Impact of intratumoural heterogeneity on the assessment of Ki67 expression in breast cancer

Aleskandarany, Mohammed A.; Green, Andrew; Ashankyty, Ibraheem; Elmouna, Ahmed; Diez-Rodriguez, Maria; Nolan, Christopher C.; Ellis, Ian O.; Rakha, Emad A.

doi:10.1007/s10549-016-3893-x

Cited by 26 publications

(25 citation statements)

References 42 publications

(46 reference statements)

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“…Moreover, metastatic tumor cells were highly proliferative and associated with Ki-67 levels in the highest expression hot spots in primary tumors. This may reflect the temporal heterogeneity through clonal expansion of the primary tumor growth fraction with metastatic potential ( 92 ).…”

Section: Intratumor Heterogeneitymentioning

confidence: 99%

Tumor Heterogeneity in Breast Cancer

2017

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Breast cancer is a heterogeneous disease and differs greatly among different patients (intertumor heterogeneity) and even within each individual tumor (intratumor heterogeneity). Clinical and morphologic intertumor heterogeneity is reflected by staging systems and histopathologic classification of breast cancer. Heterogeneity in the expression of established prognostic and predictive biomarkers, hormone receptors, and human epidermal growth factor receptor 2 oncoprotein is the basis for targeted treatment. Molecular classifications are indicators of genetic tumor heterogeneity, which is probed with multigene assays and can lead to improved stratification into low- and high-risk groups for personalized therapy. Intratumor heterogeneity occurs at the morphologic, genomic, transcriptomic, and proteomic levels, creating diagnostic and therapeutic challenges. Understanding the molecular and cellular mechanisms of tumor heterogeneity that are relevant to the development of treatment resistance is a major area of research. Despite the improved knowledge of the complex genetic and phenotypic features underpinning tumor heterogeneity, there has been only limited advancement in diagnostic, prognostic, or predictive strategies for breast cancer. The current guidelines for reporting of biomarkers aim to maximize patient eligibility for targeted therapy, but do not take into account intratumor heterogeneity. The molecular classification of breast cancer is not implemented in routine clinical practice. Additional studies and in-depth analysis are required to understand the clinical significance of rapidly accumulating data. This review highlights inter- and intratumor heterogeneity of breast carcinoma with special emphasis on pathologic findings, and provides insights into the clinical significance of molecular and cellular mechanisms of heterogeneity.

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Section: Intratumor Heterogeneitymentioning

confidence: 99%

Tumor Heterogeneity in Breast Cancer

2017

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“…7B). A number of studies have confirmed that Ki67 protein expression is a strong indicator of patient outcome [52]; therefore, we determined the Ki67 expression in each group. Tumor tissues were collected, and Ki67 expression was assessed using immunohistochemistry (IHC).…”

Section: Combination Treatment Suppresses Tumor Growth In Xenograft Mmentioning

confidence: 99%

Metabolic Shift Induced by ω -3 PUFAs and Rapamycin Lead to Cancer Cell Death

Zhu

Feng

Lin

et al. 2018

Cell Physiol Biochem

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Background/Aims: Rapamycin (Rp), the main mammalian target of rapamycin complex inhibitor, is a promising therapeutic agent for breast cancer. However, metabolic disorders and drug resistance reduce its efficacy. Epidemiological, clinical, and experimental studies have demonstrated that omega-3 polyunsaturated fatty acids (ω-3 PUFAs) significantly reduce the incidence and mortality of breast cancer and improve metabolic disorders. Methods: Three breast cancer cell lines and immunocompetent and immunodeficient mice were used to evaluate the therapeutic effects of Rp plus ω-3 PUFA treatment. The production of reactive oxygen species (ROS) and glucose uptake were examined by flow cytometry. Metabolic shift was examined by metabonomics, seahorse experiments, and western blot analysis. Results: We found that ω-3 PUFAs and Rp synergistically induced cell cycle arrest and apoptosis in vitro and in vivo, accompanied by autophagy blockage. In addition, Rp-induced hypertriglyceridemia and hypercholesterolemia were completely abolished by ω-3 PUFA supplementation. Moreover, the combined treatment of ω-3 PUFA and Rp significantly inhibited glycolysis and glutamine metabolism. The anti-tumor effects of this combination treatment were dependent on ROS production, which was increased by β-oxidation and oxidative phosphorylation. Conclusion: Our study revealed that ω-3 PUFA enhanced the anti-tumor activity of Rp while minimizing its side effects in vitro and in vivo. These results provide novel insights into the mechanisms underlying the potential beneficial effects of Rp combined with ω-3 PUFAs on the prevention of breast cancer.

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“…Recently, we evaluated the expression of Ki67 in multiple areas from a subset of primary invasive BC and in the corresponding lymph node metastasis [96], and found a high degree of variation in the expression across the areas on the slide from the same tumour block as well as between slides from different tumour blocks. Interestingly, the highest scores of Ki67 in primary tumours coincided with those in the nodal metastatic deposits (Fig.…”

Section: Heterogeneity and The Efficacy Of Targeted Therapymentioning

confidence: 99%

Tumour Heterogeneity of Breast Cancer: From Morphology to Personalised Medicine

et al. 2018

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Breast cancer (BC) displays striking clinical, morphological, and behavioural diversity within a single tumour and between tumours. Currently, mounting evidence indicates that the morphological heterogeneity of BC reflects an underlying spectrum of genetic and epigenetic portraits that control BC behaviour. Further understanding of BC heterogeneity will have an impact, not only on the routine diagnostic practices but also on patients' management decisions. Phenomena like diagnostic inconsistencies and therapeutic resistance, both primary and acquired, could be attributed, at least in part, to tumour heterogeneity within the same cancer and between the primary disease and subsequent recurrences. From a practical standpoint, and to minimise the impact of BC intratumoral heterogeneity, pragmatic approaches for adequate tumour sampling have been suggested in translational biomarker discovery and validation research studies and in the clinical setting. Here, we provide a brief overview of BC heterogeneity, with an emphasis on the clinical consequences of intratumoral heterogeneity.

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Impact of intratumoural heterogeneity on the assessment of Ki67 expression in breast cancer

Cited by 26 publications

References 42 publications

Tumor Heterogeneity in Breast Cancer

Tumor Heterogeneity in Breast Cancer

Metabolic Shift Induced by ω -3 PUFAs and Rapamycin Lead to Cancer Cell Death

Tumour Heterogeneity of Breast Cancer: From Morphology to Personalised Medicine

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