Advances in Analyzing the Breast Cancer Lipidome and Its Relevance to Disease Progression and Treatment

Abstract Introduction Brain metastasis (BrM) occurs in 10-30% of patients with advanced breast cancer (BC). BrM is increasing in incidence and confers a poor prognosis. We aimed to investigate the contribution of global epi-transcriptomic alterations in N6-methyladenosine (m6A) RNA-methylation as a therapeutic target in brain metastatic breast cancer. Method In preliminary studies we have demonstrated m6A demethylase – FTO as the main contributor to the progression of ER+ breast cancer. Furthermore an association between FTO and reduced disease-free-survival (n=870, p=0.018) was observed. Here we conducted an epigenetic inhibitor screen using two therapeutic agents, ethyl-ester-meclofenamic acid (MA2) and FB23-2 on matched 2D cell line, 3D organoid cultures and patient-derived xenografts (PDX) explant models of brain metastasis. Result Upon integration of mapped global RNA methylation landscape with matched proteomic analysis, we observed genome-wide RNA hypo-methylation of key pluripotency genes, including SOX2 and KLF4, as key players underlying tumour progression to the brain. Genetic and pharmacological inhibition of FTO in novel ex vivo models of BrM significantly reduced protein expression levels of KLF4 and SOX2. Moreover, pharmacological inhibition of FTO with MA2 and FB23-2, inhibited cell proliferation in endocrine-resistant BC and patient BrM cells. We translate our findings to the clinic by demonstrating the efficacy of anti-FTO therapies in several unique PDX and 3D organoid BrM models. Conclusion Our results reveal epi-transcriptional remodelling events as a key mechanism in BrM. This study establishes an early role for targeting RNA methylation in the management of disease progression and presents FTO as a potential therapeutic target in BrM. Take-home message This study establishes an early role for targeting RNA methylation in the management of disease progression and presents FTO as a potential therapeutic target in brain metastatic breast cancer.

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Plasma D- dimer and fibrinogen levels correlates with tumour size and disease progression in Nigerian breast cancer patients

Cancer Investigation ◽

10.1080/07357907.2021.1909059 ◽

2021 ◽

pp. 1-25

Author(s):

Ogochukwu O Izuegbuna ◽

Olayide S Agodirin ◽

Hannah O Olawumi ◽

Samuel A Olatoke

Keyword(s):

Breast Cancer ◽

Disease Progression ◽

Cancer Patients ◽

Tumour Size ◽

Breast Cancer Patients ◽

D Dimer

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139P Association of baseline neutrophil-lymphocyte and platelet-lymphocyte ratios with disease progression in high-risk breast cancer patients

Annals of Oncology ◽

10.1016/j.annonc.2021.03.153 ◽

2021 ◽

Vol 32 ◽

pp. S81

Author(s):

R. Cahyono ◽

S.L. Anwar ◽

H.Y. Budiman ◽

T. Aryandono ◽

W.A. Harahap

Keyword(s):

Breast Cancer ◽

High Risk ◽

Disease Progression ◽

Cancer Patients ◽

Breast Cancer Patients ◽

High Risk Breast Cancer ◽

High Risk Breast ◽

Risk Breast Cancer

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Patterns of Progression in Metastatic Estrogen Receptor Positive Breast Cancer: An Argument for Local Therapy

International Journal of Breast Cancer ◽

10.1155/2017/1367159 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Patrick Kelly ◽

Zhe Ma ◽

Said Baidas ◽

Rebecca Moroose ◽

Nikita Shah ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Disease Progression ◽

Systemic Therapy ◽

Local Therapy ◽

Disease Course ◽

Mechanisms Of Resistance ◽

Diffuse Disease ◽

Estrogen Receptor Positive ◽

Positive Breast Cancer

Purpose. Despite advances in endocrine therapy (ET), metastatic estrogen receptor positive breast cancer (BrCA) remains incurable. Though the mechanisms of resistance to ET have been studied extensively, the anatomic pattern of disease progression remains poorly characterized. The purpose of this study was to characterize the pattern of progression for patients receiving ET for metastatic BrCA. Methods. The records of 108 patients with metastatic BrCA who progressed on ET were reviewed. Progression was characterized as follows: diffuse progression, progression in greater than 3 sites; oligoprogression, progression in fewer than 3 sites with prior diffuse metastases; and oligometastatic disease with progression, progression in 3 or fewer sites with prior limited metastases. Results. Seventy-four patients (69%) displayed only diffuse disease progression. Conversely, 23 patients (21%) displayed oligoprogression and 11 patients (10%) displayed oligometastases with progression at least once in their disease course. Further analysis of the patients with oligoprogression suggested that in 14 patients the sites of progression would have been amenable to local therapy. Conclusion. Oligoprogressive disease occurs in a significant subset of patients with metastatic BrCA treated with ET. These patients with oligoprogressive disease may be eligible for local therapy, potentially obviating the need to change of systemic therapy.

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The efficacy of the combination of eribulin and trastuzumab in advanced HER2-positive breast cancer: the results of Russian observational study

Modern Oncology ◽

10.26442/18151434.2020.1.200058 ◽

2020 ◽

Vol 22 (1) ◽

pp. 53-59

Author(s):

Elena I. Kovalenko ◽

Elena V. Artamonova ◽

Elena V. Karabina ◽

Irina I. Andreiashkina ◽

Ekaterina A. Prokof’eva ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Practice ◽

Observational Study ◽

Disease Progression ◽

Objective Response Rate ◽

Response Rate ◽

Objective Response ◽

Breast Cancer Patients ◽

Luminal Subtype ◽

Her2 Breast Cancer

The article presents the experience of 19 Russian medical institutions on the use of eribulin in combination with trastuzumab in various treatment lines of metastatic HER2+ breast cancer in routine clinical practice. Aim. The main objective of this retrospective observational study was to evaluate the efficacy and tolerability of eribulin and trastuzumab combo in HER2+ breast cancer patients pretreated with anthracyclines and taxanes. The analysis included 60 patients who received at least 2 cycles of eribulin in combination with trastuzumab. 2 patients (3.3%) received treatment as the 1st line, as the 2nd 14 (23.3%), as the 3rd 16 (26.7%), and as the 4th and more 28 (46.7%). Materials and methods. Complete response was achieved in 2 (3.3%) patients, partial response in 9 (15%), stable disease in 33 (55%), stabilization for more than 6 months in 11 (18.3%), disease progression was detected in 16 (26.7%) patients. The objective response rate was 18.3% in the whole group, the clinical benefit rate 36.7%. Results. The objective response rate in the group of the luminal subtype (ER/PR+HER2+) was 26.9%, in HER2-overexpressed subtype (ER-PR-HER2+) 8.8% and 64.7%, respectively, disease progression was recorded 2.3 times more often 35.3% versus 15.5% in the luminal subtype group. The median progression-free survival in patients with HER2+ breast cancer was 4.95 months (95% confidence interval CI 3.048.29 months), in luminal subtype 6.38 months (95% CI 3.338.54 months), in non-luminal 4.44 months (95% CI 2.47.96 months); p=0.306. The treatment was well tolerated, the spectrum of adverse events corresponded to the eribulin toxicity profile. Conclusions. The uniqueness of this study lies in the fact that on a large clinical material from the standpoint of real clinical practice, a very promising treatment regimen that is not used routinely in a number of countries has been studied, its effectiveness and satisfactory tolerance have been confirmed.

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Outcome of breast cancer patients regarding obesity and complications: Analysis of risk factors

Romanian Medical Journal ◽

10.37897/rmj.2021.1.14 ◽

2021 ◽

Vol 68 (1) ◽

pp. 77-86

Author(s):

Iuliana Pantelimon ◽

◽

Laurentia Nicoleta Gales ◽

Maria Daniela Tanasescu ◽

Irina Nita ◽

...

Keyword(s):

Breast Cancer ◽

Body Mass Index ◽

Prognostic Factors ◽

Disease Progression ◽

Body Mass ◽

Type Ii Diabetes ◽

The Body ◽

Proliferation Index ◽

Her2 Overexpression ◽

Type Ii

Introduction. Breast cancer is the leading cause of cancer death in Romania. In the context in which the treatments available for this pathology have increased curability, the identification of negative prognostic factors involved in the evolution of this disease seems essential to improve the overall survival as well as the time to disease progression. Aim. The aim of this study is to identify the role of prognostic factors such as ki67 proliferation index, the presence of tumour estrogen receptors, HER2 overexpression, the presence of secondary determinations at diagnosis, the association of obesity and type II diabetes. Methods. 50 patients diagnosed with breast cancer treated in the Elias University Emergency Hospital Bucharest were retrospectively followed, for which the progression was documented at the time of elaboration of this study. Thus, a database was developed in which data were entered on age, body mass index, immunohistochemical characteristics of breast tumours, the presence/absence of metastases at diagnosis and the association of type II diabetes. Statistical calculations were performed to highlight a possible correlation between obesity (quantified by measuring body mass index) and tumour aggressiveness (quantified by ki67 proliferation index) as well as statistical evaluation of potential prognostic factors that would influence time, until the disease progresses. Results. Within this group, no correlation could be established between the presence of an increased body mass index and the value of the ki67 proliferation index (p = 0.38). The mean value of the body mass index for this group of unselected patients was 28.76 ± 4.81 (DS) most patients are therefore overweight or obese. The factors involved in the evolution of breast cancer that influenced the early progression of the disease were: the proliferation index ki67 (p <0.05), the presence of metastases at diagnosis (p < 0.0001) and the association of type II diabetes (p = 0.0085). The value of the body mass index did not influence the time to disease progression according to statistical calculations in this group probably due to the small number of normal weight patients included (p = 0.34).

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Circulating tumor DNA as a dynamic biomarker of response to palbociclib and fulvestrant in metastatic breast cancer patients

Breast Cancer Research ◽

10.1186/s13058-021-01411-0 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Lauren Darrigues ◽

Jean-Yves Pierga ◽

Alice Bernard-Tessier ◽

Ivan Bièche ◽

Amanda Bartolini Silveira ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Metastatic Breast Cancer ◽

Disease Progression ◽

Somatic Mutations ◽

Metastatic Breast ◽

Circulating Tumor Dna ◽

Prognostic Impact ◽

Radiological Evaluation ◽

Tumor Dna

Abstract Background Following the PALOMA-3 study results, the combination of palbociclib, a CDK4/6 inhibitor, with fulvestrant, a selective estrogen receptor degrader, has become a standard therapy in women with estrogen receptor-positive (ER+) HER2-negative (HER2−) metastatic breast cancer (MBC). Palbociclib has been shown to increase the progression-free survival (PFS) overall but no predictive biomarker of palbociclib efficacy has been validated so far. We thus evaluated whether early changes of circulating tumor DNA (ctDNA) levels are associated with palbociclib plus fulvestrant efficiency. Methods ER+ HER2− MBC patients were included in a prospective observational cohort before treatment initiation. Tumor response was assessed by radiological evaluation (RECIST v1.1) every 3 months. Plasma samples were collected before treatment (baseline), at day 15 (D15), at day 30 (D30), and at disease progression. We searched for somatic mutations from archived tumor tissues by targeted deep sequencing. For patients with somatic mutations identified, circulating tumor DNA (ctDNA) was tracked using digital droplet PCR. Ratios of ctDNA levels ([D15/baseline] and [D30/baseline]) were then correlated with prospectively registered patient characteristics and outcomes. Results Twenty-five of the 61 patients enrolled had a somatic mutation testable in plasma (NPIK3CA = 21, NTP53 = 2, NAKT1 = 2). At baseline, 84% of patients had detectable ctDNA levels but ctDNA levels had no prognostic impact on PFS (p = 0.10). Among those patients, ctDNA was still detected in 82% at D15 and 68% at D30. ctDNA clearance observed at day 30 was associated with longer PFS (HR = 7.2, 95% CI = 1.5–32.6, p = 0.004). On the contrary, a [D30/baseline] ctDNA ratio > 1 was associated with a shorter PFS (HR = 5.1, 95% CI = 1.4–18.3, p = 0.02) and all 5 patients with increased ctDNA levels at D30 showed disease progression after 3 months under palbociclib-fulvestrant. Finally, at the time of radiological tumor progression, ctDNA was detected in all patients tested. Conclusion Our study demonstrates that the efficiency of palbociclib and fulvestrant can be monitored by serial analyses of ctDNA before radiological evaluation and that early ctDNA variation is a prognostic factor of PFS.

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