For decades, anthracyclines have been the gold standard of treatment for
women with breast cancer, but that could be changing.
Ever since Dennis J. Slamon, MD, director of
clinical/translational research at UCLAs Jonsson Comprehensive Cancer
Center, first released data at the 2007 San Antonio Breast Cancer Symposium
that challenged the routine use of anthracyclines, several studies have shown
that taxanes provide superior survival in some patients. Eric P. Winer, MD,
of Dana-Farber Cancer Institute, has been quoted saying that anthracyclines
will be phased out eventually. Slamon thinks that there is little reason to
The overwhelming data, and I do mean overwhelming, indicates there
is only a small subpopulation of women who incrementally benefit from
anthracyclines over non-anthracyclines in breast cancer, he told
That was initially thought to be all HER2-positive
patients, about 20% to 25% of all breast cancer patients, leaving the other 75%
to 80% not benefitting incrementally but certainly experiencing all the
toxicities, he said. You can argue for their use if there is some
incremental benefit, but when other drugs have the same or better effects
without the toxicity, why is this even being discussed?
Slamons opinion is further supported by the results of U.S.
Oncology Research Trial 9735. In that trial, researchers showed that the
combination of docetaxel and cyclophosphamide resulted in superior DFS compared
with doxorubicin plus cyclophosphamide. After seven years of follow-up, DFS was
81% in the docetaxel/cyclophosphamide arm compared with 75% in the
doxorubicin/cyclophosphamide arm (HR=0.74; 95% CI, 0.56-0.98). Similarly,
patients in the docetaxel/cyclophosphamide arm had superior OS: 87% vs. 82%
(HR=0.69; 95% CI, 0.50-0.97).
Dennis J. Slamon, MD, of UCLA, thinks the time to phase out
anthracyclines is now.
Photo courtesy of UCLA
If physicians are being evidence-based and data-driven, then this
fight is over, Slamon said. At UCLA anthracyclines have been eliminated
for the treatment of patients with breast cancer, he said.
Of course, not everyone is ready to dismiss a treatment that has been
used effectively since the 1960s. Even some of the experts who do believe
anthracyclines are on the way out do not believe that the class of drugs will
disappear anytime soon. Kathleen Pritchard, MD, a senior scientist and
medical oncologist at Sunnybrook Odette Cancer Centre in Toronto, sees no
reason to eliminate an effective therapy.
Why stop using some of the most successful drugs weve ever
had? The argument doesnt make sense, she said. Twenty-five
years ago we were treating patients with CMF [cyclophosphamide, methotrexate
and 5-FU] chemotherapy.
Have those drugs gone out of fashion a little bit? Yes. Do we
still use them? Yes. They are still active drugs. I dont think drugs that
are as active as anthracyclines will disappear from breast cancer care. I think
theyll still be used very widely for some time to come, Pritchard
Slamon argued that patients do not need anthracyclines because the same
effects are possible with trastuzumab (Herceptin, Genentech) but without the
increased risk for heart disease and leukemia that is associated with
anthracyclines. Trastuzumab is an antibody that binds selectively to the
HER2 protein and is approved for the treatment of HER2-overexpressing
node-positive or negative breast cancer.
He pointed to results of the BCIRG 006 study, for which he served as
lead author. The Cancer International Research Group, which conducted the
study, released a press release with the findings last year, and the study is
under review for publication.
The FDA approved both the docetaxel/carboplatin/trastuzumab (TCH) and
doxorubicin/cyclophosphamide/docetaxel/trastuzumab (AC-TH) treatment plans
tested in the study based on the results.
BCIRG 006 recruited 3,222 women with HER2-positive node-positive
and high-risk node-negative operable breast cancer. The AC-TH group (n=1,073)
was randomly assigned doxorubicin plus cyclophosphamide every three weeks for
four cycles, followed by docetaxel. The TCH group (n=1,075) was assigned
docetaxel, carboplatin and trastuzumab every three weeks for six cycles, and
then trastuzumab monotherapy to complete one year of trastuzumab treatment.
A control group of 1,074 patients was assigned doxorubicin plus
cyclophosphamide every three weeks for four cycles, followed by docetaxel every
three weeks for four cycles (AC-T).
The TCH regimen reduced the risk of disease recurrence by 33% compared
with the AC-T arm (95% CI, 0.54-0.83). AC-TH reduced the risk of disease
recurrence by 39% compared with the AC-T arm (HR=0.61; 95% CI, 0.49-0.77).
In addition, the study found that TCH and AC-TH improved DFS regardless
of patient age, hormone receptor status or nodal status. There was no
statistically significant difference in DFS between the two experimental arms.
TCH was also associated with a 34% reduced risk for death compared to
the control group (95% CI, 0.47-0.93). AC-TH was associated with a 42%
reduction in the risk of death (95% CI, 0.40-0.83). There was no statistically
significant difference in OS between the two experimental arms.
The only patients who benefited from an anthracycline (AC-T) over
a non-anthracycline regimen (TCH or AC-TH) was a subset of the HER2-
positives, the ones who are topoisomerase II-alpha co-amplified, Slamon
Those patients benefited equally; they have a Herceptin-like
effect without Herceptin if you use anthracyclines, but they still have the
toxicity of anthracyclines. Herceptin gives you the same benefit as
anthracycline, so why would you use anthracycline unless youre in a
country where you dont have access to the targeted agents?
Hyman Muss, MD, a professor of medicine at the University of
North Carolina and director of geriatric oncology at the Lineberger
Comprehensive Cancer Center, agreed that the evidence for taxane-based non-
anthracycline therapy is compelling for patients with
HER2-positive, node-positive disease; however, there is a
paucity of data with non-anthracycline regimens in patients with
node-positive, HER2-negative disease.
Based on NSABP-B30 trial results, presented last year at the San Antonio
Breast Cancer Symposium by Sandra Swain, MD, medical director of the
Washington Cancer Institute, the data supporting taxanes over anthracyclines
are not clear cut.
What she showed was that one of the arms in that study one
was an AC plus a taxane and one was TAC for four cycles TAC was less
effective than the ACT, Muss said. I dont know if that was
due to duration of therapy, but it seems to me that if four cycles of the TAC
regimen were not as effective as the eight cycles of the
anthracycline-containing regimen, the current style of giving people TC
regimens, lets say for four cycles, while omitting anthracycline is not
ready for primetime in high-risk patients.
Kevin R. Fox, MD, medical director of the Rena Rowan Breast
Center at the University of Pennsylvanias Abramson Cancer Center, said
the percentage of breast cancer patients at his center assigned to
anthracyclines has dropped from 100% five years ago to about 20% today. With a
few qualifications, he said, he is convinced that some patients can be treated
effectively without anthracyclines.
If a patient has a HER2-positive cancer, regardless of its
hormone receptor status, the evidence from BCIRG 006 is that those patients may
be served well by a non-anthracycline regimen such as
Taxotere/carboplatin/Herceptin, Fox told HemOnc Today.
The only reservation we have at the moment is that the BCIRG 006 study is
as yet unpublished. We have seen it presented on many occasions with results
that appear to be convincing for the equivalence of the non-anthracycline arm
and the anthracycline arm, but there is always some reassurance in seeing it
published in a peer-reviewed journal.
Pritchard argued that the only study to date that shows that trastuzumab
can fully replace anthracyclines is BCIRG 006. And like many of the experts
contacted for this story, she noted that those results have not been published.
Slamon, however, does not think that is particularly relevant.
Everyone has seen the data, he said. We made it public as
soon as we generated it. Its been downloaded by multiple people, and
its been submitted to the FDA and approved. Its pending review as
Another reason for the discontinuation of treatment with anthracyclines
is the increased risk for toxicities, specifically serious chronic heart
failure, Slamon said. Although there is no doubt that anthracyclines can cause
type 1 chemotherapy-related cardiac dysfunction, there is some question about
how much anthracyclines increase the risk for cardiotoxicity.
In an expert opinion published in Annals of Oncology in
January, researchers from several institutions in the United Kingdom noted that
studies have used different definitions of cardiotoxicity, different methods of
measurement for heart function and different estimates of the underlying risk
to patients. They cautioned that most studies on the topic have been
retrospective and long-term data are not yet available.
Citing a 1979 study by Von Hoff, Layard and Basa, the researchers said
the incidence of chronic heart failure is about 3.0% for patients receiving a
cumulative doxorubicin dose of 400 mg/m 2. The incidence increased
to 7.5% at a 550 mg/m2 dose and 18.0% at a 700 mg/m2
Another study, conducted in 1998 by Nielsen et al, showed that the
cumulative risk for cardiotoxicity increased by 1.9% for patients assigned to
800 mg/m2 epirubicin. The risk increased to 4.3% for those assigned
to a 900 mg/m 2 dose and to 15.0% at a 1,000 mg/m2 dose.
People worry about heart disease, but if you look at the papers
that have explored the issue, like UCLAs Patricia Ganzs review of
patients in an anthracycline trial, the incidence of serious heart disease is
low, probably 0.5% to 1%, Muss said. If you actually look at
whats been published about anthracycline toxicity in the adjuvant studies
in early breast cancer, it hasnt been overly toxic.
If you look at our study in older people we just published in
The New England Journal of Medicine, we did AC for four cycles in
the standard fashion, and it was well tolerated by older people. Theres
been no leukemia and we havent reported any heart disease. This concept
that anthracyclines are so overwhelmingly bad has been overstated, Muss
There is some concern about cardiotoxicity, but I think the doses
and schedules used today cause a minimum of that problem, said Fox.
It is not an overwhelming problem.
We know some patients benefit from anthracyclines, but we
cant predict who they are, Pritchard said. The argument is
that if patients are HER2-positive and theyre getting Herceptin,
they dont need anthracyclines. In fact, studies like the HERA trial show
that patients who were treated with anthracyclines still get additional benefit
from Herceptin. The fact that you can give Herceptin doesnt mean you
shouldnt also give anthracyclines. Furthermore, I dont think you
can accurately select patients who will or wont respond to Herceptin by
Slamon said one of the reasons BCIRG 006 has yet to be published is that
researchers are still working on the role of topoisomerase as a biomarker for
anthracycline sensitivity. Several studies support his contention that
topoisomerase effectively predicts the subset of patients who will benefit from
The Scandinavian Breast Group Trial 9401, for example, found that
patients with topoisomerase II-alpha-amplified tumors had a superior
relapse-free survival rate when treated with tailored and dose-escalated
fluoroucil, epirubicin and cyclophosphamide (FEC) compared with standard FEC
followed by bone marrowsupported cyclophosphamide, thiotepa and
carboplatin (HR=0.45, P=.049). There was no such difference between the
two treatments in patients with no topoisomerase II-alpha amplification
Di Leo and colleagues concluded in a 2002 study published in
Clinical Cancer Research that TOP II Α could be
the most attractive candidate for predicting the efficacy of an
anthracycline-based regimen, and the predictive value of HER2 could be
most likely be related to the concomitant amplification of these two genes
located on the same arm of chromosome 17.
They warned, however, that results were only hypothesis-generating
because of a limited number of patients in which both HER2 and
TOP II Α gene amplifications could be evaluated.
In a study published earlier this year, OMalley and colleagues
reported that patients with the topoisomerase II-alpha amplification were more
responsive to anthracycline-based chemotherapy than treatment with a
non-anthracycline. They said the response was similar to that of patients with
the HER2 amplification.
The default biomarker we have now that drives the perceived need
for anthracyclines is nothing more than absence of hormone receptor and the
absence of HER2. Other than topo, I dont know if a biomarker
exists that would drive the decision to use or not use anthracyclines,
Fox said. The way that I view the current data regarding topoisomerase is
that the presence or absence of topo activity has not been clearly linked with
either the usefulness or lack of usefulness of anthracyclines in a conclusive
I do not think were at a point where we can comfortably
apply that to patient decision-making. In theory, patients with topo excess
would be better candidates for anthracycline-based therapy, but I do not think
thats been proven conclusively enough in patients in clinical trials to
be able to use that as a decision point. I just dont think the data are
robust enough to make that part of the care standards, Fox said.
Francisco J. Esteva, MD, and Gabriel N. Hortobagyi, MD, both of
The University of Texas M.D. Anderson Cancer Center, noted in an editorial
published in The Journal of Clinical Oncology that the data
supporting the use of topoisomerase II-alpha as a predictor for anthracycline
sensitivity is fairly mixed.
In summary, topo II Α expression can be used as a prognostic
marker, they wrote. However, currently available evidence does not
support use of thetopoisomerase II-alpha gene amplification or deletion to
select patients for anthracycline-based chemotherapy in the adjuvant
The experts who spoke to HemOnc Today are eagerly awaiting
the results of the TAC Versus TC for Adjuvant Breast Cancer trial, colloquially
known as Tic Tac. The phase-3, randomized, open-label trial compares a
combination of docetaxel, doxorubicin and cyclophosphamide vs. docetaxel and
Final results are not expected until 2022, but Muss believes that
theyll be released earlier if theyre a slam dunk.
In the meantime, for lower-risk patients node-negative,
patients with intermediate scores on Oncotype where youre considering
either randomizing them to the TAILOR X trial or treating them off trial
giving non-anthracycline regimens like TC is reasonable. For the higher-risk,
node-positive patients its not reasonable to omit anthracyclines with the
data we have right now, Muss said.
Is topoisomerase II alpha a valid biomarker for taxane sensitivity?
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