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You are here: Home: BCU 6|2002: Editor's Note
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Editor’s Note |
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| A novel targeted
therapy for breast cancer becomes available |
“There is so much excitement about Gleevec® being
the first rationally designed, targeted drug in oncology.
That’s baloney! In 1896, George Beatson first performed
an oophorectomy and removed a growth factor, estrogen, from
its receptor. This hormonal manipulation led to responses
in two out of three women with locally advanced disease. In
my opinion, that was the beginning of true designer drug molecular
medicine. We have known about targetdirected therapy for 100
years!
"We now have several options for endocrine therapy.
The issues are how, when and in what order we should use these
agents. As these agents make it to the clinic, I receive phone
calls from my colleagues asking, ‘What order do I use
these in?’ I do not think we know the answer. The challenge
for the cooperative groups and pharmaceutical companies is
to conduct trials evaluating sequential and combination endocrine
therapies.
"I believe we will find that different subgroups of
patients will respond differently to individual endocrine
therapies. Just as we use ER status to decide who will receive
endocrine therapy, in the future we may use the progesterone
receptor, HER1, 2, 3 and 4 receptor or some of the coactivators
and corepressors. These markers may indicate which patients
should receive tamoxifen, an aromatase inhibitor or fulvestrant.”
— Daniel Hayes, MD |
Dr Hayes’ reflection on the rapid pace of research surrounding
endocrine interventions brings to mind my first introduction to
the “brave new world” of targeted therapy in breast
cancer, which occurred in a presentation in San Diego on the last
afternoon of the 1992 ASCO meeting. Sitting in the back of an almost
empty meeting room somewhat dazed from several days of information
overload, I was jolted to attention by Dr Tony Howell’s early
laboratory data on a fascinating new compound that seemed to have
a unique effect on the estrogen receptor system. The substance was
then called ICI 182,780, or as Tony referred to it, "182."
At that time, it was widely considered the first “pure antiestrogen.”
Dr Howell’s slide of the estrogen receptor cascade was far
more complex than any I had previously seen. It brought back memories
of earlier simplified endocrine schemas with “Pac Man-like”
estrogen molecules diffusing into the cytoplasm, complexing with
the estrogen receptor and then mysteriously triggering DNA replication
in the nucleus. In the ten years since Dr Howell’s presentation,
quantum leaps have been made in understanding both the estrogen
receptor cascade and the effects of “182,” which is
now available as the intramuscular injection, fulvestrant or Faslodex®.
As described by Dr John Robertson in the enclosed program, fulvestrant
is the first and, at this point, only “estrogen receptor downregulator.”
Unlike the SERMS, which compete for estrogen receptor binding, and
the LHRH agonists and aromatase inhibitors, which dramatically lower
estrogenic ligands, fulvestrant results in the disappearance of
the target receptor. This appears to be a phenotypic alteration
that occurs only during therapy, and patients whose tumors progress
while on fulvestrant will respond to other endocrine manipulations.
Not only does fulvestrant have a unique mechanism of action, but
also the clinical risk-to-benefit ratio is very promising. In a
randomized trial in postmenopausal women, fulvestrant demonstrated
an equivalent response rate and a superior duration of response
compared to anastrozole — a finding that was predicted by
laboratory scientists, including Dr Kent Osborne.
Fulvestrant’s side-effect profile also seems very favorable
and similar to that of the aromatase inhibitors. Individual patients
will view the monthly intramuscular injections as either a positive
or negative attribute. Notwithstanding, we now have a new and very
promising addition to the armamentarium of target-directed breast
cancer therapies.
Dr Hayes and Dr Robertson also note that while clinical research
has yet to demonstrate an advantage for combining endocrine interventions
— citing the disappointing results of the tamoxifen/anastrozole
arm in the ATAC trial as an example — they believe that combining
fulvestrant with other biologic or endocrine agents may be more
beneficial. Dr Robertson has performed extensive neoadjuvant trials
looking at the effects of fulvestrant and other endocrine agents
in vivo, and it seems likely that over the next few years we will
dramatically increase our understanding about how these therapies
can be utilized optimally.
— Neil Love, MD
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