The in- or exclusion of non-breast cancer related death and contralateral breast cancer significantly affects estimated outcome probability in early breast cancer.
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ABSTRACT:
SUBMITTER: Nout RA
PROVIDER: S-EPMC2668629 | biostudies-other | 2008 Jun
REPOSITORIES: biostudies-other
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Project description:Brain metastases in patients with breast cancer are associated with a poor survival rate. A small number of studies have challenged this premise, suggesting that survival times following brain metastasis differ significantly between breast cancer subtypes. In the current study, overall survival (OS), brain metastases-free survival (BMFS) and survival following brain metastases (SFBM) were found to be associated with the intrinsic breast cancer subtype. A total of 1,147 patients with invasive breast cancer who were treated at the Hannover Medical School between January 2004 and December 2010 were included, from which 54 patients with brain metastases were identified. The Kaplan-Meier method or Cox regression analyses were performed for analysis of survival. OS was found to differ significantly between breast cancer subtypes: OS was significantly shorter in patients with triple-negative (TN) cancer compared with patients with human epidermal growth factor receptor (HER2)-enriched tumors (P<0.001). In addition, median BMFS times differed significantly between luminal (1,003 days), HER2-enriched (514 days) and TN breast cancer patients (460 days) (P=0.045). The median durations of SFBM were 386 days in luminal, 310 days in HER2-enriched and 147 days in TN breast cancer patients (P=0.029). The results suggested that patients with luminal breast cancer have a lower risk of brain metastases and the most favorable outcome with regard to BMFS, whereas patients with HER2-positive or TN breast cancer have a significantly higher risk of developing brain metastases. Compared with TN breast cancer, the duration of SFBM was doubled in HER2-enriched cancers. These findings may have important implications for treatment and follow-up strategies in patients with breast cancer.
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Project description:Bridging the gap between animal or in vitro models and human disease is essential in medical research. Researchers often suggest that a biological mechanism is relevant to human cancer from the statistical association of a gene expression marker (a signature) of this mechanism, that was discovered in an experimental system, with disease outcome in humans. We examined this argument for breast cancer. Surprisingly, we found that gene expression signatures-unrelated to cancer-of the effect of postprandial laughter, of mice social defeat and of skin fibroblast localization were all significantly associated with breast cancer outcome. We next compared 47 published breast cancer outcome signatures to signatures made of random genes. Twenty-eight of them (60%) were not significantly better outcome predictors than random signatures of identical size and 11 (23%) were worst predictors than the median random signature. More than 90% of random signatures >100 genes were significant outcome predictors. We next derived a metagene, called meta-PCNA, by selecting the 1% genes most positively correlated with proliferation marker PCNA in a compendium of normal tissues expression. Adjusting breast cancer expression data for meta-PCNA abrogated almost entirely the outcome association of published and random signatures. We also found that, in the absence of adjustment, the hazard ratio of outcome association of a signature strongly correlated with meta-PCNA (R(2) = 0.9). This relation also applied to single-gene expression markers. Moreover, >50% of the breast cancer transcriptome was correlated with meta-PCNA. A corollary was that purging cell cycle genes out of a signature failed to rule out the confounding effect of proliferation. Hence, it is questionable to suggest that a mechanism is relevant to human breast cancer from the finding that a gene expression marker for this mechanism predicts human breast cancer outcome, because most markers do. The methods we present help to overcome this problem.
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Project description:Low DLC1 expression is found to frequently co-occur with aberrant expression of cell cycle genes including CDK6 in human lung and colon cancer. Here, we explore the influence of the synergistic effect of DLC1 and CDK6 on human breast cancer survival at the genetic, transcriptional, and translational levels. We found that high DLC1 and low CDK6 expression are associated with good prognosis. The DLC1 intronic SNP rs561681 is found to fit a recessive model, complying with the tumor suppressive role of DLC1. The heterozygote of the DLC1 SNP is found to increase the hazard when the CDK6 intronic SNP rs3731343 is rare homozygous, and it becomes protective when rs3731343 is common homozygous. We propose that DLC1 expression is the lowest in patients harboring the rare homozygote of rs561681 and functional DLC1 is the lowest when rs561681 is heterozygous and rs3731343 is rare homozygous. We are the first to report such synergistic effects of DLC1 and CDK6 on breast cancer survival at the transcriptional level, the overdominant model fitted by the SNP pair, and the dominant negative effect at the translational level. These findings link the germline genetic polymorphisms and synergistic effect of DLC1 and CDK6 with breast cancer progression, which provide the basis for experimentally elucidating the mechanisms driving differential tumor progression and avail in tailoring the clinical treatments for such patients based on their genetic susceptibility.
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Project description:Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.
| S-EPMC7675034 | biostudies-literature
Project description:BackgroundCytochrome P450 (CYPs) are heme proteins involved in the metabolism of a variety of endogenous and exogenous substances and play an important role in the carcinogenesis mechanisms of environmental and hereditary factors. The objective of this study was to investigate how polymorphisms of CYPs correlate with lung cancer (LC) susceptibility.MethodsSix single nucleotide polymorphisms (SNPs) were genotyped in this study. The chi-square test and unconditional logistic regression model were used to evaluate the correlation between SNPs and LC susceptibility. The expressions and survival data of genes in patients with LC were mined using Oncomine and Kaplan-Meier Plotter database.ResultsFour SNPs were found to be significantly associated with the risk of LC development (P < 0.05). The most significant correlation was that the A allele and AA genotype of CYP2D6 rs1065852 were associated with increased risk of LC development (adjusted odds ratio [OR] = 1.35, 95% confidence interval [95%CI] = 1.13-1.60, P = 9.04e-4; OR = 1.83, 95%CI = 1.29-2.59, P = 0.001 respectively). Similar association of this variant was also found in the subgroups of male patients, cases in III-IV stages, positive lymph node, squamous cell carcinomas and adenocarcinomas. Whereas rs1065852 was considered as protective factor in females (adjusted OR = 0.33, 95% CI = 0.16-0.70, P = 0.004). In stratified analyses, the association of CYP24A1 rs2762934, CYP24A1 rs6068816, CYP20A1 rs2043449 polymorphism with LC risk appeared stronger in some subgroups. CYP2D6, CYP24A1 and CYP20A1 are overexpressed in some pathological types of LC (P < 0.05), and high levels of CYP2D6 and CYP20A1 indicate poor and good prognosis of LC, respectively.ConclusionThis study revealed that rs1065852, rs2043449, rs2762s934, and rs6068816 of CYPs were associated with LC susceptibility in the Northwestern Chinese Han population; CYP2D6 and CYP20A1 were overexpressed and correlated with prognosis of LC.
| S-EPMC6712450 | biostudies-literature
Project description:We aimed to assess contralateral breast cancer (CBC) risk in patients with ductal carcinoma in situ (DCIS) compared with invasive breast cancer (BC). Women diagnosed with DCIS (N = 28,003) or stage I-III BC (N = 275,836) between 1989 and 2017 were identified from the nationwide Netherlands Cancer Registry. Cumulative incidences were estimated, accounting for competing risks, and hazard ratios (HRs) for metachronous invasive CBC. To evaluate effects of adjuvant systemic therapy and screening, separate analyses were performed for stage I BC without adjuvant systemic therapy and by mode of first BC detection. Multivariable models including clinico-pathological and treatment data were created to assess CBC risk prediction performance in DCIS patients. The 10-year cumulative incidence of invasive CBC was 4.8% for DCIS patients (CBC = 1334). Invasive CBC risk was higher in DCIS patients compared with invasive BC overall (HR = 1.10, 95% confidence interval (CI) = 1.04-1.17), and lower compared with stage I BC without adjuvant systemic therapy (HR = 0.87; 95% CI = 0.82-0.92). In patients diagnosed ≥2011, the HR for invasive CBC was 1.38 (95% CI = 1.35-1.68) after screen-detected DCIS compared with screen-detected invasive BC, and was 2.14 (95% CI = 1.46-3.13) when not screen-detected. The C-index was 0.52 (95% CI = 0.50-0.54) for invasive CBC prediction in DCIS patients. In conclusion, CBC risks are low overall. DCIS patients had a slightly higher risk of invasive CBC compared with invasive BC, likely explained by the risk-reducing effect of (neo)adjuvant systemic therapy among BC patients. For support of clinical decision making more information is needed to differentiate CBC risks among DCIS patients.
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Project description:OBJECTIVES:The study's goals were to characterize decisional conflict and preparedness for making the decision about having CPM among breast cancer patients considering CPM who do not carry cancer-predisposing mutation and to evaluate correlates of decisional conflict and preparedness. METHODS:93 women considering CPM completed a survey of decisional conflict and preparedness for the CPM decision, knowledge, perceived risk, self-efficacy, reasons for CPM, input from others and discussion with the doctor about CPM, and cancer worry. RESULTS:Between 8% and 27% of women endorsed elevated decisional conflict. Most women were satisfied with preparatory information that they were provided. Knowledge was low. Top reasons for choosing CPM were the desire for peace of mind, lowering the chance of another breast cancer, and improving survival. CONCLUSIONS:Decisional conflict is elevated in a subset of patients considering CPM. A more well-informed decision may be fostered by a comprehensive discussion about CPM with the patient's clinician, fostering self-efficacy in managing cancer worry, and helping patients understand their motivations for CPM. PRACTICE IMPLICATIONS:Clinicians working with breast cancer patients considering CPM should discuss the CPM decision, foster self-efficacy in managing cancer worry, and help patients understand their motivations for the surgery.
| S-EPMC7666877 | biostudies-literature
Project description:PurposePatients diagnosed with invasive breast cancer (BC) or ductal carcinoma in situ are increasingly choosing to undergo contralateral prophylactic mastectomy (CPM) to reduce their risk of contralateral BC (CBC). This is a particularly disturbing trend as a large proportion of these CPMs are believed to be medically unnecessary. Many BC patients tend to substantially overestimate their CBC risk. Thus, there is a pressing need to educate patients effectively on their CBC risk. We develop a CBC risk prediction model to aid physicians in this task.MethodsWe used data from two sources: Breast Cancer Surveillance Consortium and Surveillance, Epidemiology, and End Results to build the model. The model building steps are similar to those used in developing the BC risk assessment tool (popularly known as Gail model) for counseling women on their BC risk. Our model, named CBCRisk, is exclusively designed for counseling women diagnosed with unilateral BC on the risk of developing CBC.ResultsWe identified eight factors to be significantly associated with CBC-age at first BC diagnosis, anti-estrogen therapy, family history of BC, high-risk pre-neoplasia status, estrogen receptor status, breast density, type of first BC, and age at first birth. Combining the relative risk estimates with the relevant hazard rates, CBCRisk projects absolute risk of developing CBC over a given period.ConclusionsBy providing individualized CBC risk estimates, CBCRisk may help in counseling of BC patients. In turn, this may potentially help alleviate the rate of medically unnecessary CPMs.
| S-EPMC5224985 | biostudies-literature
Project description:ImportanceCoping with the current and future burden of cancer requires an in-depth understanding of trends in cancer incidences and deaths. Estimated projections of cancer incidences and deaths will be important to guide future research funding allocations, health care planning, and health policy efforts.ObjectiveTo estimate cancer incidences and deaths in the United States to the year 2040.Design and settingThis cross-sectional study's estimated projection analysis used population growth projections and current population-based cancer incidence and death rates to calculate the changes in incidences and deaths to the year 2040. Cancer-specific incidences and deaths in the US were estimated for the most common cancer types. Demographic cancer-specific delay-adjusted incidence rates from the Surveillance, Epidemiology, and End Results Program were combined with US Census Bureau population growth projections (2016) and average annual percentage changes in incidence and death rates. Statistical analyses were performed from July 2020 to February 2021.Main outcomes and measuresTotal cancer incidences and deaths to the year 2040.ResultsThis study estimated that the most common cancers in 2040 will be breast (364 000 cases) with melanoma (219 000 cases) becoming the second most common cancer; lung, third (208 000 cases); colorectal remaining fourth (147 000 cases); and prostate cancer dropping to the fourteenth most common cancer (66 000 cases). Lung cancer (63 000 deaths) was estimated to continue as the leading cause of cancer-related death in 2040, with pancreatic cancer (46 000 deaths) and liver and intrahepatic bile duct cancer (41 000 deaths) surpassing colorectal cancer (34 000 deaths) to become the second and third most common causes of cancer-related death, respectively. Breast cancer (30 000 deaths) was estimated to decrease to the fifth most common cause of cancer death.Conclusions and relevanceThese findings suggest that there will be marked changes in the landscape of cancer incidence and deaths by 2040.
| S-EPMC8027914 | biostudies-literature
Project description:BACKGROUND: We assessed the sensitivity to adjuvant chemotherapy in cell cycle checkpoint kinase 2 (CHEK2) vs non-CHEK2 breast cancer patients by comparing the contralateral breast cancer incidence and distant disease-free and breast cancer-specific survival between both groups, stratified for adjuvant chemotherapy. METHODS: One Dutch hereditary non-BRCA1/2 breast cancer patient cohort (n=1220) and two Dutch cohorts unselected for family history (n=1014 and n=2488, respectively) were genotyped for CHEK2 1100delC. Hazard ratios for contralateral breast cancer, distant disease-free and breast cancer-specific death for mutation carriers vs noncarriers were calculated using the Cox proportional hazard method, stratified for adjuvant chemotherapy. RESULTS: The CHEK2 mutation carriers (n=193) had an increased incidence of contralateral breast cancer (multivariate hazard ratio 3.97, 95% confidence interval 2.59-6.07). Distant disease-free and breast cancer-specific survival were similar in the first 6 years in mutation carriers compared with noncarriers, but diverted as of 6 years after breast cancer diagnosis (multivariate hazard ratios and 95% confidence intervals 2.65 (1.79-3.93) and 2.05 (1.41-2.99), respectively). No significant interaction between CHEK2 and adjuvant chemotherapy was observed. CONCLUSIONS: The CHEK2 1100delC-associated breast cancer is associated with a higher contralateral breast cancer rate as well as worse survival measures beyond 6 years after diagnosis. No differential sensitivity to adjuvant chemotherapy was observed in CHEK2 patients.
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