ADAMTS Mutations Linked to Ovarian Cancer Survival

Ovarian carcinoma patients with mutations in any of the eight ADAMTS genes are more likely to benefit from platinum-based chemotherapy than those with wild-type ADAMTS tumours

medwireNews: Women with serous ovarian carcinoma harbouring mutations in the ADAMTS gene family have significantly better chemotherapy sensitivity and survival than those with Wild-type ADAMTS tumours, research indicates.

“The finding has important implications for clinical prediction and trial design and may be a useful addition to BRCA mutation assessment for patients with ovarian cancer”, write Wei Zhang, from University of Texas MD Anderson Cancer Center in Houston, USA, and team in JAMA Oncology.

Using whole-exome sequencing data from the Cancer Genome Atlas, the researchers identified an association between mutations in any of the eight members of the ADAMTS family of genes (ADAMTS16, ADAMTSL1, ADAMTS1, ADAMTS15, ADAMTS6, ADAMTS9, ADAMTS18 and ADAMTS13) and sensitivity to platinum-based chemotherapy in 210 women with high-grade serous ovarian cancer. And they validated it in samples from a further 302 patients.

When the discovery and validation cohorts were pooled, all 53 patients with ADAMTS-mutated tumours displayed chemosensitivity – this was significantly higher than the 64% rate seen in wild-type ADAMTS cases.

Women with ADAMTS-mutated tumours had significantly longer overall and progression-free survival than those with wild-type ADAMTS cancers, at a median of 58.0 versus 41.3 months and 31.8 versus 15.3 months, respectively.

Median platinum-free duration was also significantly improved in ADAMTS-mutated compared with wild-type cases, at 21.7 and 10.1 months, respectively.

And multivariate analysis, adjusting for age, stage, residual tumour and BRCA1 or BRCA2 mutations, confirmed an independent and significant link between ADAMTS mutations and overall, progression-free and platinum-free survival, with hazard ratios of 0.53, 0.40 and 0.45, respectively.

The presence of ADAMTS mutations did not correlate significantly with BRCA1 or BRCA2 mutations, but was significantly associated with tumours with a high mutation rate, a positive Prognostic marker for ovarian cancer.

Wei Zhang et al suggest: “These data together with a small overlap between tumours with ADAMTS and BRCA1 or BRCA2 mutations suggest that ADAMTS mutations may play a similar role in response to DNA-damaging agents, leading to better survival and improved chemosensitivity in the patients with ovarian cancer whose tumours did not harbour BRCA1 or BRCA2 mutations.”

The authors add that the role of ADAMTS genes in vasculature, a key marker of ovarian cancer prognosis, may also contribute to the improved survival of women with ADAMTS-mutated tumours.

Reference

Liu Y, Yasukawa M, Chen K, et al. Association of Somatic Mutations of ADAMTS Genes With Chemotherapy Sensitivity and Survival in High-Grade Serous Ovarian Carcinoma. JAMA Oncol; Advance online publication 11 June 2015. doi:10.1001/jamaoncol.2015.1432

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