Evidence Mounts on Heart Failure After Trastuzumab in Breast Cancer Survivors

[Hopeful]

IMNG Medical Media. 2012 Aug 30, M E. Tucker

Trastuzumab, whether given with or without anthracyline-based chemotherapy, was associated with significant increases in heart failure and cardiomyopathy in a large population-based, retrospective cohort study of women treated for breast cancer.

In the "real world" study, which used data from the health maintenance organization Cancer Research Network, the adjusted risk of heart failure (HF) and/or cardiomyopathy increased fourfold among women who received trastuzumab (Herceptin) alone and sevenfold in those who received anthracycline plus trastuzumab, compared with women who received no chemotherapy.

In all, the risk of anthracycline-associated HF/cardiomyopathy among women younger than 65 years was similar to results from randomized clinical trials, while the trastuzumab-associated HF/cardiomyopathy risk - whether administered alone or following an anthracycline - was greater than that previously reported.

"Our results highlight the importance of generalizability in applying clinical trial findings to community settings; although similar to clinical trial results, these population-based results cannot be attributed to any single patient in clinical practice," wrote Erin J. Aiello Bowles of Group Health Research Institute, Seattle, and her associates.

Randomized trials have typically excluded older women and those with major comorbidities, and therefore the association between the two agents and HF/cardiomyopathy in this population is not well understood, Ms. Bowles and her associates noted (J. Natl. Cancer Inst. 2012 Aug. 30 [doi:10.1093/jnci/djs317]).

The current study population comprised 12,500 women diagnosed with incident, invasive breast cancer from Jan. 1, 1999, through Dec. 31, 2007, at eight integrated Cancer Research Network health systems. Women diagnosed with HF/cardiomyopathy prior to breast cancer diagnosis or initiation of chemotherapy were excluded. They had a mean age of 60 years (range, 22-99), and 85.8% were white.

In a median follow-up of 4.4 years, nearly half (46.5%) had received no chemotherapy. Just under a third, 29.6%, had received anthracycline-based chemotherapy alone, 0.9% received trastuzumab-based therapy without anthracycline, 3.5% received anthracycline plus trastuzumab, and 19.5% received other chemotherapy.

Compared with the women who received other chemotherapy or no chemotherapy, the women who received anthracycline alone or anthracycline plus trastuzumab were younger, diagnosed at later stages, had fewer comorbidities, and were slightly more likely to receive radiation therapy. These findings "suggest substantial individualization of adjuvant chemotherapy administration by age and comorbidity in community practice," Ms. Bowles and her associates wrote.

The incidence of HF/cardiomyopathy increased with increasing follow-up time for all of the chemotherapy types, but to a greater degree with trastuzumab. The cumulative HF/cardiomyopathy incidence increased from 1.2% at year 1 to 4.3% at year 5 for the anthracycline recipients, which was similar to the increase from 1.3% to 4.5% for those on other chemotherapies. For those with no chemotherapy, the cumulative incidence rose from 0.9% to 3.1%.

In contrast, the cumulative HF/cardiomyopathy incidence among recipients of anthracycline plus trastuzumab was 6.2% after 1 year of follow-up and continued to increase to 20.1% by 5 years.

Compared with no chemotherapy, the risk of incident HF/cardiomyopathy among all women was statistically significantly increased for anthracycline alone (adjusted hazard ratio, 1.40), trastuzumab without anthracycline (HR, 4.12), anthracycline plus trastuzumab (HR, 7.19), and other chemotherapy (HR, 1.49), the investigators said.

The 5-year cumulative incidence for HF/cardiomyopathy associated with each of the chemotherapies was greater in the older age groups, but the hazard ratios for HF/cardiomyopathy associated with chemotherapy use decreased with increasing age. For example, the hazard ratio for HF/cardiomyopathy associated with anthracycline use alone was statistically significant among women younger than 55 years (HR, 2.52) but not among women 55-64 years (HR, 1.61) or older.

According to Ms. Bowles and her associates, this study demonstrates the importance of observational comparative safety and effectiveness studies in providing complementary data to those obtained in clinical trials. "Observational studies allow for estimation of risks and benefits in community practice, which includes patients who may not be eligible for clinical trials. Clinical trials may provide more relevant estimates for patients who are eligible candidates, but many people are not and still receive these treatments in community practice," they wrote.

In an accompanying editorial, Ann M. Geiger, Ph.D., said that the development of trastuzumab for the treatment of nonmetastatic invasive breast cancer tumors expressing human epidermal growth factor receptor 2 has been an important step in the field of personalized medicine (J. Natl. Cancer Inst. 2012 Aug. 30[doi:10.1093/jnci/djs342]).

Multiple trials have documented clinically and statistically significant improvements in overall and disease-free survival for women receiving adjuvant treatment including trastuzumab, compared with those receiving other chemotherapy agents, she noted. Unlike most new cancer chemotherapies, trastuzumab's use in early-stage HER2-positive breast cancer also appears to be cost effective (Ann. Pharmacother. 2009;43:296-303).

This benefit, however, has been offset by safety concerns, with a pooled analysis of the early breast cancer trials suggesting a fivefold increase in risk of congestive heart failure for women who receive trastuzumab versus those who do not, with consistent results across varying treatment regimens (Cochrane Database Syst. Rev. 2012;4:CD006243).

The current study adds an additional year of follow-up to previous trials, during which the incidence of congestive heart failure continues to increase with no indication of a plateau. This justifies long-term surveillance for congestive heart failure in women who have received trastuzumab, as well as extended follow-up of women enrolled in trials, said Dr. Geiger of the division of public health sciences at Wake Forest University, Winston Salem, N.C.

Although most previous randomized clinical trials have included anthracycline in both treatment and comparison arms, the current observational study found that, in real life, about 40% of women undergoing chemotherapy received regimens excluding anthracycline, probably due in part to the older age and higher comorbidity burden relative to participants in clinical trials, she wrote.

Finally, this study raises concern in that roughly a quarter of the women who received adjuvant trastuzumab had been treated well before the publication of peer-reviewed results of relevant randomized controlled trials. Clinicians may have been basing their decision on findings from trials in women with metastatic breast cancer and preliminary data from the early breast cancer trials. The interim findings, however, were based on follow-up periods too short to account for the longer life expectancy of women with early breast cancer relative to women with metastatic disease, she pointed out.

There have been many instances in which new treatments disseminate based on preliminary reports of benefit, only to be withdrawn after additional safety data become available. Patients, clinicians, and researchers must temper their enthusiasm about the benefits of new cancer therapies with the recognition that estimates of the long-term risk of adverse events are based on short-term observations among carefully selected clinical trial participants, Dr. Geiger said.

This work was supported by the National Cancer Institute through an administrative supplement to the Cancer Research Network. Ms. Bowles did not report any financial disclosures, but one of her coauthors, Dr. Larry A. Allen, has received consulting fees from Amgen, Janssen Scientific Affairs, and the Robert Wood Johnson Foundation. Dr. Geiger said that she has no conflicts of interest.

Hopeful

[michka]

Hopeful, thanks, this is very important. Maybe you should post it on the "HER2 group" forum also. Michka

[gdpawel]

There are a number of issues on the subject of Herceptin. In addition to taking this drug for a long time, these kind of individual, targeted oral drugs would be taken in addition to an existing repertoire of chemotherapy mixtures a cancer patient is already taking, instead of taking them alone. Adding even more potential toxicities and thousands of dollars to treatment.

Overt congestive heart failure is a very late and serious manifestation of heart muscle damage. For every patient with frank congestive heart failure, there is probably another two, three, four or five patients with heart muscle damage short of congestive heart failure. The sort of heart muscle damage which can cause fatigue and/or shortness of breath with moderate or mild exertion, which otherwise wouldn't occur.

We don't know what will happen 10 or 20 years from now in women who didn't need any adjuvant therapy at all, who would have been cured by surgery alone. Only a minority of patients who receive adjuvant therapy benefit from it. Adjuvant therapy is worth it if the women have to suffer only short term, temporary toxicity, and if it even slightly reduces the probability that their cancers will come back. But if it produces permanent toxicity, whether "chemo brain" or "heart muscle damage," that is a whole different order of magnitude in terms of risk.

Aside from the issue of congestive heart failure, past studies have suggested a potentially very serious weakness in the drug, the problem with central nervous system (CNS) metastasis. A study from the Dana Farber Cancer Institute identified central nervous system (CNS) metastases in women who receive trastuzumab-based (Herceptin) therapy for metastatic breast carcinoma. Central nervous system disease is defined as one or more brain metastases or leptomeningeal carcinomatosis (carcinomatous meningitis).

Central nervous system metastases was identified in 34% of patients at a median of 16 months after diagnosis of metastatic breast cancer and 6 months from the beginning of Herceptin treatment. Patients receiving Herceptin as first-line therapy for metastatic disease frequently developd brain metastases while responding to or stable on Herceptin. The authors of the study say that efforts to characterize other risk factors for development of CNS disease, optimal screening algorithms, and new treatment strategies may be warranted.

The potential benefits and risks of Herceptin have renewed concerns about the reliability of HER2 testing. Some studies have shown that the test produces false positives as often as 26% of the time, and may also carry some risk of false negatives. Herceptin also doesn't offer any benefit to women with HER2-negative cancer.

Lastly, monoclonal antibodies like Herceptin (and Erbitux) are "large" molecules. These very large molecules don't have a convenient way of getting access to the large majority of cells. Plus, there is multicellular resistance, the drugs affecting only the cells on the outside may not kill these cells if they are in contact with cells on the inside, which are protected from the drug. The cells may pass small molecules back and forth.

Exciting results have come from studies of multitargeted tyrosine kinase inhibitors,"small" molecules that act on multiple receptors in the cancerous cells, like Tyberb and Sutent. Targeted "small-molecule" therapies ruled at last years annual ASCO meeting of oncologists. The trend is away from the monoclonals to the small molecules, a trend in which a new predictive test may be able to hasten (Cancer 2003 Jun 15;97(12):2972-7).

Rrisk of Heart Failure in Breast cancer Patients After Anthracycline and trastuzumab treatment: A retrospective cohort Study

http://www.oxfordjournals.org/our_jo...wlesdjs317.pdf

Editorial: Herceptin and Congestive Heart Failure

[url]http://www.oxfordjournals.org/our_journals/jnci/press_releases/geigerdjs342.pdf