Dataset Information

No association between SNPs regulating TGF-β1 secretion and late radiotherapy toxicity to the breast: results from the RAPPER study.

ABSTRACT:

Background and purpose

Several small studies have reported associations between TGFB1 single nucleotide polymorphisms (SNPs), considered to increase secretion of TGF-β1, and greater than 3-fold increases in incidence of fibrosis - an indicator of late toxicity after radiotherapy in breast cancer patients.

Materials and methods

Two SNPs in TGFB1, C-509T (rs1800469) and L10P (rs1800470), were genotyped in 778 breast cancer patients who had received radiotherapy to the breast. Late radiotherapy toxicity was assessed two years after radiotherapy using a validated photographic technique, clinical assessment and patient questionnaires.

Results

On photographic assessment, 210 (27%) patients showed some degree of breast shrinkage, whilst 45 (6%) patients showed marked breast shrinkage. There was no significant association of genotype at either of the TGFB1 SNPs with any measure of late radiation toxicity.

Conclusion

This adequately powered trial failed to confirm previously reported increases in fibrosis with TGFB1 genotype - any increase greater than 1.36 can be excluded with 95% confidence. Similar frequent failures to replicate associations with candidate genes have been resolved using genome-wide association scans: this methodology detects common, low risk alleles but requires even larger patient numbers for adequate statistical power.

SUBMITTER: Barnett GC

PROVIDER: S-EPMC3120654 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

No association between SNPs regulating TGF-β1 secretion and late radiotherapy toxicity to the breast: results from the RAPPER study.

Barnett Gillian C GC Coles Charlotte E CE Burnet Neil G NG Pharoah Paul D P PD Wilkinson Jennifer J West Catharine M L CM Elliott Rebecca M RM Baynes Caroline C Dunning Alison M AM

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 20100122 1

<h4>Background and purpose</h4>Several small studies have reported associations between TGFB1 single nucleotide polymorphisms (SNPs), considered to increase secretion of TGF-β1, and greater than 3-fold increases in incidence of fibrosis - an indicator of late toxicity after radiotherapy in breast cancer patients.<h4>Materials and methods</h4>Two SNPs in TGFB1, C-509T (rs1800469) and L10P (rs1800470), were genotyped in 778 breast cancer patients who had received radiotherapy to the breast. Late r ...[more]

PMID: 20096948

Similar Datasets

Project description:Radiation-induced normal-tissue toxicities are common, complex, and distressing side effects that affect 90% of patients receiving breast-cancer radiotherapy and 40% of patients post radiotherapy. In this study, the authors investigated the use of spectrophotometry and ultrasound to quantitatively measure radiation-induced skin discoloration and subcutaneous-tissue fibrosis. The study's purpose is to determine whether skin discoloration correlates with the development of fibrosis in breast-cancer radiotherapy.Eighteen breast-cancer patients were enrolled in our initial study. All patients were previously treated with a standard course of radiation, and the median follow-up time was 22 months. The treated and untreated breasts were scanned with a spectrophotometer and an ultrasound. Two spectrophotometer parameters-melanin and erythema indices-were used to quantitatively assess skin discoloration. Two ultrasound parameters-skin thickness and Pearson coefficient of the hypodermis-were used to quantitatively assess severity of fibrosis. These measurements were correlated with clinical assessments (RTOG late morbidity scores).Significant measurement differences between the treated and contralateral breasts were observed among all patients: 27.3% mean increase in skin thickness (p < 0.001), 34.1% mean decrease in Pearson coefficient (p < 0.001), 27.3% mean increase in melanin (p < 0.001), and 22.6% mean increase in erythema (p < 0.001). All parameters except skin thickness correlated with RTOG scores. A moderate correlation exists between melanin and erythema; however, spectrophotometer parameters do not correlate with ultrasound parameters.Spectrophotometry and quantitative ultrasound are objective tools that assess radiation-induced tissue injury. Spectrophotometer parameters did not correlate with those of quantitative ultrasound suggesting that skin discoloration cannot be used as a marker for subcutaneous fibrosis. These tools may prove useful for the reduction of radiation morbidities and improvement of patient quality of life.

Project description:Radiotherapy is widely applied in breast cancer treatment, while radiotherapy resistance is inevitable. TGF-β1 has been considered to be an endogenous factor for the development of radiotherapy resistance. As a large portion of TGF-β1 is secreted in an extracellular vesicles-associated form (TGF-β1EV), particularly in radiated tumors. Thus, the understanding of the regulation mechanisms and the immunosuppressive functions of TGF-β1EV will pave a way for overcoming the radiotherapy resistance in cancer treatment. The superoxide-Zinc-PKC-ζ-TGF-β1EV pathway in breast cancer cells was identified through sequence alignments of different PKC isoforms, speculation and experimental confirmation. A series of functional and molecular studies were performed by quantitative real-time PCR, western blot and flow cytometry analysis. Mice survival and tumor growth were recorded. Student's t test or two-way ANOVA with correction was used for comparisons of groups. The radiotherapy resulted in an increased expression of the intratumoral TGF-β1 and an enhanced infiltration of the Tregs in the breast cancer tissues. The intratumoral TGF-β1 was found mainly in the extracellular vesicles associated form both in the murine breast cancer model and in the human lung cancer tissues. Furthermore, radiation induced more TGF-β1EV secretion and higher percentage of Tregs by promoting the expression and phosphorylation of protein kinase C zeta (PKC-ζ). Importantly, we found that naringenin rather than 1D11 significantly improved radiotherapy efficacy with less side effects. Distinct from TGF-β1 neutralizing antibody 1D11, the mechanism of naringenin was to downregulate the radiation-activated superoxide-Zinc-PKC-ζ-TGF-β1EV pathway. The superoxide-zinc-PKC-ζ-TGF-β1EV release pathway was elucidated to induce the accumulation of Tregs, resulting in radiotherapy resistance in the TME. Therefore, targeting PKC-ζ to counteract TGF-β1EV function could represent a novel strategy to overcome radiotherapy resistance in the treatment of breast cancer or other cancers. The using of patient tissues with malignant Non-Small Cell Lung Cancer (NSCLC) was approved by the ethics committees at Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (NCC2022C-702, from June 8th, 2022).

Project description:BackgroundRadiation-induced heart disease is mainly caused by activation of the fibrotic process. Transforming growth factor-beta 1 (TGF-β1) and platelet-derived growth factor (PDGF) are pro-fibrotic mediators. The aim of our study was to evaluate the behavior of TGF-β1 and PDGF during adjuvant radiotherapy (RT) for breast cancer and the association of these cytokines with echocardiographic changes.MethodsOur study included 73 women with early-stage breast cancer or ductal carcinoma in situ (DCIS) receiving post-operative RT but not chemotherapy. TGF-β1 and PDGF levels in serum samples taken before and on the last day of RT were measured by an enzyme-linked immunosorbent assay. Echocardiography was also performed at same time points. Patients were grouped according to a ≥ 15% worsening in tricuspid annular plane systolic excursion (TAPSE) and pericardium calibrated integrated backscatter (cIBS).ResultsIn all patients, the median TGF-β1 decreased from 25.0 (IQR 21.1-30.3) ng/ml to 23.6 (IQR 19.6-26.8) ng/ml (p = 0.003), and the median PDGF decreased from 18.0 (IQR 13.7-22.7) ng/ml to 15.6 (IQR 12.7-19.5) ng/ml (p < 0.001). The baseline TGF-β1, 30.7 (IQR 26.0-35.9) ng/l vs. 23.4 (IQR 20.1-27.3) ng/l (p < 0.001), and PDGF, 21.5. (IQR 15.7-31.2) ng/l vs. 16.9. (IQR 13.0-21.2) ng/ml, were higher in patients with a ≥ 15% decrease in TAPSE than in patients with a < 15% decrease. In patients with a ≥ 15% decrease in TAPSE, the median TGF-β1 decreased to 24.7 (IQR 20.0-29.8) ng/ml (p < 0.001), and the median PDGF decreased to 16.7 (IQR 12.9-20.9) ng/ml (p < 0.001). The patients with a < 15% decrease had stable TGF-β1 (p = 0.104), but PDGF decreased to 15.1 (IQR 12.5-18.6), p = 0.005. The patients with a ≥ 15% increase in cIBS exhibited a decrease in TGF-β1 from 26.0 (IQR 21.7-29.7) to 22.5 (IQR 16.6.-26.7) ng/ml, p < 0.001, and a decrease in PDGF from 19.8 (IQR 14.6-25.9) to 15.7 (IQR 12.8-20.2) ng/ml, p < 0.001. In patients with a < 15% increase, TGF-β1 and PDGF did not change significantly, p = 0.149 and p = 0.053, respectively.ConclusionWe observed a decrease in TGF-β1 and PDGF levels during adjuvant RT for breast cancer. Echocardiographic changes, namely, in TAPSE and cIBS, were associated with a greater decrease in TGF-β1 and PDGF levels. Longer follow-up times will show whether these changes observed during RT translate into increased cardiovascular morbidity.

Project description:Radiotherapy (RT) induced toxicity in elderly patients is not well documented in the available literature due to the inhomogeneous and fragmentary data. Aim of this study was to review literature data on acute and late toxicity in elderly breast cancer patients treated with RT. The primary endpoint was RT-related acute and late toxicity in elderly breast cancer (BC) patients. The secondary endpoint was RT interruption rate in this patients' population. All studies reporting RT-related acute and/or late toxicity in elderly women with breast cancer were included. All types of RT settings were included and no restriction was applied regarding other primary/adjuvant associated treatment. A bibliographic search was performed on PubMed. Only articles in English were considered while no chronological limitation was applied. Twenty-two studies were included in this analysis: 12 retrospective, 5 prospective observational trials, 1 phase III trial sub-analysis, and 4 phase I-II trials. Thirteen studies reported results about whole breast irradiation (WBI) delivered by external beams (EB) RT ± boost on the tumor bed. Nine studies reported results about accelerated partial breast irradiation (APBI) based on EB RT (2 studies), intraoperative RT (IORT: 2 studies), and brachytherapy (BRT: 2 studies); three studies compared different treatment techniques. Overall, reported acute grade (G) ≥3 toxicity ranged from 0.0% to 10.5% and late toxicity from 0.0% to 13.0%. RT discontinuation/interruption rates ranged between 0.0% and 2.0%. Acute G ≥3 toxicity rates were 2.0%, 6.7%, and 5.2% with EB-APBI, BRT, and IORT, respectively. Late G ≥3 toxicity with EB-APBI was 2.8%. No late G ≥3 toxicity was recorded in studies reporting on BRT and IORT. With WBI, the overall rates of G ≥3 toxicity were 3.0% (acute) and 1.8% (late). Higher toxicity rates were observed with weekly hypofractionation. None of the studies directly comparing age subgroups found age-related differences. Our findings suggest that RT of breast cancer is well tolerated even in elderly patients with toxicity rates comparable to those of the general population. Given these considerations, RT omission in elderly patients with breast cancer should be carefully evaluated limiting this option to very selected critical patients.

Dataset Information

No association between SNPs regulating TGF-β1 secretion and late radiotherapy toxicity to the breast: results from the RAPPER study.

Background and purpose

Materials and methods

Results

Conclusion

Publications

No association between SNPs regulating TGF-β1 secretion and late radiotherapy toxicity to the breast: results from the RAPPER study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets