Modulating the Radiation Response for Improved Outcomes in Breast Cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Pesch AM
PROVIDER: S-EPMC8232831 | biostudies-literature | 2021
REPOSITORIES: biostudies-literature
Publications
Modulating the Radiation Response for Improved Outcomes in Breast Cancer.
Pesch Andrea M AM Pierce Lori J LJ Speers Corey W CW
JCO precision oncology 20210125
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Project description:PurposeProphylactic cranial irradiation (PCI) involves giving radiation to the entire brain with the goals of reducing the incidence of brain metastasis and improving overall survival. Experimentally, we have demonstrated that PCI prevents brain metastases in a breast cancer mouse model. We developed a computational model to expand on and aid in the interpretation of our experimental results.Methods and materialsMATLAB was used to develop a computational model of brain metastasis and PCI in mice. Model input parameters were optimized such that the model output would match the experimental number of metastases per mouse from the unirradiated group. An independent in vivo-limiting dilution experiment was performed to validate the model. The effect of whole brain irradiation at different measurement points after tumor cells were injected was evaluated in terms of the incidence, number of metastases, and tumor burden and was then compared with the corresponding experimental data.ResultsIn the optimized model, the correlation between the number of metastases per mouse and the experimental fits was >95. Our attempt to validate the model with a limiting dilution assay produced 99.9% correlation with respect to the incidence of metastases. The model accurately predicted the effect of whole-brain irradiation given 3 weeks after cell injection but substantially underestimated its effect when delivered 5 days after cell injection. The model further demonstrated that delaying whole-brain irradiation until the development of gross disease introduces a dose threshold that must be reached before a reduction in incidence can be realized.ConclusionsOur computational model of mouse brain metastasis and PCI correlated strongly with our experiments with unirradiated mice. The results further suggest that early treatment of subclinical disease is more effective than irradiating established disease.
| S-EPMC5702256 | biostudies-literature
Project description:Prostate cancer (PCa) is the most common non-cutaneous cancer in men and a notable cause of cancer mortality when it metastasises. The unfolded protein response (UPR) can be cytoprotective but when acutely activated can lead to cell death. In this study, we sought to enhance the acute activation of the UPR using radiation and ONC201, an UPR activator. Treating PCa cells with ONC201 quickly increased the expression of all the key regulators of the UPR and reduced the oxidative phosphorylation, with cell death occurring 72 h later. We exploited this time lag to sensitize prostate cancer cells to radiation through short-term treatment with ONC201. To understand how priming occurred, we performed RNA-Seq analysis and found that ONC201 suppressed the expression of cell cycle and DNA repair factors. In conclusion, we have shown that ONC201 can prime enhanced radiation response.
| S-EPMC7896060 | biostudies-literature
Project description:Importance:The association between exposure to hormone-modulating therapy (HMT) as breast cancer treatment and neurodegenerative disease (NDD) is unclear. Objective:To determine whether HMT exposure is associated with the risk of NDD in women with breast cancer. Design, Setting, and Participants:This retrospective cohort study used the Humana claims data set from January 1, 2007, to March 31, 2017. The Humana data set contains claims from private-payer and Medicare insurance data sets from across the United States with a population primarily residing in the Southeast. Patient claims records were surveyed for a diagnosis of NDD starting 1 year after breast cancer diagnosis for the duration of enrollment in the claims database. Participants were 57 843 women aged 45 years or older with a diagnosis of breast cancer. Patients were required to be actively enrolled in Humana claims records for 6 months prior to and at least 3 years after the diagnosis of breast cancer. The analyses were conducted between January 1 and 15, 2020. Exposure:Hormone-modulating therapy (selective estrogen receptor modulators, estrogen receptor antagonists, and aromatase inhibitors). Main Outcomes and Measures:Patients receiving HMT for breast cancer treatment were identified. Survival analysis was used to determine the association between HMT exposure and diagnosis of NDD. A propensity score approach was used to minimize measured and unmeasured selection bias. Results:Of the 326 485 women with breast cancer in the Humana data set between 2007 and 2017, 57 843 met the study criteria. Of these, 18 126 (31.3%; mean [SD] age, 76.2 [7.0] years) received HMT, whereas 39 717 (68.7%; mean [SD] age, 76.8 [7.0] years) did not receive HMT. Mean (SD) follow-up was 5.5 (1.8) years. In the propensity score-matched population, exposure to HMT was associated with a decrease in the number of women who received a diagnosis of NDD (2229 of 17 878 [12.5%] vs 2559 of 17 878 [14.3%]; relative risk, 0.89; 95% CI, 0.84-0.93; P < .001), Alzheimer disease (877 of 17 878 [4.9%] vs 1068 of 17 878 [6.0%]; relative risk, 0.82; 95% CI, 0.75-0.90; P < .001), and dementia (1862 of 17 878 [10.4%] vs 2116 of 17 878 [11.8%]; relative risk, 0.88; 95% CI, 0.83-0.93; P < .001). The number needed to treat was 62.51 for all NDDs, 93.61 for Alzheimer disease, and 69.56 for dementia. Conclusions and Relevance:Among patients with breast cancer, tamoxifen and steroidal aromatase inhibitors were associated with a decrease in the number who received a diagnosis of NDD, specifically Alzheimer disease and dementia.
| S-EPMC7093781 | biostudies-literature
Project description:PurposePrevious reports suggest that radiation therapy for breast cancer (BC) can cause ischemic heart disease, with the radiation-related risk increasing linearly with mean whole heart dose (MWHD). This study aimed to validate these findings in younger BC patients and to investigate additional risk factors for radiation-related myocardial infarction (MI).Methods and materialsA nested case-control study was conducted within a cohort of BC survivors treated during 1970 to 2009. Cases were 183 patients with MI as their first heart disease after BC. One control per case was selected and matched on age and BC diagnosis date. Information on treatment and cardiovascular risk factors was abstracted from medical and radiation charts. Cardiac doses were estimated for each woman by reconstructing her regimen using modern 3-dimensional computed tomography planning on a typical patient computed tomography scan.ResultsMedian age at BC of cases and controls was 50.2 years (interquartile range, 45.7-54.7). Median time to MI was 13.6 years (interquartile range, 9.9-18.1). Median MWHD was 8.9 Gy (range, 0.3-35.2 Gy). MI rate increased linearly with increasing MWHD (excess rate ratio [ERR] per Gy, 6.4%; 95% confidence interval, 1.3%-16.0%). Patients receiving ≥20 Gy MWHD had a 3.4-fold (95% confidence interval, 1.5-7.6) higher MI rate than unirradiated patients. ERRs were higher for younger women, with borderline significance (ERR<45years, 24.2%/Gy; ERR≥50years, 2.5%/Gy; Pinteraction = .054). Whole heart dose-volume parameters did not modify the dose-response relationship significantly.ConclusionsMI rate after radiation for BC increases linearly with MWHD. Reductions in MWHD are expected to contribute to better cardiovascular health of BC survivors.
| S-EPMC6361769 | biostudies-literature
Project description:The microenvironment of breast cancer actively participates in tumorigenesis and cancer progression. The changes observed in the architecture of the extracellular matrix initiate an oncogene-mediated cell reprogramming, that leads to a massive triggering of YAP nuclear entry, and, therefore, to cancer cell proliferation, invasion and probably to increased radiation-resistance. However, it is not yet fully understood how radiotherapy regulates the expression and subcellular localization of YAP in breast cancer cells experiencing different microenvironmental stiffnesses. To elucidate the role of extracellular matrix stiffness and ionizing radiations on YAP regulation, we explored the behaviour of two different mammary cell lines, a normal epithelial cell line (MCF10A) and a highly aggressive and invasive adenocarcinoma cell line (MDA-MB-231) interacting with polyacrylamide substrates mimicking the mechanics of both normal and tumour tissues (∼1 and ∼13 kPa). We report that X-ray radiation affected in a significant way the levels of YAP expression, density, and localization in both cell lines. After 24 h, MCF10A and MDA-MB-231 increased the expression level of YAP in both nucleus and cytoplasm in a dose dependent manner and particularly on the stiffer substrates. After 72 h, MCF10A reduced mostly the YAP expression in the cytoplasm, whereas it remained high in the nucleus of cells on stiffer substrates. Tumour cells continued to exhibit higher levels of YAP expression, especially in the cytoplasmic compartment, as indicated by the reduction of nuclear/cytoplasmic ratio of total YAP. Then, we investigated the existence of a correlation between YAP localization and the expression of the nuclear envelope protein lamin A/C, considering its key role in modulating nuclear deformability and changes in YAP shuttling phenomena. As supposed, we found that the effects of radiation on YAP nucleus/cytoplasmic expression ratio, increasing in healthy cells and decreasing in tumour ones, were accompanied by lower and higher lamin A/C levels in MCF10A and MDA-MB-231 cells, respectively. These findings point to obtain a deeper knowledge of the role of the extracellular matrix and the effects of X-rays on YAP and lamin A/C expression that can be used in the design of doses and timing of radiation therapy.
| S-EPMC9450017 | biostudies-literature
Project description:We sought to determine whether dysregulation of the retinoblastoma (RB) tumor suppressor pathway was associated with improved response to neoadjuvant chemotherapy in breast cancer.An RB-loss signature was used to analyze the association between pathway status and pathologic complete response in gene expression datasets encompassing three different neoadjuvant regimens. Parallel immunohistochemical analysis of the RB pathway was conducted on pretreatment biopsies to determine the association with pathologic response to neoadjuvant chemotherapy.An RB-loss gene expression signature was associated with increased pathologic complete response in datasets from breast cancer patients treated with 5-fluorouracil/adriamycin/cytoxan (FAC; P < 0.001), T/FAC (P < 0.001), and Taxane/Adriaymcin (P < 0.001) neoadjuvant therapy encompassing approximately 1,000 patients. The association with improved response to neoadjuvant chemotherapy was true in both estrogen receptor (ER)-positive and ER-negative breast cancer. Elevated expression of p16ink4a is associated with the RB-loss signature (R = 0.493-0.5982), and correspondingly p16ink4a mRNA levels were strongly associated with pathologic complete response in the same datasets analyzed. In an independent cohort, immunohistochemical analyses of RB and p16ink4a revealed an association of RB loss (P = 0.0018) or elevated p16ink4a (P = 0.0253) with pathologic complete response. In addition, by Miller-Payne and clinicopathologic scoring analyses, RB-deficient tumors experienced an overall improved response to neoadjuvant chemotherapy.Disruption of the RB pathway as measured by several independent methods was associated with improved response to neoadjuvant chemotherapy. The RB-pathway status was relevant for pathologic response in both ER-positive and ER-negative breast cancer with similar results observed with multiple chemotherapy regimens. Combined, these data indicate that RB status is associated with the response to neoadjuvant chemotherapy in breast cancer and could be used to inform treatment.
| S-EPMC4436088 | biostudies-other
Project description:BackgroundFor low risk breast cancer, the TARGIT-A randomized trial supported lumpectomy with intraoperative radiation therapy (IORT) and selective whole breast radiation (WBXRT). Selection criteria for WBXRT vary.MethodsWomen with hormone-receptor positive, clinically node-negative breast cancer were categorized retrospectively as suitable for IORT alone or also needing WBXRT by TARGIT-A or expanded TARGIT criteria (TARGIT-MCC). We evaluated local recurrence (LR) by selection criteria and receipt of WBXRT.ResultsAmong 194 cases followed a median of 44 months, 54 (27.8%) met TARGIT-MCC criteria for WBXRT (34 met TARGIT-A criteria). Thirty patients were recommended and 21 (10.8%) received WBXRT. Of 13 patients with LR, none received WBXRT. LR was 10.5% in patients meeting TARGIT-MCC criteria who did not receive WBXRT versus 0% after WBXRT (p = 0.299).ConclusionsSelective WBXRT may have mitigated LR. Nearly all LR were in patients not recommended WBXRT. Further work should refine criteria for WBXRT after IORT.SummaryPrior work among women with early breast cancer supported lumpectomy with intraoperative radiation therapy and selective adjuvant radiation using a risk-adapted approach. An expanded set of criteria for adjuvant radiation appear to further mitigate local recurrence risk. Local recurrence after lumpectomy with IORT could be further minimized by identification of additional high-risk features, as well as greater adherence to adjuvant endocrine therapy.
| S-EPMC7810130 | biostudies-literature
Project description:RNA-Seq analysis of prostate cancer cells primed to irradiation for 24hours with ONC201 shows a sustained suppression of transcripts encoding cell cycle regulators as well as components of the DNA damage response pathways.
2021-02-21 | GSE136975 | GEO
Project description:BackgroundPathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) is associated with improved overall survival (OS) in patients with breast cancer, but it is unclear how post-NACT response influences radiation therapy administration in patients presenting with node-positive disease. We sought to determine whether nodal pCR is associated with likelihood of receiving nodal radiation and whether radiation therapy among patients experiencing nodal pCR is associated with improved OS.Methods and materialsClinical N1 (cN1) female breast cancer patients diagnosed during 2010 to 2015 who were ypN0 (ie, nodal pCR; n = 12,341) or ypN1 (ie, residual disease; n = 13,668) after NACT were identified in the National Cancer Database. Multivariate logistic regression was used to identify factors associated with receiving radiation therapy. Cox proportional hazards modeling was used to estimate the association between radiation therapy and adjusted OS.ResultsThe study included 26,009 patients; 43.9% (n = 5423) of ypN0 and 55.3% (n = 7556) of ypN1 patients received nodal radiation. Rates of nodal radiation remained the same over time among ypN0 patients (trend test, P = .29) but increased among ypN1 patients from 49% in 2010 to 59% in 2015 (trend test, P < .001). After adjusting for covariates, nodal pCR (vs no stage change) was associated with decreased likelihood of nodal radiation after mastectomy (∼20% decrease) and lumpectomy (∼30% decrease; both P < .01). After mastectomy, nodal (vs no) radiation conferred no significant survival benefit in ypN0 patients, but it approached significance for ypN1 patients (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.69-0.99, P = .04; overall P = .11). After lumpectomy, nodal radiation was associated with improved adjusted OS for ypN0 (HR, 0.38; 95% CI, 0.22-0.66) and ypN1 patients (HR, 0.44; 95% CI, 0.30-0.66; both P < .001), but this improvement was not significantly greater than that associated with breast-only radiation.ConclusionsypN0 patients were less likely to receive nodal radiation than ypN1 patients were, suggesting that selective omission already occurs and, in the context of limited survival data, could potentially be appropriate for select patients.
| S-EPMC6957225 | biostudies-literature
Project description:The relationship between solar ultraviolet radiation and the risk of breast cancer is conflicting. The purpose of our study was to quantitatively assess the relationship between solar ultraviolet radiation and breast cancer risk and to analyze related factors such as age and sunscreen use.Articles indexed in PubMed and Embase and published between January 2005 and March 2020 were searched for relevant keywords. The relative risk was calculated using random-effect or fixed-effect models in the meta-analysis and dose-response meta-analysis, which were conducted according to the Meta-Analyses of Observational Studies in Epidemiology reporting guidelines. Sensitivity analyses for heterogeneity and publication bias were evaluated.Six studies were eligible for inclusion in the meta-analysis, and three of these were included in the dose-response analysis. We found a correlation between exposure to solar ultraviolet radiation and breast cancer risk (relative risk: 0.70, 95% confidence interval: 0.65, 0.75). We also found a linear dose-response relationship between the exposure and breast cancer risk (relative risk: 0.86, 95% confidence interval: 0.81, 0.91) in women over 40. Not tanning and covering the limbs were associated with breast cancer risk, but sunscreen use was not.Exposure to solar ultraviolet radiation is negatively correlated with breast cancer risk, and the association is linear in women over 40. This is the first dose-response meta-analysis on the topic, and the influence of factors such as estrogen receptor status, occupational exposure, and ethnicity requires in-depth study.
| S-EPMC7647621 | biostudies-literature