Faculty Opinions recommendation of High expression of lymphocyte-associated genes in node-negative HER2+ breast cancers correlates with lower recurrence rates.

e13025 Background: Invasive lobular carcinomas (ILC) account for approximately 10-15% of all invasive breast cancers, with the majority of cases presenting as ER/PR positive and HER2 negative. As a result, they often exhibit more robust responses to hormone therapy than adjuvant chemotherapy. Oncotype Recurrence Score (RS) RS is a 21-gene assay used to predict the rate of distant recurrence and response to chemotherapy in women with node-negative, hormone-positive breast cancers. Limited evidence exists regarding oncotype scores for ILC tumors, thus the aim of this study was to examine the distribution and risk stratification of Oncotype RS in ILC tumors. Methods: We analyzed patient and tumor characteristics of 492 patients- 417 (85%) IDC (intraductal carcinoma) and 75 (15%) ILC. Chi-square tests and Wilcoxon rank-sum tests were used to compare categorical and numerical outcomes, respectively. Results: No significant difference was found between IDC and ILC in terms of age and ER/PR positivity. The RS raw scores were also not significantly different between the two groups (both had median scores of 16). ILC patients were significantly more likely to be in the lower RS risk groups using the traditional (Paik) cutoff than ILC patients (61%, 39% and 0% in low, medium and high-risk groups as compared to 57%, 33% and 10% in IDC, p < 0.01). Of 417 patients with IDC, there were 16 recurrences (4%) with a median time from diagnosis to recurrence of 43 months (IQR: 28 Ð 58 months), while 1 in 75 ILC patients had recurrence at 50 months. Conclusions: Oncotype RS scores have the potential to guide treatment decisions in node-negative breast cancers. Though mean RS were similar between ILC and IDC patients, ILC were more likely to be distributed in low-risk groups. Our study was limited by a small sample size and a single ILC recurrence. Further research is needed to determine oncotype RS and recurrence rates. Future studies with longer term follow up can help better elucidate patterns of recurrence scores and recurrence rates based on histologic tumor type. [Table: see text]

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Sequencing of Tamoxifen and Radiotherapy After Breast-Conserving Surgery in Early-Stage Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2005.01.198 ◽

2005 ◽

Vol 23 (1) ◽

pp. 24-29 ◽

Cited By ~ 84

Author(s):

Lori J. Pierce ◽

Laura F. Hutchins ◽

Stephanie R. Green ◽

Danika L. Lew ◽

Julie R. Gralow ◽

...

Keyword(s):

Breast Cancer ◽

Survival Data ◽

Randomized Clinical Trials ◽

Early Stage ◽

Disease Free Survival ◽

Breast Conserving Surgery ◽

Antagonistic Effect ◽

Breast Cancers ◽

Recurrence Rates ◽

Node Negative

Purpose Tamoxifen (TAM) is thought to exert a cytostatic effect on hormone-sensitive breast cancer cells. Some preclinical studies show reduced radiosensitivity in irradiated malignant mammary epithelial cells when pretreated with TAM; other studies refute these results. Recent randomized clinical trials suggest an antagonistic effect of TAM on cytotoxic therapy, with improved disease-free survival (DFS) with sequential versus concurrent TAM. An exploratory analysis was undertaken to evaluate the optimal sequencing of TAM and radiotherapy (RT) after breast-conserving surgery. Patients and Methods Southwest Oncology Group trial 8897 (Intergroup 0102) randomly assigned node-negative women with T1-3 breast cancers to cyclophosphamide, doxorubicin, fluorouracil (CAF); CAF → TAM; cyclophosphamide, methotrexate, fluorouracil (CMF); and CMF → TAM. For this analysis, data are reported only in the TAM groups. RT was allowed either before adjuvant therapy (sequential [SEQ] RT; 107 patients) or after chemotherapy but concurrent with TAM (concurrent [CONC] RT; 202 patients). Survival data were adjusted for receptor status, age, and tumor size. Results With a median follow-up of 10.3 years, 10-year DFS values were 83% and 83% for CONC versus SEQ RT groups (log-rank P = .73; P = .76 adjusted for patient characteristics), and 10-year overall survivals were 88% and 90%, respectively (log-rank P = .59; adjusted P = .65). Patterns of failure showed no increase in in-breast recurrence rates between CONC RT and SEQ RT groups, with 10-year local recurrence rates of 7% for CONC RT and 5% for SEQ RT (hazard ratio, 0.73; 95% CI, 0.26 to 2.04; P = .54). Conclusion The current analysis does not suggest an adverse effect on local or systemic control with CONC versus SEQ TAM and RT in node-negative breast cancer. A randomized trial is encouraged to validate these results.

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734 A novel NQO1 specific anti-tumor agent, SBSC-S3001, selectively regresses the growth of tumors with high NQO1 expression

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0734 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A778-A778

Author(s):

Minhyuk Yun ◽

Goo-Young Kim ◽

Sang Woo Jo ◽

Changhoon In ◽

Gyu-Young Moon ◽

...

Keyword(s):

Energy Metabolism ◽

Cancer Cells ◽

Poor Prognosis ◽

High Expression ◽

List Type ◽

Dependent Manner ◽

Breast Cancers ◽

Quinone Oxidoreductase ◽

Key Enzymes

BackgroundNAD(P)H-quinone oxidoreductase 1 (NQO1) is a cytosolic two-electron oxidoreductase overexpressed in many types of cancers, including breast cancer, pancreatic cancer, colorectal cancer, cholangiocarcinoma, uterine cervical cancer, melanoma, and lung cancer.1Up-regulation of NQO1 protects cells from oxidative stress and various cytotoxic quinones and is associated with late clinical stage, poor prognosis and lymph node metastasis.2 3 NQO1 increases stability of HIF-1α protein, which has been implicated in survival, proliferation, and malignance of cancer.1 Therefore, accumulating evidences suggest NQO1 as a promising therapeutic target for cancer. Accordingly, we have characterized the effect of a novel synthetic NQO1 substrate SBSC-S3001, and demonstrated its selective cytotoxic effects in cancer cells with high expression of NQO1.MethodsIn vitro cytotoxicity was determined by sulforhodamine B (SRB) assay in cancer cells with high NQO1 expression and CRISPR-mediated NQO1 knockout cells. The effect of SBSC-S3001 on the energy metabolism pathway was evaluated by western blot analysis of metabolism associated proteins from NQO1-overexpressed cancer cells treated with the compound for 24 hours. In vivo anti-tumor activity was evaluated in MC38 syngeneic and DLD-1 orthotopic mice models.ResultsSBSC-S3001 exhibited selective cytotoxicity in cancer cells with high expression of NQO1 in a dose-dependent manner. The cytotoxicity was observed in both normoxia and hypoxia conditions, correlating with the energy metabolism, mitochondrial biogenesis, and cancer proliferative pathways. Also, stronger cytotoxicity was observed in NQO1-overexpressed cancer cells treated with SBSC-S3001 compared to beta-lapachone and analogue treatment.4 When evaluated in vivo, SBSC-S3001 effectively inhibited the growth of syngeneic and orthotopic tumors when administered as a monotherapy. SBSC-S3001 treatment associated with reduction in key enzymes of the glycolytic pathway (LDHa and GAPDH) and HIF-1α and increase in levels of mitochondrial oxidative phosphorylation (OXPHOS) complex.ConclusionsTreatment of SBSC-S3001, a novel, NQO1-specific substrate reduces HIF-1α and key enzymes associated with glycolysis and suppresses the growth of tumors overexpressing NQO1. Further characterization of SBSC-S3001 as a novel metabolic anti-cancer agent for cancers with NQO1 overexpression is warranted.Ethics ApprovalThe study was approved by Samyang Biopharmaceuticals Institution’s Ethics Board, approval number SYAU2031.ReferencesOh ET, Kim JW, Kim JMet. al., NQO1 inhibits proteasome-mediated degradation of HIF-1α. Nat Commun 2016; 14:13593.Ma, Y. et al. NQO1 overexpression is associated with poor prognosis in squamous cell carcinoma of the uterine cervix. BMC Cancer 2014;14: 414Yang, Y. et al. Clinical implications of high NQO1 expression in breast cancers. J. Exp. Clin. Cancer Res 2014;33:144.Yang Y, Zhou X, Xu M, et al., β-lapachone suppresses tumour progression by inhibiting epithelial-to-mesenchymal transition in NQO1-positive breast cancers. Sci Rep 2017;7:2681.

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Prognostic impact of Ki-67 labeling indices with 3 different cutoff values, histological grade, and nuclear grade in hormone-receptor-positive, HER2-negative, node-negative invasive breast cancers

Breast Cancer ◽

10.1007/s12282-013-0464-4 ◽

2013 ◽

Vol 22 (2) ◽

pp. 141-152 ◽

Cited By ~ 25

Author(s):

Makiko Ono ◽

Hitoshi Tsuda ◽

Mayu Yunokawa ◽

Kan Yonemori ◽

Chikako Shimizu ◽

...

Keyword(s):

Hormone Receptor ◽

Histological Grade ◽

Nuclear Grade ◽

Prognostic Impact ◽

Breast Cancers ◽

Ki 67 ◽

Node Negative ◽

Hormone Receptor Positive ◽

Cutoff Values

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Classical Cyclophosphamide, Methotrexate, and Fluorouracil Chemotherapy Is More Effective in Triple-Negative, Node-Negative Breast Cancer: Results From Two Randomized Trials of Adjuvant Chemoendocrine Therapy for Node-Negative Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.25.9549 ◽

2010 ◽

Vol 28 (18) ◽

pp. 2966-2973 ◽

Cited By ~ 102

Author(s):

Marco Colleoni ◽

Bernard F. Cole ◽

Giuseppe Viale ◽

Meredith M. Regan ◽

Karen N. Price ◽

...

Keyword(s):

Breast Cancer ◽

Endocrine Therapy ◽

Triple Negative ◽

Alkylating Agents ◽

Growth Factor Receptor ◽

Breast Cancers ◽

Her2 Positive ◽

Node Negative ◽

Tumor Subtypes ◽

Node Negative Breast Cancer

Purpose Retrospective studies suggest that primary breast cancers lacking estrogen receptor (ER) and progesterone receptor (PR) and not overexpressing human epidermal growth factor receptor 2 (HER2; triple-negative tumors) are particularly sensitive to DNA-damaging chemotherapy with alkylating agents. Patients and Methods Patients enrolled in International Breast Cancer Study Group Trials VIII and IX with node-negative, operable breast cancer and centrally assessed ER, PR, and HER2 were included (n = 2,257). The trials compared three or six courses of adjuvant classical cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without endocrine therapy versus endocrine therapy alone. We explored patterns of recurrence by treatment according to three immunohistochemically defined tumor subtypes: triple negative, HER2 positive and endocrine receptor absent, and endocrine receptor present. Results Patients with triple-negative tumors (303 patients; 13%) were significantly more likely to have tumors > 2 cm and grade 3 compared with those in the HER2-positive, endocrine receptor–absent, and endocrine receptor–present subtypes. No clear chemotherapy benefit was observed in endocrine receptor–present disease (hazard ratio [HR], 0.90; 95% CI, 0.74 to 1.11). A statistically significantly greater benefit for chemotherapy versus no chemotherapy was observed in triple-negative breast cancer (HR, 0.46; 95% CI, 0.29 to 0.73; interaction P = .009 v endocrine receptor–present disease). The magnitude of the chemotherapy effect was lower in HER2-positive endocrine receptor–absent disease (HR, 0.58; 95% CI, 0.29 to 1.17; interaction P = .24 v endocrine receptor–present disease). Conclusion The magnitude of benefit of CMF chemotherapy is largest in patients with triple-negative, node-negative breast cancer.

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