[Effect of axillary lymph node status on prognosis of different types of invasive breast cancer].

Objective: To investigate the effect of axillary lymph node status on the prognosis of different types of invasive breast cancer. Methods: Patients with invasive breast cancer of different molecular subtypes diagnosed in the breast cancer prevention and treatment center of Beijing Cancer Hospital from January 2000 to July 2011 were collected as a historical cohort, and the influence of lymph node status on the prognosis of different types of breast cancer was analyzed. Results: A total of 4 269 female breast cancer patients with molecular subtypes [aged (50.8±11.2) years] information and 3 824 female breast cancer patients with complete axillary lymph node status information [aged (50.5±10.9) years] were included in the study, including 3 135 cases with both molecular subtypes and lymph node status information. The 10-year event free survival (EFS) rates of hormone receptor (HR)+/human epidermal growth factor receptor-2(HER2)-, HR-/HER2-and HER2+were 82.2%, 79.0% and 76.8%, respectively; the 10-year overall survival (OS) rates were 88.1%, 83.1% and 84.4%, respectively, and the differences of 3 molecular subtypes in EFS and OS were statistically significant (both P<0.001). The 10-year EFS rate of lymph node positive and negative patients was 68.8% and 88.2%, respectively; the 10-year OS rate was 76.7% and 92.5%, respectively, and the differences of lymph node status in EFS and OS were statistically significant (both P<0.001). In lymph node negative subgroup, 3 subtypes showed similar EFS and OS rate (both P>0.05); In lymph node positive subgroup, 3 subtypes showed significantly different EFS and OS (both P<0.05). No modification effect was detected of lymph node status on the correlation of molecular subtypes and EFS, DDFS and OS(all Pinteractive>0.1). Conclusions: Different molecular subtypes of breast cancer have different prognosis. Compared with molecular subtype, lymph node status may be a more important prognostic factor.

Computed tomography reconstruction for evaluating response in axillary lymph nodes of breast cancer after neoadjuvant chemotherapy.

PURPOSE: To assess the performance of computed tomography (CT) reconstruction in evaluating the response in metastatic lymph nodes after neoadjuvant chemotherapy (NAC) in breast cancer patients. METHODS: Patients undergoing pre-NAC and post-NAC CT were identified from the Peking University Cancer Hospital database. Axillary Lymph nodes (ALNs) that shrunk to < 5 mm in short-axis diameter after NAC on CT reconstruction images were classified as clinical complete response. Evaluations of CT reconstruction on ALNs were correlated with residual nodal disease in the final pathology. Overall, 53 invasive breast cancer patients between October 2016 and March 2018 were eligible for our study. The median age was 48 (range 35-70) years. Most women presented with T2 tumors (35/53, 66.0%). RESULTS: After NAC, 20 (37.7%) patients without residual nodal disease were defined as pCR. Of 53 patients, 18 (33.9%) showed negative conversion of ALNs on CT reconstruction evaluation; axillary pCR was present in 16/18 (88.9%) patients. Among 35 patients with abnormal nodes on post-NAC CT reconstruction, 31 (88.6%) had axillary metastasis on the final pathology. The sensitivity and specificity of CT reconstruction in predicting node-negative status were 80.0% and 93.9%, respectively. The positive predictive value was 84.9% for lymph node pCR. The area under the receiver operating characteristic curve of each imaging modality was 0.870 (95% confidence interval 0.755-0.984). CONCLUSIONS: CT reconstruction was useful for evaluating ALNs response following NAC and may be used to predict axillary nodes' pCR with adequate accuracy.

[Long-term recurrence rate and survival in different aged patients with breast cancer undergoing breast conserving therapy].

Objective: To examine the difference of long-term recurrence rate and survivals between the young patients and the old patients undergoing breast conserving therapy (BCT). Methods: Women with primary invasive breast cancer receiving BCT between December 1999 and December 2014 were selected retrospectively from the database of Breast Cancer Center, Peking University Cancer Hospital & Institute. The median age of all patients was 47 years (range: 21 to 91 years). The cases were categorized according to age at diagnosis into two subgroups: the ≤40 years group and the>40 years group. A total of 2 778 patients were included: 677 patients in the ≤40 years group and 2 101 patients in the >40 years group. Clinicopathological characteristics between two groups were compared. The recurrence rate and survival were calculated using the Kaplan-Meier method. The differences of outcomes were compared in different aged groups using the Log-rank test. Factors affecting local recurrence, distant disease-free survival (DDFS), disease-free survival (DFS), and breast cancer-specific survival (BCSS) were assessed by multivariable Cox proportional hazard models. Results: Proportions of T1 (301/677 vs. 1 160/2 101, χ²=37.660, P<0.01), involved lymph node (314/677 vs. 713/2 101, χ²=34.966, P<0.01) hormone receptor-negative (490/677 vs. 1 581/2 101, χ²=6.981, P=0.030) and neoadjuvant chemotherapy (413/677 vs. 1 010/2 101, χ²=34.272,P<0.01)in the ≤40 years group were higher than that in the>40 years group. Median follow-up duration was 102 months. No significant difference in 10-year local recurrence was found between the two groups (2.5% vs. 1.6%, P=0.147). Ten-year DDFS rate in the ≤40 years group and in the>40 years group was 90.6% and 95.3%, respectively (P<0.01). Ten-year DFS rate in the ≤40 years group and in the>40 years group was 86.5% and 91.1%, respectively (P=0.001). Ten-year BCSS rate in the ≤40 years group and in the >40 years group was 91.0% and 93.7%, respectively (P=0.105). Age was not the prognosis factor of local recurrence. Lymph node status (positive vs. negative: HR=2.73, 95%CI: 1.94 to 3.84, P<0.01), age (≤40 years vs.>40 years: HR=1.73, 95%CI: 1.24 to 2.42, P=0.001) and T stage (>2 cm vs. ≤2 cm: HR=1.61, 95%CI: 1.14 to 2.28, P=0.001) were the prognosis factors of DDFS, and also for DFS. Hormone receptor status (positive vs. negative: HR=0.54, 95%CI: 0.39 to 0.74, P<0.01), lymph node status (positive vs. negative: HR=2.94, 95%CI: 2.12 to 4.07, P<0.01) and T stage (>2 cm vs. ≤2 cm: HR=1.45, 95%CI: 1.05 to 2.01, P=0.025) were the prognosis factors of BCSS. Conclusions: The risk of local recurrence was similar between ≤40 years patient and >40 years patients receiving breast conserving therapy. Worse survivals in the ≤40 years group were found comparing to those in the >40 years group.

[Safety and short-term efficacy analysis of breast-conserving surgery combined with intraoperative radiotherapy for early-stage breast cancer].

Objective: To analyze the safety and short-term efficacy of breast-conserving surgery combined with intraoperative radiotherapy for early-stage breast cancer. Methods: A total of 101 consecutive patients who received breast-conserving surgery plus intraoperative radiotherapy were recruited to summarize the recent follow-up results and clinicopathological data. Univariate analysis and Logistic regression model were used to evaluate the factors affecting the postoperative adverse reactions and cosmetic effects. Results: Among 101 patients, 4 patients had recurrence or metastasis. The 3-years disease free survival rate was 94.9%, and the 3-years cumulative recurrence rate was 5.1%. Univariate analysis showed that the menstrual status and postoperative whole breast radiotherapy were associated with the postoperative adverse reactions (P<0.05). The T stage and applicator diameter were associated with the cosmetic effect (P<0.05). Multivariate analysis indicated that the diameter of the applicator (OR=3.701, P=0.026) and postoperative whole breast radiotherapy (OR=5.962, P=0.005) were independent factors for the postoperative adverse reactions, and the diameter of the applicator (OR=2.522, P=0.037) was an independent factor for the cosmetic effect. Conclusion: Breast-conserving surgery combined with intraoperative radiotherapy shows safety and good short-term efficacy in low-risk early-stage breast cancer.

[Clinical analysis of 382 immediately breast reconstruction after mastectomy in Beijing City, Tianjin City and Hebei Province from 2012 to 2016].

Objective: To summarize the status of immediate breast reconstruction (IBR) after mastectomy in Beijing City, Tianjin City and Hebei Province. Methods: A retrospective analysis was made on the data of 382 cases with breast cancer who were treated and followed up successfully with immediate breast reconstruction after mastectomy from January 2012 to December 2016 in Beijing City, Tianjin City and Hebei Province. Clinic data of the followed-up 382 cases (all female, age (38.5±4.2) years (range: 24 to 70 years)), including general information, tumor information, sugery methods, and treatments after surgery were collected. The survival status, metastasis,complications and prognosis were followed up. Cosmetic effcet was evalated by Harris method, and life quality by Functional Assessment of Cancer Therapy-Breast scale (FACT-B). χ(2) test was used to compare the difference between year 2012 and year 2013 to 2016. Bonferroni method was used to correct the inspection level, which was 0.05/10=0.005. The trend of IBR rate (ratio of IBR to modified radical mastectomy) from 2013 to 2016 was analyzed by trend χ(2) test. Results: There was 46 cases in stage 0, 152 cases in stage Ⅰ, 165 cases in stage Ⅱ, 19 cases in stage Ⅲ. Twenty-five cases was treated by neoadjuvant chemotherapy, 231 by chemotherapy and 35 by radiotherapy. The proportion of implant reconstruction was 48.7% (186/382), more than expanded of 21.5% (82/382), with latissimus dorsi of 12.0% (46/382), TRAM of 8.9% (34/382), DIEP of 2.1% (8/382), and latissimus plus implant of 6.8% (26/382). According to the Harris standard, the excellent and good rate of the cosmetic effect of the reconstructed breast was 93.7%. The score of FACT-B was 108.20±16.9 (range: 67 to 144) 1 year postoperatively. Compared with 2012, the IBR rate was significant increased, till 2015, the IBR rate was 153/10 000 cases (χ(2)=47.028, P=0.000). Conclusions: There is a significant increase on IBR rate in Beijing City, Tianjin City and Hebei province by year. Most of cases received IBR is stage Ⅰ to Ⅱ. Implant reconstruction is the main reconstructive method. Postoperative cosmetic effects and quality of life are both meet patients' demon.

Delivery of drugs into brain tumors using multicomponent silica nanoparticles.

Glioblastomas are highly lethal cancers defined by resistance to conventional therapies and rapid recurrence. While new brain tumor cell-specific drugs are continuously becoming available, efficient drug delivery to brain tumors remains a limiting factor. We developed a multicomponent nanoparticle, consisting of an iron oxide core and a mesoporous silica shell that can effectively deliver drugs across the blood-brain barrier into glioma cells. When exposed to alternating low-power radiofrequency (RF) fields, the nanoparticle's mechanical tumbling releases the entrapped drug molecules from the pores of the silica shell. After directing the nanoparticle to target the near-perivascular regions and altered endothelium of the brain tumor via fibronectin-targeting ligands, rapid drug release from the nanoparticles is triggered by RF facilitating wide distribution of drug delivery across the blood-brain tumor interface.

Associations between RAD51D germline mutations and breast cancer risk and survival in BRCA1/2-negative breast cancers.

Background: RAD51D is involved in DNA double-strand break repair by homologous recombination and plays an important role in the maintenance of genomic stability. The associations between RAD51D germline mutations and breast cancer risk and survival are not fully elucidated. Patients and methods: RAD51D germline mutations were determined using a multigene panel in 7657 unselected breast cancer patients who were negative for BRCA1/2 germline mutations. The RAD51D recurrent mutation p.K91fs was screened in 7947 healthy controls by Sanger sequencing. Results: A total of 29 cases (0.38%) carried deleterious RAD51D germline mutations among this cohort of 7657 unselected breast cancer patients. The RAD51D recurrent mutation p.K91fs was identified in 18 cases (0.24%) of these 7657 patients. In contrast, the p.K91fs mutation was found in 8 of 7947 healthy controls with a frequency of 0.10%. The RAD51D p.K91fs mutation was significantly associated with increased breast cancer risk in unselected breast cancer [odds ratio = 2.34, 95% confidence interval (CI) 1.02-5.38; P = 0.040]. RAD51D mutation carriers were diagnosed at a younger age (P = 0.006) and were more likely to be triple-negative breast cancer (P = 0.003), estrogen receptor negative (P = 0.005) and high-grade cancers (P = 0.023) than noncarriers. Furthermore, RAD51D mutation carriers had a significantly worse recurrence-free survival [unadjusted hazard ratio (HR) = 3.00, 95% CI 1.56-5.80; P = 0.001] and distant recurrence-free survival (unadjusted HR = 2.54, 95% CI 1.14-5.67; P = 0.023) than noncarriers. Conclusion: The RAD51D recurrent mutation, p.K91fs, confers a moderately increased breast cancer risk, and RAD51D mutation carriers have an unfavorable survival compared with noncarriers.

Prevalence of BRCA1/2 large genomic rearrangements in Chinese women with sporadic triple-negative or familial breast cancer.

The prevalence of BRCA1/2 large genomic rearrangements (LGRs) and their underlying mechanisms have not been fully evaluated in Chinese women with breast cancer. In this study, we determined the prevalence of BRCA1/2 LGRs in 834 patients with familial breast cancer (FBC) and 660 patients with sporadic triple-negative breast cancer (TNBC) who were negative for BRCA1/2 small-range mutations using the multiplex ligation-dependent probe amplification method. We found that 20 index patients (2.4%) in the FBC group carried a BRCA1 or BRCA2 LGR, and the frequencies of BRCA1 and BRCA2 LGRs were 1.6% and 0.8%, respectively. Seven index patients (1.1%) carried a BRCA1 LGR in 660 sporadic TNBC patients, whereas no BRCA2 LGRs were found in these patients. Among the BRCA1/2 LGRs, 48.1% (13/27) were novel, and the breakpoints of the majority of the LGRs were identified. ΨBRCA1-mediated homologous recombination (HR) and Alu-mediated HR/non-homologous end-joining (NHEJ) accounted for 40% and 30% of the BRCA1 LGRs, respectively. Alu-mediated HR accounted for 71.4% of the BRCA2 LGRs, and the remaining one-third was generated through Long interspersed nuclear elements (LINE)-mediated NHEJ. Our findings suggest that both FBC patients and sporadic TNBC patients should be tested for BRCA1/2 LGRs.

[Application of decision curve on evaluation of MRI predictive model for early assessing pathological complete response to neoadjuvant therapy in breast cancer].

Objective: To construct a dynamic enhanced MR based predictive model for early assessing pathological complete response (pCR) to neoadjuvant therapy in breast cancer, and to evaluate the clinical benefit of the model by using decision curve. Methods: From December 2005 to December 2007, 170 patients with breast cancer treated with neoadjuvant therapy were identified and their MR images before neoadjuvant therapy and at the end of the first cycle of neoadjuvant therapy were collected. Logistic regression model was used to detect independent factors for predicting pCR and construct the predictive model accordingly, then receiver operating characteristic (ROC) curve and decision curve were used to evaluate the predictive model. Results: ΔArea(max) and Δslope(max) were independent predictive factors for pCR, OR=0.942 (95%CI: 0.918-0.967) and 0.961 (95%CI: 0.940-0.987), respectively. The area under ROC curve (AUC) for the constructed model was 0.886 (95%CI: 0.820-0.951). Decision curve showed that in the range of the threshold probability above 0.4, the predictive model presented increased net benefit as the threshold probability increased. Conclusions: The constructed predictive model for pCR is of potential clinical value, with an AUC>0.85. Meanwhile, decision curve analysis indicates the constructed predictive model has net benefit from 3 to 8 percent in the likely range of probability threshold from 80% to 90%.

[Impact of adjuvant chemotherapy on the prognosis of hormone receptor negative breast cancer with residual lymph node disease after neoadjuvant chemotherapy].

Objective: To explore the influence of adjuvant chemotherapy on the prognosis of hormone receptor negative breast cancer with residual lymph node disease(RLND)after neoadjuvant chemotherapy. Methods: A total of 110 hormone receptor negative breast cancer patients treated with 4-8 cycles of neoadjuvant chemotherapy were respectively analysed between 2002 and 2012. Residual lymph node disease was comfirmed by subsequent radical mastectomy. Then all these patients were classified into two groups: patients treated with adjuvant chemotherapy(group A) and patients untreated with adjuvant chemotherapy(group B). Results: All patients were female, the median age was 54.5 years old(IQR: 47-59 years). The median follow-up time was 61 months(IQR: 51-88 months). There were 82 patients (74.5%) in group A, and 28 patients (25.5%) in group B. The five-year disease-free survival (DFS) rate was 76.2% in group A and 57.6% in group B. The distant disease-free survival (DDFS) rate was 78.9% in group A and 60.4% in group B. Overall survival (OS) rate was 81.0% in group A and 60.0% in group B. Multivariate analysis showed that there were significant differences for DDFS rate (group A vs group B, P=0.033; hazard ratio [HR], 5.256; 95% confidence interval [95%CI], 1.14-24.17) and OS rates (group A vs group B, P=0.011; HR, 7.478; 95%CI, 1.58-35.30) between two groups. Conclusion: The patients who have hormone receptor negative breast cancer with RLND after neoadjuvant chemotherapy, may benefit from postoperative adjuvant chemotherapy.

[Breast-conserving surgery with immediate partial breast reconstruction using pedicled thoracodorsal artery perforator flap: a clinical analysis of 33 patients].

Objective: To explore the application value of pedicled thoracodorsal artery perforator flap in immediate partial breast reconstruction for breast cancer. Methods: This study is a prospective case series studies. Totally 128 cases of primary breast cancer patients who prepared to receive the breast-conserving surgery combine with immediate partial breast reconstruction of pedicled thoracodorsalartery perforator flap were enrolled in Breast Cancer Prevention and Treatment Center of Peking University Cancer Hospital from June 2013 to March 2016. Finally, the operations had been completed successfully in 33 eligible cases. All patients were female with a median age of 40 years (ranging from 22 to 52 years). The perforator vessel location, the donor area design, the post-operative complications, the influence of radiation and chemotherapy had been evaluated. Results: The average diameter of thoracic dorsal artery perforators measured by Doppler ultrasound before the operation was (1.5±0.4) mm (ranging from 0.6 to 2.7 mm). The average size of flaps was 15 cm×6 cm. The average time of operations was (271±72) minutes (ranging from 120 to 245 minutes). Drainage tube removed on (4.7±2.1) days after operation (ranging from 3 to 12 days). All patients received follow-up, and there was no local recurrence and distant metastasis during a median follow-up of 17(12) months (M(Q(R))) (ranging from 5 to 38 months). All TDAP flaps were survival, the wound complication rates was 6% (2/33). Conclusions: The breast reconstruction of pedicled thoracodorsal artery perforator flap is a good choice of repairing local breast defect of breast conserving surgery.Its advantages are no-influence of latissimus dorsi function and little complications in donor area.

[Impact of the response of primary tumor to preoperative chemotherapy and anti-HER2 therapy on survival of HER2-positive breast cancer patients].

OBJECTIVE: To study the impact of anti-HER2 therapy and response of primary tumor on distant disease free survival (DDFS) of the patients with HER2-positive breast cancer. METHODS: The clinical data of the patients with HER2-positive breast cancer treated with neoadjuvant systemic therapy were analyzed retrospectively. RESULTS: Patients treated with preoperative anti-HER2 therapy and chemotherapy had a significant improved pathological complete response (pCR) rate (48.4%) compared with those treated with preoperative chemotherapy (17.2%) (P=0.000). The median follow-up period was 62(6-160) months. The 5-year DDFS in patients with anti-HER2 therapy and patients without anti-HER2 therapy was 93.5% and 83.3% respectively (P=0.006). The 5-year DDFS in patients achieving a pCR and patients not achieving a pCR was 94.7% and 82.6% respectively(P=0.001). Among patients achieving a pCR, anti-HER2 therapy did not improve DDFS significantly (P=0.960). Benefits of anti-HER2 therapy in DDFS among patients without a pCR achieved statistical significance (P=0.028). CONCLUSIONS: Combination of neoadjuvant anti-HER2 therapy and chemotherapy resulted in a higher pCR rate in HER2-overexpressing primary breast cancer. Patients treated with neoadjuvant systemic therapy who achieved a pCR have excellent outcome regardless of whether they received anti-HER2 therapy.

[Relationship of clinicopathological features and chemotherapeutic outcomes in women with BRCA1 and BRCA2 mutation-negative familial breast cancer].

OBJECTIVE: To explore the relationship of clinicopathological features and response to neoadjuvant chemotherapy in women with BRCA1 and BRCA2 mutation-negative familial breast cancer. METHODS: A total of 6 200 women with breast cancer were treated at our hospital from October 2003 to December 2012. All subjects underwent genetic testing for BRCA1 and BRCA2 genes. Patients with BRCA1 and BRCA2 mutations were excluded. This cohort of 5 842 patients with BRCA1 and BRCA2 mutation-negative breast cancer was classified as two groups: familial breast cancer patients (n=480) and sporadic breast cancer patients (n=5 362). The clinicalpathological data and response to neoadjuvant chemotherapy of the 480 patients with BRCA1 and BRCA2 mutation-negative familial breast cancer and the 5 362 patients with BRCA1 and BRCA2 mutation-negative sporadic breast cancer were compared retrospectively. Then the influencing factors of response to neoadjuvant chemotherapy were analyzed. RESULTS: Among the BRCA1 and BRCA2 mutation-negative breast cancer patients, 4.4% of the patients were diagnosed before 30 years of age in the familial breast cancer group, significantly higher than that of 2.6% in the sporadic breast cancer group(P=0.020). 5.0% of the patients in the familial breast cancer group had bilateral breast cancer, significantly higher than that of 2.7% in the sporadic breast cancer group (P=0.004). Compared with BRCA1 and BRCA2 mutation-negative sporadic breast cancer patients, the relative risk of early-onset breast cancer (≤ 30 years) and bilateral breast cancer were 1.73 and 1.91, respectively, significantly higher than that in the BRCA1 and BRCA2 mutation-negative familial breast cancer cases (P=0.020 and P=0.004). 2 964 patients in this cohort of 5 842 case sreceived neoadjuvant chemotherapy.The pathologic complete response (pCR) rate was significantly higher in the BRCA1 and BRCA2 mutation-negative familial breast cancer group than in the BRCA1 and BRCA2 mutation-negative sporadic breast cancer group (21.7% vs. 14.0%, P=0.001). Independent factors associated with pCR in BRCA1 and BRCA2 mutation-negative breast cancer patients were tumor size less than 2 cm (P=0.012), histologic grade Ⅲ (P<0.001), triple-negative breast cancers (P<0.001), and BRCA1 and BRCA2 mutation-negative familial breast cancer(P=0.001). CONCLUSIONS: Compared with BRCA1 and BRCA2 mutation-negative sporadic breast cancer, BRCA1 and BRCA2 mutation-negative familial breast cancer is more likely diagnosed before the age of 30 years and has a higher risk to develop bilateral breast cancer. BRCA1 and BRCA2 mutation-negative familial breast cancers are more likely to respond to neoadjuvant chemotherapy than BRCA1 and BRCA2 mutation-negative sporadic breast cancer.

Prevalence of BRCA1 mutations and responses to neoadjuvant chemotherapy among BRCA1 carriers and non-carriers with triple-negative breast cancer.

BACKGROUND: The frequency of BRCA1 germline mutations among Chinese women with triple-negative breast cancer is unclear, and the association between BRCA1 mutations and the response to neoadjuvant chemotherapy in women with triple-negative breast cancer has not been determined. PATIENTS AND METHODS: Nine hundred and fifty-six triple-negative breast cancer patients were treated at our institute between 2003 and 2012; we tested the BRCA1/2 mutations for 956 patients and 953 patients in this cohort, respectively. Among the 956 patients, 652 patients received neoadjuvant chemotherapy. RESULTS: In this cohort, 7.1% (68/956) and 2.3% (22/953) of patients carried a BRCA1 or BRCA2 mutation, respectively. The BRCA1/2 mutation rates were 10.5% and 3.0% among the patients who were diagnosed at or before the age of 50 in this cohort, respectively. The pCR (pathologic complete response) rate was 31.6% in the 652 patients who received neoadjuvant chemotherapy. BRCA1 carriers had a significantly higher pCR rate than non-carriers (BRCA1 carriers versus non-carriers, 53.8% versus 29.7%, P < 0.001). Among women treated with anthracycline with or without taxane regimens, the pCR rate was 57.1% for BRCA1 carriers, 29.0% for non-carriers (P < 0.001); among women treated with taxane regimens, the pCR rate was 40.0% for BRCA1 carriers, 32.9% for non-carriers (P = 0.73). At a median follow-up of 43 months, the recurrence-free survival was similar between BRCA1 carriers and non-carriers among the 947 patients of this study (adjusted hazard ratio = 0.92; 95% confidence interval: 0.45-1.90; P = 0.82). CONCLUSIONS: Chinese women with triple-negative breast cancer who are diagnosed at or before age of 50 are candidates for BRCA1 genetic testing. Among triple-negative breast cancer patients, BRCA1 carriers are more likely to respond to neoadjuvant anthracycline-based regimens than are non-carriers.

Association between the HER2 Ile655Val polymorphism and response to trastuzumab in women with operable primary breast cancer.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) Ile655Val polymorphism may affect the efficacy of trastuzumab treatment of breast cancer. PATIENTS AND METHODS: HER2 Ile655Val polymorphism was determined in 4167 patients with primary breast cancer using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. We investigated the associations between the HER2 Ile655Val polymorphism and clinical outcomes in women with HER2-negative breast cancer and with HER2-positive breast cancer who received trastuzumab or who did not. RESULTS: At a median follow-up of 44 months, HER2 Ile655Val polymorphism was not significantly associated with survival either in the entire study population of 4167 patients or in 2976 HER2-negative breast cancer patients. Among 816 HER2-positive patients who received adjuvant chemotherapy and/or endocrine therapy without trastuzumab treatment, patients with the Val/Ile or the Val/Val genotype had a significantly worse disease-free survival (DFS) and distant DFS (DDFS) than those with the Ile/Ile genotype (DFS, adjusted hazard ratio [HR] 1.5; 95% confidence interval [CI] 1.0-2.3; P = 0.037; DDFS, adjusted HR 1.9; 95% CI 1.2-2.9 P = 0.005). In contrast, among 212 HER2-positive patients who received chemotherapy in combination with trastuzumab treatment, patients with the Val/Ile or the Val/Val genotype had a significantly better DFS and DDFS than those with the Ile/Ile genotype (5-year DFS, 100% versus 83%; P = 0.008; 5-year DDFS, 100% versus 89%; P = 0.031). CONCLUSIONS: HER2 Ile655Val polymorphism affects the function of HER2 gene only restricted in HER2-positive breast cancers. HER2-positive breast cancer patients with the Val variant have an aggressive phenotype, but are sensitive to trastuzumab treatment.

Promoter methylation of BRCA1 in triple-negative breast cancer predicts sensitivity to adjuvant chemotherapy.

BACKGROUND: BRCA1 function is inactivated through BRCA1 promoter methylation in a substantial number of triple-negative breast cancers. We investigated the impact of BRCA1-methylation status on the efficacy of adjuvant chemotherapy in patients with triple-negative breast cancer or with non-triple-negative breast cancer. METHODS: BRCA1 promoter methylation was assessed in 1163 unselected breast cancer patients. Methylation was evaluated using a methylation-specific PCR (MSP) assay. RESULTS: In the subgroup of 167 triple-negative breast cancer patients who received adjuvant chemotherapy, patients with BRCA1-methylated tumors had a superior 10-year disease-free survival (DFS)(78% versus 55%, P = 0.009) and 10-year disease-specific survival (DSS) (85% versus 69%, P = 0.024) than those with BRCA1-unmethylated tumors, and BRCA1 methylation was an independent favorable predictor of DFS and DSS in a multivariate analysis in this subgroup [DFS: hazard ratio (HR) = 0.45; 95% confidence interval (CI) 0.24-0.84; P = 0.019; DSS: HR = 0.43; 95% CI = 0.19-0.95; P = 0.044]. In contrast, in 675 non-triple-negative breast cancer patients who received adjuvant chemotherapy, BRCA1 methylation was an unfavorable predictor of DFS and DSS in univariate analysis (DFS: HR = 1.56; 95% CI 1.16-2.12; P = 0.003; DSS: HR = 1.53; 95% CI = 1.05-2.21; P = 0.026). CONCLUSIONS: Triple-negative breast cancer patients with BRCA1-methylated tumors are sensitive to adjuvant chemotherapy and have a favorable survival compared with patients with BRCA1-unmethylated triple-negative tumors.

HER2 and response to anthracycline-based neoadjuvant chemotherapy in breast cancer.

BACKGROUND: The predictive role of human epidermal growth factor receptor 2 (HER2) to adjuvant anthracycline-based chemotherapy remains controversial. Here, we investigated the association between HER2 status and pathological response in breast cancer patients who received neoadjuvant anthracycline-based regimens. PATIENTS AND METHODS: Women (n = 538) with operable primary breast cancer received neoadjuvant anthracycline-based chemotherapy. Pathological complete response (pCR) was defined as no invasive breast tumor cells in breast after completion of neoadjuvant chemotherapy. HER2 status was determined by immunohistochemistry and/or by fluorescence in situ hybridization in core biopsy breast cancer tissue obtained before initiation of neoadjuvant chemotherapy. RESULTS: In this cohort of 538 patients, 23.9% of patients achieved a pCR in their breast. HER2-positive tumors had a lower rate of pCR than did HER2-negative tumors (14.7% versus 25.7%, P = 0.013); negative HER2 status remained as an independent favorable predictor of pCR after adjusted for age, estrogen receptor, progesterone receptor, tumor size, chemotherapy cycles, and tumor grade in a multivariate analysis (odds ratio = 3.14; 95% confidence interval = 1.60-6.16, P = 0.001). Furthermore, patients with a pCR had a higher 3-year disease-free survival (DFS) rate than did patients without a pCR (P = 0.007). CONCLUSION: Women with HER2-negative breast cancers rather than HER2-positive tumors benefit from anthracycline-based neoadjuvant chemotherapy.

Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment.

BACKGROUND: Human cytochrome P450 2D6 (CYP2D6) genotype may affect the efficacy of tamoxifen treatment in Caucasian women with breast cancer. The most common polymorphism of CYP2D6 in Chinese women is variant 10 (188 C to T). PATIENTS AND METHODS: Tamoxifen and 4-hydroxytamoxifen (4OHtam) were measured in the serum of 37 women with breast cancer who were receiving tamoxifen treatment. The association between CYP2D6 *10 genotype and survival was determined in a cohort of 293 women with breast cancer who received tamoxifen (n = 152) or who did not (n = 141). RESULTS: The serum 4OHtam concentrations were significantly lower in women with the CYP2D6 *10 homozygous variant T/T genotype than in those with the homozygous wild-type C/C genotype (P = 0.04). Among tamoxifen-treated women, women with the T/T genotype had a significantly worse disease-free survival (DFS) than those with the C/C or C/T genotype, and the T/T genotype remained an independent prognostic factor of DFS in multivariate analysis (hazard ratio = 4.7; 95% confidence interval = 1.1-20.0; P = 0.04). Among women who did not receive tamoxifen, there was no significant association between CYP2D6 *10 genotype and survival. CONCLUSION: In tamoxifen-treated patients, women with the CYP2D6 *10 T/T genotype have a lower 4OHtam level in the serum and a worse clinical outcome.

Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway.

More than half of anaplastic large-cell lymphomas (ALCLs) have a chromosomal translocation t(2;5) that leads to the expression of a hybrid protein composed of the nucleolar phosphoprotein nucleophosmin (NPM) and the anaplastic lymphoma kinase (ALK) that exhibits an unregulated tyrosine kinase activity. We have previously identified PLC-gamma as a crucial downstream signaling molecule of NPM-ALK that contributes to its mitogenic potential. Here, we show that NPM-ALK recruits the C-terminal SH2 domain of the phosphatidylinositol 3-kinase (PI 3kinase) p85 subunit. PI 3-kinase assays revealed that the kinase is activated by NPM-ALK in vivo, in turn activating PKB/Akt in NPM-ALK-expressing cells. The use of 2 specific PI 3-kinase inhibitors, wortmannin and LY294002, demonstrated the requirement of PI 3-kinase for the growth of NPM-ALK-transformed cell lines, as well as a cell line established from a patient with ALCL. Primary murine bone marrow retrovirally transduced with NPM-ALK showed a transformed phenotype that was reversible on treatment with PI 3-kinase inhibitors. Flow cytometric analysis revealed that wortmannin-treated NPM-ALK-transformed cell lines underwent apoptosis. Furthermore, apoptosis induced by overexpression of the proapoptotic molecule Bad could be partially blocked by the overexpression of NPM-ALK. Thus, NPM-ALK activates the antiapoptotic PI 3-kinase/Akt pathway, which likely contributes to the molecular pathogenesis of ALCL. (Blood. 2000;96:4319-4327)

[Orbital fat preservation and orbicularis muscle flap suspension for lower eyelid pouches].

OBJECTIVE: This is to introduce the experience in the treatment of lower eyelid pouches by orbital fat preservation and orbicularis oculi muscle flap suspension techniques. METHODS: From Sept. 1996 to May 1997, thirty patients with lower eyelid pouches were treated using Hamra's procedure. During the operation, the arcus marginalis was incised. The orbital fat was released and advanced beyond the infraorbital rim and sutured. A lateral-based orbicularis oculi muscle flap was created, and its pedicle was repositioned to the periosteum of the upper lateral orbital rim in a superiomedial direction. RESULTS: A total of 26 patients were available for postoperative follow-up for 3 to 8 months (mean 5.6 months). Of them one patient developed unilateral lower eyelid ectropion due to flabby reposition of the orbicularis oculi muscle flap. The rest obtained excellent cosmetic results without complications. CONCLUSION: This new method has following advantages: 1. The lower eyelid pouches and the infraorbital rim show that may be corrected simultaneously: 2. Sunken eyelids and scleral show that may follow fat removal in conventional lower blepharoplasty can be effectively avoided. 3. "Cheek lift" and a youthful eyelid-cheek complex contour can be obtained.