- Joined: 1/1/2005
For those who are HER2+
Tuesday, October 07, 2008 8:29 PM
This is from the Medscape Week in Review. Sorry it is so long, but it is of interest to us.
Adjuvant Therapy for HER2-Positive Breast Cancer: An Expert Interview With Dr. Harold Burstein
In 2005, results of 4 adjuvant breast cancer trials[1-4]
demonstrated unequivocably that the monoclonal antibody trastuzumab
plus chemotherapy significantly reduced disease recurrence in patients
whose tumors overexpressed the HER2 protein. Prognosis for women with
HER2-positive disease has improved substantially since then, and
research in this area has been extremely active. Margie Miller, Group
Editorial Director for Medscape Oncology, recently sat down with Harold
J. Burstein, MD, PhD, Assistant Professor of Medicine at Harvard
Medical School in Boston, Massachusetts, as well as a member of the
Medscape Oncology Editorial Board, to talk about some of the treatment
issues that clinicians continue to grapple with and how ongoing
research may inform therapeutic strategies for women with
HER2-overexpressing breast cancer in the future. The overall theme of
the conversation was, "What do clinicians need to know in 2008 and
Medscape: To provide a bit of contextual
background, can you clarify whether HER2 overexpression in breast
cancer, regardless of tumor size, nodal status, or hormonal
sensitivity, is considered a significant negative prognostic marker,
automatically classifying a patient as having high-risk disease?
Historically, patients with HER2-positive tumors have done much less
well than those with HER2-negative tumors. That was part of Dr. Dennis
Slamon's original observation in 1987 and remains true to
this day. Women who are diagnosed with HER2-positive disease in 2008
will be candidates for adjuvant anti-HER2 therapy. Having said that,
the trastuzumab adjuvant trials[1-4] typically enrolled
patients with node-positive disease and/or other high-risk factors. We
actually have very few data on smaller, node-negative Stage I tumors
that are HER2-positive. Because the threshold for detection of a breast
tumor is about 1 cm, we don't usually see women with smaller lesions,
although we do encounter them on occasion.
We've all wondered
whether there is some sort of size threshold below which adjuvant
treatment may not be necessary. Historically, the line in the sand has
been drawn at 5 or 6 mm. Treatment guidelines, such as the NCCN
[National Comprehensive Cancer Network] Breast Cancer Guidelines,
indicate that tumors smaller than 5 mm wouldn't warrant adjuvant
chemotherapy. Guidelines also indicate that adjuvant treatment should
be considered for patients with small tumors -- approximately 10 mm --
when other high-risk features, such as lack of hormone receptors, high
grade, or HER2 overexpression, are present.
What are some of the questions that ongoing research is seeking to
answer and that are likely to affect how clinicians treat patients?
On a practical, clinical level, practitioners are still interested in
the optimal duration of trastuzumab treatment. We have data from most
of the adjuvant trials that looked at 1 year of trastuzumab therapy,
which has emerged as the standard. Nevertheless, we know that a shorter
course can be effective. In the FinHER trial, a limited
exposure of 9 weeks of chemotherapy plus trastuzumab was better than
nothing at all. And, we are waiting for final data from the HERA trial,[3,4] which looked at 0, 1, or 2 years of trastuzumab-based treatment. Those data may be available as early as December of this year.
of the complexities inherent in interpreting those data centers on the
fact that the HERA trial administered trastuzumab sequentially, after
the chemotherapy component of the adjuvant regimen. Many of us believe
that that may be a less effective way -- compared with concurrent
administration -- of giving trastuzumab. So, whatever the results, the
question of the duration of trastuzumab, when it is given concurrently,
will remain unresolved by this trial.
We have been involved in a
study looking at the potential benefit of adjuvant treatment for
patients with lower-risk HER2-positive tumors. Patients are offered a
combination of paclitaxel for 12 weeks plus standard duration of
trastuzumab (52 weeks). The accrual goal is about 400 patients, and we
hope to discover whether this shorter, simpler adjuvant regimen will
adequately protect these women from disease progression. Compared with
a standard adjuvant course, such as doxorubicin/cyclophosphamide (AC)
followed by paclitaxel for 20 weeks or more plus trastuzumab, this
abbreviated regimen is attractive, and the multicenter trial is
accruing briskly. Moreover, avoiding the anthracycline (ie, AC) part of
the standard regimen may spare the patient the risk of cardiotoxicity.
Trastuzumab is usually given either with or after chemotherapy. What
should clinicians know about selecting the chemotherapy backbone for
combination with trastuzumab?
Determining the best adjuvant chemotherapy program to link trastuzumab
with is very much an open question. In clinical practice, AC followed
by a taxane plus trastuzumab or docetaxel, carboplatin, and
trastuzumab (TCH) have emerged as the most commonly used regimens. The
discussion primarily focuses on the risks of cardiotoxicity.
Medscape: Can you elaborate about how clinicians should prevent or manage cardiotoxicity when selecting a chemotherapy regimen?
Dr. Burstein: The BCIRG 006 trial
suggested that there was a lower risk, about 1%, of cardiomyopathy with
the TCH regimen compared with the 2% risk expected with the AC followed
by taxane plus trastuzumab regimen. So, while there was a difference,
it was a pretty small numerical difference. In addition, the National
Surgical Adjuvant Breast and Bowel Project (NSABP) and the North
American Intergroup have proposed risk factors that may help identify
patients who are at risk for cardiomyopathy: older than 60-65 years of
age, borderline pre-existing cardiac function (ejection fraction, 50%
to 55%), and pre-existing heart disease, particularly hypertension. I
think that those are variables that can inform our treatment choices.
In patients with pre-existing cardiac risk factors, it may be helpful
to obtain a cardiology consult. I still feel quite comfortable using AC
followed by a taxane and trastuzumab for most women with HER2-positive
disease because they tend to be younger than 65 years of age and are
generally in good health, with no hypertension and a strong ejection
fraction at baseline.
One of the dilemmas with the BCIRG 006
trial was that it was not powered to really compare the efficacy of the
AC arm with that of the TC arm. It is likely that trastuzumab is such a
potent drug that it becomes the trump card, and the issue of the
chemotherapy backbone matters less. We don't actually know that.
the TCH regimen is often characterized as the "non-anthracycline"
regimen, which, of course, it is, but there were some other differences
between the 2 regimens used in BCIRG 006. There was a longer period of
overlap between chemotherapy and trastuzumab in the TCH arm (18 weeks)
than in the AC arm (12 weeks); they used carboplatin (instead of
cyclophosphamide) in the non-anthracycline arm, which may or may not be
a necessary component of the regimen and may have influenced the
results; and, perhaps most importantly, the trastuzumab was
administered up front instead of after the 4 cycles of
anthracycline-based chemotherapy. So there were many differences
between the regimens used in BCIRG 006 that can't be attributed to
"anthracycline" vs "non-anthracycline."
Medscape: Has the question of concurrent vs sequential trastuzumab been resolved?
The issue of concurrent trastuzumab vs sequential has not been
resolved. The data that were originally presented from the North
American Intergroup Trial and the B 31 trial suggest that
concurrent therapy is better than sequential therapy. Many of us have
tilted that way. We've also been impressed that a very short exposure
to concurrent chemotherapy and trastuzumab, as in the FinHER trial,
seems to be effective. Nevertheless, there are data showing that some
trastuzumab therapy -- concurrent or sequential -- is better than none.
We know from practice pattern data that the majority of patients in the
United States are receiving concurrent therapy. In Europe and
elsewhere, however, the pattern of starting with the chemotherapy
backbone followed sequentially by trastuzumab is still in use.
Medscape: Are there any patients for whom a sequential program might be considered more prudent?
It's an interesting question. There may be a slightly lower risk of
cardiomyopathy with sequentially administered trastuzumab than
concurrent, but that has not been well established.
Medscape: How would you advise clinicians to manage a dropping ejection fraction during adjuvant trastuzumab-based treatment?
First of all, we have to remember to monitor cardiac ejection fraction!
Typically, ejection fraction should be measured at baseline, after the
AC or TC phase of the regimen and before the trastuzumab is added, and
then after the taxane/trastuzumab and before starting the maintenance
phase. We do see some patients who have asymptomatic declines in
ejection fraction. Usually these are fairly modest, from 67%, for
example, to 59%. Because we know that trastuzumab is such a powerful
drug, we are generally willing to tolerate those minor asymptomatic
changes, as long as the ejection fraction remains well above normal.
Where it gets trickier is when the patient is having symptoms; in which
case, the trastuzumab should be stopped, at least for the short term.
Another challenging situation occurs when the patient is still
asymptomatic but the drop in ejection fraction is more substantial and
dips below the lower limits of normal. In some cases, although the
patient is asymptomatic, the decline in ejection fraction -- while
still within the lower limits of normal -- is dramatic. In those cases,
one has to individualize therapy on the basis of the risk of the tumor,
where the patient is in her trastuzumab treatment course, and what
other cardiac risk factors she has. A cardiology consult is usually
very helpful at this point. I also think that it's prudent to interrupt
the treatment at some point to determine whether the ejection fraction
Medscape: Is there a role for assessment of topoisomerase II-alpha gene (TOP2A) in helping to select adjuvant chemotherapy for high-risk early breast cancer?
Dr. Burstein: At the moment, there really are no clear reasons to use TOP2A to select treatment for early-stage breast cancer. TOP2A traffics near the HER2 oncogene and is a potential target of anthracyclines. Retrospective work from the UCLA group and others has suggested that TOP2A
may account for the relationship between anthracycline sensitivity and
HER2-positive breast cancer. At the moment, though, it's not a
clinically relevant test. Those with HER2-positive disease are going to
receive trastuzumab with either of the 2 chemotherapy options. In
contrast, for those who are HER2-negative, TOP2A gene amplification is rare. The question thus arises as to whether women with HER2-negative
disease need anthracyclines. That's an area where we are likely to see
more data emerging to suggest that other non-anthracycline regimens may
be adequate. Having said that, anthracyclines remain the backbone of
our active chemotherapy regimens, both in the United States and
world-wide. We'll probably be seeing declining use of anthracyclines
over time, as other regimens come along, but for most women with
high-risk early breast cancer, anthracyclines and taxanes remain
important drugs, and TOP2A should not be used to select therapy outside of a clinical trial.
How should other adjuvant therapies, such as endocrine therapies and
bisphosphonates, be integrated into adjuvant treatment for patients
with HER2-positive disease?
About half of HER2-positive tumors will also be hormone
receptor-positive, and there's no reason to handle endocrine treatment
differently in these patients. The emerging bisphosphonate data are
very exciting. As we saw at ASCO 2008, the ABCSG 12 randomized study
looked at young women who received endocrine therapy, with or without
bisphosphonates. And the data suggested that those who received the
bisphosphonates had a lower risk of disease recurrence. These are
certainly very provocative data. We expect data within the next 6-12
months from the AZURE trial, which is a larger study of bisphosphonates
in the adjuvant setting. If the results are confirmatory, we will
probably be using bisphosphonates more frequently in the adjuvant
Medscape: Would you describe ongoing research
that is exploring how to improve outcomes in women with HER2-positive
Dr. Burstein: The global adjuvant studies, the neo-ALTTO and ALTTO trials,
are looking at: (1) trastuzumab alone vs (2) lapatinib alone vs (3) the
combination vs (4) trastuzumab and lapatinib administered sequentially.
Clearly, the questions being evaluated are whether the dual-kinase
inhibitor lapatinib will do as well as trastuzumab and whether there is
anything to be gained by using both agents. There have been some
provocative data from the metastatic setting by Dr. Joyce O'Shaughnessy
and colleagues suggesting that the combination of
lapatinib plus trastuzumab appeared to be better than lapatinib alone
in patients who had previously received trastuzumab-based therapy. So
one of the questions that is raised is whether we really need this
complicated 4-arm ALTTO trial when a simpler design, looking at
trastuzumab alone vs trastuzumab plus lapatinib, might give us the
answers we are looking for. The other point is that there are
preliminary reports both from Memorial Sloan-Kettering Cancer Center
and the Intergroup that the combination of trastuzumab plus lapatinib
plus paclitaxel, as originally scripted in the ALTTO protocol, was
associated with prohibitive toxicities, such as diarrhea, that
prevented patients from successfully completing their full courses of
therapy. Although the drug doses have since been reduced, these
findings serve as a reminder that just because drugs are characterized
as targeted therapies or biologicals doesn't mean that they lack side
effects. Clinicians should be very cautious about pairing up these
drugs just for the sake of trying to do something different. We learned
a similar lesson earlier this year when a combination of sunitinib and
bevacizumab caused an unexpected thrombocytopenic purpura.
think the most important biological issue still to be addressed for
trastuzumab-based therapy in HER2-positive disease is identifying which
tumors are going to prove resistant and which are very sensitive. We've
made a great deal of progress selecting patients based on HER2 status,
and there has been a substantial effort invested in improving HER2
testing. I think we have a pretty good handle on how to define a
HER2-positive tumor. Nevertheless, of the women with HER2-positive
disease who received trastuzumab in the adjuvant trials, a substantial
fraction will experience recurrent disease. We'd like to understand the
underlying biology better. Perhaps these women would benefit from
different therapy or should be offered new agents as part of a clinical
trial. Understanding the biology of those who recur, and identifying
them, are important goals.
Stage I,Grade 3 both sides
RB:dx 3/19/07,IDC 1.0cm with DCIS
LB:dx 4/17/07,IDC 1.5cm with DCIS
Bilateral mastectomy 4/30/07
DD A/C+T, Herceptin done!