NSAID Hope for Postmenopausal Breast Cancer Recurrence Risk Reduction

Obese women at risk of postmenopausal breast cancer recurrence may benefit from COX-2 inhibition

medwireNews: Daily use of non-steroidal anti-inflammatory drugs (NSAID) has the potential to reduce the risk of recurrent postmenopausal breast cancer in obese patients, US research suggests.

"Clinicians are finding that the five-year recurrence rate for postmenopausal women is much higher on aromatase inhibitors when the patient is obese," explained author Linda deGraffenried, from the University of Texas at Austin, in a press release.

"We would like to identify which women are most likely to benefit from interventions like adding NSAIDs to treatment regimens."

Findings from 440 women with invasive Oestrogen receptor (ER)α-positive breast cancer indicated that the 159 women who used NSAIDs every day were 52% less likely to develop local, contralateral, distant or metastatic recurrence than the 281 non-users.

And the reduced risk of recurrence with daily aspirin, ibuprofen or a COX-2 inhibitor continued even after taking into consideration the use of other anti-inflammatory agents, such as statins or omega 3 fatty acids.

Women who took NSAIDs also had significantly longer disease-free survival than non-users, at 78.5 versus 50.6 months, reports the team in Cancer Research.

Furthermore, the majority of patients in the study were overweight (25.0–29.9 kg/m2) or obese (≥30 kg/m2); these individuals were 1.86 times more likely to experience recurrence than their counterparts with a normal BMI of 18.5 to 24.9 kg/m2.

The researchers also investigated potential mechanisms mediating the protective effect of NSAIDs in breast cancer patients using sera from breast cancer patients with a normal or obese BMI.

Cultured macrophages expressed higher levels of COX-2 after exposure to sera from obese patients than normal-weight patients and showed significantly higher levels of macrophage PGE2 production following sera removal.

The researchers explain that expression of these two factors are promoted by saturated fatty acids and that obese patient sera had significantly higher levels of saturated fatty acids and fatty acid substrates than sera taken from normal-weight patients.

In addition, pre-adipocytes cultured using media from macrophages grown in sera from obese patients had higher levels of aromatase expression than those cultured from normal-weight patient sera. But treating the macrophages with the COX-2 inhibitor celecoxib neutralised this difference.

The increase in aromatase expression correlated with Amplification of the pre-adipocyte oestradiol production in cells grown in sera from obese patients but adding the aromatase inhibitor anastrozole to the culture again negated the difference between cells grown in obese and normal-weight patient sera.

“Our current investigation strongly suggests that local estradiol production, induced by macrophage COX-2 activity, may be a key mediator in the link between obesity and postmenopausal, hormone-responsive breast cancer progression”, the researchers explain.

“This conclusion is supported by the clinical observation of a 52% lower recurrence rate and 28-month extension in time to recurrence with NSAID use in a largely overweight/obese and postmenopausal patient population with ERα-positive disease.”

They conclude: “Collectively, our results provide a strong rationale for further studies about the clinical benefit of aromatase inhibitor/COX-2 inhibitor combination treatment for obese, postmenopausal patients with breast cancer.”

Reference

Bowers L, Maximo I, Brenner A, et al. NSAID use reduces breast cancer recurrence in overweight and obese women: Role of prostaglandin-aromatase interactions. Cancer Res 2014; 74: 4446–4457. doi: 10.1158/0008-5472.CAN-13-3603

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