Development and Validation of a Robust Ferroptosis-Related Gene Panel for Breast Cancer Disease-Specific Survival

Background: New biomarker combinations have been increasingly developed to improve the precision of current diagnostic and therapeutic modalities. Recently, researchers have found that tumor cells are more vulnerable to ferroptosis. Furthermore, ferroptosis-related genes (FRG) are promising therapeutic targets in breast cancer patients. Therefore, this study aimed to identify FRG that could predict disease-specific survival (DSS) in breast cancer patients.Methods: Gene expression matrix and clinical data were downloaded from public databases. We included 960, 1,900, and 234 patients from the TCGA, METABRIC, and GSE3494 cohorts, respectively. Data for FRG were downloaded from the FerrDb website. Differential expression of FRG was analyzed by comparing the tumors with adjacent normal tissues. Univariate Cox analysis of DSS was performed to identify prognostic FRG. The TCGA-BRCA cohort was used to generate a nine-gene panel with the LASSO cox regression. The METABRIC and GSE3494 cohorts were used to validate the panel. The panel’s median cut-off value was used to divide the patients into high- or low-risk subgroups. Analyses of immune microenvironment, functional pathways, and clinical correlation were conducted via GO and KEGG analyses to determine the differences between the two subgroups.Results: The DSS of the low-risk subgroup was longer than that of the high-risk subgroup. The panel’s predictive ability was confirmed by ROC curves (TCGA cohort AUC values were 0.806, 0.695, and 0.669 for 2, 3, and 5 years respectively, and the METABRIC cohort AUC values were 0.706, 0.734, and 0.7, respectively for the same periods). The panel was an independent DSS prognostic indicator in the Cox regression analyses. (TCGA cohort: HR = 3.51, 95% CI = 1.792–6.875, p < 0.001; METABRIC cohort: HR = 1.76, 95% CI = 1.283–2.413, p < 0.001). Immune-related pathways were enriched in the high-risk subgroup. The two subgroups that were stratified by the nine-gene panel were also associated with histology type, tumor grade, TNM stage, and Her2-positive and TNBC subtypes. The patients in the high-risk subgroup, whose CTLA4 and PD-1 statuses were both positive or negative, demonstrated a substantial clinical benefit from combination therapy with anti-CTLA4 and anti-PD-1.Conclusion: The new gene panel consisting of nine FRG may be used to assess the prognosis and immune status of patients with breast cancer. A precise therapeutic approach can also be possible with risk stratification.

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113P Impact of local recurrence on disease-specific survival in breast cancer patients who underwent breast-conserving surgery

Annals of Oncology ◽

10.1016/j.annonc.2020.03.216 ◽

2020 ◽

Vol 31 ◽

pp. S54

Author(s):

D.G. Tiezzi ◽

L. de Mattos ◽

L.F. Orlandini ◽

F.J. Candido Dos Reis ◽

H.H. Carrara ◽

...

Keyword(s):

Breast Cancer ◽

Local Recurrence ◽

Cancer Patients ◽

Breast Conserving Surgery ◽

Disease Specific Survival ◽

Breast Cancer Patients ◽

Disease Specific

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Survival in Early Breast Cancer Patients Is Favorably Influenced by a Natural Humoral Immune Response to Polymorphic Epithelial Mucin

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.3.574 ◽

2000 ◽

Vol 18 (3) ◽

pp. 574-574 ◽

Cited By ~ 153

Author(s):

S. von Mensdorff-Pouilly ◽

A.A. Verstraeten ◽

P. Kenemans ◽

F.G. M. Snijdewint ◽

A. Kok ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Early Breast Cancer ◽

Humoral Response ◽

Disease Specific Survival ◽

Breast Cancer Patients ◽

Antibody Levels ◽

Pretreatment Serum ◽

Test Result ◽

Disease Specific

PURPOSE: Polymorphic epithelial mucin (PEM or MUC1) is being studied as a vaccine substrate for the immunotherapy of patients with adenocarcinoma. The present study analyzes the incidence of naturally occurring MUC1 antibodies in early breast cancer patients and relates the presence of these antibodies in pretreatment serum to outcome of disease.MATERIALS AND METHODS: We measured immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to MUC1 with an enzyme-linked immunoassay (PEM.CIg), which uses a MUC1 triple-tandem repeat peptide conjugated to bovine serum albumin, in pretreatment serum samples obtained from 154 breast cancer patients (52 with stage I disease and 102 with stage II) and 302 controls. The median disease-specific survival time of breast cancer patients was 74 months (range, 15 to 118 months). A positive test result was defined as MUC1 IgG or IgM antibody levels equal to or greater than the corresponding rounded-up median results obtained in the total breast cancer population.RESULTS: A positive test result for both MUC1 IgG and IgM antibodies in pretreatment serum was associated with a significant benefit in disease-specific survival in stage I and II (P = .0116) breast cancer patients. Positive IgG and IgM MUC1 antibody levels had significant additional prognostic value to stage (P = .0437) in multivariate analysis. Disease-free survival probability did not differ significantly. However, stage II patients who tested positive for MUC1 IgG and IgM antibody and who relapsed had predominantly local recurrences or contralateral disease, as opposed to recurrences at distant sites in the patients with a negative humoral response (P = .026).CONCLUSION: Early breast cancer patients with a natural humoral response to MUC1 have a higher probability of freedom from distant failure and a better disease-specific survival. MUC1 antibodies may control hematogenic tumor dissemination and outgrowth by aiding the destruction of circulating or seeded MUC1-expressing tumor cells. Vaccination of breast cancer patients with MUC1-derived (glyco)peptides in an adjuvant setting may favorably influence the outcome of disease.

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Impact of Different Modules of 21-Gene Assay in Early Breast Cancer Patients

Frontiers in Endocrinology ◽

10.3389/fendo.2021.759338 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mengdi Chen ◽

Deyue Liu ◽

Weilin Chen ◽

Weiguo Chen ◽

Kunwei Shen ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Cancer Patients ◽

Low Risk ◽

Breast Cancer Patients ◽

Younger Patients ◽

Gene Assay ◽

Risk Patients ◽

Gene Modules ◽

The Impact

BackgroundThe 21-gene assay recurrence score (RS) provides additional information on recurrence risk of breast cancer patients and prediction of chemotherapy benefit. Previous studies that examined the contribution of the individual genes and gene modules of RS were conducted mostly in postmenopausal patients. We aimed to evaluate the gene modules of RS in patients of different ages.MethodsA total of 1,078 estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients diagnosed between January 2009 and March 2017 from Shanghai Jiao Tong University Breast Cancer Data Base were included. All patients were divided into three subgroups: Group A, ≤40 years and premenopausal (n = 97); Group B, >40 years and premenopausal (n = 284); Group C, postmenopausal (n = 697). The estrogen, proliferation, invasion, and HER2 module scores from RS were used to characterize the respective molecular features. Spearman correlation and analysis of the variance tests were conducted for RS and its constituent modules.ResultsIn patients >40 years, RS had a strong negative correlation with its estrogen module (ρ = −0.76 and −0.79 in Groups B and C) and a weak positive correlation with its invasion module (ρ = 0.29 and 0.25 in Groups B and C). The proliferation module mostly contributed to the variance in young patients (37.3%) while the ER module contributed most in old patients (54.1% and 53.4% in Groups B and C). In the genetic high-risk (RS >25) group, the proliferation module was the leading driver in all patients (ρ = 0.38, 0.53, and 0.52 in Groups A, B, and C) while the estrogen module had a weaker correlation with RS. The impact of ER module on RS was stronger in clinical low-risk patients while the effect of the proliferation module was stronger in clinical high-risk patients. The association between the RS and estrogen module was weaker among younger patients, especially in genetic low-risk patients.ConclusionsRS was primarily driven by the estrogen module regardless of age, but the proliferation module had a stronger impact on RS in younger patients. The impact of modules varied in patients with different genetic and clinical risks.

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Adjuvant Chemotherapy Guidance for pT1-3N0-1 Breast Cancer Patients with HR+, HER2- subtype: a study based on SEER database

10.21203/rs.3.rs-154913/v1 ◽

2021 ◽

Author(s):

juanjuan Qiu ◽

Li Xu ◽

Yu Wang ◽

Jia Zhang ◽

Jiqiao Yang ◽

...

Keyword(s):

Breast Cancer ◽

Prognostic Factors ◽

High Risk ◽

Cancer Patients ◽

Risk Group ◽

High Risk Group ◽

Low Risk ◽

Rank Test ◽

Breast Cancer Patients ◽

Group Score

Abstract Background Although the results of gene testing can guide early breast cancer patients with HR+, HER2- to decide whether they need chemotherapy, there are still many patients worldwide whose problems cannot be solved well by genetic testing. Methods 144 735 patients with HR+, HER2-, pT1-3N0-1 breast cancer from the Surveillance, Epidemiology, and End Results database were included from 2010 to 2015. They were divided into chemotherapy (n = 38 392) and no chemotherapy (n = 106 343) group, and after propensity score matching, 23 297 pairs of patients were left. Overall survival (OS) and breast cancer-specific survival (BCSS) were tested by Kaplan–Meier plot and log-rank test and Cox proportional hazards regression model was used to identify independent prognostic factors. A nomogram was constructed and validated by C-index and calibrate curves. Patients were divided into high- or low-risk group according to their nomogram score using X-tile. Results Patients receiving chemotherapy had better OS before and after matching (p < 0.05) but BCSS was not significantly different between patients with and without chemotherapy after matching: hazard ratio (HR) 1.005 (95%CI 0.897, 1.126). Independent prognostic factors were included to construct the nomogram to predict BCSS of patients without chemotherapy. Patients in the high-risk group (score > 238) can get better OS HR 0.583 (0.507, 0.671) and BCSS HR 0.791 (0.663, 0.944) from chemotherapy but the low-risk group (score ≤ 238) cannot. Conclusion The well-validated nomogram and a risk stratification model was built. Patients in the high-risk group should receive chemotherapy while patients in low-risk group may be exempt from chemotherapy.

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Shorter disease-specific survival of ER-positive breast cancer patients with high cytoplasmic Src kinase expression after tamoxifen treatment

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-011-1096-8 ◽

2011 ◽

Vol 138 (2) ◽

pp. 327-332 ◽

Cited By ~ 11

Author(s):

B. Elsberger ◽

D. M. Paravasthu ◽

S. M. Tovey ◽

J. Edwards

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Src Kinase ◽

Tamoxifen Treatment ◽

Disease Specific Survival ◽

Breast Cancer Patients ◽

Er Positive ◽

Kinase Expression ◽

Disease Specific ◽

Positive Breast Cancer

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Impact of the EndoPredict-clin score on risk stratification in ER-positive, HER2-negative breast cancer after considering clinical guidelines.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.542 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 542-542

Author(s):

Martin Filipits ◽

Peter Christian Dubsky ◽

Margaretha Rudas ◽

Jan C. Brase ◽

Ralf Kronenwett ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Cancer Patients ◽

Endocrine Therapy ◽

Clinical Guidelines ◽

Risk Groups ◽

Low Risk ◽

Breast Cancer Patients ◽

Free Survival ◽

Er Positive

542 Background: Many ER-positive, HER2-negative breast cancer patients are treated by adjuvant chemotherapy according to current clinical guidelines. We retrospectively assessed whether the combined gene expression/ clinicopathological EndoPredict-clin (EPclin) score improved the accuracy of risk classification in addition to considering clinical guidelines. Methods: Three clinical breast cancer guidelines (National Comprehensive Cancer Center Network (NCCN), German S3 and St. Gallen 2011), and the EPclin score - assessed by quantitative RT-PCR in formalin-fixed paraffin-embedded tissue - were used to assign risk groups in 1,702 ER-positive, HER2-negative breast cancer patients from two randomized phase III trials (Austrian Breast and Colorectal Cancer Study Group 6 and 8) treated with endocrine therapy only. Results: Although all analyzed clinical guidelines identified a low-risk group with improved metastasis-free survival, the overwhelming majority of all patients (81-94%) were classified as intermediate / high risk. In contrast to that, the EPclin classified only 37% of all patients as high risk and that stratification resulted in the best separation between low and high risk groups (p < 0.001, HR = 5.11 (3.48-7.51). Consequently, the majority of all patients deemed intermediate / high risk by the clinical guidelines was re-classified as low risk by the EPclin score. Kaplan Meier analyses demonstrated that the re-classified subgroups (47 to 57% of all patients) had an excellent 10-year metastasis-free survival of 95% comparable to the clinical assigned low-risk groups although encompassing a higher proportion of the trial patients. Conclusions: The EPclin score predicted distant recurrence more accurately than all three clinical guidelines and is especially useful to reclassify patients considered as intermediate / high risk by the guidelines. The data suggests that the EPclin score provides clinically useful prognostic information beyond common clinical guidelines and can be used to accurately identify the clinically relevant group of patients who are adequately and sufficiently treated with adjuvant endocrine therapy alone.

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Effect of an adjuvant breast cancer vaccine on disease-specific survival of breast cancer patients with depressed lymphocyte immunity.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3087 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3087-3087

Author(s):

Robert Lange Elliott ◽

Jonathan F. Head

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Cell Vaccine ◽

Disease Specific Survival ◽

Breast Cancer Patients ◽

Adjuvant Setting ◽

Whole Cell ◽

Historic Control ◽

Lymphocyte Immunity ◽

Disease Specific

3087 Background: Breast cancer patients were vaccinated in the adjuvant setting with an autologous, allogeneic whole cell vaccine to evaluate the effect on host lymphocyte immunity and disease-specific survival. Methods: We began preparing whole cell preparations for a vaccine study in 1995. Stage I and II breast cancer patients had host lymphocyte immunity against tumors associated antigens evaluated before and after vaccination. Those patients with depressed immunity, determined by a lymphocyte blastogenesis assay (LBA), were offered the whole cell vaccine. Patients were given six intradermal injections (three weekly followed by three monthly). Ten weeks after the last injection the LBA was repeated. Thirty-seven patients were vaccinated in the adjuvant setting with the whole cell autologous, allogeneic vaccine. Results: The vaccine was well tolerated with no severe toxicities. Some patients experienced slight pain and swelling at the injection site and slight chills and fever. The vaccinated patients had a mean follow-up of 12.7 years with mean follow-up of 8.9 and 9.2 years for the patients with normal and depressed immunity, respectively, in the historic control. The 10-year survival was 95% (20 of 21 patients) in the normal immunity historic control, 59% (33 of 56 patients) in the depressed immunity historic control and 89% (33 of 37 patients) in the patients with depressed immunity that were vaccinated in the present clinical trial. Conclusions: The disease-specific survival of the vaccinated patients with depressed immunity in this trial is significantly greater than that of the historic controls of unvaccinated patients with depressed immunity to their tumor associated antigens. This study confirms the importance of maintaining good host lymphocyte immunity after completion of standard therapy and validates the value of cancer immunotherapy in the adjuvant setting.

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Comparative performance of Breast Cancer Index (BCIN+) and CTS5 in hormone receptor-positive (HR+) lymph node-positive (N+) breast cancer patients with one to three positive nodes (N1).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.555 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 555-555

Author(s):

Dennis Sgroi ◽

Yi Zhang ◽

Catherine A. Schnabel

Keyword(s):

Breast Cancer ◽

High Risk ◽

Cancer Patients ◽

Endocrine Therapy ◽

Tumor Size ◽

Risk Groups ◽

Cox Proportional Hazards ◽

Low Risk ◽

Intermediate Risk ◽

Breast Cancer Patients

555 Background: Identification of N+ breast cancer patients with a limited risk of recurrence improves selection of those for which chemotherapy and/or extended endocrine therapy (EET) may be most appropriate to reduce overtreatment. BCIN+ integrates gene expression with tumor size and grade, and is highly prognostic for overall (0-10yr) and late (5-10yr) distant recurrence (DR) in N1 patients. Clinical Treatment Score post-5-years (CTS5) is a prognostic model based on clinicopathological factors (nodes, age, tumor size and grade) and significantly prognostic for late DR. The current analysis compares BCIN+ and CTS5 for risk of late DR in N1 patients. Methods: 349 women with HR+, N1 disease and recurrence-free for ≥5 years were included. BCIN+ results were determined blinded to clinical outcome. CTS5 was calculated as previously described (Dowsett et al, JCO 2018; 36:1941). Kaplan-Meier analysis and Cox proportional hazards regression for late DR (5-15y) were evaluated. Results: 64% of patients were > 50 years old, 34% with tumors > 2cm, 79% received adjuvant chemotherapy and 64% received up to 5 years of ET. BCIN+ stratified 23% of patients as low-risk with 1.3% risk for late DR vs those classified as high-risk with 16.1% [HR 12.4 (1.7-90.4), p = 0.0014]. CTS5 classified patients into 3 risk groups: 29% of patients as low-risk (4.2% DR), 37% as intermediate-risk (10.6% DR), and 34% as high-risk (22.1% DR) [HR intermediate vs. low: 2.3 (0.7-7.0), p = 0.16; high vs. low: 5.3 (1.8-15.5), p = 0.002]. In a subset of patients who completed 5 years of ET (N = 223), BCIN+ identified 22% of patients as low-risk with a late DR rate of 2.1%, while CTS5 identified 29% and 37% of patients as low- and intermediate-risk with late DR rates of 5.2% and 10.3%, respectively. Conclusions: BCIN+ classified N1 patients into binary risk groups and identified 20% patients with limited risk of late DR ( < 2%) that may be advised to forego EET and its attendant toxicities/side effects. In comparison, CTS5 classified patients into 3 risk groups, with low- and intermediate-risk of late DR of 4-5% and 10%, wherein the risk-benefit profile for extension of endocrine therapy is less clear.

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Application of MammaPrint test on Chinese patient with breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13671 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e13671-e13671

Author(s):

Chen Tian ◽

Lili Fu ◽

Jiyu Wei ◽

Pengfei Yin ◽

Henghui Zhang

Keyword(s):

Breast Cancer ◽

High Risk ◽

Cancer Patients ◽

Clinical Characteristics ◽

Clinical Pathology ◽

Low Risk ◽

Chinese Patients ◽

Her2 Status ◽

Clinical High Risk ◽

Breast Cancer Patients

e13671 Background: A 70-gene prognosis-signature, known as MammaPrint (MP), is validated as a good predictor of recurrence in patients with ER+/HER2- early stage breast cancer in Europe and America. Previous studies on Japanese and Korean breast cancer patients showed that the proportion of MP Low-Risk tumours is significantly lower than the percentage which reported in previous studies. Here we use MammaPrint to determine the gene profiles of breast cancer tumours from Chinese patients and investigate the test’s potential clinical applications. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumour samples or fresh tumour samples from 594 eligible breast cancer patients were collected from 97 hospitals in China. Tumor RNAs were isolated from samples and analyzed using RNA sequencing technology. Clinical risk was categorized based on the Adjuvant! algorithm as used in the MINDACT trial. Concordance between risk predicted by the MammaPrint and clinical characteristics were evaluated. We also analyzed the clinical-pathology features of patients and compared them to previous studies. Results: Overall, 315 patients were categorized as clinical high risk (182 were MP Low-Risk and 133 MP High-Risk), while 279 patients were categorized as clinical low risk (203 were MP Low-Risk and 76 MP High-Risk). The concordance rate between risk predicted by the MammaPrint and clinical characteristics was 56.57%. Among the clinical-pathology features, age, ER/PR/HER2 status, tumour grade and tumour size were significantly related to the genomic risk (p = 0.009, 0.003, < 0.001, 0.001, < 0.001, and 0.007 respectively). Conclusions: The proportion of MP Low-Risk tumours was 64.81%, which is similar to previous validated studies in Europe and America. Of the patients that were clinical high risk, 58% was categorized as MP Low-Risk, and this group of patients may have limited benefit from chemotherapy. Our results indicate that MammaPrint is applicable to Chinese patients and has potential value in clinical practice to avoid over-treatment.

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