SPAG5 Expression Linked To Breast Cancer Outcomes

SPAG5 proposed as biomarker for breast cancer-specific survival and chemosensitivity

medwireNews: Protein and gene markers for sperm-associated antigen 5 (SPAG5) may help predict breast cancer-specific survival and chemotherapy response, say researchers who believe the marker could be particularly useful for oestrogen receptor-negative patients.

SPAG5 gene gain or amplification on chromosome 17q11.2 was identified as a marker of interest using artificial neural network analysis of 2400 breast cancer patients in the Nottingham discovery, Uppsala and METABRIC cohorts, explain Stephen Chan from Nottingham University Hospitals NHS Trust in the UK, and co-workers.

Further analysis was then performed on these three cohorts plus data for a multicentre cohort of 5439 patients, a pooled cohort of 684 patients with untreated lymph node-positive disease, 508 patients from the MD Anderson taxane plus anthracycline-based neoadjuvant chemotherapy cohort and 253 patients from a phase II neoadjuvant clinical trial.

Three additional Nottingham cohorts were also included: 1650 patients with early-stage breast cancer, 697 patients with early-stage oestrogen receptor-positive breast cancer given adjuvant chemotherapy, and 200 patients given anthracycline neoadjuvant chemotherapy.

The team reports in The Lancet Oncology that both copy number aberration resulting in SPAG5 gain or amplification and high SPAG5 transcript levels in METABRIC participants were associated with significantly shorter breast cancer-specific survival, with hazard ratios of 1.50 and 1.68, respectively.

And Nottingham discovery patients who had elevated SPAG5 protein levels also had significantly poorer disease-specific survival (HR=1.68).

Indeed, multivariate analysis confirmed that high versus low transcript levels and protein expression were associated with a reduced likelihood of 10-year breast cancer-specific survival, with HRs in the different cohorts ranging from 1.27 to 1.73.

Furthermore, for patients with oestrogen receptor-negative breast cancer who had a high SPAG5 protein expression, receipt of anthracycline-based adjuvant chemotherapy improved breast cancer-specific survival, with an HR of 0.37 compared with nonuse of chemotherapy.

Additional multivariate analysis revealed that high SPAG5 transcript levels was a significant predictor of longer relapse-free survival in patients who were treated with taxane plus anthracycline neoadjuvant chemotherapy (HR=0.68).

The likelihood of achieving a pathological complete response after combination cytotoxic chemotherapy was also significantly predicted by higher SPAG5 transcript and SPAG5 protein levels in two different cohorts, with odds ratios of 1.71 and 8.75, respectively.

“Validation of our results in a randomised trial of anthracycline-based neoadjuvant chemotherapy would determine whether patients whose predicted tumour response would be poor could be spared from the unnecessary risk of cardiac toxicity when other more effective agents could be used”, the researchers suggest.

“Although the mechanism linking SPAG5 upregulation and anthracycline response is unknown and further investigation is warranted, it could be because of the accumulation of DNA damage, abnormal mitoses, and subsequent mitotic catastrophe.”

However, the authors of an accompanying comment caution that “several challenges” must be overcome before SPAG5 can be used as a clinical biomarker, including determination of whether SPAG5 protein or messenger RNA is the best predictor, and what the optimal thresholds for survival and/or chemosensitivity are.

“A major clinical challenge will be to prospectively demonstrate the usefulness of SPAG5 as a marker of benefit for anthracycline-based chemotherapy compared with the various candidate tests under development”, continue François Bertucci, from Institut Paoli-Calmettes in Marseille, France, and colleagues.

“The predictive value of SPAG5 with respect to other drug classes such as those targeting the mitotic spindle (eg, taxanes) or the cell cycle (eg, CDK4 and CDK6 inhibitors) will also need to be established.”

References

Abdel-Fatah TMA, Agarwal D, Liu D-X, et al. SPAG5 as a prognostic biomarker and chemotherapy sensitivity predictor in breast cancer: a retrospective, integrated, genomic, trancriptomic, and protein analysis. Lancet Oncol 2016; Advance online publication 13 June. DOI: http://dx.doi.org/10.1016/S1470-2045(16)00174-1 

Bertucci F, Viens P, Birnbaum D. SPAG5: the ultimate marker of proliferation in early breast cancer? Lancet Oncol 2016; Advance online publication 13 June. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30092-4

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