http://www.practiceupdate.
com/ExpertOpinion/586 Comment: Thisis an important study looking at the benefits of adding platinum as
Conference Coverage December 04, 2013
SABCS 2013 Recommended Abstracts: New Data on Breast Cancer Therapies
Kimberly L Blackwell MD
Dr. Kimberly Blackwell, Professor of Medicine and Assistant Professor in Radiation
Oncology at Duke University School of Medicine, recommends the following
abstracts in metastatic breast cancer being presented at this year’s San Antonio
Breast Conference Symposium, held December 10–14, 2013.
S1-01. The association between event-free survival and pathological complete
response to neoadjuvant lapatinib, trastuzumab or their combination in HER2-
positive breast cancer. Survival follow-up analysis of the NeoALTTO study (BIG 1-
06). Presented by M Piccart-Gebhart.
Comment: The NeoALTTO study will be the most important one presented at this
year’s SABCS. We have a lot of trials in the HER2 realm that looked at
chemotherapy, and—in the new adjuvant study—even though we saw a larger
response to certain types of chemo, it didn’t predict a long-term improvement in
survival. The data presented here will correlate neoadjuvant response, in this case
to either lapatinib or trastuzumab, or both, to long-term outcome. The NeoALTTO
study very closely mimics the design of the adjuvant ALTO study, for which we
won’t have the results until at least late next year.
Oncologists, including those who have followed the whole neoadjuvant strategy as
an accelerated approval mechanism in breast cancer, are very anxious to see these
data. If we use doublets of HER2 inhibitors in a neoadjuvant setting and it makes a
difference in long-term outcome, it would strengthen the argument about using the
neoadjuvant setting for drug approval and drug development.
S1-03. Primary results from BETH, a phase 3 controlled study of adjuvant
chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive,
node-positive or high risk node-negative breast cancer. Presented by DJ Slamon.
Comment: The second most important trial at this year’s SABCS is BETH, a clinically
relevant study in an adjuvant setting in which bevacizumab is added—or not
added—to trastuzumab.
Although a lot of people have kind of given up on bevacizumab, this is one of the
largest studies done, and, if it ends up showing a signal for a benefit with
bevacizumab, it would change the landscape, I think.
S1-04. A phase II study of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for
node-negative, HER2-positive breast cancer (BC). Presented by SM Tolaney.
Comment: The third trial, which people have been interested in for a while, is a
single-arm, multicenter study of a 12-week regimen of weekly paclitaxel and
trastuzumab for low-risk disease. I think that’s important because a lot of us hate
having to give chemo to women with stage 1, HER2-driven breast cancer in order to
provide the benefit of trastuzumab; so, we’re always trying to figure out the least
amount of chemo we can give. It’s not a randomized study, but people are very
attracted to the idea of just giving 12 weeks of taxol to patients with low-risk
disease, and still getting the same benefit of the trastuzumab as you would if you
gave ACT or TCH.
Martine Piccart is really going to help us understand if what we see in the
neoadjuvant setting predicts long-term outcome in breast cancer in the era of very
effective therapies such as lapatinib and trastuzumab. I don’t know what the results
are. But, the BETH study is going to reintroduce the idea that bevacizumab
increased the cure rate in HER2-positive breast cancer. And, then, I think people
have long awaited this single-agent taxol–trastuzumab study just because it’s a very
attractive regimen. Patients aren’t very sick on it, and it was a large phase II study;
people have been waiting for the results for some time.
S3-01. First results of the International breast cancer intervention study II (IBIS-II): A
multicentre prevention trial of anastrozole versus placebo in postmenopausal
women at increased risk of developing breast cancer. Presented by J Cuzick.
Comment: IBIS IIis a very important prevention study of anastrozole vs placebo. The
study was designed at the time when there was a lot of controversy as to whether
or not tamoxifen has true preventative benefits, because there had been other
studies showing that tamoxifen doesn’t. This will be the only placebo-controlled
prevention study looking at aromatase inhibitors vs placebo.
S5-01. Impact of the addition of carboplatin (Cb) and/or bevacizumab (B) to
neoadjuvant weekly paclitaxel (P) followed by dose-dense AC on pathologic
complete response (pCR) rates in triple-negative breast cancer (TNBC): CALGB
40603 (Alliance). Presented by WM Sikov.
well as the benefits of adding bevacizumab in the neoadjuvant setting.
S5-07.SWOG S0500—A randomized phase III trial to test the strategy of changing
therapy versus maintaining therapy for metastatic breast cancer patients who have
elevated circulating tumor cell (CTC) levels at first follow-up assessment. Presented
by JBSmerage.
Comment: This is the SWOG study, looking at circulating tumor cells as an early
predictor of response. Patients were started on treatment in the metastatic setting,
and, if their circulating tumor cell level stayed the same, they were randomized to
either continuing with the treatment or switching to a different therapy.
Conference Coverage December 02, 2013
SABCS 2013 Neoadjuvant Focus (Episode 1)
Lee S. Schwartzberg MD, FACP
A number of these will deal with the neoadjuvant treatment of breast cancer.
Neoadjuvant therapy has really been gaining in popularity recently because it is a
wonderful platform to experiment with early response and difficult to treat
subtypes of breast cancer.
This year we’re going to hear the first results of the I-SPY Trial, which is an adaptive
study, which we’ve been waiting for the results with bated breath because it is such
an innovative treatment.
And the first thing we’re going to hearing about is the use of carboplatinum and
veliparib in patients who are undergoing neoadjuvant chemotherapy for high-risk
breast cancer.
Now both of these drugs are interesting. Carboplatinum because there's a fair
amount of evidence that cisplatinum and carboplatinum may play a role in
improving response rates and outcome for patients with triple-negative breast
cancer. And for other patients with high risk, the PARP inhibitors of which veliparib
is one, have been a factor of interest for not only triple-negative breast cancer in
general, but also that subgroup of patients who have BRCA-I or II mutations.
In addition, we’ll be hearing the results of another carboplatinum or bevacizumab-
added trial in the neoadjuvant setting, two other drugs that, in past years, have
shown some activity.
So I think when we hear these results, we’ll know better where the use of platinum
falls for triple-negative breast cancer in the neoadjuvant setting.
The other area that we’re very interested in the neoadjuvant setting is in HER2
positive breast cancer, and we’ll be hearing the final results of the neo-ALTTO
study, which was a study that looked at either lapatinib or trastuzumab, alone or in
combination with chemotherapy, given to HER2 positive breast cancer patients. We
have seen in the past that the combination of anti-HER2 therapy has increased the
pathologic complete response rate and primary endpoint for neoadjuvant trials.
What we will be hearing at San Antonio this year is the correlation between the
pathologic complete response rate and the overall survival and progression-free
survival in this population.
This is really a key linkage, because if pathologic complete response is to be a good
surrogate marker, it must indicate an improvement down the road in progression-
free survival.
We will also hear the final results of the TRIO B07 Trial. Another neoadjuvant study
looking at lapatinib, trastuzumab, and chemotherapy, either together or alone with
regard to the HER2 agents, and see the final results of this randomized phase 2
study.
Between all of these trials, we’ll have a good idea of the neoadjuvant therapy with
lapatinib, trastuzumab, and chemotherapy, both with regard to pathologic
complete response rates of the antibodies alone and in combination with chemo,
and the long-term outcome from this combination.
Conference Coverage December 02, 2013
SABCS 2013 Adjuvant Focus (Episode 2)
Lee S. Schwartzberg MD, FACP
There’ll be a lot of studies presented talking about the adjuvant treatment of breast
cancer, and one of the most eagerly awaited studies is the BETH trial— a large
randomized trial that looked at the addition of bevacizumab to standard
chemotherapy and trastuzumab in HER2-positive breast cancer patients. We will
find out if there is benefit with regard to progression-free survival and possible
overall survival from the BETH study.
In addition, we’ll be hearing some very interesting data regarding tumor-infiltrating
lymphocytes, which is a relatively new area for breast cancer. We’ve known for a
long time that breast cancers, when you look at them under the microscope,
occasionally have an infiltration of lymphocytes, and it hasn’t been totally clear
what the meaning of that is and whether it is prognostic for a better outcome,
which some studies have suggested, or perhaps predictive for particular
treatments. This year, we’re going to hear about some very provocative studies in
the neoadjuvant setting that look at tumor-infiltrating lymphocytes and the way
that they may predict for outcome when trastuzumab is added in HER2-positive
breast cancer or other drugs are added in triple-negative breast cancer therapy.
In addition, we’ll be hearing an analysis of two large ECOG adjuvant trials, and the
impact of tumor-infiltrating lymphocytes in the pathology studied there.
Now, that may be a really interesting platform for the future because
immunotherapy for solid tumors is coming of age after many, many years of
promise, and it may be that we’ll be able to look at the tumors themselves and get
a clue as to which patients would be most eligible for additional immune therapies
or which patients may have intrinsic immunity, which is reflected in the pathology
that can be seen on the simple H & E sections that every pathologist generates.
The standard adjuvant treatment for patients with estrogen receptor–positive
breast cancer is to use endocrine therapy, and the treatment of choice is aromatase
inhibitors. While these drugs are very effective, we understand they're not
completely free of side effects, and, particularly, musculoskeletal symptoms are the
biggest problems with aromatase inhibitors, which lead some patients to switch or
discontinue therapy.
At San Antonio this year, we’ll be hearing about a number of innovative trials that
look at why this might be and some strategies to change it. There will be a trial
presented that looked at patient-reported outcomes and symptoms related to
aromatase inhibitors, perhaps pre- and post-treatment when we see the data,
which will allow us perhaps to predict which patients may be at risk for
discontinuing their therapy.
We’ll also be hearing about the difference in outcome for patients who take generic
vs brand-name aromatase inhibitors, and that’s a study that will be particularly
intriguing because it’s an area that we rarely hear much about or have much data
on.
Finally, there’ll be a presentation of a provocative trial looking at the effects of
exercise on discontinuation of or continuation with aromatase inhibitors. We do
understand that exercise, in general, is a great thing for breast cancer patients and
may actually contribute to a decreased risk of recurrence of breast cancer in
general. Wouldn’t it be good if we can find out that exercise not only has its effects
on the cancer but also on the therapy that can keep the cancer from coming back?
We will wait and see what these studies show us.
Conference Coverage December 04, 2013
SABCS 2013 New Approaches to Targeted Therapy in Metastatic Breast Cancer
(Episode 3)
Lee S. Schwartzberg MD, FACP
Commentary
This is Dr. Lee Schwartzberg for PracticeUpdate. Today I’d like to discuss the recent
advances in targeted therapy for metastatic breast cancer.
We understand that breast cancer is comprised of several different subgroups.
Using a genomic classification, we can characterize breast cancer into the estrogen
receptor–rich subgroups, luminal A and luminal B; the HER2-enriched subgroup in
which HER2 is overexpressed and the protein is seen in increased amounts on the
surface, and there is amplification of the HER2 gene as well; and the triple-negative,
or basal, subgroup, in which estrogen receptor, progesterone receptor, and HER2
are not found by immunohistochemistry, and the genomic markers correlate with
that in the large majority of cases.
Because we can now sort breast cancer into several different subgroups, we have
started to establish targeted therapies for each. And the areas in which we’ve been
most successful are those where we have an abundant amount to target, and that
includes the estrogen receptor–positive group and the HER2-positive group.
We have seen the results of targeted therapies in metastatic breast cancer, and
there has been some very good success in these subgroups. In the past year or two,
we have seen that the addition of the mTOR inhibitor everolimus to an estrogen-
receptor antagonist like an aromatase inhibitor increases the progression-free and
overall survival in patients with estrogen receptor–positive metastatic breast
cancer, and this has become an established therapy.
The reason that this probably works is because the PI3-kinase/mTOR pathway is a
resistance mechanism in patients who have been treated with an estrogen-receptor
antagonist, like an aromatase inhibitor, but, the cancer cells, over time, can use
breakthrough pathways to continue to grow and evade the inhibitory effects of
these drugs. Blocking both the estrogen-receptor pathway and the escape
pathway—the PI3 kinase/mTOR pathway—is one way to improve the outcome, and
this has clearly been shown clinically.
One of the most exciting areas also under development in estrogen receptor–
positive breast cancer is blocking another downstream pathway, which is that of
the cell cycle, particularly as it relates to the cyclins. Cyclins 4 and 6, or CDK4 and 6,
are important factors that control a protein called retinoblastoma, or RB protein,
which is a central switch in turning the cell cycle on or off.
In a randomized phase II trial in estrogen receptor–positive breast cancer, the
addition of a CDK4/6 inhibitor markedly improved the progression-free survival in
patients treated with an aromatase inhibitor, and that drug has now gone into
phase III testing to see if those results can be confirmed. If so, that will be another
paradigm shift for treatment of estrogen receptor–positive metastatic breast
cancer, where we will not only have the mTOR inhibitor currently approved for
patients who have progressed after first-line treatment, but also, possibly, the
CDK4/6 inhibitor in the first-line setting, where it’s currently being tested.
In the HER arena, we’ve learned a tremendous amount because HER2 is such an
important target. HER2 is an oncogene, and, when turned on through dimerization
with one of the other members of the HER family, it confers downstream signaling
from major pathways that promote cell proliferation, anti-apoptosis, or
programmed cell death, metastatic potential, and generation of angiogenesis. So,
switching off HER2 can be a tremendous control signal for metastatic breast cancer
cells that overexpress that particular protein, which occurs in about 20% to 25% of
breast cancers.
We have several drugs that target HER2. Trastuzumab has been used for over a
decade and is approved in the adjuvant, neoadjuvant, and metastatic setting.
Recently, we’ve had pertuzumab approved, which blocks the dimerization of HER2
and HER3. And, most recently, we’ve had a whole new group of drugs as
exemplified by TDM1, which is an antibody drug conjugate. TDM1 is the
trastuzumab molecule, the antibody which binds in the same way as naked
trastuzumab to the HER2 molecule, but contains chemotherapy covalently linked to
it through a novel linker mechanism, which keeps it intact through the circulation.
The drug that is covalently linked to trastuzumab is a very toxic chemotherapy,
which cannot be given intravenously because it has no therapeutic margin.
However, when bound in TDM1 to the trastuzumab molecule, it stays intact until it
binds to HER2, is internalized in the cell, degraded in the cell, and the toxic
molecule is then released only, presumably, in the breast cancer cells that are HER2
positive.
This is basically the equivalent of a smart bomb, if you will, because the payload,
which is the DM1 part of the molecule, is only released intracellularly and,
therefore, should have few or limited side effects in the rest of the body. It turns
out that that’s true. TDM1, although it contains chemotherapy, is highly effective
and, although it has some toxicity, it is much less toxic than intravenous
chemotherapy, for the most part.
So, what we have found now is that the combination of any of these anti-HER2
therapies—as well as lapatinib, a small molecule that also impacts HER2 signaling
intracellularly—with or without chemotherapy can be combined in various ways.
And we’ve seen patients with HER2-positive metastatic breast cancer go from the
group with the worst prognosis to, arguably, the group with the best prognosis with
the use of anti-HER2 therapy.
Most experts now believe that anti-HER2 therapy should be given with another
partner, either chemotherapy or another anti-HER2 molecule, from the time the
patient is diagnosed with metastatic disease continuously as a chronic therapy
because the signaling of HER2 is so important.