Cardiac Monitoring Lacking in Breast Cancer Patients, but Is All-Comer Approach Outdated?

Patrice Wendling

August 08, 2018

Less than half of women with early breast cancer underwent recommended cardiac monitoring after receiving trastuzumab (Herceptin, Genentech/Roche) — a drug that has redefined the treatment of HER2-positive disease but also carries a higher risk for cardiotoxicity.

The rate of heart failure (HF) was 8.3% in women who took trastuzumab-based chemotherapy vs 2.7% in those who did not (P < .001). Rates were roughly halved in patients using vs not using anthracyclines — an older class of cancer drugs also associated with cardiotoxicity (4.6% vs 4.0%; P = .048).

The study was published August 7 in a special "Imaging in Cardio-oncology" issue of JACC Cardiovascular Interventions.

The National Comprehensive Cancer Network recommends cardiac monitoring — usually performed with echocardiography or multigated acquisition (MUGA) scanning — before patients start trastuzumab and every 3 months while on treatment.

Of the 4325 women in the cohort to receive the human epidermal growth factor receptor (HER2)–targeted agent, 73.5% underwent guideline-adherent cardiac monitoring before treatment but only 46.2% did so during treatment.

"The high cardiac monitoring rates at baseline, as opposed to follow-up, are likely due to the tendency for cardiotoxicity to appear in the first 3 months of treatment," lead author Mariana L. Henry, BS, University of Texas MD Anderson Cancer Center, Houston, and colleagues say. "Other factors may include a lack of awareness of cardiac monitoring and a perceived lack of clinical relevance or need among physicians."

Chau T. Dang, MD, Memorial Sloan Kettering Cancer Center, New York City,  who coauthored a related editorial, said in an interview, "Perhaps the low adherence rate in cardiac monitoring may be due to the fact that it is unclear if asymptomatic LVEF decline, detected by serial monitoring, is associated with true symptomatic heart failure in the oncology setting, when compared with the significant benefit of trastuzumab-based treatment."  

In pivotal trastuzumab trials, she said, about 15% to 20% of patients experienced asymptomatic declines in left ventricular ejection fraction (LVEF) but rates of symptomatic NYHA class 3 to 4 HF have not increased after a decade of follow-up and remain very low.

"So clinicians are pushing on with giving therapy, doing less monitoring," Dang said. "I'm not saying that we shouldn't monitor, but what this gives us is information that perhaps we should move forward on conducting trials on whom we can monitor less."

But Who's at Risk?

The investigators note there is very little information about patterns of cardiac monitoring in patients with breast cancer, but they previously showed that 64% of 2203 Medicare beneficiaries (aged at least 65 years) received suboptimal cardiac monitoring during treatment with trastuzumab.

The current study focused on younger women, who tend to have fewer comorbidities and longer life expectancy but may receive more aggressive chemotherapy — thus making them "a critical group for analysis," they say.

Using data from the Truven Health MarketScan database, investigators identified 16,456 female patients (median age, 56 years) with nonmetastatic invasive breast cancer diagnosed between 2009 and 2014. Patients were followed from diagnosis until death or loss of insurance coverage, with the last follow-up December 31, 2015.

In all, 692 patients (4.2%) developed HF after chemotherapy (median time, 8 months). As expected, the risk for HF increased with age.

After multivariate adjustment, patients treated with trastuzumab (hazard ratio [HR], 2.01; 95% confidence interval [CI], 1.72 - 2.36) and those given anthracycline-containing regimens (HR, 1.53; 95% CI, 1.30 - 1.80) were more likely to develop HF.

Other independent predictors were valve disease (HR, 1.93; 95% CI, 1.48 - 2.51), hypertension (HR, 1.28; 95% CI, 1.09 - 1.51), and Deyo comorbidity scores of 1 (HR, 1.38; 95% CI, 1.15 - 1.66) and 2 or more (HR, 2.47; 95% CI, 1.94 - 3.15).

Patients aged 35 years or less had the lowest risk for HF (HR, 0.37; 95% CI, 0.19 - 0.75). Interestingly, taxanes were found to be cardioprotective (HR, 0.70; 95% CI, 0.53 - 0.94). Although this has not been shown in clinical trial data and the mechanisms for it are unclear, "it has been reported that combination treatments with taxanes may be less cardiotoxic, and that modern adjuvant regimens of taxanes apparently do not increase anthracycline cardiotoxicity," the authors say.

HF was more frequently identified in patients undergoing recommended cardiac monitoring (10.4% vs 6.5%; P < .001), they note, "suggesting that, as more patients are screened, more patients are likely to be found having HF."

That said, the investigators say that while cardiac monitoring is recommended in different guidelines, "such recommendations are not based on category 1 data and the timing recommended and the intervals of testing are arbitrary."

Knowledge Gaps

Although it's been 20 years since the approval of trastuzumab, and with guidance in place on LVEF monitoring every 3 months, physicians are still not following the guidelines, Dang said.

"Perhaps we should reevaluate these guidelines and conduct research to do more appropriate, more tailored monitoring," she said. "There are high-risk patients who need to be monitored closely, but also recognizing that there are low-risk patients getting low-risk treatments. We have hard evidence of how low-risk patients survive breast cancer without early or late cardiac events."

The editorialists point out, however, that several knowledge gaps will have to be addressed before the cardio-oncology community can move from an all-comer to tailored monitoring approach. There is a lack of consistent data for the utility of biomarkers, such as troponin I and T and brain natriuretic peptide, for early detection of cardiotoxicity. Echocardiography with strain imaging is being explored as a tool to detect early LV dysfunction, but its utility in standard practice is still unclear with regard to its impact on the decision to hold curative therapy or not, they say.

The prophylactic use of cardioprotective drugs, such as angiotensin receptor blockers or β-blockers, have also produced mixed results in clinical trials, including MANTICORE, PRADA, and CECCY.

Finally, several risk prediction models have been developed, including a 7-factor clinical risk score that a recent Canadian study showed had a negative predictive value of 0.93 for the development of permanent HF or cardiomyopathy in trastuzumab-treated women with HER2-positive breast cancer. The problem is that none of the risk tools have been validated, Dang said.

"I think the conversation should now be to identify a risk tool that would be agreed upon by the cardiology community so that we can use it in the clinic and identify patients at high risk for a cardiac event," she said. "I think there's a lot of interest in this because at the end of the day, the oncologists are on the front line and we can be educated on when to refer our high-risk patients to cardiology or primary care clinicians."

The study was supported by a grant from the National Cancer Institute Cancer Center to MD Anderson Cancer Center and by a grant from the Cancer Prevention and Research Institute of Texas. Henry reported having no relevant industrial relationships. Dang has received research funding to her institution from Roche/Genentech and PUMA.

J Am Coll Cardiol Imag. 2018;11:1084-1093, 1094-1097. Abstract, Editorial

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