For years, personalized medicine–the concept that
treatments could be tailored to a person’s unique genetic makeup–has been more
buzzword than reality. One of the first diseases expected to benefit from a
personalized approach is cancer, which appears in many genetically distinct
forms. A new study led by Lecia
Sequist, an instructor at Harvard Medical School
and an oncologist at Massachusetts
General Hospital Cancer Center ,
offers an initial demonstration that cancer treatment can be tailored to the
genetic profile of a patient’s tumor. In a small clinical trial published
recently in the Journal of Clinical Oncology, patients
with lung tumors were genetically screened to identify those likely to respond
to a targeted therapy. Those receiving a drug matched to their tumor fared better
than is typically seen with standard chemotherapy.
A genetic match: These CAT scans show the best response to a targeted cancer drug in a lung-cancer patient deemed likely to respond based on a genetic screen. Before treatment (top), the left side of the lung, normally black, is nearly filled with a whitish tumor. After just a month of treatment (bottom), the tumor has shrunk dramatically.
“It’s really a giant step forward,” says William Pao, a cancer
researcher at Memorial
Sloane-Kettering Cancer Center,
who was not involved in the clinical trial. “The ultimate goal is to take a
molecular fingerprint of someone’s tumor and assign treatment based on
molecular defects.”
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Standard cancer drugs are designed to preferentially kill
cancer cells, but they can still be toxic to normal tissue. But cancer
researchers have been working toward the goal of developing an array of drugs
that could hit precise molecular targets in tumors, while being less toxic to
normal cells. For example, non-small-cell lung cancer is an aggressive form of
cancer that is typically treated with chemotherapy; however, in recent years,
new drugs for the disease have been developed that target a specific molecule
in cancer cells, called the epidermal growth factor receptor (EGFR). The drug
examined in this study, Iressa, was the first EGFR inhibitor to come on the
market in 2003, but its initial hype fizzled after larger trials showed that it
did not lengthen survival for patients in the United States. Currently, EGFR
inhibitors are used only after chemotherapy.
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Increasingly, scientists have realized that cancers arise
from different genetic mutations and have different points of weakness that
might vary from person to person. Further research identified specific EGFR
mutations in the tumors of a subset of patients that made them more susceptible
to EGFR inhibitors. Many scientists have argued that the drugs could provide a
greater benefit to these specific patients. In Sequist’s trial, which was
funded by AstraZeneca, researchers first screened patients with metastatic lung
cancer for EGFR mutations and gave those with the mutations the option of
receiving Iressa as a first treatment over chemotherapy. “This is a proof of
concept,” says Sequist. “We were trying to see if personalized medicine or
genetically driven cancer therapy was feasible.”
Among 31 patients who took Iressa during the trial, 55
percent had their tumors shrink noticeably in a CAT scan, and all but two had
tumors that either shrank or did not grow for at least a month. The median rate
of time that patients survived without their cancer progressing was about nine
months. Sequist says that chemotherapy typically has response rates of 20 to 30
percent, with a survival advantage of about four months. “We had quite an
improvement over what we typically see when we give a general one-size-fits-all
treatment,” she says. Because Iressa is an oral pill taken daily, the patients
avoided the toxic side effects of daily intravenous chemotherapy treatments.
The two patients who experienced a worsening of their disease were later found
to have a type of EGFR mutation that confers resistance to the drug; the
distinction between EGFR mutations had not been discovered when the trial
began.
Iressa’s maker, AstraZeneca,
stopped marketing the drug in the United States after this study
began, because of its poor showing in clinical trials. However, a similar drug,
Tarceva, is available and is thought to have similar effects in patients.
In an accompanying editorial, Frances
Shepherd, a lung-cancer researcher at Princess
Margaret Hospital,
in Toronto,
said that while the study showed that screening tumors for their molecular
makeup before treatment is feasible, it does not yet provide solid evidence
that EGFR inhibitors should be used before chemotherapy. Shepherd points to
previous studies showing that people with EGFR mutations survive longer under
standard chemotherapy than patients without these mutations, suggesting that
they might fare better regardless of their therapy. To know whether the drug is
truly better than chemotherapy would require a randomized trial of the two
therapies in this patient population. An ongoing study in Spain is currently
addressing this question.
Pao says that while the study doesn’t provide definitive
answers about how to use EGFR inhibitors, it represents an important step
toward personalized cancer treatment. The study, he says, is one of the first
attempts to genetically screen cancer patients before treatment as a way to
guide clinical decision making, rather than identifying susceptible patient
populations after the fact.
