Abstract PD2-11: Ki-67 (30-9) scoring and differentiation in Luminal A and Luminal B breast cancer subtypes

Abstract Purpose To correlate quantitative T1, T2, and proton density (PD) values from synthetic MRI with breast cancer subtypes. Methods Twenty-eight breast cancer patients underwent MRI of the breast including synthetic MRI. T1, T2, and PD values were correlated with Ki-67. T1, T2, and PD values were compared between estrogen receptor (ER) positive and ER negative cancers, and between Luminal A and Luminal B cancers. The effectiveness of T1, T2, and PD in differentiating the ER-negative from the ER-positive group and Luminal A from Luminal B cancers was evaluated using receiver operating characteristic analysis.Results Mean T2 relaxation of ER-negative cancers was significantly higher than that of ER-positive cancers (p < .05). The T1, T2, and PD values exhibited a strong positive correlation with Ki-67 (Pearson's r = 0.75, 0.69, and 0.60 respectively; p < .001). Among ER-positive cancers (n=23), T1, T2, and PD values of Luminal A cancers were significantly lower than those of Luminal B cancers (p < .05). The areas under the curve (AUCs) of T1, T2, and PD for discriminating ER-negative from ER-positive cancers were 0.74 (95% confidence interval (CI): 0.54-0.88), 0.87 (95% CI: 0.69-0.97), and 0.62 (95% CI: 0.42-0.79), respectively. The AUCs of T1, T2, and PD values for discriminating Luminal A from Luminal B cancers were 0.83 (95% CI: 0.61-0.95), 0.75 (95% CI: 0.52-0.90), and 0.75 (95% CI: 0.53-0.91), respectively.Conclusion Quantitative values from synthetic MRI significantly correlate with subtypes of invasive breast cancers and may classify subtypes with reasonably good accuracy.

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Can Oncotype DX recurrence score (RS) be used in luminal A and luminal B breast cancer patients (pts) to predict the likely benefit of chemotherapy? A retrospective study in the Spanish population.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e11006 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e11006-e11006 ◽

Cited By ~ 1

Author(s):

Laura García-Estevez ◽

Ana C Contreras ◽

Isabel Calvo ◽

Maria Fernandez Abad ◽

Juan J de la Cruz ◽

...

Keyword(s):

Breast Cancer ◽

Adjuvant Chemotherapy ◽

Oncotype Dx ◽

Breast Cancer Subtypes ◽

Treatment Recommendation ◽

Nuclear Staining ◽

Luminal A ◽

Ki 67 ◽

Cancer Subtypes ◽

Luminal B

e11006 Background: The 2011 St Gallen guidelines recommend the use of Ki67 as a surrogate marker for luminal A and Luminal B breast cancer subtypes. Pts with luminal B subtypes should be considered for adjuvant chemotherapy. The guidelines also recognize the Oncotype DX RS as a predictor of chemotherapy benefit. The aim of this study is to assess the distribution of the RS in luminal A and luminal B breast cancer subtypes as defined by Ki67. Methods: Data from 91 pts with invasive breast cancer for which Oncotype DX results and pathology data were available. Pathological assessment was evaluated by the same pathologist. Estrogen (ER) and progesterone (PR) receptor was assessed by immunostaining (cut-off 10% nuclear staining). Ki67 was assessed by IHC [high (≥14%) and low (< 14%)]. Grading was performed by using Nottingham grading system. Results: Median age: 50 years (range: 35-78); premenopausal status: 49 pts (53.8%). Median tumor size: 1.5 cm (0, 3-6); Median of Ki 67 index: 15. 5 (range: 3-63); Median ER: 93 (35-100) and PR: 85(0-100). Sixty nine pts (75.8%) had negative-lymph nodes. RS was low in 56 (61. 5%) cases, intermediate in 24 (26. 4%), and high in 11 (12. 1%). The median RS was 16 (range 3-55). Forty six (51%) tumors were classified as luminal B (according to high Ki 67) and 38 (41.7%) as Luminal A. In the Luminal B group RS was low in 28 (61%) pts, intermediate in 10 (22%) and high in 8 (17%) while in the Luminal A group 23 (61%) had low RS; 13 (34%) intermediate and 2 (5%) high RS. RS changed the first treatment recommendation in 23 (50%) cases of Luminal B subtype vs. 10 (26%) cases in Luminal A subtype (p=0.013). Conclusions: Although based in a small case series, the results show that a substantial number (61%) pts with Luminal B breast cancer subtype had a low RS, therefore preserving them from adjuvant chemotherapy treatment. In addition, 5% of patients with Luminal A breast cancer had a high RS and thereby likely to benefit from chemotherapy. The wide range of RS in both Luminal B and Luminal A breast cancer subtypes confirm the important role of Oncotype DX in treatment decision- making.

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Can Oncotype DX Recurrence Score (RS) be used in Luminal A and Luminal B breast cancer patients (pts) to predict the likely benefit of chemotherapy? A retrospective unicentric study in Spanish population.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.26_suppl.40 ◽

2013 ◽

Vol 31 (26_suppl) ◽

pp. 40-40 ◽

Cited By ~ 2

Author(s):

Laura G. Estevez ◽

Isabel Calvo ◽

Maria Fernandez-Abad ◽

Juan Jose Cruz ◽

Ana Suarez ◽

...

Keyword(s):

Breast Cancer ◽

Adjuvant Chemotherapy ◽

Recurrence Score ◽

Oncotype Dx ◽

Breast Cancer Subtypes ◽

Treatment Recommendation ◽

Luminal A ◽

Ki 67 ◽

Cancer Subtypes ◽

Luminal B

40 Background: The 2011 St Gallen guidelines recommend the use of Ki67 as a surrogate marker for luminal A and Luminal B breast cancer subtypes. Pts with luminal B subtypes should be treated with adjuvant chemotherapy. The guidelines also recognize the Oncotype DX RS as a predictor of chemotherapy benefit. The aim of this study is to assess the distribution of the RS in luminal A and luminal B breast cancer subtypes as defined by Ki67. Methods: Data from 131 pts with invasive breast cancer for which Oncotype DX results and pathology data were available. Pathological assessment was evaluated by the same pathologist. Estrogen (ER) and progesterone (PR) receptor was assessed by immunostaining (cut-off 10% nuclear staining). Ki67 was assessed by IHC [high (≥14%) and low (< 14%)]. Histological grade was performed by using Nottingham grading system. Results: Median age: 50 (range: 35-78); premenopausal status: 53 pts (44.2%). Median tumor size: 1, 5 cm (0, 3-5); Median of Ki 67 index: 15 (range: 3-63); 79 pts (66.4%) had negative-lymph nodes. Seventy (58.3%) tumors were classified as Luminal B (Ki 67 ≥14%) and 50 (41.7%) as Luminal A. Grade III were more common in Luminal B 14 (20.3%) than in Luminal A 1 pts (2%) patients (p=0.003). Chemotherapy was the first recommendation in 29 pts (41.4%) with Luminal B vs. 7 pts (14%) with Luminal A; hormonotherapy was the first recommendation in 32 pts (45.7%) with Luminal B and 37 pts (74%) in Luminal A (p =0.003). In the Luminal B group, Recurrence Score results was low in 42 (60%) pts, intermediate in 19 (27.1%) and high in 9 (12.9%) while in the Luminal A group 31 (62%) had low; 16 (32%) intermediate and 3 (6%) high Recurrence Score results (p=0.433). RS changed the first treatment recommendation in 35 (50%) cases of Luminal B subtype vs. 14 (28%) cases in Luminal A subtype (p=0.016). Conclusions: The results show that a substantial number (60%) pts with Luminal B breast cancer subtype had a low RS, therefore preserving them from adjuvant chemotherapy treatment. The wide range of RS in both Luminal B and Luminal A breast cancer subtypes confirm the important role of Oncotype DX in treatment decision making.

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Difference between Luminal A and Luminal B Subtypes According to Ki-67, Tumor Size, and Progesterone Receptor Negativity Providing Prognostic Information

Clinical Medicine Insights Oncology ◽

10.4137/cmo.s18006 ◽

2014 ◽

Vol 8 ◽

pp. CMO.S18006 ◽

Cited By ~ 54

Author(s):

Zorka Inic ◽

Milan Zegarac ◽

Momcilo Inic ◽

Ivan Markovic ◽

Zoran Kozomara ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Nodes ◽

Breast Cancer Subtypes ◽

Luminal A ◽

Chi Square ◽

Ki 67 ◽

Cancer Subtypes ◽

Luminal B ◽

Chi Square Test ◽

The Difference

Background The St. Gallen International Expert Consensus of 2011 proposes a new classification system for breast cancer based on its division into five subgroups. The criteria to identify these subtypes were recently refined at the 2013 Conference. In this respect, the authors of this paper have conducted a retrospective analysis of breast cancer subtypes, related to Ki-67 and involvement of the axillary lymph nodes (ALNs). The analysis was performed only in the cases of invasive breast cancer in the pT2 stages. The research and results of the paper have shown that investigating the value of these parameters could be of great benefit in future treatment strategies of invasive breast cancer. Methods A retrospective analysis of breast cancer subtypes, tumor nodal metastatic staging, and histopathological grading of 108 cases has been performed according to the methods recommended and provided by the St. Gallen International Expert Consensus Report, 2011. The estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), and Ki-67 of 108 tumor samples were all investigated by immunohistochemistry according to the methods used to classify breast cancer subtypes as proposed in the St. Gallen Consensus Report, 2011. Invasive breast cancers (n = 108) were immunohistochemically classified as follows: 28 (25.92%) as Luminal A, 51 (47.22%) as Luminal B (HER2 negative), 21 (19.44%) as Luminal B-like (HER2 negative), 2 (1.85%) as HER2 positive, and 6 (5.55%) as being a triple-negative subtype. Results The conclusion was made that when Ki-67 was found to be higher, patients also showed a higher involvement in their ALNs. The chi-square test shows the difference to be significant (chi-square = 4.757; P = 0.029). Luminal B subtypes had the highest percentage (54.9%) of involvement of lymph nodes when compared to the other four subtypes. The Luminal B subtype had a higher percentage (51.4%) of involvement of lymph nodes than did Luminal A (10.7%). The chi-square test also shows the difference to be significant ( P < 0.05). Conclusion A combination of the Ki-67 index, HER negative tumors, PR negativity, and a low value that can be used to segregate ER positive pT2 tumors into prognostically significantly different clinical outcomes may be utilized clinically to guide patient management in accordance with these tumor characteristics.

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Response to neoadjuvant chemotherapy and outcome based on breast cancer subtype

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e11516 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e11516-e11516

Author(s):

A. Guerrero-Zotano ◽

J. Gavila ◽

M. A. Climent ◽

M. J. Juan ◽

V. Guillem ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Breast Cancer Subtypes ◽

Nuclear Staining ◽

Luminal A ◽

Long Term Outcome ◽

Cancer Subtypes ◽

Luminal B ◽

Her 2

e11516 Background: Gene expression profiling identifies several breast cancer subtypes with different chemosensitivity and outcome. We used immunohistochemistry surrogate markers to classify tumors according to known breast cancer subtypes and examined the relationship between neoadjuvant chemotherapy (NAC) response and long-term end points, including distant disease-free survival (DDFS) and overall survival (OS). Methods: Review of clinical and pathological data from 271 breast cancer patients treated in our institution with NAC between 1991–2008. Breast cancer subtypes were defined as follows: Luminal A: Estrogen receptor positive (ER+) and/or progesterone peceptor positive (PR+), human epidermal growth factor receptor 2-positive (Her-2+); Luminal B: ER+ and/or PR+,Her-2+; Basal: ER-,PR-,Her-2-;HER2: ER-,PR-,Her-2 +. ER and PR positive scored as positive if tumor cell nuclear staining was at least 2+. Her-2 scored as positive if test DAKO scored 3+ or FISH ratio Her-2/CEP-17>2.2. Results: 121 (45.8%) patients were classifed as Luminal A; 22 (8.1%) as Luminal B; 75 (27.7%) as Basal, and 50 (18.5%) as HER2. Most patients (63%) received NAC based on anthracyclines and taxanes. 36% Her-2+ patients were treated with NAC based on trastuzumab, and 43% received trastuzumab as adjuvant treatment. Response and outcome results are shown below (Table). Independently from subtype, only four patients out of 58 with pCR relapsed. Among patients who didn´t achieved pathologic complete response (pCR), basal and HER2 subtypes have the worst outcome (4 years SG 80% and 72% respectevely) compared with Luminal A (4 years SG: 94.7%), (log-rank p=0.009). Conclusions: Basal and HER2 tumor despite high chemosensitivity have worst long term outcome, particularly if pCR is not achieved after NAC. [Table: see text] No significant financial relationships to disclose.

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Epigenetic aspects of triple-negative in patients with breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.1041 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 1041-1041

Author(s):

Joaquina Martínez-Galan ◽

Sandra Rios ◽

Juan Ramon Delgado ◽

Blanca Torres-Torres ◽

Jesus Lopez-Peñalver ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Dna Methylation ◽

Triple Negative ◽

Breast Cancer Subtype ◽

Regulation Of Gene Expression ◽

Breast Cancer Subtypes ◽

Luminal A ◽

Cancer Subtypes ◽

Luminal B

1041 Background: Identification of gene expression-based breast cancer subtypes is considered a critical means of prognostication. Genetic mutations along with epigenetic alterations contribute to gene-expression changes occurring in breast cancer. However, the reproducibility of differential DNA methylation discoveries for cancer and the relationship between DNA methylation and aberrant gene expression have not been systematically analysed. The present study was undertaken to dissect the breast cancer methylome and to deliver specific epigenotypes associated with particular breast cancer subtypes. Methods: By using Real Time QMSPCR SYBR green we analyzed DNA methylation in regulatory regions of 107 pts with breast cancer and analyzed association with prognostics factor in triple negative breast cancer and methylation promoter ESR1, APC, E-Cadherin, Rar B and 14-3-3 sigma. Results: We identified novel subtype-specific epigenotypes that clearly demonstrate the differences in the methylation profiles of basal-like and human epidermal growth factor 2 (HER2)-overexpressing tumors. Of the cases, 37pts (40%) were Luminal A (LA), 32pts (33%) Luminal B (LB), 14pts (15%) Triple-negative (TN), and 9pts (10%) HER2+. DNA hypermethylation was highly inversely correlated with the down-regulation of gene expression. Methylation of this panel of promoter was found more frequently in triple negative and HER2 phenotype. ESR1 was preferably associated with TN(80%) and HER2+(60%) subtype. With a median follow up of 6 years, we found worse overall survival (OS) with more frequent ESR1 methylation gene(p>0.05), Luminal A;ESR1 Methylation OS at 5 years 81% vs 93% when was ESR1 Unmethylation. Luminal B;ESR1 Methylation 86% SG at 5 years vs 92% in Unmethylation ESR1. Triple negative;ESR1 Methylation SG at 5 years 75% vs 80% in unmethylation ESR1. HER2;ESR1 Methylation SG at 5 years was 66.7% vs 75% in unmethylation ESR1. Conclusions: Our results provide evidence that well-defined DNA methylation profiles enable breast cancer subtype prediction and support the utilization of this biomarker for prognostication and therapeutic stratification of patients with breast cancer.

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Evaluation of FGFR targeting in breast cancer through interrogation of patient-derived models

Breast Cancer Research ◽

10.1186/s13058-021-01461-4 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Nicole J. Chew ◽

Terry C. C. Lim Kam Sian ◽

Elizabeth V. Nguyen ◽

Sung-Young Shin ◽

Jessica Yang ◽

...

Keyword(s):

Breast Cancer ◽

Therapeutic Target ◽

Breast Cancer Subtype ◽

Breast Cancer Subtypes ◽

Cancer Tissue ◽

Breast Cancers ◽

Luminal A ◽

Tissue Samples ◽

Cancer Subtypes ◽

Luminal B

Abstract Background Particular breast cancer subtypes pose a clinical challenge due to limited targeted therapeutic options and/or poor responses to the existing targeted therapies. While cell lines provide useful pre-clinical models, patient-derived xenografts (PDX) and organoids (PDO) provide significant advantages, including maintenance of genetic and phenotypic heterogeneity, 3D architecture and for PDX, tumor–stroma interactions. In this study, we applied an integrated multi-omic approach across panels of breast cancer PDXs and PDOs in order to identify candidate therapeutic targets, with a major focus on specific FGFRs. Methods MS-based phosphoproteomics, RNAseq, WES and Western blotting were used to characterize aberrantly activated protein kinases and effects of specific FGFR inhibitors. PDX and PDO were treated with the selective tyrosine kinase inhibitors AZD4547 (FGFR1-3) and BLU9931 (FGFR4). FGFR4 expression in cancer tissue samples and PDOs was assessed by immunohistochemistry. METABRIC and TCGA datasets were interrogated to identify specific FGFR alterations and their association with breast cancer subtype and patient survival. Results Phosphoproteomic profiling across 18 triple-negative breast cancers (TNBC) and 1 luminal B PDX revealed considerable heterogeneity in kinase activation, but 1/3 of PDX exhibited enhanced phosphorylation of FGFR1, FGFR2 or FGFR4. One TNBC PDX with high FGFR2 activation was exquisitely sensitive to AZD4547. Integrated ‘omic analysis revealed a novel FGFR2-SKI fusion that comprised the majority of FGFR2 joined to the C-terminal region of SKI containing the coiled-coil domains. High FGFR4 phosphorylation characterized a luminal B PDX model and treatment with BLU9931 significantly decreased tumor growth. Phosphoproteomic and transcriptomic analyses confirmed on-target action of the two anti-FGFR drugs and also revealed novel effects on the spliceosome, metabolism and extracellular matrix (AZD4547) and RIG-I-like and NOD-like receptor signaling (BLU9931). Interrogation of public datasets revealed FGFR2 amplification, fusion or mutation in TNBC and other breast cancer subtypes, while FGFR4 overexpression and amplification occurred in all breast cancer subtypes and were associated with poor prognosis. Characterization of a PDO panel identified a luminal A PDO with high FGFR4 expression that was sensitive to BLU9931 treatment, further highlighting FGFR4 as a potential therapeutic target. Conclusions This work highlights how patient-derived models of human breast cancer provide powerful platforms for therapeutic target identification and analysis of drug action, and also the potential of specific FGFRs, including FGFR4, as targets for precision treatment.

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