What is the clinical evidence from this study?

Study design: Observational. Population: Primary breast cancer (n=12). Intervention: Multi-agent chemotherapy vs. Baseline. Primary outcome: High density lipoprotein cholesterol (HDL-C) levels (mmol/L) (p=0.02).

What does this research mean for the field?

Multi-agent chemotherapy significantly reduces mean HDL-C levels and increases apoB levels in breast cancer patients, with specific agents like doxorubicin driving these changes by downregulating ABCA1 and apoA1 via PPARγ and LXRα pathways. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

January 25, 2016Open Access

Chemotherapy Agents Alter Plasma Lipids in Breast Cancer Patients and Show Differential Effects on Lipid Metabolism Genes in Liver Cells

Key Result

Multi-agent chemotherapy significantly reduced mean HDL-C levels from 1.45 mmol/L to 1.13 mmol/L and increased apoB levels in breast cancer patients.

Study Design

Type

Observational (n=12)

Multicenter

Structured PICO

Does multi-agent chemotherapy alter plasma lipid profiles in women with newly diagnosed primary breast cancer?

Population

12 women (aged 25-65) with newly diagnosed primary breast cancer undergoing multi-agent chemotherapy. Excluded: recurrent breast cancer, distant metastases, known thyroid problems or diabetes. Also includes an in vitro model using HepG2 hepatocarcinoma cells.

Intervention

Multi-agent chemotherapy: 4 cycles of doxorubicin and cyclophosphamide followed by 12 weekly treatments of paclitaxel (n=7), or 3 cycles of epirubicin, cyclophosphamide and 5'-fluorouracil followed by 3 cycles of docetaxel (n=5). In vitro: doxorubicin, epirubicin, paclitaxel, and cyclophosphamide.

Comparator

Baseline (pre-chemotherapy) lipid levels for patients; untreated control cells for in vitro experiments.

Outcome

Changes in plasma lipid and apolipoprotein levels (Total cholesterol, HDL-C, LDL-C, triglycerides, Lp(a), apoA1, apoB) measured at baseline, midpoint, and final point of treatment.surrogate

Breast cancer chemotherapy regimens containing anthracyclines and taxanes induce an unfavorable atherogenic lipid profile, driven by agent-specific alterations in hepatic lipid metabolism genes.

Main Result

Absolute Event Rate: 1.13% vs 1.45%

p-value: p=0.02

Limitations

Lack of follow-up lipid data to establish if the lipid changes were maintained
Investigated a limited number of lipid metabolism targets
Small sample size of 12 subjects

Abstract

Cardiovascular complications have emerged as a major concern for cancer patients. Many chemotherapy agents are cardiotoxic and some appear to also alter lipid profiles, although the mechanism for this is unknown. We studied plasma lipid levels in 12 breast cancer patients throughout their chemotherapy. Patients received either four cycles of doxorubicin and cyclophosphamide followed by weekly paclitaxel or three cycles of epirubicin, cyclophosphamide and 5'-fluorouracil followed by three cycles of docetaxel. Patients demonstrated a significant reduction (0.32 mmol/L) in high density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (apoA1) levels (0.18 g/L) and an elevation in apolipoprotein B (apoB) levels (0.15 g/L) after treatment. Investigation of the individual chemotherapy agents for their effect on genes involved in lipoprotein metabolism in liver cells showed that doxorubicin decreased ATP binding cassette transporter A1 (ABCA1) via a downregulation of the peroxisomal proliferator activated receptor γ (PPARγ) and liver X receptor α (LXRα) transcription factors. In contrast, ABCA1 levels were not affected by cyclophosphamide or paclitaxel. Likewise, apoA1 levels were reduced by doxorubicin and remained unaffected by cyclophosphamide and paclitaxel. Doxorubicin and paclitaxel both increased apoB protein levels and paclitaxel also decreased low density lipoprotein receptor (LDLR) protein levels. These findings correlate with the observed reduction in HDL-C and apoA1 and increase in apoB levels seen in these patients. The unfavourable lipid profiles produced by some chemotherapy agents may be detrimental in the longer term to cancer patients, especially those already at risk of cardiovascular disease (CVD). This knowledge may be useful in tailoring effective follow-up care plans for cancer survivors.

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