The TP53 Arg72Pro and MDM2 309G>T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers

Background:

The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance.

Methods:

To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework.

Results:

No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93–1.10, P_trend=0.77; MDM2: HR=0.96, 95%CI: 0.84–1.09, P_trend=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87–1.12, P_trend=0.83; MDM2: HR=0.98, 95%CI: 0.80–1.21, P_trend=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association.

Conclusion:

There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers.     

Association of glutathione S-transferase T1 and M1 polymorphisms with prostate cancer susceptibility in populations of Asian descent: a meta-analysis

Background

Genetic polymorphism was hypothesized to be reason of variation in prostate cancer incidence among different racial group. Based on that published data on the association of prostate cancer susceptibility with polymorphisms in genes encoding Glutathione S-transferases (GSTs) were inconclusive, the aim of this study was to more precisely address the role of GSTs polymorphisms (especially, GSTT1 and GSTM1 deletions) on prostate cancer risk in Asian descent.

Methods

A meta-analysis including 8 articles with 711 cases and 1122 controls for GSTT1 and 1098 cases and 1588 controls for GSTM1 was performed.

Results

Significantly increased prostate cancer risk was found among subjects carrying GSTM1 null genotype (odds ratio (OR) = 1.403; 95% confidence interval (CI) = 1.088 – 1.808) but not among subjects carrying GSTT1 deletion genotype (OR = 0.959; 95%CI = 0.709 – 1.297). When stratified by country, the null genotype of GSTT1 neither increased nor decreased prostate cancer risk significantly in China (OR = 1.355; 95%CI = 0.895 – 2.049), Japan (OR = 0.812; 95%CI = 0.545 – 1.211), and Korea (OR = 1.056; 95%CI = 0.727 – 1.534). While significant association of elevated prostate cancer risk with GSTM1 deletion were found in China (OR = 1.665; 95%CI = 1.324 – .094) and Korea (OR = 1.914; 95%CI = 1.311 – 2.793) but not in Japan (OR = 0.980; 95%CI = 0.726 – 1.321).

Conclusion

In summary, this meta-analysis suggested that the null genotype of GSTM1 rather than GSTT1 may be involved in the etiology of prostate cancer in Asian population.     

Association of TP53 mutations with TP53 codon 72 polymorphism and outcome in triple-negative breast cancer

Despite recent improvements, triple-negative breast cancer (TNBC) remains a breast cancer subtype with poor prognosis. TP53 mutations are commonly associated with TNBC, suggesting a role in breast cancer carcinogenesis. In addition to mutations, several reports focused on TP53 polymorphisms and their association with breast cancer risk and outcome. TP53 codon Pro72Arg polymorphism may predict response to anti-cancer therapy as Pro72 is apparently less effective in the induction of apoptosis.Here, we investigated a potential association of TP53 mutations with TP53 codon 72 polymorphism and clinical outcome in a homogeneous cohort of TNBC patients.DNA isolated from formalin-fixed paraffin-embedded tissue of 35 consecutive TNBC patients was investigated for TP53 mutation and TP53 codon 72 polymorphic status by Sanger sequencing.The kind of TP53 mutations were associated with particular polymorphic Pro72Arg genotypes. Frameshift mutations were significantly correlated with Pro/Pro carriers, nonsense mutations showed a trend for Pro/Arg carriers. Despite this observation no association with clinical outcome was observed.Further studies with larger and more homogeneous cohorts are warranted in order to elucidate a potential association of TP53 Pro72Arg polymorphism and particular TP53 mutations with TNBC carcinogenesis and outcome.     

Association of MUTYH Gln324His and APEX1 Asp148Glu with colorectal cancer and smoking in a Japanese population

Background

Genetic polymorphisms of DNA repair enzymes may lead to genetic instability and colorectal cancer carcinogenesis. Our objective was to measure the interactions between polymorphisms of repair genes and tobacco smoking in colorectal cancer.

Methods

The case-control study involved sixty-eight colorectal cancer patients and 121 non-cancer controls divided into non-smokers and smokers according to pack-years of smoking. The genetic polymorphisms of DNA repair enzymes,OGG1 Ser326Cys, MUTYH Gln324His, APEX1 Asp148Glu and XRCC1 Arg399Gln, were examined using PCR-RFLP.

Results

The MUTYH Gln324His showed strong significant associations with a risk of colorectal cancer (crude odds ratio [OR] 3.30, 95% confidence interval [95%CI] 1.44–7.60, p = 0.005; adjusted OR3.53, 95%CI 1.44–8.70, p = 0.006). The ORs for the APEX1 Asp148Glu were statistically significant (crude OR 2.69, 95%CI 1.45–4.99, p = 0.002; adjusted OR 2.33, 95%CI 1.21–4.48, p = 0.011). The ORs for the MUTYH Gln324His and the APEX1 Asp148Glu were statistically significant for colon cancer (adjusted OR 3.95, 95%CI 1.28–12.20, p = 0.017 for MUTYH Gln324His ; adjusted OR 3.04, 95%CI 1.38–6.71, p = 0.006 for APEX1 Asp148Glu). The joint effect of tobacco exposure and the MUTYH Gln324His showed a significant association with colorectal cancer risk in non-smokers (adjusted OR 4.08, 95%CI 1.22–13.58, p = 0.022) and the APEX1 Asp148Glu was significantly increased in smokers (adjusted OR 5.02, 95%CI 1.80–13.99, p = 0.002). However, the distributions of OGG1 Ser326Cys and XRCC1 Arg399Gln were not associated with a colorectal cancer risk.

Conclusion

Our findings suggest that the MUTYH Gln324His and the APEX1 Asp148Glu constitutes an increased risk of colorectal cancer, especially colon cancer. The MUTYH Gln324His is strongly associated with colorectal cancer susceptibility in never smoking history, whereas the APEX1 Asp148Glu genotype constitutes an increased risk of colorectal cancer when accompanied by smoking exposure.     

High frequency of complex TP53 mutations in CNS metastases from breast cancer

Background:

Brain metastasis from breast cancer is usually associated with a poor prognosis and early death. Alteration of p53 may contribute to malignant progression by abrogation of apoptosis induced by oncogene activation and by acquisition of gain-of-function properties, which promote tumour aggression. Mutation in TP53 occurs at high frequency in carcinomas of the lung and gastro-intestinal tract, but is much less frequent, at 25%, in primary breast cancer. The frequency of TP53 alteration in the central nervous system (CNS) metastatic breast cancer is not known.

Methods:

In all, 23 cases of histologically confirmed CNS metastatic breast cancer were identified and the coding sequence of TP53 determined. TP53 was also sequenced in two control series of primary breast carcinomas from independent clinical centres.

Results:

We demonstrate a strikingly high frequency of TP53 mutation in the CNS metastatic lesions with an over-representation of complex mutations (non-sense/deletions/insertions). Complex mutations occur in metastatic lesions in both triple-negative breast cancer and hormone receptor/HER2-positive cases. Analysis of paired primary carcinomas and brain metastatic lesions revealed evidence for both clonal selection and generation of new mutations (missense and complex) in progression from a primary breast carcinoma to brain metastasis.

Conclusion:

Mutation in TP53 is the most common genetic alteration reported during metastasis to the brain in breast cancer.     

Molecular markers of response and toxicity to FOLFOX chemotherapy in metastatic colorectal cancer

Background:

To investigate three genetic alterations (TP53 mutation, Kras mutation and microsatellite instability (MSI)) and three polymorphisms (methylene tetrahydrofolate reductase (MTHFR) C677T, excision repair cross complementing group 1 (ERCC1)-118 and X-ray repair cross complementing group 1 (XRCC1)-399) for their ability to predict response, survival and toxicity to FOLFOX first line chemotherapy in the treatment of metastatic colorectal cancer (mCRC).

Methods:

Tumour tissues from 118 mCRC patients who underwent FOLFOX treatment from three successive phase II trials were evaluated for mutations in TP53 (exons 5–8) and Kras (codons 12 and 13) and for MSI using PCR-based analysis. Genotyping for common single nucleotide polymorphisms in the MTHFR (codon 677), ERCC1 (codon 118) and XRCC1 (codon 399) genes was also carried out using PCR techniques. These genetic markers were correlated with clinical response, survival and toxicity to treatment.

Results:

Patients with the T allele of ERCC1-118 showed significantly worse progression-free survival in univariate analysis (HR=2.62; 95% CI=1.14–6.02; P=0.02). None of the genetic alterations or polymorphisms showed significant association with clinical response to FOLFOX. The MTHFR, ERCC1 and XRCC1 polymorphisms showed no associations with overall haematological, gastrointestinal or neurological toxicity to FOLFOX, although MTHFR 677 TT genotype patients showed a significantly higher incidence of grade 3 or 4 diarrhoea (26%) compared with CC or CT genotype patients (6%, P=0.02).

Conclusions:

The ERCC1-118 and MTHFR C677T polymorphisms were associated with progression and severe diarrhoea, respectively, after FOLFOX treatment in mCRC. Although our findings require confirmation in large prospective studies, they reinforce the concept that individual genetic variation may allow personalized selection of chemotherapy to optimize clinical outcomes.     

Increasingly strong reduction in breast cancer mortality due to screening

Background:

Favourable outcomes of breast cancer screening trials in the 1970s and 1980s resulted in the launch of population-based service screening programmes in many Western countries. We investigated whether improvements in mammography and treatment modalities have had an influence on the effectiveness of breast cancer screening from 1975 to 2008.

Methods:

In Nijmegen, the Netherlands, 55 529 women received an invitation for screening between 1975 and 2008. We designed a case–referent study to evaluate the impact of mammographic screening on breast cancer mortality over time from 1975 to 2008. A total number of 282 breast cancer deaths were identified, and 1410 referents aged 50–69 were sampled from the population invited for screening. We estimated the effectiveness by calculating the odds ratio (OR) indicating the breast cancer death rate for screened vs unscreened women.

Results:

The breast cancer death rate in the screened group over the complete period was 35% lower than in the unscreened group (OR=0.65; 95% CI=0.49–0.87). Analysis by calendar year showed an increasing effectiveness from a 28% reduction in breast cancer mortality in the period 1975–1991 (OR=0.72; 95% CI=0.47–1.09) to 65% in the period 1992–2008 (OR=0.35; 95% CI=0.19–0.64).

Conclusion:

Our results show an increasingly strong reduction in breast cancer mortality over time because of mammographic screening.     

The association of XRCC1 gene single nucleotide polymorphisms with response to neoadjuvant chemotherapy in locally advanced cervical carcinoma

Background

Platinum-based neoadjuvant chemotherapy (NAC) is new therapeutic strategy for locally advanced cervical carcinoma, but the variables used to predict NAC response are still infrequently reported. The aim of our study was to investigate the association between XRCC1 gene single nucleotide polymorphisms (SNPs) and NAC response.

Methods

Seventy patients with locally advanced cervical carcinoma who underwent NAC were collected. SNPs of XRCC1 (at codon 194 and 399) and XRCC1 protein expression were detected. The association of XRCC1 gene SNPs and protein expression with NAC response were analyzed.

Results

Response to NAC was not statistically significant in three genotypes, Arg/Arg, Arg/Trp, Trp/Trp of XRCC1 at codon 194(X² = 1.243, P = 0.07), while responses were significantly different in genotypes Arg/Arg, Arg/Gln, Gln/Gln of XRCC1 at codon 399 (X² = 2.283, P = 0.020). The risk of failure to chemotherapy in the patients with a Gln allele(Arg/Gln+Gln/Gln) was significantly greater than that with Arg/Arg(OR = 3.254, 95%CI 1.708 ~ 14.951). The expression level of XRCC1 protein was significantly associated with response to NAC. Moreover, the genotype with the Gln allele(Arg/Gln+Gln/Gln) at codon 399, but not codon at 194, presented a significantly higher level of XRCC1 protein expression than that with Arg/Arg genotype (F = 2.699, p = 0.009).

Conclusion

SNP of XRCC1 gene at codon 399 influences the response of cervical carcinoma to platinum-based NAC. This is probably due to changes in expression of XRCC1 protein, affecting response to chemotherapy.     

Quantitative assessment of the influence of EPHX1 gene polymorphisms and cancer risk: a meta-analysis with 94,213 subjects

Purpose

Previous studies investigating the association between EPHX1 polymorphisms (Tyr113His and His139Arg) and cancer risk have yielded inconsistent results. This meta-analysis was performed to derive a more precise estimation of relationship between two EPHX1 polymorphisms and risk of different types of cancer.

Methods

Data were extracted from relevant studies detected by a systematic literature search. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of the association between EPHX1 polymorphisms and cancer risk.

Results

This meta-analysis carefully collected 99 studies on these two polymorphisms and cancer risk published up to March 2014, consisting of 45 studies (20,091 cases and 27,396 controls) for Tyr113His and 54 studies (19,437 cases and 27,289 controls) for His139Arg. The results in overall population did not show any significant association between these two polymorphisms and cancer risk for all genetic models. However, EPHX1 Tyr113His homozygote individuals have a significantly increased risk of cancer among Asians (homozygote model: OR =1.46, 95% CI=1.05–2.03; recessive model: OR =1.39, 95% CI =1.10–1.76) and mixed population (homozygote model: OR =1.17, 95% CI =1.02–1.34; recessive model: OR =1.17, 95% CI =1.02–1.33), but not Caucasians.

Conclusion

His/His genotype of EPHX1 Tyr113His polymorphism is a risk factor for developing caner for Asian and mixed population, while no evidence was found for the association between the EPHX1 His139Arg polymorphism and increased cancer risk.

Electronic supplementary material

The online version of this article (doi:10.1186/s13046-014-0082-9) contains supplementary material, which is available to authorized users.     

NT5E CpG island methylation is a favourable breast cancer biomarker

Background:

Relapse risk assessment and individual treatment recommendations remain suboptimal for breast cancer patients. In the light of existing preclinical and clinical data, we studied NT5E (5′-nucleotidase, ecto) expression and NT5E CpG island methylation in breast cancer.

Methods:

We used RT–PCR, qPCR, methylation-specific PCR and pyrosequencing to analyse NT5E in breast carcinoma cell lines and primary and breast carcinomas.

Results:

NT5E CpG island methylation was inversely associated with NT5E expression in breast carcinoma cell lines. In clinical series, patients whose primary tumours had NT5E CpG island methylation were less likely to develop metastasis (P=0.003, OR=0.34, 95% CI: 0.17–0.69). In 3/4 paired samples, NT5E was methylated in primary tumours and demethylated in CNS metastases. Patients progressing to non-visceral as compared with visceral metastases were more likely to have NT5E CpG island methylation in primary tumours (P=0.01, OR=11.8). Patients with tumours lacking detectable methylation had shorter disease-free survival (DFS) (P=0.001, HR=2.7) and overall survival (OS) (P=0.001, HR=3). The favourable prognostic value of NT5E methylation was confirmed in oestrogen receptor negative (P=0.011, HR=3.27, 95% CI: 1.31–8.12) and in triple negative cases (P=0.004; HR=6.2, 95% CI: 1.9–20). Moreover, we observed a more favourable outcome to adjuvant chemotherapy in patients whose tumours were positive for NT5E CpG island methylation: DFS (P=0.0016, HR=5.1, 95% CI: 1.8–14.37) and OS (P=0.0005, HR=7.4, 95% CI: 2.416–23.08).

Conclusion:

NT5E CpG island methylation is a promising breast cancer biomarker.     

Relationships between CYP2D6 phenotype, breast cancer and hot flushes in women at high risk of breast cancer receiving prophylactic tamoxifen: results from the IBIS-I trial

Background:

Several studies have reported discordant results regarding the impact of the CYP2D6 phenotype on both the effectiveness and the degree of endocrine symptoms associated with tamoxifen. Other studies have suggested that menopausal symptoms may be a predictive factor to tamoxifen response.

Methods:

We investigated the relationship between the CYP2D6-predicted phenotype and tamoxifen response in a nested case–control study among women from the International Breast cancer Intervention Study (IBIS-I), which evaluated tamoxifen in the preventive setting.

Results:

In this retrospective analysis of the tamoxifen-treated women in the IBIS-I study, 9 women (16.6%) who developed oestrogen receptor-positive invasive breast cancer had a 2D6 poor or intermediate metaboliser phenotype compared with 45 (20.6%) controls. Adjusted matched logistic regression revealed no significant difference between cases and controls for extensive vs intermediate metaboliser phenotype (OR=0.81 (0.30–2.23), P=0.7) or extensive vs poor metaboliser phenotype (OR=1.02 (0.31–3.32), P=0.9). Controls in the tamoxifen group with a poor metaboliser phenotype developed nonsignificantly fewer hot flushes compared with those with an extensive metaboliser phenotype (OR=0.40 (0.12–1.31)), but those with the intermediate phenotype developed nonsignificantly more hot flushes (OR=1.38 (0.58–3.29)) in an unadjusted analysis.

Conclusion:

Data from the preventive IBIS-I study did not support an association between the CYP2D6 phenotype and breast cancer outcome or the development of endocrine symptoms in tamoxifen-treated women.     

SNPs in DNA repair or oxidative stress genes and late subcutaneous fibrosis in patients following single shot partial breast irradiation

Background

The aim of this study was to evaluate the potential association between single nucleotide polymorphisms related response to radiotherapy injury, such as genes related to DNA repair or enzymes involved in anti-oxidative activities. The paper aims to identify marker genes able to predict an increased risk of late toxicity studying our group of patients who underwent a Single Shot 3D-CRT PBI (SSPBI) after BCS (breast conserving surgery).

Methods

A total of 57 breast cancer patients who underwent SSPBI were genotyped for SNPs (single nucleotide polymorphisms) in XRCC1, XRCC3, GST and RAD51 by Pyrosequencing technology. Univariate analysis (ORs and 95% CI) was performed to correlate SNPs with the risk of developing ≥ G2 fibrosis or fat necrosis.

Results

A higher significant risk of developing ≥ G2 fibrosis or fat necrosis in patients with: polymorphic variant GSTP1 (Ile105Val) (OR = 2.9; 95%CI, 0.88-10.14, p = 0.047).

Conclusions

The presence of some SNPs involved in DNA repair or response to oxidative stress seem to be able to predict late toxicity.

Trial Registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01316328","term_id":"NCT01316328"}}NCT01316328     

Birth characteristics and childhood carcinomas

Background:

Carcinomas in children are rare and have not been well studied.

Methods:

We conducted a population-based case–control study and examined associations between birth characteristics and childhood carcinomas diagnosed from 28 days to 14 years during 1980–2004 using pooled data from five states (NY, WA, MN, TX, and CA) that linked their birth and cancer registries. The pooled data set contained 57 966 controls and 475 carcinoma cases, including 159 thyroid and 126 malignant melanoma cases. We used unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs).

Results:

White compared with ‘other'' race was positively associated with melanoma (OR=3.22, 95% CI 1.33–8.33). Older maternal age increased the risk for melanoma (OR_{per 5-year age increase}=1.20, 95% CI 1.00–1.44), whereas paternal age increased the risk for any carcinoma (OR=1.10_{per 5-year age increase}, 95% CI 1.01–1.20) and thyroid carcinoma (OR_{per 5-year age increase}=1.16, 95% CI 1.01–1.33). Gestational age <37 vs 37–42 weeks increased the risk for thyroid carcinoma (OR=1.87, 95% CI 1.07–3.27). Plurality, birth weight, and birth order were not significantly associated with childhood carcinomas.

Conclusion:

This exploratory study indicates that some birth characteristics including older parental age and low gestational age may be related to childhood carcinoma aetiology.     

High-risk HPV infection after five years in a population-based cohort of Chilean women

Background

Single-nucleotide polymorphisms within TP53 gene (codon 72 exon 4, rs1042522, encoding either arginine or proline) and MDM2 promoter (SNP309; rs2279744), have been independently associated with increased risk of several cancer types. Few studies have analysed the role of these polymorphisms in the development of hepatocellular carcinoma.

Methods

Genotype distribution of TP53 codon 72 and MDM2 SNP309 in 61 viral hepatitis-related hepatocellular carcinoma cases and 122 blood samples (healthy controls) from Italian subjects were determined by PCR and restriction fragment length polymorphism (RFLP).

Results

Frequencies of TP53 codon 72 alleles were not significantly different between cases and controls. A significant increase of MDM2 SNP309 G/G and T/G genotypes were observed among hepatocellular carcinoma cases (Odds Ratio, OR = 3.56, 95% Confidence Limits, 95% CI = 1.3-9.7; and OR = 2.82, 95% CI = 1.3-6.4, respectively).

Conclusions

These results highlight a significant role of MDM2 SNP309 G allele as a susceptibility gene for the development of viral hepatitis-related hepatocellular carcinoma among Italian subjects.     

TP53 codon 72 polymorphism and breast cancer risk in Bangladeshi population

Background

Breast cancer, a hereditary or heterogeneous sporadic disease, is the most common cancer in women worldwide. The tumor suppressor TP53 gene has been found to be the most commonly mutated genes in many types of human cancers, including breast cancer. This study aimed to investigate the association of codon 72 polymorphism of TP53 gene with breast cancer risk in Bangladeshi females.

Methods

The study included 125 cases and 125 healthy controls. Genotyping and polymorphism were determined by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) analysis.

Results

The frequencies of the three genotypes Arg/Arg, Arg/Pro, and Pro/Pro were 43.2, 33.6, and 23.2% in cases, whereas 48.8, 40.8, and 10.4% in controls, respectively. The frequency of mutant homozygous (Pro/Pro) genotype was significantly increased in breast cancer patients as compared with controls (23.2 vs 10.4%), and showed 2.52-fold significantly increased risk for breast cancer (OR 2.5199, 95% CI 1.19–5.33, p = 0.0157). The frequencies of Pro/Pro genotype were significantly higher in breast cancer cases with non-breast feeding status. Pro allele frequency was found to be significantly increased in breast cancer cases (OR 1.4978, 95% CI 1.0357–2.1662, p = 0.0318).

Conclusions

Our data suggest that mutant (Pro/Pro) homozygosity at codon 72 of TP53 gene is significantly associated with breast cancer susceptibility in Bangladeshi women. In addition, this association was significantly related to lactating status.

     

Breast cancer, cytomegalovirus and Epstein�CBarr virus: a nested case�Ccontrol study

Background:

We investigated whether elevation in serum cytomegalovirus (CMV) or Epstein–Barr virus (EBV) immunoglobulin G (IgG) antibody levels precedes the development of breast cancer.

Methods:

A nested case–control study was carried out within the Janus Serum Bank cohort. Two serum samples, one taken at least 4 years before diagnosis (sample 2) and an earlier sample (sample 1) from 399 women with invasive breast cancer and from 399 controls, matched for date of blood samples and age were tested for CMV and EBV IgG antibodies. Odds ratios (ORs) with 95% confidence intervals (CIs) for CMV and EBV seroconversion between the samples and unit changes in IgG optical density (OD) examined as a continuous variable were calculated using conditional logistic regression.

Results:

Eleven cases and three controls seroconverted for CMV IgG between the first and second blood samples, with an adjusted OR for CMV IgG seroconversion of 4.0 (95% CI=1.1–14.4). The risk of breast cancer, adjusted for parity, increased per unit difference in CMV OD between samples (OR=1.7, 95% CI=1.1–2.5). In an analysis restricted to parous cases and age-matched parous controls, the OR for CMV seroconversion for IgG between the two samples, adjusted for parity and age at first birth, was 9.7 (95% CI=1.2–77.3). The EBV seroconversion or change in EBV OD was not associated with risk of breast cancer.

Conclusion:

Our hypothesis that elevation in serum CMV IgG antibody levels precedes the development of breast cancer in some women is supported by the results of this study. Changes in EBV IgG antibody are not associated with risk of breast cancer.     

The association between different night shiftwork factors and breast cancer: a case–control study

Background:

Research on the possible association between shiftwork and breast cancer is complicated because there are many different shiftwork factors, which might be involved including: light at night, phase shift, sleep disruption and changes in lifestyle factors while on shiftwork (diet, physical activity, alcohol intake and low sun exposure).

Methods:

We conducted a population-based case–control study in Western Australia from 2009 to 2011 with 1205 incident breast cancer cases and 1789 frequency age-matched controls. A self-administered questionnaire was used to collect demographic, reproductive, and lifestyle factors and lifetime occupational history and a telephone interview was used to obtain further details about the shiftwork factors listed above.

Results:

A small increase in risk was suggested for those ever doing the graveyard shift (work between midnight and 0500 hours) and breast cancer (odds ratio (OR)=1.16, 95% confidence interval (CI)=0.97–1.39). For phase shift, we found a 22% increase in breast cancer risk (OR=1.22, 95% CI=1.01–1.47) with a statistically significant dose–response relationship (P=0.04). For the other shiftwork factors, risks were marginally elevated and not statistically significant.

Conclusion:

We found some evidence that some of the factors involved in shiftwork may be associated with breast cancer but the ORs were low and there were inconsistencies in duration and dose–response relationships.     

Overdiagnosis due to breast cancer screening: updated estimates of the Helsinki service study in Finland

Background:

Overdiagnosis is the most important adverse event of breast cancer screening with the estimates ranging from 0% to 40–50% depending on invitational age and methods. We updated the estimates of overdiagnosis in Helsinki service screening study in Finland by comparing the observed and expected cumulative incidence of all breast carcinomas and invasive breast carcinomas.

Methods:

Women aged 50–59 years have been invited to Helsinki service screening since 1986. The incidence of breast carcinoma in the first invited birth cohorts born in 1935–1939 was compared with older, non-invited cohorts. The minimum follow-up time of the invitees after the last screening round was 14 years. Expected cumulative incidence rates were estimated with two alternative approaches.

Results:

For both any breast carcinoma and invasive breast carcinoma, the estimates of overdiagnosis varied from 5% (95% CI=−1, 11%) to 7% (95% CI=1, 13%) depending on the approach.

Conclusions:

Our estimates of overdiagnosis are of the same magnitude than other plausible estimates in Europe. Both alternative approaches produced similar estimates for the expected cumulative incidence, which increased the confidence in the estimates of overdiagnosis.     

Difference between observed and expected number of involved lymph nodes reflects the metastatic potential of breast cancer independent to intrinsic subtype

Purpose

Poor prognosis associated with metastasis in breast cancer patients highlights the critical need to develop an effective evaluation model for metastatic potential (MP). We hypothesized that MP could be also indicated by primary tumor size and involved lymph nodes (LNs).

Methods

The expected number of involved LNs is defined as tumor size (cm) divided by 1.5. The effect of the surrogate for MP (defined as difference between the number of observed and expected involved LNs) on breast cancer-specific survival (BCSS) was investigated in the first cohort from SEER (n = 108,814). Validation was performed in another SEER cohort (n = 50,414) and a third cohort (n = 3,755).

Results

MP is an independent predictor for BCSS in the overall population [hazard ratio (HR) for high MP: 2.92; 95% confidence interval (CI): 2.80–3.03] and in subgroups. The effect of surrogate for MP on survival was independent to intrinsic subtype, with adjusted HRs of 3.46 (95%CI, 2.02–5.93), 2.30 (95%CI, 1.64–3.24), 4.05 (95%CI, 2.85–5.76), and 1.45 (95%CI, 1.04–2.03) in luminal-A, luminal-B, triple-negative, and HER2-positive subtypes, respectively.

Conclusion

Difference between the observed and expected number of involved LNs serves as an indicator for MP, which is independent to intrinsic subtype and could predict survival. Our findings need further validation.     

A systematic review to establish the frequency of cyclooxygenase-2 expression in normal breast epithelium, ductal carcinoma in situ, microinvasive carcinoma of the breast and invasive breast cancer

Background:

Epidemiological studies have suggested a protective effect of cyclooxygenase (COX)-inhibiting non-steroidal anti-inflammatory drugs in breast cancer risk and disease progression. We performed a systematic review to evaluate the frequency of COX-2 expression in normal breast epithelium, ductal carcinoma in situ of breast (DCIS), DCIS-adjoining invasive breast cancer, microinvasive carcinoma of the breast (MICB) and invasive breast cancer.

Methods:

Literature searches were carried out on MEDLINE, EMBASE and Web of Science from their commencement until September 2010. Primary studies examining COX-2 expression by immunohistochemistry methodology were included. Meta-analyses were carried out using random effects models for individual study estimates of COX-2 expression and pooled to give an overall estimate.

Results:

The pooled prevalences (95% confidence intervals) of COX-2 expressions were 53% (44–61) in DCIS studies and 42% (36–49) in the invasive breast cancer studies. There were too few studies involving normal breast epithelium, DCIS-adjoining invasive breast cancer and MICB to conduct meta-analyses.

Conclusion:

The findings from our meta-analyses have shown similar COX-2 expression in DCIS and invasive breast cancer. This may suggest the involvement of COX-2 in early carcinogenesis. Further studies of COX-2 expression in DCIS are required to investigate the use of COX-2 as a potential drug target for prevention of disease progression in DCIS.