Low mitochondrial DNA points to breast cancer anthracycline efficacy
medwireNews: Among women with breast cancer treated with anthracyclines in the adjuvant or advanced setting, outcomes are better for those with low versus high levels of mitochondrial (mt)DNA in their primary tumors, suggests an analysis of biobank specimens.
Anthracyclines can induce severe oxidative stress and damage mtDNA, say the Dutch researchers who hypothesize that tumor cells with low mtDNA content would be more susceptible to such damage than cells with high mtDNA content, which would be reflected in improved outcomes.
And indeed, in a group of 118 patients with nonmetastatic lymph node-positive disease who received adjuvant treatment with a combination of 5-fluorouracil, anthracycline (doxorubicin or epirubicin) and cyclophosphamide, distant metastasis-free survival was significantly longer for those with low than high mtDNA content (dichotomized by the median of 758 molecules/cell), at a median of 85 and 34 months, respectively. After adjustment for multiple factors, the hazard ratio (HR) was a significant 0.46.
Similarly, among 77 women given the same anthracycline-based regimens for the first-line treatment of locoregional or distant recurrence, those with low mtDNA (dichotomized by the median of 694 molecules/cell) had significantly prolonged median progression-free survival relative to their counterparts with high mtDNA, at 9.20 versus 5.91 months and a multivariate HR of 0.49.
By contrast, survival outcomes did not vary significantly by mtDNA content among women treated with methotrexate-based chemotherapy in either the adjuvant (n=56) or advanced (n=44) setting – this finding was anticipated by the study authors as “methotrexate induces only low levels of oxidative stress.”
“Our observations indicate that the frequently observed decrease in mtDNA content in primary breast tumors may be exploited by guiding chemotherapeutic regimen decision-making,” Marjolein Weerts and colleagues, from the Erasmus MC Cancer Institute in Rotterdam, write in Clinical Cancer Research.
They admit, however, that “[l]arger (prospective) cohorts of uniformly treated patients are necessary to validate our results and to determine the clinical relevance of mtDNA content quantification in cancer.”
Given the common use of taxanes in breast cancer patients, Weerts et al add that “exploring the impact of mtDNA content on outcome of taxane-treated patients is warranted,” although they do not expect differences in efficacy by mtDNA status as taxanes, like methotrexate, are not active at the DNA level and induce only low degrees of oxidative stress.
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