survival (DDFS) than non-carriers (5-year DFS: 58.0% vs. 83.2%, P < 0.001; 5-year DDFS: 70.3% vs. 86.4%, P = 0.024). Furthermore, in multivariate regression analysis, TP53 and PIK3CA co-mutation carriers showed a significantly worse DFS (adjusted hazard ratio = 3.70; 95% confidence interval, 1.79-7.63; P < 0.001). CONCLUSIONS: Patients with somatic co-mutation of TP53 and PIK3CA were associated with unfavorable survival compared with non-carriers. Co-mutation of TP53 and PIK3CA could be used as a potential prognosis marker in post-neoadjuvant chemotherapy breast cancer patients.