Past CV disease, diabetes up trastuzumab cardiotoxicity risk in elderly with breast cancer
August 11, 2011 Nick Mulcahy
Barcelona, Spain - The risk of cardiotoxicity from trastuzumab (Herceptin, Genentech), already an issue for women receiving the drug for breast cancer, is even higher in elderly women who have a history of heart disease or diabetes, according to a small single-center study .
It's the first ever to carefully examine trastuzumab-related cardiotoxicity in elderly breast-cancer patients, in this case 70 years of age and older, according to the authors, led by Dr César Serrano (Vall d'Hebron University Hospital, Barcelona, Spain). The pivotal clinical trials of trastuzumab were conducted in younger women, 65 years and younger, who had "optimal performance status," they write. Their study was published online August 9, 2011 in the Annals of Oncology.
In a chart review of 45 patients aged 70 years and older who had been treated with trastuzumab for early or advanced breast cancer at one center since 2005, the investigators found that 12 (26.7%) of the women developed heart problems, usually heart failure or asymptomatic systolic LV dysfunction. This rate of cardiotoxicity is slightly higher than what was seen in the pivotal clinical trials, note Serrano and colleagues.
Asymptomatic cardiotoxicity (about 18% of cases) was defined as an absolute drop of 10% or more in LVEF with a final LVEF below 50% or an absolute drop above 20%. The median duration of trastuzumab-based treatment was 49 weeks.
Most of the cases of cardiotoxicity (92%) resolved in a median of five weeks. "One of the main characteristics of trastuzumab cardiotoxicity is its reversibility. It is a well-known phenomenon that differs from other chemotherapeutic agents such as anthracyclines. Reversibility normally happens with treatment discontinuation but also can also occur spontaneously," explained Serrano, who is now at Brigham and Women's Hospital (Boston, MA), in a press statement . "The decision to reintroduce trastuzumab or to continue with it must be taken case by case together with a cardiologist."
The investigators saw that 33% of women with a history of heart disease developed asymptomatic or symptomatic cardiotoxic effects as a result of receiving trastuzumab, compared with only 9.1% of women without such a history (p=0.01); 33.3% of women with diabetes developed such problems, compared with only 6.1% without diabetes (p=0.017).
In univariate analysis, development of trastuzumab-related cardiotoxicity was significantly associated with obesity (p=0.045), history of heart disease events—including heart failure, arrhythmias, myocardial ischemia, or valvular heart disease (p=0.047)—and diabetes (p=0.017). Not significantly related to cardiotoxicity were prior or current anthracycline exposure, prior treatment for hypertension, baseline LVEF, and smoking history.
But only a history of heart-disease events and diabetes were significant on multivariate analysis.
Despite its limitations, the new paper is a valuable addition to the literature about trastuzumab, according to an expert not involved in the study. "This paper starts to define what puts older women at increased risk for cardiotoxicity on this drug," Dr Ilene Browner (Johns Hopkins University, Baltimore, MD) said in an interview.
It also suggests that there is an "apparent similar tolerance" to trastuzumab in this older population when compared with the younger patients in the drug's pivotal trials, she said. "Most clinicians assume that older patients can't tolerate chemotherapeutic agents used in the treatment of cancer as well as younger patients do."
Patients with or without cardiovascular risk factors require "aggressive monitoring," according to Browner, who said that the standard of care is "frequent monitoring with echocardiograms," as indicated by the drug's package insert.
But, she said, "If a woman has cardiotoxicity risk factors, be even more vigilant." Clinicians may need to weigh the risks and benefits of trastuzumab for some of these patients, she advised.
The authors acknowledge the limited number of patients in their series and say that their findings need to be interpreted cautiously. But, they note, "The fact that the mortality rate at five years after diagnosis of congestive heart failure is about 50% in patients [older than] 65 years warrants close surveillance of early symptoms and cardiac function in the elderly breast-cancer population to be treated with trastuzumab." http://www.theheart.org/article/1262359.do
From the ALF resource "Making A Killing";
Why Animal Tests Don’t
The number of drugs that pass as safe in animal
experiments and then either fail in human clinical
trials or go on to cause death and disability is
testament to the failure of animal tests in protecting
people. Animal tests cannot reliably predict how a
drug will affect people for several crucial reasons:
1) Species differences in anatomy, organ
structure and function, metabolism,
chemical absorption, genetics, mechanism
of DNA repair, behaviour, lifespan and the
inherent sensitivity of cell populations to
toxicants. For example:
– Small animals have proportionately larger
organs, a shorter blood circulation time and their
metabolism is generally faster than that of
– Different species have different metabolising
enzymes, which breakdown chemicals. The
breakdown products generated (metabolites)
can be highly toxic. A drug may therefore
appear safe in tests on animals but be toxicto humans because of a metabolite, which is only produced when broken down by humanspecific
– The anatomy of the intestine, as well as the
variety and abundance of bacteria it harbours,
varies between species and affects the absorption
of drugs from the gastrointestinal tract.40
– The cells or organs targeted by a drug may
simply be more vulnerable to toxins in some
species than in others.41, 42 For example,
human liver damage is the most frequent
reason cited for withdrawal of a drug, with more
than half of acute liver failures being caused by
drugs. Yet liver toxicity in animal tests and
human clinical trials correlate only 50 per cent
of the time.43
– The placenta is more permeable in some
species, such as rats and rabbits, than in
humans, so teratogenicity (birth defect) tests in
animals may give misleading results.44 Even
tests using non-human primates correlate with
human teratogens only 50 per cent of the time.45
2) A homogenous group of animals living in
well-controlled experimental settings cannot
predict the response of varied human
patients living in natural conditions.46
– Test animals are usually all the same age,
strain and sex (it is still common practice to use
exclusively male rats47) and are not exposed to
the variety of pathogens and chemicals, which
free-living humans encounter on a daily basis.
– Unlike many human patients, animal models
rarely suffer from multiple illnesses
simultaneously and are not exposed to multiple
drugs or treatments at the same time.48
3) Artificially created diseases in animals in
laboratories do not reflect naturally occurring
human illness. Therefore, responses to drug
treatment cannot be extrapolated from one
to the other. For example:
– For decades, pharmaceutical companies
tested candidate anti-cancer drugs in animals
carrying transplanted human tumours but very
few drugs that appeared effective in the
animal models worked in humans. More
importantly, according to the US National
Cancer Institute, the animal models missed
effective human drugs.49
– More than 4,000 studies have been reported
demonstrating the efficacy of more than 700
drugs in animal models of stroke.50 About
150 of these drugs have been tested in human
clinical trials and all failed to show benefit.51
4) The stress caused to animals by routine
laboratory practices such as handling, blood
collection, physical restraint, injections and
gavage, results in altered physiological
states, which compromise test results.
– A review of 80 published animal studies found
that routine laboratory procedures caused
significant physiological changes associated
with stress such as raised cortisol, prolactin and
growth hormone levels; increased heart rate
and blood pressure; and abnormal behaviours
such as excessive grooming. The changes
were pronounced and lasted for 30 minutes
– Researchers at York’s Central Science
Laboratory found that having different
experimenters perform the same test using
the same equipment and rats from the same
breeding colony within the same room of the
same laboratory produced significantly different
results depending on whether the handler
was familiar to the rats or not.53
5) Many negative side effects of drugs are
not outwardly visible or measurable and
therefore cannot be detected in animal
tests.54 For example:
– Headache, nausea, dizziness, fatigue,
depression, confusion and double vision are
some of the most common, and often most
debilitating, side effects of drugs yet there is
no way to detect them in animals. http://www.animalliberationfront.com/Philosophy/Animal%20Testing/makingakilling.pdf
On a personal note my mom is one of the people who is suffering with a heart defect after being put on Herceptin. Did the doctor not know of the risk? Is it good medical practice to treat breast cancer at the expense of a once healthy heart? Does the CEO of Genetech feel that this can be balanced out by using statistics to make it acceptable, as in how many women are cured of breat cancer in the spotlight while those who suffer with heart defects as a result are ignored and downplayed by their public relations wizards?
Here is the latest unfortunate individual to make the top of my personal "black list";
Genentech CEO Arthur Levinson - CEO pay report
April 25, 2008 — 1:44pm ET | By Maureen Martino
Arthur Levinson - Genentech
Total Compensation: .8 million
Details: Levinson declined a pay raise, keeping his base salary at 5K. He received .73 million in incentives and .77 million in stock option grants, bringing his total direct compensation to .9 million in 2007. His direct pay was .6 million lower than in 2006 due to the company's lower stock value in 2007
photo of Mr. Levinson here; http://www.fiercebiotech.com/special-reports/genentech-ceo-arthur-levinson-ceo-pay-report
Read more: Genentech CEO Arthur Levinson - CEO pay report - FierceBiotech http://www.fiercebiotech.com/special-reports/genentech-ceo-arthur-levinson-ceo-pay-report#ixzz1kPbWbP9E
Anyone out there who could help me getting the message to Mr. Levinson safely would be my hero. Otherwise i will be forced to take matters in my own hands, and as an independent "lone wolf" type let's just say that i don't follow the ALF creed of "harm none". For me this CEO Arthur Levinson would make a great dinner. Not kidding about my desires to emulate Dr. Lecter's hunger with this one.
If ALF activists can do it themselves without harming anyone, that would allow me to remain free instead of being committed to a state forensic hospital or prison for taking matters into my own hands. Though i love my freedom i feel that i need to seek justice for what was done to my mother.
Thanks again to the ALF for putting out the facts and risking their own freedom to educate people about the fallacies of animal testing.