Local recurrence following breast-conserving treatment in women aged 40 years or younger: Trends in risk and the impact on prognosis in a population-based cohort of 1143 patients

AimTo evaluate trends in the risk of local recurrences after breast-conserving treatment (BCT) and to examine the impact of local recurrence (LR) on distant relapse-free survival in a large, population-based cohort of women aged ?40 years with early-stage breast cancer.MethodsAll women (n = 1143) aged ?40 years with early-stage (pT1-2/cT1-2, N0-2, M0) breast cancer who underwent BCT in the south of the Netherlands between 1988 and 2010 were included. BCT consisted of local excision of the tumour followed by irradiation of the breast.ResultsAfter a median follow-up of 8.5 (0.1–24.6) years, 176 patients had developed an isolated LR. The 5-year LR-rate for the subgroups treated in the periods 1988–1998, 1999–2005 and 2006–2010 were 9.8% (95% confidence interval (CI) 7.1–12.5), 5.9% (95% CI 3.2–8.6) and 3.3% (95% CI 0.6–6.0), respectively (p = 0.006). In a multivariate analysis, adjuvant systemic treatment was associated with a reduced risk of LR of almost 60% (hazard ratio (HR) 0.42; 95% CI 0.28–0.60; p < 0.0001). Patients who experienced an early isolated LR (?5 years after BCT) had a worse distant relapse-free survival compared to patients without an early LR (HR 1.83; 95% CI 1.27–2.64; p = 0.001). Late local recurrences did not negatively affect distant relapse-free survival (HR 1.24; 95% CI 0.74–2.08; p = 0.407).ConclusionLocal control after BCT improved significantly over time and appeared to be closely related to the increased use and effectiveness of systemic therapy. These recent results underline the safety of BCT for young women with early-stage breast cancer.     

Genetic variation at 8q24, family history of cancer,and upper gastrointestinal cancers in a Chinese population

Genetic variation at 8q24 is associated with prostate, bladder, breast, colorectal, thyroid, lung, ovarian, UADT, liver and stomach cancers. However, a role for variation at 8q24 in familial clustering of upper gastrointestinal cancers has not been studied. In order to explore potential inherited susceptibility, we analyzed epidemiologic data from a population-based case–control study of upper gastrointestinal cancers from Taixing, China. The study population includes 204 liver, 206 stomach, and 218 esophageal cancer cases and 415 controls. Associations between 8q24 rs1447295, rs16901979, rs6983267 and these cancers were stratified by family history of cancer. Odds ratios and 95 % confidence intervals were adjusted for potential confounders: age, sex, education, tobacco smoking, alcohol consumption, and BMI at interview. We also adjusted for hepatitis B and aflatoxin (liver cancer) and Helicobacter pylori (stomach cancer). In a dominant model, among those with a family history of cancer, rs1447295 was positively associated with liver cancer (OR_adj 2.80; 95 % CI 1.15–6.80). Heterogeneity was observed (P _{heterogeneity} = 0.029) with rs6983267 and liver cancer, with positive association in the dominant model among those with a family history of cancer and positive association in the recessive model among those without a family history of cancer. When considered in a genetic risk score model, each additional 8q24 risk genotype increased the odds of liver cancer by two-fold among those with a family history of cancer (OR_adj 2.00; 95 % CI 1.15–3.47). These findings suggest that inherited susceptibility to liver cancer may exist in the Taixing population and that variation at 8q24 might be a genetic component of that inherited susceptibility.     

Polymorphism of 8q24 rsl3281615 and breast cancer risk

Several genome-wide association studies on breast cancer have reported similar findings of a new cancer susceptibility locus, 8q24 rsl3281615. Subsequent case–control studies have rapidly investigated the association between the single nucleotide polymorphism of rsl3281615 at chromosome 8q24 and breast cancer risk, but the effect of 8q24 rsl3281615 polymorphism on breast cancer is still unclear due to the inconsistence among those studies. Given the contradictory findings, a meta-analysis was performed to determine the association between 8q24 rsl3281615 polymorphism and breast cancer risk. 12 eligible case–control studies with a total of 42,508 cases and 53,928 controls were finally included into this meta-analysis by searching the PubMed, Embase, and China Biology Medicine (CBM) databases. We estimated the summary odds ratio (OR) with its corresponding 95 % confidence interval (95 % CI) to assess this association. Meta-analyses of total 12 studies showed 8q24 rsl3281615 polymorphism was significantly associated with an increased risk of breast cancer in all contrast models (OR_{G vs. A}?=?1.10, 95 % CI 1.05–1.14, P _OR?<?0.001; OR_{GG vs. AA}?=?1.20, 95 % CI 1.11–1.29, P _OR?<?0.001; OR_{AG vs. AA}?=?1.08, 95 % CI 1.05–1.12, P _OR?<?0.001; OR_{GG vs. AA +AG}?=?1.13, 95 % CI 1.07–1.19, P _OR?<?0.001; OR_{GG+AG vs. AA}?=?1.13, 95 % CI 1.07–1.19, P _OR?<?0.001). Meta-analyses of studies with high quality showed that 8q24 rsl3281615 polymorphism was still significantly associated with an increased risk of breast cancer under the five genetic contrast models. Sensitivity analyses by sequential omission of any individual studies and subgroup analyses by ethnicity further identified the significant association between 8q24 rsl3281615 polymorphism and breast cancer risk. Conclusively, this meta-analysis shows a significant association between 8q24 rsl3281615 polymorphism and breast cancer risk.     

Family history influences the tumor characteristics and prognosis of breast cancers developing during postmenopausal hormone therapy

Long term use of postmenopausal hormone therapy (HT) has been reported to increase breast cancer risk. On the other hand, observational studies suggest that breast cancers diagnosed during HT may have a more favorable prognosis. While family history is a risk factor for breast cancer, and genetic factors also influence prognosis, the role of family history in combination with HT use has been little studied. We investigated the relationship between HT, family history, and prognosis in 584 (267 exposed) familial and 952 (460 exposed) non-familial breast cancer cases, using three survival end points: death from breast cancer (BCS), distant disease free survival (DDFS), and local recurrence free survival (LRFS). Among non-familial cases, HT was associated with better BCS (HR 0.63, 95% CI 0.41–0.94; p?=?0.025), and DDFS (HR 0.58, 95% CI 0.40–0.85; p?=?0.005), with a consistent but not statistically significant effect in LRFS. This effect was not seen in familial cases (HR?>?1.0), and family history was found to interact with HT in BCS (p_{(interaction)}?=?0.0067) (BC-death) and DDFS (p_{(interaction)}?=?0.0070). There was phenotypic heterogeneity between HT-associated tumors in familial and non-familial cases, particularly on estrogen receptor (ER) status, although the interaction between HT and family history appears to be at least partially independent of these markers (p?=?0.0370 after adjustment for standard prognostic factors). If confirmed by further studies, our results suggest that family history should be taken into consideration in clinical counseling before beginning a HT regimen.     

The polymorphism of EGFR 142285G > A exerts no risk effect on breast cancer

The association between the epidermal growth factor receptor (EGFR) 142285G?>?A polymorphism and the susceptibility to breast cancer is unclear. We conducted a meta-analysis of all published studies to estimate the association of EGFR 142285G?>?A polymorphism and breast cancer risk. Systematic computerized searching of the PubMed, Web of Science, and Wanfang databases was performed for relevant publications. Overall, there were three eligible case–control studies with 1,360 cases and 1,522 controls included into our study. The pooled ORs showed that the EGFR 142285G?>?A variant genotypes did not increase or decrease the risk of breast cancer under the following gene models: A vs. G, OR?=?1.07, 95 % CI 0.96–1.19, P _OR?=?0.240; AA vs. GG, OR?=?1.14, 95 % CI 0.91–1.42, P _OR?=?0.239; GA vs. GG, OR?=?0.99, 95 % CI 0.83–1.17, P _OR?=?0.892; GA?+?AA vs. GG, OR?=?1.03, 95 % CI 0.87–1.21, P _OR?=?0.727; AA vs. GG?+?GA, OR?=?1.17, 95 % CI 0.97–1.42, P _OR?=?0.096. The between-study heterogeneity was not significant among all studies. The current meta-analysis showed no evidence for significant association between EGFR 142285G?>?A polymorphism and breast cancer risk. Subsequent studies with large sample size are needed for further elucidation.     

Vascular endothelial growth factor gene polymorphism (-634G/C) and breast cancer risk

The aim of this meta-analysis was to assess if the -634G/C polymorphism represents a predisposition factor for the risk of breast cancer. We included eight published case-control studies, in which a total of 6,175 cancer cases and 6,421 cancer-free controls were included. Pooled ORs and 95 % CIs were calculated by the fixed effects model to evaluate the association of the -634G/C polymorphism and breast cancer risk. When all studies were pooled, we did not find statistical evidence of any significant association with overall breast cancer risk (OR_{BB vs. bb}?=?1.00, 95 % CI?=?0.93–1.07, P?=?0.999; OR_{BB + Bb vs. bb}?=?1.00, 95 % CI?=?0.95–1.05, P?=?0.999; OR_{BB vs. Bb + bb}?=?1.03, 95 % CI?=?0.96-1.09, P?=?0.984; OR_{allele B vs. allele b}?=?1.01, 95 % CI?=?0.97–1.05, P?=?0.998; OR_{Bb vs. bb}?=?0.99, 95 % CI?=?0.92–1.06, P?=?0.992). In further stratified analyses by ethnicity and control source, no significant association was revealed. This study suggests that the -634G/C polymorphism does not appear to represent a risk factor for breast cancer.     

TaqI polymorphism of VDR gene contributes to breast cancer risk

Previous studies on the association of Vitamin D receptor (VDR) TaqI gene polymorphism with breast carcinogenesis have yielded inconsistent and inconclusive findings. The current meta-analysis was performed to provide a more precise assessment on the role of VDR TaqI polymorphism in breast cancer risk. 20 eligible case–control studies involving 9,055 cases and 10,516 controls were identified after a comprehensive literature search of the PubMed, Embase, Web of Science, and Wanfang databases. The pooled odds ratio (OR) with corresponding 95 % confidence interval (95 % CI) was calculated. Stratified analyses by ethnicity and study quality were conducted for further estimation. All statistical analyses were conducted by use of STATA (STATA Corporation, College Station, TX, Version 11.0). The overall ORs showed that the variant t allele and tt genotype were related to an increased risk of breast cancer (OR_{t vs. T}?=?1.05, 95 % CI 1.01–1.10, P _OR?=?0.025; OR_{tt vs. TT}?=?1.12, 95 % CI 1.03–1.23, P _OR?=?0.011; OR_{tt vs. Tt + TT}?=?1.10, 95 % CI 1.01–1.20, P _OR?=?0.023). Stratified analyses of studies in Caucasians and with high-quality further confirmed the results. However, no significant relationship was observed among Asians. This meta-analysis suggests that the VDR TaqI polymorphism confers risk effect on the breast cancer development, particularly in Caucasians.     

Circulating prolactin and breast cancer risk among pre- and postmenopausal women in the EPIC cohort

BackgroundExperimental and epidemiological evidence suggests that prolactin might play a role in the etiology of breast cancer. We analyzed the relationship of prediagnostic circulating prolactin levels with the risk of breast cancer by menopausal status, use of postmenopausal hormone replacement therapy (HRT) at blood donation, and by estrogen and progesterone receptor status of the breast tumors.Patients and methodsConditional logistic regression was used to analyze the data from a case–control study nested within the prospective European EPIC cohort, including 2250 invasive breast cancer and their matched control subjects.ResultsStatistically significant heterogeneity in the association of prolactin levels with breast cancer risk between women who were either pre- or postmenopausal at the time of blood donation was observed (P_het = 0.04). Higher serum levels of prolactin were associated with significant increase in the risk of breast cancer among postmenopausal women [odds ratio (OR)_Q4–Q1 = 1.29 (95% confidence interval, CI, 1.05–1.58), P_trend = 0.09]; however, this increase in risk seemed to be confined to women who used postmenopausal HRT at blood donation [OR_Q4–Q1 = 1.45 (95% CI 1.08–1.95), P_trend = 0.01], whereas no statistically significant association was found for the non-users of HRT [OR_Q4–Q1 = 1.11 (95%CI 0.83–1.49), P_trend = 0.80] (P_het = 0.08). Among premenopausal women, a statistically non-significant inverse association was observed [OR_Q4–Q1 = 0.70 (95% CI 0.48–1.03), P_trend = 0.16]. There was no heterogeneity in the prolactin–breast cancer association by hormone receptor status of the tumor.ConclusionOur study indicates that higher circulating levels of prolactin among the postmenopausal HRT users at baseline may be associated with increased breast cancer risk.     

Association between the p53 codon 72 Arg/Pro polymorphism and hepatocellular carcinoma risk

Previous studies regarding the association of p53 codon 72 Arg/Pro polymorphism with hepatocellular carcinoma (HCC) risk have provided conflicting and inconclusive findings. Thus, a meta-analysis of all currently available publications was performed to address this issue. Eleven individual case–control studies involving a total of 2,718 cases and 3,752 controls were identified after a systematic search of the PubMed, Embase, Web of Science, and Wanfang databases. The strength of the association of p53 codon 72 Arg/Pro polymorphism with HCC risk was estimated by the pooled odds ratio (OR) with its corresponding 95 % confidence interval (95 % CI). Subgroup analyses stratified by ethnicity, source of controls, gender, hepatitis virus infection status, and family history of HCC were also conducted to assess the association. Overall, significantly increased risk of HCC was identified among carriers of the homozygous genotype ProPro (OR_{ProPro vs. ArgArg}?=?1.38 (95 % CI, 1.03–1.85), P _OR?=?0.033; OR_{ProPro vs. ArgArg + ArgPro}?=?1.28 (95 % CI, 1.03–1.59), P _OR?=?0.026). In subgroup analysis by ethnicity, the pooled results suggested that the p53 codon 72 Arg/Pro polymorphism was associated with an increased risk of HCC in Asians and Caucasians (for Asians, OR_{ProPro vs. ArgArg + ArgPro}?=?1.17 (95 % CI, 1.02–1.34), P _OR?=?0.025; for Caucasians, OR_{ProPro vs. ArgArg}?=?1.65 (95 % CI, 1.07–2.56), P _OR?=?0.025; OR_{ProPro vs. ArgArg + ArgPro}?=?1.74 (95 % CI, 1.14–2.66), P _OR?=?0.010). Subgroup analyses by source of controls and hepatitis virus infection status further demonstrated the significant association, whereas stratification factors involving gender and family history of HCC did not modify the association between p53 codon 72 Arg/Pro polymorphism and HCC risk. This meta-analysis suggests that the p53 codon 72 Arg/Pro polymorphism may play a critical role in the development of HCC, and gender and family history of HCC may not modulate the effect of p53 codon 72 Arg/Pro in HCC risk.     

Breast Cancer Multifocality and Multicentricity and Locoregional Recurrence

Background.

The impact of multifocal (MF) or multicentric (MC) breast cancer on locoregional (LR) control rates is unknown.

Methods.

MF was defined as two or more separate invasive tumors in the same quadrant of the breast. MC was defined as two or more separate invasive tumors occupying more than one quadrant of the same breast. Patients were categorized by LR treatment: breast conservation therapy (BCT; n = 256), mastectomy (n = 466), or mastectomy plus postmastectomy radiation therapy (PMRT; n = 184). All patients with MC disease had mastectomy (10 patients treated with BCT for MC disease were excluded). The Kaplan-Meier product limit method was used to calculate 5-year LR control rate. Cox proportional hazards models were used to determine independent associations of multifocality or multicentricity with LR control.

Results.

A total of 906 patients had either MF disease (n = 673) or MC disease (n = 233). With median follow-up of 52 months, the 5-year LR control rate was 99% for MF, 96% for MC, and 98% for unifocal tumors (p = .44). Subset analysis revealed no difference in LR control regardless of the LR treatment (p = .67 for BCT, p = .37 for mastectomy, p = .29 for mastectomy plus PMRT). There were five in-breast recurrences after BCT in the MF group. MF and MC did not have an independent impact on LR control rate on multivariate analysis.

Conclusion.

MF and MC disease are not independent risk factors for LR recurrence. Patients with MF and MC breast cancer had rates of LR control similar to those of their unifocal counterparts. These data suggest that BCT is a safe option for patients with MF tumors and that MF or MC disease alone is not an indication for PMRT.     

The genomic expression test EndoPredict is a prognostic tool for identifying risk of local recurrence in postmenopausal endocrine receptor-positive,her2neu-negative breast cancer patients randomised within the prospective ABCSG 8 trial

Background:

The aim of this study was to examine whether EndoPredict (EP), a novel genomic expression test, is effective in predicting local recurrence (LR)-free survival (LRFS) following surgery for breast cancer in postmenopausal women. In addition, we examined whether EP may help tailor local therapy in these patients.

Methods:

From January 1996 to June 2004, 3714 postmenopausal patients were randomly assigned to either tamoxifen or tamoxifen followed by anastrozole within the prospective ABCSG 8 trial. Using assay scores from EP, we classified breast tumour blocks as either low or high risk for recurrence.

Results:

Data were gathered from 1324 patients. The median follow-up was 72.3 months and the cumulative incidence of LR was 2.6% (0.4% per year). The risk of LR over a 10-year period among patients with high-risk lesions (n=683) was significantly higher (LRFS=91%) when compared with patients with low-risk lesions (n=641) (10-year LRFS=97.5%) (HR: 1.31 (1.16–1.48) P<0.005). The groups that received breast conservation surgery (BCT) and mastectomy (MX) had similar LR rates (P=0.879). Radiotherapy (RT) after BCT significantly improved LRFS in the cohorts predicted by EP to be low-risk for LR (received RT: n=436, 10-year LRFS 99.8% did not receive RT: n=63, 10-year LRFS 83.6%, P<0.005).

Conclusions:

EndoPredict is an effective prognostic tool for predicting LRFS. Among postmenopausal, low-risk patients, EP does not appear to be useful for tailoring local therapy.     

Do surgical margins matter after mastectomy? A systematic review

BackgroundNo consensus exists regarding adequacy of margins after mastectomy.To determine if pathological margin proximity is associated with local (LR) or distant recurrence after mastectomy for early invasive breast cancer or ductal carcinoma in situ.MethodsA systematic review of literature published from 1980 to 2019 and meta-analysis was conducted. Unpublished data were sought from authors (PROSPERO (CRD42019127541)).Thirty-four studies comprising 34,833 breast cancer patients were included in the quantitative synthesis. Eligible studies reported on patients undergoing curative mastectomy for cancer allowing estimation of outcomes in relation to margin status/width.The association between pathological margin status and local (LR) and distant recurrence was considered using random effects modelling. PRISMA guidelines were followed.ResultsPositive margins were associated with increased LR on multivariable analyses (HR, 2·64, (95%CI 2·01–3·46)) and LR was higher regardless of the distance of tumour from the margin defined as positive. After skin-sparing mastectomy, positive margins were associated with increased LR (HR 3·40, (95%CI 1·9–6·2)). In the 4 studies reporting distant recurrence, patients with involved margins had a higher risk (HR 1·53, (95%CI 1·03–2·25)).ConclusionsFailure to achieve clear margins after mastectomy may increase the risks of local and distant recurrence. Adequate margin clearance should be recommended to minimize recurrence after mastectomy in National and International Guidelines.     

Breast‐conserving therapy in young women with invasive carcinoma of the breast

Higher local recurrence rates have been reported in young women with invasive carcinoma of the breast treated with breast‐conserving therapy (BCT). However, age itself may not be responsible for this increased risk of recurrence. To investigate this further, a computerized literature search of MEDLINE was performed using data from 1996 to May 2003. The research was limited to female patients with localized, invasive adenocarcinoma of the breast but also included patients of young age with ductal carcinoma in situ. Women of young age with breast cancer, treated with BCT are at an increased risk of recurrence ranging from 7.5 to 35%. However, the data would suggest that the increased risk is secondary to the association of young age with more aggressive tumours and a positive family history of breast cancer. Other factors that may explain the adverse prognosis in women of a young age include associated genetic abnormalities and the lack of mammographic screening programmes for women of young age. Young age is a risk factor for breast recurrence after BCT. However, management decisions should be based on tumour stage, grade and other related prognostic features rather than on young age alone.     

Breast cancer genetic risk profile is differentially associated with interval and screen-detected breast cancers

This is a report looking into the genetic differences between screen-detected and interval cancers. It is an affirmation that screen-detected and interval cancers may have unique underlying biology. Genetic risk discrimination has potential relevance in clinical care where interval cancers, which are usually rapidly growing and aggressive, do not currently benefit from mammography screening.BackgroundPolygenic risk profiles computed from multiple common susceptibility alleles for breast cancer have been shown to identify women at different levels of breast cancer risk. We evaluated whether this genetic risk stratification can also be applied to discriminate between screen-detected and interval cancers, which are usually associated with clinicopathological and survival differences.Patients and methodsA 77 single-nucleotide polymorphism polygenic risk score (PRS) was constructed for breast cancer overall and by estrogen receptor (ER) status. PRS was inspected as a continuous (per standard deviation increment) variable in a case-only design. Modification of the PRS by mammographic density was evaluated by fitting an additional interaction term.ResultsPRS weighted by breast cancer overall estimates was found to be differentially associated with 1865 screen-detected and 782 interval cancers in the LIBRO-1 study {age-adjusted odds ratio (OR)_perSD [95% confidence interval (CI)] 0.91 [0.83–0.99],P = 0.023}. The association was found to be more significant for PRS weighted by ER-positive breast cancer estimates [OR_perSD = 0.90 (0.82–0.98),P = 0.011]. This result was corroborated by two independent studies [combined OR_perSD = 0.87 (0.76–1.00),P = 0.058] with no evidence of heterogeneity. When enriched for ‘true’ interval cancers among nondense breasts, the difference in the association with PRS in screen-detected and interval cancers became more pronounced [OR_perSD = 0.74 (0.62–0.89),P = 0.001], with a significant interaction effect between PRS and mammographic density (P_interaction = 0.017).ConclusionTo our knowledge, this is the first report looking into the genetic differences between screen-detected and interval cancers. It is an affirmation that the two types of breast cancer may have unique underlying biology.     

High risk of in-breast tumor recurrence after BRCA1/2-associated breast cancer

The purpose of the study was to compare breast-conserving therapy (BCT) and mastectomy (M) in BRCA1/2 mutation carriers. Women with invasive breast cancer and a pathogenic mutation in BRCA1 or BRCA2 were included in the study (n = 162). Patients treated with BCT (n = 45) were compared with patients treated with M (n = 118). Endpoints were local recurrence as first recurrence (LR), overall survival (OS), breast cancer death, and distant recurrence. Cumulative incidence was calculated in the presence of competing risks. For calculation of hazard ratios and for multivariable analysis, cause-specific Cox proportional hazards regression was used. Compared to M, BCT was associated with an increased risk of LR in univariable analysis (HR 4.0; 95 % CI 1.6–9.8) and in multivariable analysis adjusting for tumor stage, age, and use of adjuvant chemotherapy (HR 2.9; CI 1.1–7.8). Following M, all local recurrences were seen in the first 5 years after breast cancer diagnosis. Following BCT, the rate of LR continued to be high also after the first 5 years. The cumulative incidence of LR in the BCT group was 15, 25, and 32 % after 5, 10, and 15 years, respectively. There were no significant differences between BCT and M for OS, breast cancer death, or distant recurrence. BRCA1/2 mutation carriers treated with BCT have a high risk of LR, many of which are new primary breast cancers. This must be thoroughly discussed with the patient and is an example of how rapid treatment-focused genetic testing could influence choice of treatment.     

Breast cancer risk among women with long-standing lactation and reproductive parameters at low risk level: a case–control study in Northern Tanzania

Breast cancer is the leading cause of death among women worldwide. Studies in industrialised countries identified age at menarche, age at first full-term pregnancy, and lactation as determining factors in the aetiology of breast cancer. 115 female breast cancer patients (cases) and 230 age- and district-matched women clinically free from breast cancer (controls) were interviewed about their reproductive history and socioeconomic condition. Semi-structured interviews including anthropometric measurements were conducted by trained enumerators. The median age was 50 years (min/max 26 to 85 years). Estimated median BMI at age 20 was 21 kg/m² in both cases and controls. Median lifelong lactation of the mothers was 96 months (cases) and 108 months (controls). A high BMI at 20 years was associated with an increased breast cancer risk (OR 1.31 95% CI 1.11–1.55, P < 0.01). The odds ratio for lifelong lactation was slightly below one (OR 0.99 95% CI 0.98–1.00, P < 0.01). There was no significant association in risk for BMI at interview (median 25 kg/m² of cases and 26 kg/m² of controls), age at menarche (median 16 years), and age at first full-term pregnancy (median 20 years). The association of increased risk with higher BMI at age 20 years remained significant after stratification for menopause (premenopausal: OR 1.41 95% CI 1.10–1.81, P = 0.01; postmenopausal: OR 1.38 95% CI 1.06–1.80, P = 0.02). Late age at menarche and prolonged lifelong lactation were associated with a risk reduction among premenopausal women (OR_menarche 0.74 95% CI 0.56–1.00, P = 0.05; OR_lactation 0.98 95% CI 0.97–0.99, P < 0.01). In conclusion, long-standing lactation and reproductive behaviour are associated with a lower breast cancer risk in the region. As current changes in lifestyle affect age at menarche, reproductive behaviour, and nutritional status, an increased incidence of breast cancer is to be expected. Preventive efforts should include advice on reproductive and breastfeeding behaviour.     

Association between X-ray repair cross-complementing group 1 Arg194Trp polymorphism and colorectal cancer risk

The polymorphism of X-ray repair cross-complementing group 1 (XRCC1) Arg194Trp, a substitution of Arg to Gln at position 194, has been implicated in the development of colorectal cancer (CRC) in a number of case–control studies with contradictory and inconclusive findings. The current meta-analysis of all currently available publications was conducted to assess the gene susceptibility to CRC and improve our understanding of the CRC pathogenesis. The pooled odds ratio (OR) with corresponding 95 % confidence interval (95 % CI) was calculated by use of fixed-effects model or random-effects model when appropriate. A total of 15 eligible case–control studies with 4,501 cases and 8,038 controls were retrieved after a comprehensive search of the PubMed, Embase, Web of science, and Chinese Biomedicine (CBM) databases up to December 2012. The overall meta-analysis identified a positive but not statistically significant association between the XRCC1 Arg194Trp polymorphism and CRC risk under all genetic contrast models (OR_{Trp vs. Arg}?=?1.07, 95 % CI 0.90–1.26, P _OR?=?0.441; OR_{TrpTrp vs. ArgArg}?=?1.28, 95 % CI 0.91–1.81, P _OR?=?0.163; OR_{ArgTrp vs. ArgArg}?=?1.00, 95 % CI 0.85–1.19, P _OR?=?0.956; OR_{ArgTrp + TrpTrp vs. ArgArg}?=?1.06, 95 % CI 0.90–1.24, P _OR?=?0.502; OR_{TrpTrp vs. ArgArg + ArgTrp}?=?1.11, 95 % CI 0.91–1.34, P _OR?=?0.306). The genotype TrpTrp carriers among Caucasians were more susceptible to CRC, although lack statistical evidence (OR_{TrpTrp vs. ArgArg}?=?2.69, 95 % CI 0.97–7.49, P _OR?=?0.058; OR_{TrpTrp vs. ArgArg + ArgTrp}?=?2.77, 95 % CI 0.99–7.72, P _OR?=?0.051). Interestingly, the XRCC1 Arg194Trp variant was significantly associated with an increased risk of colon cancer. The present meta-analysis suggests that the XRCC1 Arg194Trp polymorphism may modify the risk for CRC, particularly colon cancer. However, the precise genetic association needs to be further estimated in future studies.     

Association between the NBS1 Glu185Gln polymorphism and breast cancer risk: a meta-analysis

Nijmegen breakage syndrome 1 (NBS1), a vital DNA repair protein in the homologous recombination repair pathway and a signal modifier in the intra-S phase checkpoint, plays a critical role in cellular response to DNA damages and the maintenance of genomic stability. The NBS1 Glu185Gln (NBS1 E185Q, NBS1 8360G>C, rs1805794) polymorphism has been indicated to be involved in the development of cancer, but results of previous individual studies on the association between NBS1 Glu185Gln polymorphism and breast cancer risk remain controversial and inconclusive. Our meta-analysis investigated this association for the first time by pooling the odds ratios with corresponding 95 % confidence intervals (95 % CIs) of all individual publications available to date. Overall, 14 separate studies with 6,642 cases and 7,138 controls were finally included into the present meta-analysis after a comprehensive literature search of the PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases up to October 21, 2012. Overall analysis and subgroup analyses by ethnicity and source of controls were performed. Meta-analysis of total studies showed that the NBS1 Glu185Gln variant carriers were not susceptible to breast cancer (OR_{Gln vs. Glu}?=?1.05, 95 % CI 0.80–1.39, P _OR?=?0.719; OR _{Gln/Gln vs. Glu/Glu}?=?0.82, 95 % CI 0.62–1.08, P _OR?=?0.154; OR _{Glu/Gln vs. Glu/Glu}?=?1.00, 95 % CI 0.90–1.13, P _OR?=?0.939; OR_{Gln/Gln + Glu/Gln vs. Glu/Glu}?=?0.96, 95 % CI 0.83–1.11, P _OR?=?0.551; OR_{Gln/Gln vs. Glu/Glu + Glu/Gln}?=?0.84, 95 % CI 0.67–1.05, P _OR?=?0.134). Similar results were observed in heterogeneity-adjusted meta-analysis of all studies. Furthermore, subgroup analyses by ethnicity and source of controls did not identify any appreciable relationship of the NBS1 Glu185Gln polymorphism with breast cancer susceptibility in any populations. Sensitivity analysis by sequentially omitting individual studies confirmed the stability and reliability of our results. Our meta-analysis of currently available data shows no association between the NBS1 Glu185Gln polymorphism and breast cancer risk.     

High local recurrence risk after breast-conserving therapy in node-negative premenopausal breast cancer patients is greatly reduced by one course of perioperative chemotherapy: A European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group Study.

PURPOSE: Patients with invasive breast cancer may develop a local recurrence (LR) after breast-conserving therapy (BCT). Younger age has been found to be an independent risk factor for LR. Within a group of premenopausal node-negative breast cancer patients, we studied risk factors for LR and the effect of perioperative chemotherapy (PeCT) on LR. PATIENTS AND METHODS: The European Organization for Research and Treatment of Cancer (EORTC) conducted a randomized trial (EORTC 10854) to compare surgery followed by one course of PeCT (fluorouracil, doxorubicin, and cyclophosphamide) with surgery alone. From patients treated on this trial, we selected premenopausal patients with node-negative breast cancer who were treated with BCT to examine whether histologic characteristics and the expression of various proteins (estrogen receptor, progesterone receptor, p53, Ki-67, bcl-2, CD31, c-erbB-2/neu) are risk factors for subsequent LR. Also, the effect of one course of PeCT on the LR risk (LRR) was studied. RESULTS: Using multivariate analysis, age younger than 43 years (relative risk [RR], 2.75; 95% confidence interval [CI], 1.46 to 5.18; P =.002), multifocal growth (RR, 3.34; 95% CI, 1.27 to 8.77; P =.014), and elevated levels of p53 (RR, 2. 14; 95% CI, 1.13 to 4.05; P =.02) were associated with higher LRR. Also, PeCT was found to reduce LRR by more than 50% (RR, 0.47; 95% CI, 0.25 to 0.86; P =.02). Patients younger than 43 years who received PeCT achieved similar LR rates as those of patients younger than 43 years who were treated with BCT alone. CONCLUSION: In premenopausal node-negative patients, age younger than 43 years is the most important risk factor for LR after BCT; this risk is greatly reduced by one course of PeCT. The main reason for administering systemic adjuvant treatment is to improve overall survival. The important reduction of LR after BCT is an additional reason for considering systemic treatment in young node-negative patients with breast cancer.