Late effects of adjuvant chemotherapy on cognitive function: a follow-up study in breast cancer patients.

BACKGROUND: Neuropsychological examinations have shown an elevated risk for cognitive impairment 2 years after therapy in breast cancer patients randomized to receive adjuvant high-dose cyclophosphamide, thiotepa, carboplatin (CTC) chemotherapy compared with a non-treated control group of stage I breast cancer patients. Patients randomized to receive standard-dose fluorouracil, epirubicin, cyclophosphamide (FEC) chemotherapy showed no elevated risk compared with controls. However, breast cancer patients treated with conventional cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy showed a higher risk of cognitive impairment. The present study was designed to obtain a greater insight into these long-term neuropsychological sequelae following chemotherapy and their course in time. PATIENTS AND METHODS: At 4 years post-therapy, 22 of the original 34 CTC patients, 23 of 36 FEC patients, 31 of 39 CMF patients and 27 of 34 control patients were re-examined with neuropsychological tests. RESULTS: Improvement in performance was observed in all chemotherapy groups, whereas in the control group there was a slight deterioration in test results. A differential attrition was observed among the groups, with a relatively high percentage of initially cognitively impaired patients from the CTC group dropping out due to factors related to disease progression. CONCLUSIONS: The results suggest that cognitive dysfunction following adjuvant chemotherapy in breast cancer patients may be transient. Additional studies are needed to investigate the differential attrition of patients with cognitive impairment.     

Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer

This comparative phase III trial of mitoxantrone+vinorelbine (MV) versus 5-fluorouracil+cyclophosphamide+either doxorubicin or epirubicin (FAC/FEC) in the treatment of metastatic breast cancer was conducted to determine whether MV would produce equivalent efficacy, while resulting in an improved tolerance in relation to alopecia and nausea/vomiting. This multicentre study recruited and randomised 281 patients with metastatic breast cancer; 280 were evaluable for response survival and toxicity (138 received FAC/FEC, 142 received MV). Patient characteristics were matched in each arm and stratification for prior exposure to adjuvant therapy was made prospectively. The overall response rate (ORR) was equivalent in the two arms (33.3% for FAC/FEC versus 34.5% for MV), but MV was more effective in patients who had received prior adjuvant therapy (13% (95% confidence interval (CI) 3-23) for FAC/FEC versus 33% (95% CI 20-47) for MV P=0.025) with a better progression-free survival (PFS) (5 months (range 1-18 months) versus 8 months (range 1-27 months); P=0.0007 for FAC/FEC versus MV, respectively) while FAC/FEC was more effective in previously untreated patients (ORR 43% (95% CI 33-53) versus 35% (95% CI 25-45), P=0.26; PFS 9 months (range 0-29 months) versus 6 months (range 0-26 months) P=0.014). Toxicity was monitored through the initial six cycles of therapy; febrile neutropenia and delayed haematological recovery was more frequent for MV (P=0.001), while nausea/vomiting of grades 3-4 was greater for FAC/FEC (P=0.031), as was alopecia (P=0.0001), cardiotoxicity was the same for the two regimens. MV represents a chemotherapy combination with equivalent efficacy to standard FAC/FEC and improved results for patients who have previously received adjuvant chemotherapy. Toxicity must be balanced to allow for increased haematological suppression and risk of febrile neutropenia with MV compared with a higher risk of subjectively unpleasant side-effects such as nausea/vomiting and alopecia with FAC/FEC.     

Long-term follow-up of the SBG 9401 study comparing tailored FEC-based therapy versus marrow-supported high-dose therapy.

BACKGROUND: The purpose was to investigate adjuvant marrow-supportive high-dose chemotherapy compared with an equitoxicity-tailored comparator arm. PATIENTS AND METHODS: Five hundred and twenty-five women below the age of 60 years with operated high-risk primary breast cancer were randomised to nine cycles of granulocyte colony-stimulating factor supported and individually tailored FEC (5-fluorouracil, epirubicin, cyclophosphamide), (n = 251) or standard FEC followed by marrow-supported high-dose therapy with CTCb (cyclophosphamide, thiotepa, carboplatin) therapy (n = 274), followed by locoregional radiotherapy and tamoxifen for 5 years. RESULTS: There were 104 breast cancer relapses in the tailored FEC group versus 139 in the CTCb group (double triangular method by Whitehead, P = 0.046), with a median follow-up of all included patients of 60.8 months. The event-free survival demonstrated 121 and 150 events in the tailored FEC- and CTCb group, respectively [P = 0.074, hazard ratio (HR) 0.804, 95% confidence interval (CI) 0.633-1.022]. Ten patients in the tailored FEC regimen developed acute myeloid leukaemia (AML)/myelodysplasia (MDS). One hundred deaths occurred in the tailored FEC group and 121 in the CTCb group (P = 0.287, HR 0.866, 95% CI 0.665-1.129). CONCLUSION: The update of this study shows an improved outcome linked to the tailored FEC treatment in relation to breast cancer relapse, but also an increased incidence of AML/MDS.     

Six-month follow-up of patient-rated outcomes in a randomized controlled trial of exercise training during breast cancer chemotherapy.

BACKGROUND: Few exercise trials in cancer patients have reported longer-term follow-up. Here, we report a 6-month follow-up of exercise behavior and patient-rated outcomes from an exercise trial in breast cancer patients. METHODS: Breast cancer patients initiating adjuvant chemotherapy (n = 242) were randomly assigned to usual care (n = 82), resistance exercise training (RET; n = 82), or aerobic exercise training (AET; n = 78) for the duration of their chemotherapy. At 6-month follow-up, participants were mailed a questionnaire that assessed quality of life, self-esteem, fatigue, anxiety, depression, and exercise behavior. RESULTS: Two hundred one (83.1%) participants provided 6-month follow-up data. Adjusted linear mixed-model analyses showed that, at 6-month follow-up, the RET group reported higher self-esteem [adjusted mean difference, 1.6; 95% confidence interval (95% CI), 0.1-3.2; P = 0.032] and the AET group reported lower anxiety (adjusted mean difference, -4.7; 95% CI, -0.0 to -9.3; P = 0.049) compared with the usual care group. Moreover, compared with participants reporting no regular exercise during the follow-up period, those reporting regular aerobic and resistance exercise also reported better patient-rated outcomes, including quality of life (adjusted mean difference, 9.5; 95% CI, 1.2-17.8; P = 0.025). CONCLUSIONS: Improvements in self-esteem observed with RET during breast cancer chemotherapy were maintained at 6-month follow-up whereas reductions in anxiety not observed with AET during breast cancer chemotherapy emerged at 6-month follow-up. Moreover, adopting a combined aerobic and resistance exercise program after breast cancer chemotherapy was associated with further improvements in patient-rated outcomes. Exercise training during breast cancer chemotherapy may result in some longer-term and late effects for selected patient-rated outcomes.     

Phase II multicentre randomised study of docetaxel plus epirubicin vs 5-fluorouracil plus epirubicin and cyclophosphamide in metastatic breast cancer

The purpose of the study was to evaluate the efficacy and safety of docetaxel plus epirubicin (ET) and of 5-fluorouracil plus epirubicin and cyclophosphamide (FEC) as first-line chemotherapy for metastatic breast cancer. A total of 142 patients (intent-to-treat (ITT)) with at least one measurable lesion were randomised to receive docetaxel 75 mg m(-2) plus epirubicin 75 mg m(-2) or 5-fluorouracil 500 mg m(-2) plus epirubicin 75 mg m(-2) and cyclophosphamide 500 mg m(-2) intravenously once every 3 weeks for up to eight cycles. Prophylactic granulocyte-colony-stimulating factor was only permitted after the first cycle, if required. Per-protocol analysis (n=132) gave an overall response rate for ET of 63.1% (95% confidence interval (CI), 50-78%) and for FEC 34.3% (95% CI, 23-47%) after a median seven and six cycles, respectively. Intent-to-treat population (n=142) gave an overall response rate for ET of 59% (95% CI, 47-70%) and for FEC 32% (95% CI, 21-43%) after a median seven and six cycles, respectively. The median response duration for ET was 8.6 months (95% CI, 7.2-9.6 months) and for FEC 7.8 months (95% CI, 6.5-10.4 months). The median time to progression (ITT) for ET was 7.8 months (95% CI, 5.8-9.6 months) and for FEC 5.9 months (95% CI, 4.6-7.8 months). After a median follow-up of 23.8 months, median survival (ITT) for ET and FEC were 34 and 28 months, respectively. Nonhaematologic grade 3-4 toxicities were infrequent in both arms. Haematologic toxicity was more common with ET and febrile neutropenia was reported in 13 patients (18.6%) in the ET group. Two deaths in the ET group were possibly related to study treatment. In conclusion, both ET and FEC were associated with acceptable toxicity. ET is a highly active first-line therapy for metastatic breast cancer.     

A randomised trial of goserelin versus control after adjuvant, risk-adapted chemotherapy in premenopausal patients with primary breast cancer - GABG-IV B-93

GABG-IV B-93 is a prospective, randomised study comparing goserelin (n=384) with no further treatment (n=392) in hormone receptor (HR)-negative breast cancer patients (n=465) after 3 cycles cyclophosphamide, methotrexate, 5-fluorouracil (CMF) for patients with 0-3 positive lymph nodes (LN) or 4 cycles epirubicin, cyclophosphamide (EC) followed by 3 cycles CMF for patients with 4-9 positive LN. After completion of the ZEBRA trial the study was amended to enrol also HR-positive patients with 1-9+LN (n=311). After a median follow-up of 4.7 years neither HR-negative nor HR-positive patients showed a benefit for goserelin. The adjusted estimated hazard ratio for event-free survival in HR-negative patients was 1.01 (goserelin versus control, 95% confidence interval [CI] 0.72-1.42, P=0.97) and 0.77 in HR-positive patients (95% CI 0.47-1.24, P=0.27). These results do not support the general use of goserelin after adjuvant chemotherapy in this group of premenopausal patients.     

Serum concentrations of estrogens, sex hormone-binding globulin, and androgens and risk of breast cancer in postmenopausal women

We assessed the relationship between serum concentrations of estrogens, androgens, and sex hormone-binding globulin and risk of breast cancer among postmenopausal women. Study participants provided serum prior to breast biopsy or mastectomy in 3 hospitals in Grand Rapids, Michigan between 1977 and 1987. A total of 179 subjects with localized breast cancer were compared to 152 subjects with nonproliferative breast changes that have not been associated with elevated breast cancer risk. Increasing serum concentrations of estrone and estrone sulfate were associated with increases in breast cancer risk; the odds ratios (ORs) in the fourth quartiles compared to the first were 2.3 (95% confidence interval (CI) 1.1-4.6) for both (p-trend = 0.02 and 0.03, respectively). Estradiol and bioavailable estradiol concentrations were associated with nonstatistically significant increases in risk. Androstenediol levels were associated with risk (p-trend = 0.01); the OR in the fourth compared to the first quartile was 2.2 (95% CI 1.0-4.6). Testosterone, dehydroepiandrosterone and androstenedione levels were not associated with increased risk. Sex hormone-binding globulin was associated with a nonsignificant decrease in risk. Associations with estrone and estrone sulfate persisted after adjustment for androstenediol (ORs for fourth compared to first quartiles were 2.0 (95% CI 0.9-4.5) and 2.2 (95% CI 1.0-4.6), respectively (p-trend = 0.16 for both). The association with androstenediol was attenuated after adjustment for estrone (OR for fourth compared to first quartile was 1.6 (95% CI 0.7-3.6); p-trend = 0.13). Higher serum concentrations of estrogens were associated with increased breast cancer risk in postmenopausal women. Androgen levels were not independently associated with substantially increased risk.     

Method of Cooking and Risk of Breast Cancer in the Philippines

Objective Among Asian countries, the highest age-standardized rates of breast cancer have been reported for the Philippines. The influence of diet and lifestyle factors as possible contributors to these high rates has not been well-studied. We conducted a case-control study in Manila to examine the association between methods of cooking and the risk of breast cancer. Methods Eligible subjects were women undergoing evaluation at the Philippine General Hospital (PGH), Manila for a breast problem. All of the women completed a risk factor questionnaire prior to the determination of their case (n = 240) or control (n = 240) status. Information regarding current, as well as usual method of cooking in the household at 12 years of age was obtained. Results Boiling food in coconut milk was associated with a significantly increased risk of breast cancer (odds ratio (OR) = 2.2; 95% confidence interval (CI) 1.3–3.8). There were positive associations between boiling food in coconut milk and the risk of breast cancer currently (OR = 1.9; 95% CI 1.0–3.3), and at 12 years of age (OR = 2.9; 95% CI 1.6–5.5). A positive association between frying food and breast cancer risk was restricted to women whose household fried food at 12 years of age (OR = 1.89; 95% CI 1.1–3.4). Conclusions The results of this study suggest that various cooking methods during adolescence and possibly in adulthood may be associated with an increased risk of breast cancer. These findings require confirmation.     

胃癌术后辅助放化疗与辅助化疗比较的荟萃分析

目的 采用偱证医学荟萃分析的方法比较胃癌术后辅助放化疗与辅助化疗间的疗效差异。方法 计算机检索PubMed、EMbase、Cochrane图书馆、万方、维普、CNKI及中国生物医学等数据库,搜集有关胃癌术后辅助放化疗和辅助化疗比较的临床对照研究资料,汇总数据采用RevMan 5.2.5和Stata 12.0软件进行分析。两组间差异采用优势比(OR)及95%可信区间(95% CI)描述。结果 根据纳入和排除标准,最终纳入12个包括1674例患者的临床对照研究资料。荟萃分析结果显示,与胃癌术后辅助化疗相比,辅助放化疗的3、5年生存率更高(OR=2.96,95% CI= 1.75~5.03,P=0.000;OR=1.45,95% CI=1.06~1.99,P=0.020),辅助放化疗的局部复发率更低(OR=0.50,95% CI=0.34~0.72,P=0.000),但远处转移率两组相似(OR=0.79,95% CI=0.58~1.07,P=0.130)。结论 现有研究结果的荟萃分析显示,与胃癌术后辅助化疗相比,胃癌术后辅助放化疗是一种较为安全和有效的治疗方法。     

胰岛素水平升高及脂类代谢紊乱与乳腺癌发生的相关性

目的 探讨血清胰岛素水平升高、脂类代谢紊乱与乳腺癌发生的相关性,为乳腺癌的防治寻找科学依据.方法 收集术前乳腺癌患者血清90例,乳腺良性疾病患者40例,健康对照100例.采用酶联免疫吸附法测定血清胰岛素水平,放射免疫分析法测定血清瘦素,全自动生化分析仪测定血脂水平.采用SPSS10.0软件包进行t检验、方差、相关、Logistic回归分析等统计学处理.结果 乳腺癌组血清胰岛素、瘦素和甘油三酯(TG)水平与乳腺良性疾病组和健康对照组比较明显升高,而高密度脂蛋白(HDL)明显降低,差异有统计学意义(P值均＜0.01).乳腺癌组和乳腺良性疾病及健康对照组绝经前后血清胰岛素水平比较,差异均无统计学意义(P＞0.05);乳腺癌组未发生淋巴转移与发生转移的血清胰岛素水平进行比较,差异无统计学意义(P=0.642).乳腺癌组血清胰岛素水平与体质指数(BMI)无相关性(r=0.164,P＞0.05),胰岛素水平的升高独立于饮食及其他已知的乳腺癌危险因素.Logistic回归分析显示:胰岛素、瘦素、TG及HDL与乳腺癌发生有一定的相关性(OR=1.120、95% CI 1.017～1.209;OR=1.117、95%CI1.046～1.193;OR=1.879、95% CI1.148～3.076和OR=0.035、95%CI0.007～0.162).结论 血清胰岛素、瘦素和TG水平增高可能是导致乳腺癌发生的危险因素,而HDL水平升高可能对乳腺癌的发生有保护作用.     

Breast carcinoma in situ: risk factors and screening patterns.

BACKGROUND: Risk factors associated with invasive breast cancer are well documented, but those associated with breast carcinoma in situ are not well defined. METHODS: We conducted a population-based, case-control study among female residents of Connecticut to identify risk factors for breast carcinoma in situ. Case patients, diagnosed with ductal carcinoma in situ (DCIS) (n = 875) or lobular carcinoma in situ (LCIS) (n = 123), were matched by 5-year age groups with control subjects (n = 999). Case patients were diagnosed between September 15, 1994, through March 14, 1998, and all subjects were between the ages of 20 and 79 years. Information on risk factors and cancer-screening history was collected by telephone interviews. Conditional logistic regression was used to determine odds ratios (ORs) for the association of these factors with the risk of DCIS and LCIS. RESULTS: Case patients with DCIS were more likely than control subjects to report a family history of breast cancer (OR = 1.48; 95% confidence interval [CI] = 1.19 to 1.85) or previous breast biopsy (OR = 3.56; 95% CI = 2.86 to 4.43). They also had fewer full-term pregnancies (OR = 0.86; 95% CI = 0.80 to 0.93) and were older at first full-term pregnancy (OR for being 20-29 years old relative to being <20 years old = 1.68; 95% CI = 1.17 to 2.43) and at menopause (OR for being > or =55 years old relative to being <45 years old = 1.71; 95% CI = 1.05 to 2.77). DCIS case patients were more likely than control subjects to have had a mammographic examination (OR = 2.46; 95% CI = 1.78 to 3.40) or an annual clinical breast examination (OR = 1.83; 95% CI = 1.48 to 2.26). DCIS patients and control subjects did not differ with respect to oral contraceptive use, hormone replacement therapy, alcohol consumption or smoking history, or breast self-examination. Associations for LCIS were similar. CONCLUSIONS: The risk factors associated with DCIS and LCIS are similar to those associated with invasive breast cancer. Diagnosis of DCIS is associated with increased mammography screening.     

Peripheral blood circulating cytokeratin-19 mRNA-positive cells after the completion of adjuvant chemotherapy in patients with operable breast cancer.

BACKGROUND: The purpose of this study was to evaluate the prognostic significance of the molecular detection of cytokeratin 19 (CK-19) mRNA-positive cells in the peripheral blood of women with operable breast cancer after the completion of adjuvant chemotherapy. PATIENTS AND METHODS: Blood from 161 patients with stage I and II breast cancer, obtained after the completion of adjuvant chemotherapy, was tested by nested RT-PCR for CK-19 mRNA detection. Using univariate and multivariate analyses possible interactions with other prognostic factors and association of CK-19 mRNA detection with risk of relapse, disease-free interval (DFI) and overall survival were investigated. RESULTS: After completion of adjuvant chemotherapy, 27.3% of patients had peripheral blood CK-19 mRNA-positive cells; there was no association of this finding with any other prognostic factors or the type of chemotherapy regimen used. For patients with less than four involved axillary lymph nodes the risk of relapse was 3.81 [95% confidence interval (CI) 1.06-13.71] times higher, and the DFI was significantly reduced (P = 0.028) if CK-19 mRNA-positive cells were detectable in the blood after the completion of adjuvant chemotherapy. In contrast, for patients with four or more involved lymph nodes, the presence of CK-19 mRNA-positive cells after adjuvant chemotherapy did not significantly affect the risk of relapse or DFI. Furthermore, the risk of relapse was higher (hazards ratio 3.70; 95% CI 1.09-13.89) and the DFI was reduced (P = 0.022) for patients with detectable CK-19 mRNA-positive cells following adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) as compared with epirubicin, cyclophosphamide and 5-fluorouracil (FEC) or sequential taxotere-epirubicin and cyclophosphamide (T/EC) chemotherapy. CONCLUSIONS: The detection of CK-19 mRNA-positive cells in the peripheral blood after adjuvant chemotherapy may be of clinical relevance for patients with early breast cancer and less than four involved axillary lymph nodes.     

Family history and risk of breast cancer in hispanic and non-hispanic women: the New Mexico Women's Health Study

Objectives: Many epidemiologic studies have demonstrated that an increased risk of breast cancer is associated with positive family history of this disease. Little information had been available on the relationship of breast cancer risk with family history in Hispanic women. To investigate the association of family history of breast cancer on the risk of breast cancer, we examined the data from the New Mexico Women's Health Study (NMWHS), a statewide case–control study. Methods: In this study 712 women (332 Hispanics and 380 non-Hispanic whites) with breast cancer and 844 controls (388 Hispanics and 456 non-Hispanic whites) were included. Conditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (95% CI), adjusted for sociodemographic, medical, and reproductive factors. Results: We found an increased risk in women with a history of breast cancer in one or more first-degree or second-degree relatives (OR = 1.5, 95% CI 1.2–1.9), first-degree relatives (OR = 1.3, 95% CI 1.0–1.8) and second-degree relatives (OR = 1.6, 95% CI 1.2–2.2). Hispanic women had higher risk estimates for a positive family history (OR = 1.7, 95% CI 1.1–2.5) than non-Hispanic white women (OR = 1.4, 95% CI 1.0–2.0); however, the differences were not statistically significant. In both ethnic groups a higher risk was observed in premenopausal women compared with postmenopausal women and women diagnosed with breast cancer before age 50years compared with older women. Conclusions: The results indicate that Hispanic women with a family history of breast cancer are at increased risk of breast cancer.     

HER2 expression and efficacy of dose-dense anthracycline-containing adjuvant chemotherapy in breast cancer patients

No data are available on the role of HER2 overexpression in predicting the efficacy of dose-dense anthracycline-containing adjuvant chemotherapy in breast cancer patients. We retrospectively evaluated this role in patients enrolled in a phase III study comparing standard FEC21 (5-fluorouracil, epirubicin, and cyclophosphamide, administered every 3 weeks) vs dose-dense FEC14 (the same regimen repeated every 2 weeks). HER2 status was determined for 731 of 1214 patients. Statistical analyses were performed to test for interaction between treatment and HER2 status with respect to event-free survival (EFS) and overall survival (OS); EFS and OS were compared within each HER2 subgroup and within each treatment arm. Median follow-up was 6.7 years. Among FEC21-treated patients, both EFS (HR=2.07; 95% CI 1.27-3.38) and OS (HR=2.47; 95% CI 1.34-4.57) were significantly worse in HER2 + patients than in HER2 - patients. Among FEC14-treated patients, differences in either EFS (HR=1.21; 95% CI 0.65-2.24) or OS (HR=1.85; 95% CI 0.88-3.89) between HER2 + and HER2 - patients were not statistically significant. Interaction analysis suggested that the use of dose-dense FEC14 might remove the negative prognostic effect of HER2 overexpression on EFS and OS. Our data suggest a potential role of HER-2 overexpression in predicting the efficacy of dose-dense epirubicin-containing chemotherapy and the need to confirm this hypothesis in future prospective studies.     

Sexually transmitted diseases and other urogenital conditions as risk factors for prostate cancer: a case–control study in Wayne County,Michigan

Objective To investigate associations between prostate cancer and sexually transmitted diseases (STDs), prostatitis, benign prostatic hyperplasia (BPH), and vasectomy in a population-based case–control study in Wayne County, Michigan, among African American and white men aged 50–74 years.Methods: Incident prostate cancer cases (n=700) from 1996–1998 were identified from the Metropolitan Detroit Cancer Surveillance System. Controls (n=604) were identified through random digit dialing and Medicare recipient lists, and frequency matched to cases on age and race. History of potential prostate cancer risk factors was ascertained through in-person interview.Results: Prostate cancer was not associated with STD or vasectomy history. History of prostatitis was associated with prostate cancer among all subjects (odds ratio [OR]=1.8, 95% confidence interval [CI]: 1.1, 2.9) and in African American men (OR=2.2, 95% CI: 1.1, 4.6). History of BPH was associated with prostate cancer among all subjects (OR=2.4, 95% CI: 1.8, 3.3); significant associations were observed in both African American (OR=2.7, 95% CI: 1.6, 4.4) and white (OR=2.3, 95% CI: 1.5, 3.4) men.Conclusions: Among all subjects, prostate cancer was associated with prostatitis and BPH history, but not with STD or vasectomy history. Prevention efforts could be enhanced if inflammatory or infectious etiologies are found to be of importance in the subsequent development of prostate cancer.     

SNPs in ultraconserved elements and familial breast cancer risk

Ultraconserved elements (UCEs) are segments of >200 bp length showing absolute sequence identity between orthologous regions of human, rat and mouse genomes. The selection factors acting on these UCEs are still unknown. Recent studies have shown that UCEs function as long-range enhancers of flanking genes or are involved in splicing when overlapping with exons. The depletion of UCEs among copy number variation as well as the significant under-representation of single-nucleotide polymorphisms (SNPs) within UCEs have also revealed their evolutional and functional importance indicating their potential impact on disease, such as cancer. In the present study, we investigated the influence of six SNPs within UCEs on familial breast cancer risk. Two out of six SNPs showed an association with familial breast cancer risk. Whereas rs9572903 showed only a borderline significant association, the frequency of the rare [G] allele of rs2056116 was higher in cases than in controls indicating an increased familial breast cancer risk ([G] versus [A]: odds ratio (OR) = 1.18, 95% confidence interval (CI) 1.06-1.30, P = 0.0020; [GG] versus [AA]: OR = 1.41, 95% CI 1.15-1.74, P = 0.0011). Interestingly, comparing with the older age group, the ORs were increased in woman younger than 50 years of age ([G] versus [A]: OR = 1.27, 95% CI 1.11-1.45, P = 0.0005; [GG] versus [AA]: OR = 1.60, 95% CI 1.22-2.10, P = 0.0007) pointing to an age- or hormone-related effect. This is the first study indicating that SNPs in UCEs might be associated with cancer risk.     

Association of death receptor 4 haplotype 626C-683C with an increased breast cancer risk

Dysregulation of apoptosis plays a crucial role in carcinogenesis. Tumour necrosis factor-related apoptosis-inducing ligand stimulates the extrinsic apoptotic pathway by binding to death receptor 4 (DR4). Thus, genetic alterations within the candidate tumour suppressor gene DR4 would be expected to provoke a deficient apoptotic signalling thereby facilitating the development of cancer. The DR4 variants Thr209Arg and Glu228Ala were genotyped in a series of 521 breast cancer cases and 1100 control subjects from Germany, determining their impact on breast cancer risk. Neither Thr209Arg (626C>G) nor Glu228Ala (683A>C) alone were significantly associated with breast cancer risk [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.65-1.08, P = 0.18 and OR = 0.89, 95% CI = 0.72-1.12, P = 0.30]. However, haplotype analysis revealed a 3.5-fold risk for carriers of the 626C-683C haplotype (OR = 3.52, 95% CI = 1.45-8.52, P = 0.003).     

Prediction of pathologic complete response to sequential paclitaxel and 5-fluorouracil/epirubicin/cyclophosphamide therapy using a 70-gene classifier for breast cancers

BACKGROUND.

Sequential administration of paclitaxel plus combined fluorouracil, epirubicin, and cyclophosphamide (P‐FEC) is 1 of the most common neoadjuvant chemotherapies for patients with primary breast cancer and produces pathologic complete response (pCR) rates of 20% to 30%. However, a predictor of pCR to this chemotherapy has yet to be developed. The authors developed such a predictor by using a proprietary DNA microarray for gene expression analysis of breast tumor tissues.

METHODS.

Tumor samples were obtained from 84 patients with breast cancer by core‐needle biopsy before the patients received P‐FEC, and the gene expression profile was analyzed in those samples to construct a classifier for predicting pCR to P‐FEC. In addition, the authors analyzed the gene expression profile of tumor tissues that were obtained at surgery from 105 patients with lymph node‐negative and estrogen receptor‐positive breast cancer who received adjuvant hormone therapy alone to determine the prognostic significance of the classifier.

RESULTS.

The 70‐gene classifier for predicting pCR to P‐FEC was constructed by using the training set (n = 50) and subsequently was validated successfully in the validation set (n = 34), revealing high sensitivity (88%; 95% confidence interval [CI], 47%‐100%) and high negative predictive value (93%; 95% CI, 68%‐100%). Specificity and positive predictive value were 54% (95% CI, 33%‐73%) and 37% (95% CI, 16%‐62%), respectively. Among the various parameters (estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki‐67 status, etc), the 70‐gene classifier had the strongest association with pCR (P = .015). In an additional study, genetically assumed complete responders were associated significantly (P = .047) with a poor prognosis.

CONCLUSIONS.

The 70‐gene classifier that was constructed for predicting pCR to P‐FEC for breast tumors was successful, with high sensitivity and high negative predictive value. The classifier also appeared to be useful for predicting the prognosis of patients with lymph node‐negative and estrogen receptor‐positive breast cancer who receive adjuvant hormone therapy alone. Cancer 2011. © 2011 American Cancer Society.     

Mitochondrial genetic background modifies breast cancer risk

Inefficient mitochondrial electron transport chain (ETC) function has been implicated in the vicious cycle of reactive oxygen species (ROS) production that may predispose an individual to late onset diseases, such as diabetes, hypertension, and cancer. Mitochondrial DNA (mtDNA) variations may affect the efficiency of ETC and ROS production, thus contributing to cancer risk. To test this hypothesis, we genotyped 69 mtDNA variations in 156 unrelated European-American females with familial breast cancer and 260 age-matched European-American female controls. Fisher's exact test was done for each single-nucleotide polymorphism (SNP)/haplogroup and the P values were adjusted for multiple testing using permutation. Odds ratio (OR) and its 95% confidence interval (95% CI) were calculated using the Sheehe correction. Among the 69 variations, 29 were detected in the study subjects. Three SNPs, G9055A (OR, 3.03; 95% CI, 1.63-5.63; P = 0.0004, adjusted P = 0.0057), A10398G (OR, 1.79; 95% CI, 1.14-2.81; P = 0.01, adjusted P = 0.19), and T16519C (OR, 1.98; 95% CI, 1.25-3.12; P = 0.0030, adjusted P = 0.0366), were found to increase breast cancer risk; whereas T3197C (OR, 0.31; 95% CI, 0.13-0.75; P = 0.0043, adjusted P = 0.0526) and G13708A (OR, 0.47; 95% CI, 0.24-0.92; P = 0.022, adjusted P = 0.267) were found to decrease breast cancer risk. Overall, individuals classified as haplogroup K show a significant increase in the risk of developing breast cancer (OR, 3.03; 95% CI, 1.63-5.63; P = 0.0004, adjusted P = 0.0057), whereas individuals bearing haplogroup U have a significant decrease in breast cancer risk (OR, 0.37; 95% CI, 0.19-0.73; P = 0.0023, adjusted P = 0.03). Our results suggest that mitochondrial genetic background plays a role in modifying an individual's risk to breast cancer.     

Serum CA125 elevation and risk of clinical detection of cancer in asymptomatic postmenopausal women

BACKGROUND: This study was undertaken to assess the correlation between CA125 elevation, a past history of cancer, and future risk of a diagnosis of cancer among asymptomatic postmenopausal women. METHODS: The subjects consisted of a study group of 771 women with elevated CA125 (> or =30 U/mL) and a control group of 771 women with CA125 <30 U/mL. They were selected from a prospective ovarian carcinoma screening trial of 22,000 postmenopausal women followed for a mean of 2269 days. RESULTS: Subjects in the study group were more likely to have a past history of cancer than subjects in the control group (odds ratio [OR] 2.31, 95% confidence interval [CI] 1.49-3.58). Much of the difference in cancer risk prior to CA125 testing was attributable to a past history of breast carcinoma (OR 2.53, 95% CI 1.45-4.42), but CA125 elevation did not predict recurrence of breast carcinoma. Subjects in the study group were also more likely to develop cancer in the future (OR 2.53, 95% CI 1.61-3.97). This difference was due to an increased risk of gynecologic cancer (OR 30.09, 95% CI 4.09-221.59). CA125 elevation was not associated with an increase in the future risk of developing breast carcinoma (OR 1.19, 95% CI 0.53-2.66) or nongynecologic cancer (OR 1.43, 95% CI 0.86-2.36). CONCLUSIONS: Elevated CA125 in asymptomatic postmenopausal women is not a predictor of nongynecologic cancer or recurrence of cancer, and further investigation should be limited to the detection of gynecologic cancers.