Netherlands Cancer Institute - Breast Cancer Neoadjuvant chemotherapy biomarker studies
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PROVIDER: EGAC00001002452 | EGA |
REPOSITORIES: EGA
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Project description:The concept of breast-conserving surgery is a remarkable achievement of breast cancer therapy. Neoadjuvant chemotherapy is being used increasingly to shrink the tumor prior to surgery. Neoadjuvant chemotherapy is reducing the tumor size to make the surgery with less damaging to surrounding tissue and downstage locally inoperable disease to operable. However, non-effective neoadjuvant chemotherapy could increase the risks of delaying surgery, develop unresectable disease and metastatic tumor spread. The biomarkers for predicting the neoadjuvant chemotherapy effect are scarce in breast cancer treatment. In this study, we identified that FZR1 can be a novel biomarker for breast cancer neoadjuvant chemotherapy according to clinical patient cohort evaluation and molecular mechanism investigation. Transcriptomic data analysis indicated that the expression of FZR1 is correlated with the effect of neoadjuvant chemotherapy. Mechanistically, we demonstrate that FZR1 is pivotal to the chemotherapy drugs induced apoptosis and cell cycle arrest. FZR1 is involved in the stability of p53 by impairing the phosphorylation at ser15 site. We demonstrate that the expression of FZR1 detected by quantification of IHC can be an effective predictor of neoadjuvant chemotherapy in animal experiment and clinical patient cohort. To obtain more benefit for breast cancer patient, we propose that the FZR1 IHC score using at the clinical to predict the effect of neoadjuvant chemotherapy.
| S-EPMC7519164 | biostudies-literature
Project description:Background: Early prediction of response to neoadjuvant chemotherapy (NAC) is critical in choosing appropriate chemotherapeutic regimen for patients with locally advanced breast cancer. Herein, we sought to identify potential biomarkers to predict the response to neoadjuvant chemotherapy for breast cancer patients.Methods: Three genomic profiles acquired by microarray analysis from subjects with or without residual tumors after NAC downloaded from the GEO database were used to screen the differentially expressed genes (DEGs). An array of public databases, including ONCOMINE, cBioportal, Breast Cancer Gene Expression Miner v4.0, and the Kaplan Meir-plotter, etc., were used to evaluate the potential functions, related signaling pathway, as well as prognostic values of FABP7 in breast cancer. Anti-cancer drug sensitivity assay, real-time PCR, flow cytometry and western-blotting assays were used to investigate the function of FABP7 in breast cancer cells and examine the relevant mechanism.Results: Two differentially expressed genes, including FABP7 and ESR1, were identified to be potential indicators of response to anthracycline and taxanes for breast cancer. FABP7 was associated with better chemotherapeutic response, while ESR1 was associated with poorer chemotherapeutic effectiveness. Generally, the expression of FABP7 was significantly lower in breast cancer than normal tissue samples. FABP7 mainly high expressed in ER-negative breast tumor and might regulate cell cycle to enhance chemosensitivity. Moreover, elevated FABP7 expression increased the percentage of cells at both S and G2/M phase in MDA-MB-231-ADR cells, and decreased the percentage of cells at G0/G1 phase, as compared to control group. Western-blotting results showed that elevated FABP7 expression could increase Skp2 expression, while decrease Cdh1 and p27kip1 expression in MDA-MB-231-ADR cells. In addition, FABP7 was correlated to longer recurrence-free survival (RFS) in BC patients with ER-negative subtype of BC treated with chemotherapy.Conclusion: FABP7 is a potential favorable biomarker and predicts better response to NAC in breast cancer patients. Future study on the predictive value and detail molecular mechanisms of FABP7 in contribution to chemosensitivity in breast cancer is warranted.
| S-EPMC7684949 | biostudies-literature
Project description:In estrogen receptor (ER)-positive breast cancer, changes in biomarker expression after neoadjuvant therapy indicate the therapeutic response and are prognostic. However, there is limited information about the biomarker alteration caused by neoadjuvant endocrine therapy in ER-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. We recruited ER-positive/HER2-negative breast cancer patients who received neoadjuvant chemotherapy (NCT), neoadjuvant endocrine therapy (NET), or sequential neoadjuvant endocrine-chemotherapy (NECT) at Peking University Cancer Hospital from 2015 to 2021. A total of 579 patients had paired immunohistochemistry information in both diagnostic biopsy samples and post-neoadjuvant therapy surgical samples. Through a paired comparison of the immunohistochemical information in pre-treatment and post-treatment samples, we found that progesterone receptor (PR) expression reductions were more frequent than ER expression reductions (70.8% vs. 35.2%) after neoadjuvant therapy. The percentage of patients who had a decreased Ki-67 index in the post-operative samples was similar in the three groups (79.8% vs. 79.7% vs. 78.4%). Moreover, PR losses caused by NET were related to low baseline PR expression (p = 0.001), while we did not find a significant association between PR losses and Ki-67 reductions (p = 0.428) or ER losses (p = 0.274). All three types of neoadjuvant therapies caused a reduction in ER, PR, and Ki-67 expression. In conclusion, we found that PR loss after NET was only significantly related to low baseline PR expression, and there is no significant difference in the extent of prognostic factor change including Ki-67 and ER between the PR loss and non-loss groups.
| S-EPMC9866043 | biostudies-literature
Project description:Due to the positive association between neoadjuvant chemotherapy (NACT) and the promising early response rates of patients with triple negative breast cancer (TNBC), including probabilities of pathological complete response, NACT is increasingly used in TNBC management. Liquid biopsy‑based biomarkers with the power to diagnose the early response to NACT may support established monitoring tools, which are to a certain extent imprecise and costly. Simple serum‑ or urine‑based analyses of non‑coding RNA (ncRNA) expression may allow for fast, minimally‑invasive testing and timely adjustment of the therapy regimen. The present study investigated breast cancer‑related ncRNAs [microRNA (miR)‑7, ‑9, ‑15a, ‑17, ‑18a, ‑19b, ‑21, ‑30b, ‑222 and ‑320c, PIWI‑interacting RNA‑36743 and GlyCCC2] in triple positive BT‑474 cells and three TNBC cell lines (BT‑20, HS‑578T and MDA‑MB‑231) treated with various chemotherapeutic agents using reverse transcription‑quantitative PCR. Intracellular and secreted microvesicular ncRNA expression levels were analysed using a multivariable statistical regression analysis. Chemotherapy‑driven effects were investigated by analysing cell cycle determinants at the mRNA and protein levels. Serum and urine specimens from 8 patients with TNBC were compared with 10 healthy females using two‑sample t‑tests. Samples from the patients with TNBC were compared at two time points. Chemotherapeutic treatments induced distinct changes in ncRNA expression in TNBC cell lines and the BT‑474 cell line in intra‑ and extracellular compartments. Serum and urine‑based ncRNA expression analysis was able to discriminate between patients with TNBC and controls. Time point comparisons in the urine samples of patients with TNBC revealed a general rise in the level of ncRNA. Serum data suggested a potential association between piR‑36743, miR‑17, ‑19b and ‑30b expression levels and an NACT‑driven complete clinical response. The present study highlighted the potential of ncRNAs as liquid biopsy‑based biomarkers in TNBC chemotherapy treatment. The ncRNAs tested in the present study have been previously investigated for their involvement in BC or TNBC chemotherapy responses; however, these previous studies were restricted to patient tissue or in vitro models. The data from the present study offer novel insight into ncRNA expression in liquid samples from patients with TNBC, and the study serves as an initial step in the evaluation of ncRNAs as diagnostic biomarkers in the monitoring of TNBC therapy.
| S-EPMC6910196 | biostudies-literature
Project description:The advancement in systemic neoadjuvant therapy has significantly increased the pathological complete response (pCR) rate in breast cancer. As surgeries inevitably affect patients physically and psychologically and the accuracy of pCR prediction and diagnosis by minimal invasive biopsy is improving, the necessity of surgery in neoadjuvant chemotherapy (NAC) patients who achieve pCR is under debate. Thus, we conducted a literature review of studies on the selective omission of breast surgery after NAC for breast cancer patients. We summarized the existing predictive models and technologies to predict and diagnose pCR after NAC. Our research indicates that, for nearly half a century, the extent of surgery on both breast and axillary lymph nodes is decreasing, while more precise systematic treatments are increasing. NAC has advanced significantly and its pCR rates have improved, so surgery may be omitted in certain patients. However, accurately predicting pCR after NAC is still a challenge. We also described the design for a randomized clinical trial and the potential problems of omitting surgical treatment after NAC. In summary, the decrease in breast cancer surgery is an unavoidable trend, and more high-quality clinical trials need to be conducted.
| S-EPMC9442028 | biostudies-literature
Project description:Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with higher mortality than the others. Pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is considered as a surrogate to predict survival. Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) is a negative regulator of T cell activation, and reduction in ITPKC function is known to promote Kawasaki disease. Given the role of tumor infiltrating lymphocytes in NAC and since TNBC has the most abundant immune cell infiltration in breast cancer, we hypothesized that the ITPKC expression level is associated with NAC response and prognosis in TNBC. The ITPKC gene was expressed in the mammary gland, but its expression was highest in breast cancer cells among other stromal cells in a bulk tumor. ITPKC expression was highest in TNBC, associated with its survival, and was its independent prognostic factor. Although high ITPKC was not associated with immune function nor with any immune cell fraction, low ITPKC significantly enriched cell proliferation-related gene sets in TNBC. TNBC with low ITPKC achieved a significantly higher pCR rate after NAC. To the best of our knowledge, this is the first report to demonstrate that ITPKC gene expression may be useful as a prognostic and predictive biomarker in TNBC.
| S-EPMC7601042 | biostudies-literature
Project description:PurposeNeoadjuvant chemotherapy (NAC) is widely used to treat breast cancer (BC). The prediction and evaluation of chemotherapy responses remains a significant challenge.MethodsMicroRNAs (miRNAs) play a crucial role in cancer drug resistance. We used a miRNA microarray and identified that miR-638 is downregulated in chemoresistant cases. However, the exact role of miR-638 and the underlying mechanisms of chemoresistance remain unclear. Using real-time quantitative reverse transcription polymerase chain reaction, we found significant downregulation of miR-638 in chemoresistant patients compared with chemosensitive patients. To explore the function of miR-638, we overexpressed and inhibited miR-638 expression in MDA-MB-231 and MCF-7 cells by transfecting them with miR-638 mimics and miR-638 inhibitor, respectively. Cell proliferation and apoptosis were measured using MTS and flow cytometry, respectively. A minimal patient-derived xenograft (MiniPDX™) model was established to evaluate the chemosensitivity to different drugs.ResultsThe results showed that cell proliferation decreased and cell apoptosis increased in cells transfected with the miR-638 mimic, and cell proliferation and apoptosis were reversed with transfection of miR-638 inhibitor compared with the control group. Among patients who received 5-fluorouracil (5-FU), miR-638 expression levels were lower in the chemoresistant group than in the chemosensitive group. The MiniPDX™ model showed that MDA-MB-231 cells overexpressing miR-638 were more susceptible to 5-FU treatment in vivo.ConclusionWe provided evidence of acquired resistance to 5-FU caused by miR-638 deficiency. Alterations in miR-638 may be used with 5-FU chemotherapy during NAC for BC.
| S-EPMC9250877 | biostudies-literature
Project description:Breast cancer is the most common cancer in women worldwide, affecting one in eight women in their lifetime. Taxane-based chemotherapy is routinely used in the treatment of breast cancer. The purpose of this study was to develop and validate a predictive biomarker to improve the benefit/risk ratio for that cytotoxic chemotherapy. We explicitly strived for a biomarker that enables secure translation into clinical practice. We used genome-wide gene expression data of the Hatzis et al. discovery cohort of 310 patients for biomarker development and three independent cohorts with a total of 567 breast cancer patients for validation. We were able to develop a biomarker signature that consists of just the three gene products ELF5, SCUBE2 and NFIB, measured on RNA level. Compared to Hatzis et al., we achieved a significant improvement in predicting responders and non-responders in the Hatzis et al. validation cohort with an area under the receiver operating characteristics curve of 0.73 [95% CI, 69%-77%]. Moreover, we could confirm the performance of our biomarker on two further independent validation cohorts. The overall performance on all three validation cohorts expressed as area under the receiver operating characteristics curve was 0.75 [95% CI, 70%-80%]. At the clinically relevant classifier's operation point to optimize the exclusion of non-responders, the biomarker correctly predicts three out of four patients not responding to neoadjuvant taxane-based chemotherapy, independent of the breast cancer subtype. At the same time, the response rate in the group of predicted responders increased to 42% compared to 23% response rate in all patients of the validation cohorts.
| S-EPMC7083332 | biostudies-literature
Project description:The optimal neoadjuvant chemotherapy (NACT) regimen in triple-negative breast cancer (TNBC) has not been clearly defined. Achieving a pathologic complete response (pCR) provides important prognostic information, and, especially in TNBC, is considered a surrogate endpoint for event-free survival. Thus, many neoadjuvant studies in TNBC focus on this as a primary endpoint, and such information may be used for accelerated US Food and Drug Administration approval. Current controversies in the field include: (1) the role of platinum-based compounds; (2) the optimal chemotherapy backbone; and (3) the benefits of additional therapy after surgery. Conflicting results of 2 major studies adding carboplatin to NACT have highlighted the need to balance potential benefits to disease outcomes against increased toxicity. While the PROGECT study suggests efficacy of a nonanthracycline-containing regimen, this is observational data, and evidence in the form of a clinical trial remains to be seen. Data surrounding optimal taxane use support the use of nab-paclitaxel in place of paclitaxel in limited clinical situations. Although bevacizumab may increase pCR rates, this has not translated into survival benefit. Capecitabine shows promise in patients who have not achieved pCR after NACT. The neoadjuvant setting remains an important model for drug development. This review will focus on the most important and most current neoadjuvant trials in women with TNBC.
| S-EPMC5865448 | biostudies-literature
Project description:Compared to adjuvant chemotherapy, the administration of the same regimen in the neoadjuvant setting provides women with identical improvements in disease free and overall survival. Neoadjuvant chemotherapy may offer benefits to properly selected women such as broadening surgical options and enhancing the likelihood of breast conservation. Assessment of response to neoadjuvant chemotherapy provides women with an individualized estimate of prognosis. For example, a woman who achieves a complete pathological response following neoadjuvant chemotherapy has a very low risk of recurrence compared to a woman with similar tumor characteristics and a large residual disease. In this review we will provide a historical perspective and discuss the aims of neoadjuvant chemotherapy in primary operable breast cancer; as well as appropriate patient selection, treatment strategies, response monitoring, and postoperative care. We will also discuss the attractiveness of this approach to study the mechanism of action of standard and novel agents, and the role of predictive biomarkers of response to treatment and outcomes.
| S-EPMC3758450 | biostudies-literature