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Cancer drug's link to heart ill probed

A study in mice illustrates risk in use of Herceptin

By Raja Mishra, Globe Staff, 5/1/2002

   
 THE SERIES

Part 1
An experiment begins

Part 2
A cancer patient's longest wait

Part 3
Balancing benefits and risks

Follow-up
Cancer drug's link to heart ill probed
Trials continue in different form

 PHOTO GALLERY

Photos from Adriana's experience

By Suzanne Kreiter / Globe Staff

 TIMELINE

Herceptin's history

 CLINICAL TRIAL

To gain FDA approval for widespread use, a new treatment must successively pass three phases of clinical trials, each seeking to answer different questions:

Phase I: Is a new treatment safe? What are safe dosage levels? Usually small trials, often with less than a dozen patients.
Phase II: How well does the treatment work? What are its side effects? (Adriana Jenkins is in a Phase II trial.)
Phase III: Does the treatment heal more effectively than standard treatments? Does it work consistently in a large group of patients? This phase often involves hundreds of patients in many hospitals.

 HERCEPTIN

About 30 percent of breast cancers produce excessive HER-2 proteins, which makes cancer cells proliferate. Herceptin disables HER-2. It hits only HER-2 producing cancer cells, not normal cells, minimizing side effects and earning it the title "smart" drug. UCLA's Dennis Slamon spent 13 years developing Herceptin. San Franciso-based Genentech Inc. sells it. The first large-scale clinical trial results came out in May 1998: 78 percent of patients on Herceptin plus chemotherapy survived one year; compared to 67 percent on chemo alone. The FDA approved Herceptin for treating metastatic breast cancer, where the cancer has spread. Doctors now seek to extend its use to earlier stages of cancer through clinical trials, such as the one involving Adriana Jenkins.

 RESOURCES

Dana Farber research advances
ClinicalTrials.gov
CenterWatch
CRnet from MGH and Harvard
Clinical trials search
NEMC: The Cancer Center

 ABOUT THIS SERIES

The Globe followed breast cancer patient Adriana Jenkins through a clinical trial at the Dana Farber Cancer Institute in Boston for eight months. A reporter and photographer were given access to most medical events and records. All conversations reported were witnessed. The lengthier exchanges that appear in the stories were recorded on audio tape. Jenkins' writings, as well as representations of her thoughts, were taken from contemporaneous notes written by her and supplied to the Globe on a regular basis throughout the eight months.


Researchers have discovered the likely cause of heart damage suffered by some breast cancer patients taking the promising new drug Herceptin, raising the possibility that treatments could be designed to ameliorate the potentially dangerous side effect.

Herceptin, one of the first so-called ''smart'' cancer drugs, was designed to target cancer cells that produce the HER-2 protein, but the drug can also attack healthy heart muscle cells that produce the same protein, the researchers said. Because doctors have long been on guard for Herceptin-related heart problems, yesterday's finding will probably have little immediate effect on patient care.

During their work, the California-based researchers created lab-engineered mice that simulate the physiology of patients on Herceptin, allowing scientists to probe the complex drug's effects on the human body. They hoped one day to engineer complimentary drugs that would block Herceptin's ill effects.

''We've created a mouse model that mimics a Herceptin patient, which allows us to explore its underlying mechanisms. We hope to create better medicines,'' said Dr. Kuo-Fen Lee, an associate biology professor at the Salk Institute for Biological Studies in La Jolla, Calif., and senior author of the study, published in yesterday's issue of the scientific journal Nature Medicine.

Herceptin targets HER-2-making cancer cells found in roughly 30 percent of breast cancer cases. Other, less-targeted breast cancer treatments, from standard chemotherapy to mastectomy, often cause great pain and suffering. Herceptin caused less discomfort, studies found.

But some patients developed heart problems, including rare cases of congestive heart failure, studies show. The US Food and Drug Administration has approved Herceptin for treating women with breast cancers that have spread. Dozens of US trials are examining its efficacy in women with less advanced cancers, but Herceptin's little-understood effect on the heart has proven a persistent complication.

The Globe detailed the experience of one Herceptin patient, Adriana Jenkins, 32, of Brookline, in the series ''Adriana's Trial,'' which chronicled her participation in a Dana-Farber Cancer Institute clinical trial from July 2001 to February 2002. Herceptin plus another drug, Navelbine, caused significant shrinkage of Jenkins's tumor. But in the end she was pulled from the trial after developing occasional irregular heartbeats following doses of the chemotherapy drug Adriamycin, which she took after Herceptin. Similarly, an arm of a large-scale federal government-monitored trial, combining Herceptin with chemotherapy, was halted last January after more women than anticipated appeared to develop heart problems.

Though heart problems have been listed as a Herceptin side effect since the drug debuted in 1998, its actual physical effects on the heart have been somewhat mysterious. The Salk Institute team began by developing mice conditioned to shut off production of the protein erbB2, the mouse equivalent of HER-2, said Lee. This rendered the test mice similar to Herceptin patients whose HER-2-producing cells have been wiped out, he said.

All of the several hundreds of test mice examined at one to six months of age had enlarged hearts, said Lee. It turned out their cardiomyocytes, heart muscle cells that maintain heartbeat, became less able to contract, disrupting proper blood flow - similar to the heart problems of some Herceptin patients, said Lee.

''We don't know why this happens but erbB2 seems to protect normal heart functions,'' said Lee.

In addition, Lee's team studied the effect of anthracycline drugs, chemotherapies commonly given in conjuction with Herceptin. Adriamycin, Cerubidine, and Idamycin are common drugs within this class, and are known to also cause heart muscle damage. The researchers found that the heart muscle cells of the test mice, when placed in a test tube, were 40 percent more likely to die when exposed to anthracyclines than the cells of normal mice. This suggests treatment regimens that combine Herceptin and anthracyclines are especially risky, said Lee. Doctors, acting on previous clinical data, are already particularly vigilant when using this combination.

San Francisco-based Genentech Inc. makes Herceptin. Colleen Sweeney, a company spokeswoman, said the new study will assist with ongoing research. ''We're always looking for ways to better understand our current therapies,'' she said.

Raja Mishra can be reached at rmishra@globe.com.

This story ran on page A4 of the Boston Globe on 5/1/2002.
© Copyright 2002 Globe Newspaper Company.

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