The value of adjuvant radiotherapy on survival and recurrence in triple-negative breast cancer: a systematic review and meta-analysis of 5,507 patients

BACKGROUND: The value of adjuvant radiotherapy in triple negative breast cancer (TNBC) remains unclear. A systematic review and meta-analysis was conducted in TNBC patients to assess survival and recurrence outcomes associated with radiotherapy following either breast conserving therapy (BCT) or post-mastectomy radiotherapy (PMRT). METHODS: Four electronic databases were searched from January 2000 to November 2015 (PubMed, MEDLINE, EMBASE and Web of Science). Studies investigating overall survival and/or recurrence in TNBC patients according to radiotherapy administration were included. A random effects meta-analysis was conducted using mastectomy only patients as the reference.  RESULTS: Twelve studies were included. The pooled hazard ratio (HR) for locoregional recurrence comparing BCT and PMRT to mastectomy only was 0.61 (95% confidence interval [CI] 0.41-0.90) and 0.62 (95% CI 0.44-0.86), respectively. Adjuvant radiotherapy was not significantly associated with distant recurrence. The pooled HR for overall survival comparing BCT and PMRT to mastectomy only was 0.57 (95% CI 0.36-0.88) and HR 1.12 (95% CI 0.75, 1.69). Comparing PMRT to mastectomy only, tests for interaction were not significant for stage (p=0.98) or age at diagnosis (p=0.85). However, overall survival was improved in patients with late-stage disease (T3-4, N2-3) pooled HR 0.53 (95% CI 0.32-0.86), and women <40 years, pooled HR 0.30 (95% CI 0.11-0.82). CONCLUSIONS: Adjuvant radiotherapy was associated with a significantly lower risk of locoregional recurrence in TNBC patients, irrespective of the type of surgery. While radiotherapy was not consistently associated with an overall survival gain, benefits may be obtained in women with late-stage disease and younger patients. 

Clopidogrel use and cancer-specific mortality: a population-based cohort study of colorectal, breast and prostate cancer patients

PURPOSE: Concerns were raised about the safety of antiplatelet thienopyridine derivatives after a randomized control trial reported increased risks of cancer and cancer deaths in prasugrel users. We investigate whether clopidogrel, a widely used thienopyridine derivative, was associated with increased risk of cancer-specific or all-cause mortality in cancer patients.

METHODS: Colorectal, breast and prostate cancer patients, newly diagnosed from 1998 to 2009, were identified from the National Cancer Data Repository. Cohorts were linked to the UK Clinical Practice Research Datalink, providing prescription records, and to the Office of National Statistics mortality data (up to 2012). Unadjusted and adjusted hazard ratios (HRs) for cancer-specific and all-cause mortality in post-diagnostic clopidogrel users were calculated using time-dependent Cox regression models.

RESULTS: The analysis included 10 359 colorectal, 17 889 breast and 13 155 prostate cancer patients. There was no evidence of an increase in cancer-specific mortality in clopidogrel users with colorectal (HR = 0.98 95% confidence interval (CI) 0.77, 1.24) or prostate cancer (HR = 1.03 95%CI 0.82, 1.28). There was limited evidence of an increase in breast cancer patients (HR = 1.22 95%CI 0.90, 1.65); however, this was attenuated when removing prescriptions in the year prior to death.

CONCLUSIONS: This novel study of large population-based cohorts of colorectal, breast and prostate cancer patients found no evidence of an increased risk of cancer-specific mortality among colorectal, breast and prostate cancer patients using clopidogrel.

Statin use after diagnosis of breast cancer and survival: a population-based cohort study

BACKGROUND: Preclinical studies have shown that statins, particularly simvastatin, can prevent growth in breast cancer cell lines and animal models. We investigated whether statins used after breast cancer diagnosis reduced the risk of breast cancer-specific, or all-cause, mortality in a large cohort of breast cancer patients.

METHODS: A cohort of 17,880 breast cancer patients, newly diagnosed between 1998 and 2009, was identified from English cancer registries (from the National Cancer Data Repository). This cohort was linked to the UK Clinical Practice Research Datalink, providing prescription records, and to the Office of National Statistics mortality data (up to 2013), identifying 3694 deaths, including 1469 deaths attributable to breast cancer. Unadjusted and adjusted hazard ratios (HRs) for breast cancer-specific, and all-cause, mortality in statin users after breast cancer diagnosis were calculated using time-dependent Cox regression models. Sensitivity analyses were conducted using multiple imputation methods, propensity score methods and a case-control approach.

RESULTS: There was some evidence that statin use after a diagnosis of breast cancer had reduced mortality due to breast cancer and all causes (fully adjusted HR = 0.84 [95% confidence interval = 0.68-1.04] and 0.84 [0.72-0.97], respectively). These associations were more marked for simvastatin 0.79 (0.63-1.00) and 0.81 (0.70-0.95), respectively.

CONCLUSIONS: In this large population-based breast cancer cohort, there was some evidence of reduced mortality in statin users after breast cancer diagnosis. However, these associations were weak in magnitude and were attenuated in some sensitivity analyses.

Study of influence of regulatory polymorphisms of expression in development of breast cancer

The human genome has millions of genetics variants that can affect gene expression. These variants are known as cis-regulatory variants and are responsible for intra-species phenotypic differences and individual susceptibility to disease. One of the diseases affected by cis-regulatory variants is breast cancer. Breast cancer is one of the most common cancers, with approximately 4500 new cases each year in Portugal. Breast cancer has many genes mutated and TP53 has been shown to be relevant for this disease. TP53 is one of the most commonly mutated genes in human cancer and it is involved in cell cycle regulation and apoptosis. Previous work by Maia et al has shown that TP53 has differential allelic expression (DAE), which suggests that this gene may be under the influence of cis-regulatory variants. Also, its DAE pattern is totally altered in breast tumours with normal copy number. We hypothesized that cis-regulatory variants affecting TP53 may have a role in breast cancer development and treatment. The present work aims to identify the cis-regulatory variants playing a role in TP53 expression, using in silico, in vitro and in vivo approaches. By bioinformatic tools we have identified candidate cis-regulatory variants and predicted the possible transcription factor binding sites that they affect. By EMSA we studied DNA-protein interactions in this region of TP53. The in silico analysis allowed us to identified three candidate cis-regulatory SNPs which may affect the binding of seven transcription factors. However, the EMSA experiments have not been conclusive and we have not yet confirmed whether any of the identified SNPs are associated with gene expression control of TP53. We will carry out further experiments to validate our findings.

Diversifying medical imaging of breast lesions

Dissertação de mestrado, Engenharia Informática, Faculdade de Ciências e Tecnologia, Universidade do Algarve, 2015

Pharmacogenetic analysis of the pregnane x receptor in breast cancer. Case-control study

Dissertação de Mestrado, Mestrado em Qualidade em Análises, Faculdade de Ciências e Tecnologia, Universidade do Algarve, 2015

Free breast and cervical exams

This sheet printed in Spanish and English shows how you may get free cervical and breast exams for cancer if you meet certain conditions.

The Activity of Breast Milk and Monoclonal HIV-specific Antibodies in Mother-to-Child Transmission

Mother-to-child transmission of HIV is a unique setting that allows us to explore both the correlates of protective immunity and the characteristics of transmitted variants. This thesis first describes the levels and functional capacity of breast milk HIV-specific antibodies in 19 women with high plasma viral loads. Neutralizing antibodies (Nabs) were detected in breast milk supernatant (BMS) of 4 of 19 women examined, were of low potency and were not associated with infant infection. The low NAb activity in BMS was reflected in binding antibody levels with HIV envelope specific IgG titers being 2.2 log10 lower in BMS versus plasma. In contrast, non- neutralizing antibodies (nNAbs) capable of antibody dependent cell-mediated cytotoxicity (ADCC) were detected in the BMS from all 19 women. BMS ADCC activity was associated with envelope-specific IgG titers (p = 0.014) and was inversely associated with infant infection risk (p = 0.039). Our data indicate that BMS has limited HIV neutralizing activity, however, BMS ADCC activity is a correlate of transmission that may impact infant infection risk. In the second part of this thesis the neutralization sensitivity of 111 variants of diverse subtypes obtained from mothers and infants was determined against 7 HIVspecific broadly neutralizing monoclonal antibodies (mAbs) (NIH45-46w, VRC01, PGT128, PGT121, PG9 PGT145 and b12). Maternal and infant variants did not differ in their neutralization sensitivity to these mAbs and neither did variants from transmitting versus those from non-transmitting women. However, subtype A viruses were iii significantly more sensitive to neutralization by NIH45-46w and VRC01 (p= 0.0001 in both cases) and PGT145 (p=0.03) compared to non-subtype A viruses. Together, NIH45- 46w and PGT128 neutralization profiles resulted in 100% coverage of the variants tested. These data suggest that the epitopes targeted by these mAbs are present and accessible in both circulating and transmitted variants and that a combination of antibodies would provide maximum coverage against diverse subtypes commonly found in HIV endemic regions. Overall, this data suggest that an antibody based HIV vaccine capable of eliciting antibodies of multiple specificities that can mediate ADCC and/or neutralizing activity can provide protection and conquer the genetic diversity displayed by HIV.

Resource security impacts men’s female breast size preferences

It has been suggested human female breast size may act as signal of fat reserves, which in turn indicates access to resources. Based on this perspective, two studies were conducted to test the hypothesis that men experiencing relative resource insecurity should perceive larger breast size as more physically attractive than men experiencing resource security. In Study 1, 266 men from three sites in Malaysia varying in relative socioeconomic status (high to low) rated a series of animated figures varying in breast size for physical attractiveness. Results showed that men from the low socioeconomic context rated larger breasts as more attractive than did men from the medium socioeconomic context, who in turn perceived larger breasts as attractive than men from a high socioeconomic context. Study 2 compared the breast size judgements of 66 hungry versus 58 satiated men within the same environmental context in Britain. Results showed that hungry men rated larger breasts as significantly more attractive than satiated men. Taken together, these studies provide evidence that resource security impacts upon men’s attractiveness ratings based on women’s breast size.

Prediction of breast cancer risk based on profiling with common genetic variants

BACKGROUND: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. METHODS: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. RESULTS: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. CONCLUSIONS: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.