Interview with Dr. George Simon,
Medical Oncologist at Fox Chase Cancer Center
on Molecular Markers for Selecting Chemotherapy
by Dr. Howard (Jack) West
September, 2009
Dr. West:
Hello, I’m Jack West, medical oncologist in Seattle, Washington and also
the President and CEO of GRACE, the Global Resource for Advancing
Cancer Education. I’m here today with Dr. George Simon who is a
medical oncologist and the Director of the Thoracic Oncology Program at
Fox Chase Cancer Center in Philadelphia. I’m going to talk with him about
a few novel approaches in customizing chemotherapy by molecular
markers and also talk a little about some of the highlights of a conference
that we are just at the end of, the World Conference on Lung Cancer here
in San Francisco, which was actually the largest lung cancer meeting that
has ever been assembled. So, thank you very much George for joining
me today.
Dr. Simon:
It’s my pleasure.
Dr. West:
Can you please start with just explaining the concept of individualizing
chemotherapy based on molecular variables?
Dr. Simon:
Yes. Currently the standard is to give a doublet chemotherapy regimen
that is a combination of two drugs, and the two drugs are picked randomly
usually a combination of carboplatin and Taxol®, or carboplatin and
Gemzar®, or carboplatin and Alimta®. However, we typically tend to see
only about 25%-35% of the patients respond to this treatment.
Individualizing therapy is trying to figure out by doing a genetic analysis of
the patient’s tumor, which patients are destined to respond and which
patients are not destined to respond. If we can select out the patients who
are destined to respond to a particular drug say Gemzar® or pemetrexed
or Alimta®, we could then preferably treat these patients with those drugs.
If we are know they are not destined to respond, we can then treat them
with alternative drugs like Taxotere® or other drugs.
Dr. West:
So rather than just shooting more or less blind and hoping that we do well
and know that we only see responses in about a quarter of patients, the
thought would be that if you could select based on the tumor
characteristics, molecularly, you might be able to improve those numbers.
Dr. Simon:
That’s precisely right.
Dr. West:
So, some of these markers have become increasingly used or at least
studied in clinical work in non-small cell lung cancer primarily. Can you
tell us a bit about ERCC1, what it means and how it might be used?
Dr. Simon:
So ERCC1 is one of the markers that is farthest along and it is a repair
gene. It repairs the DNA damage. And drugs like cisplatin or carboplatin
basically salts of the metal platinum, they kill cancer by causing DNA
damage. If patients have tumors with high ERCC1 function, then the DNA
damage caused by these drugs is repaired and therefore those patients
will be resistant to cisplatin or carboplatin.
And so in a way when measuring ERCC1 and seeing how high or low its
expression is in a particular tumor, we can figure out whether this
particular patient is destined to respond to that, to the platinums.
The second marker that is also farther along in development is a marker
called RRM1. RRM1 actually predicts for Gemzar® resistance. And if
RRM1 levels are high, then patients do not tend to respond to Gemzar®.
So similarly, we could biopsy tumor, measure RRM1 and based on its
expression high versus low, opt to treat with Gemzar® or not.
Dr. West:
What would you say is the current status of these markers in clinical
practice? Are they primarily research tools or are they something that you
think are or should be routinely used?
Dr. Simon:
They have to be further evaluated at this point. Now, there is mounting
evidence in clinical trials that are what we call retrospective that these
markers are relevant to predicting response and survival when treated
with platinum and gemcitabine. We have done one Phase II study
prospectively that suggests that tailoring chemotherapy based on this
molecular marker is making improved response in survival.
Dr. West:
That is the MADeIT trial. Can you tell us what that trial involved?
Dr. Simon:
That trial involved taking patients with advanced stage non-small cell lung
cancer or Stage IV disease, doing a biopsy of their tumors and then
measuring ERCC1 and RRM1. If ERCC1 was high, then we did not give
them platinum. And if RRM1 was high, we did not give them Gem. So we
tailored the chemotherapy to four different platinum doublets. If ERCC1
was low we gave them platinum and if the RRM1 is also low, we gave
them a combination of carboplatin and Gemzar®. If the ERCC1 was low
we gave them carboplatin, but if RRM1 was high we could not give
Gemzar®, so we gave another drug called Taxotere®. If ERCC1 was high
we could not give them platinum, but if the patient had low RRM1, we give
Gemzar® in combination with Taxotere® instead of a combination with
platinum. If they’re both high, we could not give platinum or Gemzar®, so
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we gave them Taxotere® and Navelbine®. [slide 4] And then we followed
these patients for response and survival and we got better than what is
considered average or normal response and survival.
Dr. West:
So, a couple of things to follow up on with that. Did you find that certain
markers just characterized for not doing as well no matter what you gave?
Or if you selected particular treatments for the molecular characteristics,
you could get people to do basically the same?
Dr. Simon:
Yeah, so certain markers like ERCC1 tends to predict that if it is high,
platinum will not work. But it also in a sense tends to predict that if you
use Taxotere® instead then Taxotere® tends to have a higher probability
of working in the ERCC1 high patients versus ERCC1 low patients. This
has been shown in retrospective studies, particularly with a marker very
much like ERCC1 called BRCA1, high BRCA1 predicts for platinum
resistance, but high BRCA1 also predicts were increasing Taxotere®
sensitivity.
Dr. West:
How is the survival on this trial of tailored treatment plans both early on
and then in longer follow-up?
Dr. Simon:
So, we published our early results and we got a 59% one-year survival.
However, we updated these data just for this meeting and we found that the
survival advantage of tailored chemotherapy versus standard chemotherapy
seemed to persist 4 years out. We were rather surprised by those results
because most of these patients got only 4 cycles of the tailored chemotherapy
and 4 cycles are typically done in approximately 3 months, and I expected the
patients to do better initially but towards the latest data, say, I expected both the
patients to do approximately the same. So the fact that the advantage to
personalize chemotherapy persists 3-4 years out, is a little surprising to me. We
believe we have some explanations for this, however, this needs to be studied in
more detail in future trials where we do serial biopsies.
Dr. West:
So where is this work going?
Dr. Simon:
Well, we are now doing a Phase III study comparing patients or
randomizing patients to the customization arm versus the noncustomization arm. All the patients randomized to the non-customization
arm gets carboplatin/gemcitabine. If they are in the customization arm,
they get one of those 4 regimens that we’ve giving on the MADeIT study.
And then we hope to compare the two cohorts of patients to see who did
better.
Dr. West:
And this trial is being done at multiple centers now?
Dr. Simon:
Yes. It’s currently being done at multiple centers in the United States and
also a couple of centers in Germany are participating.
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Dr. West:
Another marker that we’ve heard a bit about is thymidylate synthase (TS).
Can you tell us about what it is and where it is in the process of being
used as a clinical tool?
Dr. Simon:
So thymidylate synthase is the molecular target for Alimta®. And people
are now studying this marker in retrospective studies. In clinical trials that
compared cisplatin and Alimta® or cisplatin and Gemzar®, there appeared
to be an advantage for adenocarcinomas for cisplatin and Alimta®, and for
squamous cell carcinoma for cisplatin and Gemzar®. And several
investigators try to understand why these differences were seen. As it
turns out because TS is a target for Alimta®, investigators looked at TS
expression is adenocarcinoma versus squamous cell carcinomas and
found out that TS expression was higher in squamous cell carcinomas and
lower in adenocarcinomas, and that’s one of the reasons why it is believed
to be a reasonable marker for Alimta® and one of the reasons why
Alimta® is postulated to work better in adenos. However, this marker
needs to be validated in prospective studies.
Dr. West:
Up to now we’ve been talking about the advanced disease generally
Stage IV lung cancer setting. How is this kind of work moving forward in
early stage potentially curable non-small cell lung cancer?
Dr. Simon:
So, there are several studies that are looking at this strategy in trying to
increase cures in early-stage lung cancer. Most early case lung cancer
patients are treated with surgery followed by chemotherapy. Up to now,
chemotherapy in this setting is also randomly selected. However, there
are several studies in the United States as well as in Europe which are
looking at studying this resected tumor for their molecular markers and
then giving the chemotherapy in a tailored fashion afterwards. Some of
the studies testing this concept are currently ongoing in the United States
and and in Italy and France and Spain.
Dr. West:
There was some work that looked at ERCC1 as a marker of whether
patients in the postoperative setting actually got value from cisplatin-based
chemotherapy. Do you think that is a valuable way to approach the
question in terms of should we even be giving treatment, or do you think
it’s really more a question of planning to give treatment but refining what
drugs?
Dr. Simon:
So, ERCC1 has a prognostic function which means that patients, resected
patients with high ERCC1 have a much lower probability of the disease
coming back. And the different groups have taken a different approach to
the value of those prognostic functions. And as we previously talked
about, it has a predictive function, which means that it predicts for whether
the platinum works or platinum does not work. So the French group have
bought into the concept of the prognostic function of ERCC1 and in
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resected patients with non-small cell lung cancer with high ERCC1, they
are not treating with chemotherapy. The Spanish group, however, using
BRCA1 as a marker have decided to treat these patients with
chemotherapy but with Taxotere®. And the Italian group is also treating
these patients but also with Taxotere®.
Dr. West:
Do you have a sense of whether ERCC1 and the BRCA1 marker are
largely redundant or is one better than another over time?
Dr. Simon:
I think they are redundant, and the preponderance of data are for ERCC1,
and ERCC1 has been studied by several groups in several different
groups to arrive at the same conclusion, including our group in the United
States and the French group and the Spanish group and the and some
Asian groups. BRCA1, however, has been studied really by the Spanish
group has not been validated by other groups. Additionally, there just an
abstract presented at this meeting a few minutes ago which looked at
which would be a better marker, which looked at several markers including
ERCC1 and BRCA1 and the conclusions of this retrospective study called
the Fast Bio Study was that ERCC1 was a study statistically significant
predicable marker as BRCA1 was not. So the preponderance of evidence
such as that ERCC1, there’s more data with ERCC1 there are more
groups working with ERCC1 and then there are some data associated
with ERCC1 may be the better marker.
Dr. West:
You had mentioned that ERCC1 has prognostic value in that high levels of
expression are prognostic for doing better. Can you tell us about why that
would be?
Dr. Simon:
We truly don’t know. However, we believe that the function ERCC1 is to
maintain normal DNA, the normalcy of DNA or what we in medical terms
call genomic integrity. DNA is a chemical and has been stitched together
to convey a certain genetic code. The code in the DNA determines how
tall we are, the color of our eyes, the color of our hair, so on and so forth.
So nature really early on in evolution tried to protect this genetic code and
instituted several systems in place. One of them was a repair mechanism.
DNA is prone to damage when exposed to several insults like ultraviolet
radiation or carcinogenic chemicals from found in certain in tobacco
products or certain foods or toxins. So, if DNA gets damaged after
exposure to these toxins, then nature has invented a way of repairing the
damage. Now these tumors that arise from normal cells or arise from
within us have inherited this ability to repair DNA damage. If tumors have
a high capability of repairing DNA damage, then their DNA resembles and
looks more like normal DNA and these tumors tend to behave less
aggressively and generally have a more slow growing or what we call an
indolent course; and hence, we believe that these tumors are uh less
aggressive and therefore the prognostic significance.
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Dr. West:
George, thank you so much for taking the time today.
Dr. Simon:
It’s my pleasure, Jack.
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