The E2F4 prognostic signature predicts pathological response to neoadjuvant chemotherapy in breast cancer patients

Mark, Kenneth M. K.; Varn, Frederick S.; Ung, Matthew; Feng, Qian; Cheng, Chao

doi:10.1186/s12885-017-3297-2

Cited by 17 publications

(21 citation statements)

References 36 publications

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“…We investigated the association between the RPS and characteristics of the ER-positive tumor microenvironment, as well as between the TNBC-RPS and characteristics of the TNBC tumor microenvironment respectively (Figure 6). Of note, the RPS identified changes in the tumor cell proliferation rate and immune cell infiltration in ER-positive patients, which was supported by previous studies showing that the cell-cycle-related 16,[64][65][66] and immune-infiltration-related gene signatures [67][68][69] were associated with responsiveness. This observation could be further validated through the prediction performance of the 143 predictive gene signatures.…”

Section: Discussionsupporting

confidence: 79%

Gene signature‐based prediction of triple‐negative breast cancer patient response to Neoadjuvant chemotherapy

2020

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Neoadjuvant chemotherapy is the current standard of care for large, advanced, and/or inoperable tumors, including triple‐negative breast cancer. Although the clinical benefits of neoadjuvant chemotherapy have been illustrated through numerous clinical trials, more than half of the patients do not experience therapeutic benefit and needlessly suffer from side effects. Currently, no clinically applicable biomarkers are available for predicting neoadjuvant chemotherapy response in triple‐negative breast cancer; the discovery of such a predictive biomarker or marker profile is an unmet need. In this study, we introduce a generic computational framework to calculate a response‐probability score (RPS), based on patient transcriptomic profiles, to predict their response to neoadjuvant chemotherapy. We first validated this framework in ER‐positive breast cancer patients and showed that it predicted neoadjuvant chemotherapy response with equal performance to several clinically used gene signatures, including Oncotype DX and MammaPrint. Then, we applied this framework to triple‐negative breast cancer data and, for each patient, we calculated a response probability score (TNBC‐RPS). Our results indicate that the TNBC‐RPS achieved the highest accuracy for predicting neoadjuvant chemotherapy response compared to previously proposed 143 gene signatures. When combined with additional clinical factors, the TNBC‐RPS achieved a high prediction accuracy for triple‐negative breast cancer patients, which was comparable to the prediction accuracy of Oncotype DX and MammaPrint in ER‐positive patients. In conclusion, the TNBC‐RPS accurately predicts neoadjuvant chemotherapy response in triple‐negative breast cancer patients and has the potential to be clinically used to aid physicians in stratifying patients for more effective neoadjuvant chemotherapy.

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Section: Discussionsupporting

confidence: 79%

Gene signature‐based prediction of triple‐negative breast cancer patient response to Neoadjuvant chemotherapy

2020

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“…The finding that current adjuvant treatments cannot improve the prognosis of patients exhibiting high expression of this E2F4 signature also agrees with our results that only CDK4/6 inhibition, and not chemotherapy nor fulvestrant, is able to suppress completely E2F4 target gene expression. However, the same authors reported that high levels of the 199-gene E2F4 signature are predictive of pathological complete response to neoadjuvant chemotherapy in ER+ breast cancer (43). Although this might seem contradictory, transcriptional activity of E2F4 is a marker of highly proliferative tumors, which is a recognized predictive factor of an initial response to chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

ER+ Breast Cancers Resistant to Prolonged Neoadjuvant Letrozole Exhibit an E2F4 Transcriptional Program Sensitive to CDK4/6 Inhibitors

Guerrero-Zotano

Stricker

Formisano

et al. 2018

Clinical Cancer Research

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This study aimed to identify biomarkers of resistance to endocrine therapy in estrogen receptor-positive (ER) breast cancers treated with prolonged neoadjuvant letrozole. We performed targeted DNA and RNA sequencing in 68 ER breast cancers from patients treated with preoperative letrozole (median, 7 months). Twenty-four tumors (35%) exhibited a PEPI score ≥4 and/or recurred after a median of 58 months and were considered endocrine resistant. Integration of the 47 most upregulated genes (log FC > 1, FDR < 0.03) in letrozole-resistant tumors with transcription-binding data showed significant overlap with 20 E2F4-regulated genes ( = 2.56E-15). In patients treated with the CDK4/6 inhibitor palbociclib before surgery, treatment significantly decreased expression of 24 of the 47 most upregulated genes in letrozole-resistant tumors, including 18 of the 20 E2F4 target genes. In long-term estrogen-deprived ER breast cancer cells, palbociclib also downregulated all 20 E2F4 target genes and P-RB levels, whereas the ER downregulator fulvestrant or paclitaxel only partially suppressed expression of this set of genes and had no effect on P-RB. Finally, an E2F4 activation signature was strongly associated with resistance to aromatase inhibitors in the ACOSOG Z1031B neoadjuvant trial and with an increased risk of relapse in adjuvant-treated ER tumors in METABRIC. In tumors resistant to prolonged neoadjuvant letrozole, we identified a gene expression signature of E2F4 target activation. CDK4/6 inhibition suppressed E2F4 target gene expression in estrogen-deprived ER breast cancer cells and in patients' ER tumors, suggesting a potential benefit of adjuvant CDK4/6 inhibitors in patients with ER breast cancer who fail to respond to preoperative estrogen deprivation. .

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“…In MDA-MB-231 Met-DOX cells, metformin upregulated GADD45B, which is a stress-sensor and apoptosis-regulator and contributes to CDKN1A upregulation, induction of apoptosis and G2/M-phase enrichment 46 . Furthermore, metformin also upregulated E2F4 in both MCF-7 and MDA-MB-231 Met-DOX cells, which plays a key role in the suppression of proliferation-associated genes 37 . In relation to the effects of metformin on AR 49 , showed that its expression appears to play a different prognostic role in breast cancer positive and negative for estrogen receptors (ER).…”

Section: Discussionmentioning

confidence: 94%

Metformin prevention of doxorubicin resistance in MCF-7 and MDA-MB-231 involves oxidative stress generation and modulation of cell adaptation genes

Marinello

Panis

Silva

et al. 2019

Sci Rep

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Metformin was shown to sensitize multidrug resistant breast cancer cells; however, the mechanisms involved in this capacity need to be clarified. We investigated oxidative stress and inflammatory-related pathways during the induction of doxorubicin resistance in MCF-7 and MDA-MB-231 human breast cancer cells (DOX-res group), and evaluated metformin-induced cellular responses that resulted in the prevention of doxorubicin resistance (Met-DOX group). Microarray analysis demonstrated that DOX-res changed the expression of genes involved in oxidative stress (OS) and the TGF- β1 pathway. The DOX-res group presented increased thiols and reduced lipoperoxidation, increased levels of nitric oxide, nuclear NF-kB and Nrf2, and reduced nuclear p53 labelling. Analysis of the TGF-β1 signaling pathway by RT-PCR array showed that DOX-res developed adaptive responses, such as resistance against apoptosis and OS. Metformin treatment modified gene expression related to OS and the IFN-α signaling pathway. The Met-DOX group was more sensitive to DOX-induced OS, presented lower levels of nitric oxide, nuclear NF-kB and Nrf2, and increased nuclear p53. Analysis of the IFN-α signaling pathway showed that Met-DOX presented more sensitivity to apoptosis and OS. Our findings indicate that metformin is a promising tool in the prevention of chemoresistance in patients with breast cancer submitted to doxorubicin-based treatments.

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The E2F4 prognostic signature predicts pathological response to neoadjuvant chemotherapy in breast cancer patients

Cited by 17 publications

References 36 publications

Gene signature‐based prediction of triple‐negative breast cancer patient response to Neoadjuvant chemotherapy

Gene signature‐based prediction of triple‐negative breast cancer patient response to Neoadjuvant chemotherapy

ER+ Breast Cancers Resistant to Prolonged Neoadjuvant Letrozole Exhibit an E2F4 Transcriptional Program Sensitive to CDK4/6 Inhibitors

Metformin prevention of doxorubicin resistance in MCF-7 and MDA-MB-231 involves oxidative stress generation and modulation of cell adaptation genes

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