What is the clinical evidence from this study?

Study design: Cohort. Population: Breast cancer (n=166). Intervention: SNPs in RAC2, NCF4, SLC28A3, TOP2B, ABCB1, and CBR3. Primary outcome: Systolic dysfunction (ejection fraction 0.05).

What does this research mean for the field?

Single nucleotide polymorphisms in ABCB1 and CBR3 are associated with chronic cardiotoxicity in doxorubicin-treated breast cancer patients, while previously reported associations for RAC2, NCF4, and SLC28A3 could not be validated. Novelty: ClaimNovelty.CONTRADICTORY. Consensus alignment: ConsensusAlignment.CHALLENGES_CONSENSUS.

What question did this study set out to answer?

Validate candidate SNPs previously linked to anthracycline-induced cardiotoxicity and identify novel genetic associations with treatment-induced heart dysfunction.

January 22, 2016Pharmacogenomics

Evidence for Association of SNPs in ABCB1 and CBR3 , but not RAC2, NCF4, SLC28A3 or TOP2B , with Chronic Cardiotoxicity in a Cohort of Breast Cancer Patients Treated with Anthracyclines

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Key result

SNPs in ABCB1 (p=0.049) and CBR3 (p=0.012) were associated with chronic cardiotoxicity in doxorubicin-treated breast cancer patients, while RAC2, NCF4, and SLC28A3 associations were not validated.

Why the study?

Do specific SNPs predict anthracycline-induced cardiotoxicity (systolic dysfunction) in breast cancer patients treated with doxorubicin?

Key Points

Validate candidate SNPs previously linked to anthracycline-induced cardiotoxicity and identify novel genetic associations with treatment-induced heart dysfunction.
Evaluated 166 doxorubicin-treated breast cancer patients via echocardiogram, identifying 19 cases with systolic dysfunction (ejection fraction <55%) and 147 controls.
Conducted a statistically corrected primary analysis testing four high-priority SNPs (RAC2, NCF4, SLC28A3, and TOP2B) alongside an uncorrected secondary analysis of 23 candidate SNPs.
Prior associations for RAC2, NCF4, and SLC28A3 were not replicated, and no association was identified for TOP2B (all p > 0.05).
Secondary analysis identified an association with a protective SNP in ABCB1 (3435C>T, p = 0.049) and an increased risk allele in CBR3 (V244M, p = 0.012).

Study Design

Type

Cohort (n=166)

Structured PICO

Do specific SNPs predict anthracycline-induced cardiotoxicity (systolic dysfunction) in breast cancer patients treated with doxorubicin?

Population

166 breast cancer patients (stage I-III) treated with doxorubicin who underwent echocardiogram, including 19 cases with systolic dysfunction (EF <55%) and 147 controls. Median age 50 at treatment, 95% non-Hispanic white.

Intervention

Screening of 27 single nucleotide polymorphisms (SNPs), including RAC2, NCF4, SLC28A3, TOP2B, ABCB1, and CBR3, putatively relevant to anthracycline-induced cardiotoxicity.

Comparator

Patients without the specific genetic variants (comparison of genotype frequencies between cases with EF <55% and controls with EF ≥55%).

Outcome

Systolic dysfunction defined as an ejection fraction (EF) <55% on echocardiogram.safety

Main Result

p-value: p=> 0.05

Previously reported genetic associations with anthracycline-induced cardiotoxicity were not validated, but novel associations in ABCB1 and CBR3 were identified, requiring further replication.

Limitations

Inadequate power
Requires further replication in independent cohorts
inadequate power
requires further replication in independent cohorts

Discussion

No takes yet. Share an insight, caveat, or question.

Implication

Should not guide genetic screening or monitoring changes; leaves open ABCB1/CBR3 validation in prospective cohorts.

Cite This Study

Hertz et al. (2016) conducted a cohort in Breast cancer (n=166). SNPs in RAC2, NCF4, SLC28A3, TOP2B, ABCB1, and CBR3 was evaluated on Systolic dysfunction (ejection fraction <55%) (p=> 0.05). SNPs in ABCB1 (p=0.049) and CBR3 (p=0.012) were associated with chronic cardiotoxicity in doxorubicin-treated breast cancer patients, while RAC2, NCF4, and SLC28A3 associations were not validated.

synapsesocial.com/papers/6a14e36d253bd9cd3ce62707 https://doi.org/10.2217/pgs.15.162

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Evidence for Association of SNPs in ABCB1 and CBR3 , but not RAC2, NCF4, SLC28A3 or TOP2B , with Chronic Cardiotoxicity in a Cohort of Breast Cancer Patients Treated with Anthracyclines

Key Points

Study Design

Structured PICO

Main Result

Limitations

Discussion

Implication

Cite This Study

Evidence for Association of SNPs in ABCB1 and CBR3 , but not RAC2, NCF4, SLC28A3 or TOP2B , with Chronic Cardiotoxicity in a Cohort of Breast Cancer Patients Treated with Anthracyclines

Key Points

Study Design

Structured PICO

Main Result

Limitations

Discussion

Implication

Cite This Study

Also Consider

Also Consider