Extended AI Use Linked to CV Events and Bone Fractures

Roxanne Nelson, BSN, RN

August 29, 2017

Aromatase inhibitors (AIs) are commonly used as adjuvant treatment in breast cancer, and recent studies show greater benefits from extended use of these drugs (beyond the standard 5 years), but a new meta-analysis indicates that extended use is associated with a higher risk for cardiovascular events and bone fractures.

Among patients who received extended AI therapy, 7.0% of patients experienced cardiovascular events compared to 6.0% in control groups, which was a statistically significant percentage (odds ratio [OR] = 1.18, 95% confidence interval [CI], 1.00 - 1.40; P = .05). Bone fractures occurred in 6.3% (vs 4.8% of control patients), which was also statistically significant (OR = 1.34; 95% CI, 1.16 - 1.55; P < .001).

However, the risk for death from causes other than breast cancer was not increased by extended AI use.

The findings are published in the Journal of the National Cancer Institute.

"The main take-home message is there will be an increased risk of cardiovascular disease with extended AIs," said study author Eitan Amir, ChB, PhD, from the Cancer Clinical Research Unit at Princess Margaret Cancer Center, Toronto, Canada.

"Cardiovascular disease is one of the most common causes of death in women with breast cancer and, with longer follow-up, overtakes breast cancer as the leading cause of death," Dr Amir told Medscape Medical News. "As such, knowledge of interventions which may increase the risk of cardiovascular disease further is important, as this can aid in treatment selection as well as an understanding that closer cardiovascular surveillance during extended therapy may be needed in some patients."

He noted that although they did not observe an effect on death without breast cancer recurrence, it is possible that with longer follow-up, an effect will be observed. "Cardiovascular disease is treatable, and the time from diagnosis to death is typically much longer than the follow-up period of the trials which comprised our analysis," he said. "Similarly, an effect on breast cancer death may also be seen with longer follow-up. It took many years to observe survival effects from initial adjuvant therapy."

In an accompanying editorial, Paula R. Pohlmann, MD, and Claudine Isaacs, MD, both from the Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, also highlight this point.

It is still an open question whether the median follow-up periods in the included studies, which ranged from 30 to 82 months, were long enough to fully ascertain the impact of cardiovascular-related outcomes, they write.

The editorialists summarize the findings and calculate the number needed to harm (NNH).

Among patients who received prolonged therapy with an AI, there was a statistically significant but small increase in odds of cardiovascular events, with an absolute weighted pooled difference of 0.8% and an NNH of 122 patients, they note.

For bone fractures, the absolute weighted pooled difference of 1.4% and the NNH was 72.

Regarding the rate of discontinuation because of adverse events, the absolute weighted pooled difference was 4.8% and the NNH was 21.

Increase in CV, Skeletal Events

There has been concern about toxicity with prolonged use of AIs. The authors note that much of the data on extended use come from trials that compared AIs to tamoxifen. Longer exposure has been shown to be associated with more cardiovascular events and bone fractures.

But there are few data with which to compare toxicity profiles of patients who received extended treatment with AIs with toxicity profiles of patients who received no treatment, the authors note.

Dr Amir and colleagues conducted a meta-analysis that included seven randomized controlled trials that included 16349 patients. All the trials compared extended treatment with AIs to placebo or no treatment in postmenopausal women with hormone receptor–positive early breast cancer.

Cardiovascular events were reported in six of the included studies, and all studies reported on bone fractures.

In four studies, extended AI therapy was not associated with the development of second cancers, excluding breast cancer (OR = 0.93; 95% CI, 0.73 - 1.18; P = .56). The absolute risk for a secondary malignancy other than breast cancer was 2.2% in patients who received prolonged treatment with AIs and 2.4% in control patients.

The rate of discontinuation because of adverse events was higher with extended AI therapy (45% increased odds) as compared with placebo or no treatment (OR = 1.45; 95% CI, 1.25 - 1.68; P < .001). In absolute terms, 17.0% of patients who received extended therapy stopped treatment, vs 13.4% of control patients.

Five studies reported mortality in the absence of breast cancer recurrence. No statistically significant association between death without breast cancer recurrence and longer use of AIs was observed (OR = 1.11; 95% CI, 0.90 - 1.36; P = .34). In absolute terms, 3.3% of those in the AI groups and 2.9% of control patients died from causes other than breast cancer recurrence.

An exploratory analysis was conducted to assess the effect of extended therapy on overall survival. No effect on overall survival was observed (OR = 1.01; 95% CI, 0.89 - 1.14; P = .92), although disease-free survival was improved (pooled OR = 0.78; 95% CI, 0.68 - 0.88; P < .001).

Best Candidates for Prolonged Therapy

In their editorial, Dr Pohlmann and Dr Isaacs emphasize that the benefit from extended adjuvant endocrine therapy is modest, and the results from large clinical trials suggest that this treatment "is active in a small subset of patients."

But the "conundrum has been how to best define this group," they write.

"Given this scenario, understanding safety and tolerance to treatment and developing and implementing precision medicine tools are critical steps for improving treatment recommendations," they add.

A substantial number of patients will experience a recurrence despite extended adjuvant endocrine therapy, they point out, "while many others are considered for this treatment strategy without need.

"Therefore, the development of diagnostic tools to help identify patients who will benefit from this therapy, to identify those who will do well regardless and thus should be spared the needless toxicities and cost, and finally to select those with dormant-resistant disease for alternate investigational therapies is the next critical step in this field," they write.

No funding for the study has been disclosed. The study authors have disclosed no relevant financial relationships. Dr Pohlmann and Dr Isaacs have disclosed relationships with industry, as noted in their editorial.

J Natl Cancer Inst. 2018;110:djx141. Abstract, Editorial

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