Additional Research Findings on Carcinosarcoma: A Second Interview with Dr. Whitfield Growden

Introduction

The following transcript is from an interview between Dr. Whitfield Growdon (MDC), a leading GYN Oncological Surgeon from Mass General Cancer Center in Boston and Diane Redington (DR), a woman with a Gynecological Carcinosarcoma (GCS) who is seeking to motivate researchers to advance the science and uncover knowledge about carcinosarcoma and find a cure for this cancer. On January 5, 2017, Diane conducted a series of interviews with Dr. Growdon on the topic of carcinosarcoma / MMMT.

Dr-Whitfield-GrowdonDr. Whitfield Growdon was born and raised in Boston. He graduated from Williams College with a degree in Art History. After years of appreciating fine arts in the Berkshire Mountains, he attended the University of Massachusetts Medical School. He returned to Boston where he was a resident at the integrated Brigham & Women’s/MGH Combined OBGYN Residency and also completed a gynecologic oncology fellowship at the Massachusetts General Hospital. His interests include minimally invasive and robotic surgery, correlative investigation into rare gynecologic tumors and innovative clinical trial development.

This interview discusses:

1. Genomic analysis of carcinosarcoma,
2. Patterns of resistance,
3. Immunotherapy and
4. Clinical trials.

Tumor Biopsies and Genomic Analysis

(DR)
Where do you get your tumor specimens when doing the genomic analysis of carcinosarcoma? Do you use the metastatic lesion or the original tumor?

(WG)
This is such an important question. The spoiler alert is that we don’t know the final answer.

Most of our clinical trials use the initial biopsy or the initial surgical specimen to determine candidacy for whether or not we go into the trial – even if that specimen was long since removed years prior and you are actually treating something that is in a totally new space.

• There are emerging clinical trials that actually seek to get serial biopsies [a series of biopsies]. Because the limited clinical trial data from phase 1 trials have shown that these tumors change. And they change in real time.

The Impact of Tumor Changes Over Time

(WG)
• Previous treatment changes the tumor and may affect its drivers. And so you can imagine that the lineage of a cancer cell could really change based on where it goes.

• And so there have been some interesting studies that have biopsied tumors in various different areas that look the same under the microscope, but molecularly, they are about 85% the same. But if you think, every time it moves, it gets 85% the same, and then 85% the same, you could have something that is unrecognizable if it has moved many times.

• And so I believe a future movement in oncology is that we are going to have to be getting real time sampling of what these tumors are.

Patterns of Resistance and Metastasis

(WG)
As we think about candidacies for targeted therapies, for immune therapies, this is going to be of utmost importance. Particularly trying to recognize patterns of resistance. Because that is another major issue in oncology. We can have a therapy that might work for a couple of months, but then it stops working. Wouldn’t it be great to know about that as soon as it happens so that you change therapies on the precipice of that happening? So that as you said, you can always be applying something new that will be effective.

(DR)
Would it be based on obtaining the original tumor and then with reemergence, you get the new tumor? Then you look at the changes between the new tumor and the old tumor?

(WG)
The original may not even inform what you should be doing. It could be that you really need to focus on what is the current metastasis that you are trying to treat or recurrence that you are trying to treat. Because it could be different. Maybe it has even attained a new signature that makes it susceptible to a new type of therapy that we did not even know about.

Gene Amplification and Targeted Therapy

(WG)
A good example of this — in uterine carcinosarcoma, there is a gene amplification rate, which means an overexpression of genes, of something we call HER2, which is famous because of breast cancer. That was essentially the poster child for targeted therapies. Women with breast cancer in the late 80s, if you were overexpressing this protein HER2 on the tumor, you actually had a very guarded prognosis. It was a poor prognostic factor. But then we invented an antibody that neutralized those specific cells —Herceptin or trastuzumab. And we essentially turned what was a very poor prognostic factor into one of the best prognostic factors. If you have breast cancer, you want it to be HER2 positive because there is a pipeline of anti-HER2 therapy.

What is not discussed very often is that uterine cancers, particularly high-grade serous uterine cancers have the exact same rate of gene amplification as breast cancer. Carcinosarcoma also has that rate of amplification. We are running one of the only clinical trials here of HER2 therapy in uterine serous carcinoma, which is a variant of carcinosarcoma. The trial was designed and does not include carcinosarcomas, but I believe that we are going to write another trial to include carcinosarcoma. It could be that the initial specimen such as a hysterectomy specimen doesn’t have HER2 gene amplification. But it may be that the metastasis does have that. Which would mean that you would want to test both. Because it may be that anti-HER2 therapy for uterine carcinosarcoma, I believe, is going to someday be important for that subset of women.

We are trying to get pre-clinical data to really put that together and prove that that’s really going to be important.

Obtaining data and samples

(DR)

Where will you get that data? Do you need samples?
(WG)
We do, and we use the vast bank that we have here. Very commonly, we have women that agreed to donate their samples, meaning that pathology will only use about 50% of their tissue to make a diagnosis and then the rest gets thrown away.

(DR)
There are many women who have generously offered, “Take my tissue,” who want to be part of this. We would like to create a mechanism to be able to offer you the specimens. We need to understand what you need and what form is needed, so that there is a match between people who have this disease and the research.

(WG)
There has to be. I think that clinical medicine is not the way it used to be where there is the bench [laboratory] and there was the clinic. Now what happens in the office is very much informed by what happens in the laboratory.

(DR)
I think that is true here at Mass General more than most places.

Meaningful Impact

(WG)
Well we talked about how to move the bar forward. The bar is going to get moved forward in the lab. And then it is how we apply what we have learned from the lab in the clinic. HER2 is a great example. There are only about 20-30% of women with carcinosarcomas of the uterus who will overexpress HER2. But if we can identify that cohort first and then apply the right therapy, maybe we could enjoy the success that we have seen in breast cancer as well as gastric cancer.

(DR)
That would be a huge breakthrough.

(WG)
It would be a massive thing. The clinical trial that we are running in uterine serous carcinoma right now, which admittedly does not include uterine carcinosarcoma, we have already seen responses. Which is incredible! We have people on trial who are doing well who had no other options because after initial cytotoxic chemotherapy, there is no FDA-approved therapy for uterine carcinosarcoma.

(DR)
That is so exciting.

(WG)
That is how we are going to beat this. We are going to try to get meaningful impact. It is going to be incremental, but it is going to be by understanding the molecular drivers of an individual woman’s carcinosarcoma and then applying the right therapy.

Immunotherapy

(WG)
We talked about immunotherapy. I believe that we are going to be using a similar strategy with immunotherapy. I don’t think all women with endometrial cancer are going to benefit from immunotherapy. I think it is going to be the subset that expresses particular biomarkers.

Anti-PD-1 immunotherapy

We have decided to look at what’s called anti-PD-1 immunotherapy. PD-1 is a protein that is expressed on immune cells and tumor cells and also normal cells. PD-1 is a checkpoint inhibitor. What that means is that our kidney cells, our liver cells, our “self” cells don’t get attacked by our immune system – because they express these proteins that say, “I’m you. Don’t attack me.” Well, a tumor could highjack that. And then, if the tumor puts that flag out there, our immune system gets tricked and ignores the tumor. Well, these antibodies attack these checkpoint inhibitors, block them specifically, and then our immune system recognizes tumors as foreign.

I believe that the more tumors express those particular checkpoint inhibitors, the more likely you are going to see a response.

Biomarker tests

(DR)
Can you test for that?
(WG)
You can. Currently there is a medicine that is FDA-approved called pembrolizumab [Keytruda]. It comes with a companion test that is a protein assay [analysis] you can do within days on any given tumor. It is an FDA-approved companion test in order to test lung cancers to determine whether or not you are more likely to respond. The caveat: It is not perfect. Nothing ever is. We have patients that overexpress the protein that do not respond; and conversely, we have patients that don’t express the protein that respond. It is not a perfect system, but in general, if you are a high expresser, you are more likely to respond. What I want you to know is that these checkpoint proteins, they are called B7h proteins. PD-1 is actually B7h1. There is a whole family of them, like 12 or 15 of them. So, it’s not just one protein. It’s a landscape. And likely it’s a mix. Like putting the right cocktail together.

So maybe we need to be doing simultaneous immunotherapies. We need to test a tumor for all the different proteins, figure out what the landscape looks like, and then apply the right immunotherapies as cocktails. So that my cocktail for my melanoma may look different from your cocktail for a uterine [or ovarian] carcinosarcoma. And a lung cancer would look different. So that it is based on the biomarker test that you do up front.

Clinical Trials for Carcinosarcoma

(DR)
Are there any clinical trials for carcinosarcoma and PD-1s?

(WG)
That’s a good question. We do have – again, sometimes carcinosarcomas are excluded from a lot of trials. We know that in the phase 1 queue, uterine carcinosarcomas have been allowed in certain trials. We are going to be opening a clinical trial that looks at ovarian cancer that specifically does include ovarian carcinosarcoma in its eligibility. We’ve recognized that this is an unmet need. Women with ovarian carcinosarcoma – we have been applying a paradigm that we really have no right to apply because we do not have clinical trials to really back us up on it. But it is the best we have. So that is what we go with.

This is an upfront immunotherapy trial that is looking at specific checkpoint inhibitors, and it is actually opening very, very soon here at the Cancer Center. I think it is a national trial through Pfizer.

(DR)
We are going to put that on the website. Women need to know how to decide on what clinical trial in which to participate. Where do I go? It’s pretty frustrating.

Deciding about what clinical trials to join

(WG)
It’s hard because you can go to clinicaltrials.gov and type in things, and what will you get? It’s drinking from the fire hose. You’re getting hit with things that may or may not be relevant to you. There is so much there; it’s almost impossible to sift.

(DR)
It’s pretty tough if you do not have a clinical background.

(WG)

Or if you don’t have a navigator to help you. A lot of times with clinical trials, our paradigm is that we give what we believe is the standard of care first. And then we think about if it comes back or if it does not respond, then we think about clinical trials. What you are bringing up is actually really interesting. Maybe immunotherapy trials need to be up front? Maybe they are going to be even better than our conventional therapy? And it takes so many years to become a new first line standard of care because it has to be compared on a large scale to upfront therapy. But what do we know about uterine carcinosarcoma? Is it ever going to see the light of day for an upfront phase 3 clinical trial?

(DR)
It would take a long time.

(WG)
It would take 10 years.

(DR)
Women think that Phase 3 is kind of the gold standard – the randomized controlled trial is what you want to be in. It sounds like you really want to be in a Phase 1 or Phase 2 trial.

(WG)
It is interesting. We have had an explosion in the last 20 years of targeted therapies and immunotherapies. Therapies that are unlikely to work for the whole but will work for a small piece of the whole. And you could imagine that the conventional Phase 3 Trial of 1,000 people – 500 get one thing and 500 get the other thing. Well, your experimental arm is only going to work in a subset, so you are going to throw it out in any given Phase 3 trial, even though it has the potential to save completely or at least create a durable benefit for a small subset.

New developments in clinical trials

(WG)
We have had to rethink our clinical trails. And you are right. It’s been moving toward biomarker trials where you do a test up front for candidacy to get in. And then if you have the signature [biomarker], you go on a Phase 2 and we look at the response rate. That is what we have done with less common cancers. In some settings, we have been able to get FDA approval for drugs just based on biomarkers in smaller trials.

It may be that with cytotoxics, such as Taxol or carboplatin – well those work the same in pretty much everybody. And so those are amenable to a big Phase 3 trial like what we did to establish its use. But we maybe need to rethink that in an era where we know things are not going to work for everybody the same way, and probably we want to pre-select. Because guess what? Ovarian cancer all gets treated the same up front. What do we know about ovarian cancer? It is probably 7 different diseases on a molecular basis. Uterine cancer is probably the same, but it lags behind ovarian cancer in terms of clinical trials.

Eligibility for clinical trial

(DR)
One of the issues I see is that a person could be on multiple modalities. They could have original treatment and then with a recurrence they get another treatment … and that often times eliminates them from participating in a clinical trial. A lot of clinical trials say 2 previous lines of therapy.
(WG)
That is right. There are strict limitations of eligibility.

(DR)
Unless you get into the clinical trial tract fairly early then you may be eliminated from even participating in a trail down the road. Will that change or do women need to consider that when seeking treatment?

(WG)
I think they do need to consider that as they are seeking treatment. And the reason for that isn’t so much because they are trying to limit their scope. It’s that when you are trying to figure out when to use a medicine, you want to make the group of people you are studying as similar as possible. Unfortunately, that closes the door for some women that have, unbeknownst to them, gone on many therapies they thought in all earnestness were going to help.

Exploring clinical trial options at each stage in therapy

(WG)
I think that it is always good to explore clinical trial options at each stage in therapy. So that before you have surgery up front, you explore clinical trials and then you weigh the benefit of, do I do something standard or do I do something experimental? And then maybe you chose standard. Maybe your doctor says that it’s important that we do something standard because it is probably going to be better than what we have experimentally.

But then, when something comes back, again have the conversation. Is there a trial that I am eligible for? What is that trial? What does it look like? What’s the signature? What’s the general signal that that trial was based on? And then, what is the standard of care? And that goes for each recurrence that may or may not happen. And you always ask the question. Because there are some disease sites, for example in the pediatric oncology world, all children go on trial. In the upfront setting and the recurrence setting.

(DR)
Really.

(WG)
Almost all do. Childhood cancers are exceedingly uncommon. Therefore, the only way you learn anything is by essentially always having standard of care versus something new. So, in pediatric oncology, clinical trials are infinitely more common.

In adult oncology, some estimates have been [that] only about 10% of people getting treated for adult cancers go on clinical trial. That number may have changed.

(DR)
Do you think that will change…?

(WG)
With the new pipeline of agents? I think it may. But I also think that clinical trials are not right for everybody. At the end of the day, a clinical trial is an experiment. And women – in my case with gynecological oncology – are donating their experience in order to find out if this could potentially help themselves but also help other women in their shoes in the future. It is a tremendous kindness that women do, but it’s not right for everybody.

Variation in Treatment

(DR)
One of the things that I have found is that there is tremendous variation in how women are treated across treatment sites. And depending on where you go, in many cases, could determine if you are going to make it or not make it, unfortunately.

How does a woman who has this new diagnosis of a terrible rotten cancer… What do you do? Where do you go? Where do you start?

For example, I went to UPMC – great facility, world class – and I got my diagnosis. I told them that I was going to MD Anderson or Memorial Sloane Kettering. I went to all the sites. They [UPMC] told me that, “they won’t tell you anything different than we will.” Well, every place I went told me something different. Every place I went. And they told me a lot different from what they told me at UPMC. So…how do you decide where to go? I learned so much along the way. But many women don’t have that option, the opportunity, the knowledge, the wherewithal…
(WG)
Right. The wherewithal to be able to travel and to garner many opinions.
Broad set of options
• The way I think about this is…I think that whenever you are dealing with a cancer that we don’t have perfect answers for, you are going to see a broad range of opinions. And whenever you have that broad range of opinions, you really need to be thoughtful about the team that has been put together.

Multidisciplinary team
• I cannot speak to other cancer centers, but the style that we think is important, and that I personally think is very important, is that you have people from many disciplines – people that have a little bit of laboratory experience, are familiar with clinical trials, you have surgical opinions that also give chemotherapy and you have radiation types of doctors that are familiar with how we use radiation in the setting of a uterine cancer.
Clear explanations
• And they all put together a comprehensive opinion, and then they explain why. They actually try to make it so…I try to make it so that people understand why am I offering you this. What is that actually based on? Because you can go off the rails very quickly by inventing things in a vacuum.

• I think the answer to your question is that our sort of National Comprehensive Cancer Center Network (NCCN) Guidelines are very broad in this setting. There essentially is no FDA-approved standard. Therefore, what they will do is list active agents.

They will list algorithms that are suggested or recommended or for your consideration. So, how we follow this, how we treat this, how we even initially diagnose it, what studies we use can be vastly different based on what environment you are working in. And I think that accounts for the heterogeneity [diversity, differences]. If you had some other type of cancer, where it is very clear what the steps are, you are going to see a little less heterogeneity, I think. Especially at Comprehensive Cancer Centers where they are all going to be following very strict guidelines.

Whereas, with something like this, you are going to see a broad set of options. And I think that what it comes down to for me, for my sister or my family? What I would think would be the team that you have – Do you trust and believe in them? Are you comfortable with them? Is it something where they speak to you and you understand what they are saying and you trust them and you know that they are going to have your best interests and that they are going to answer your phone calls and they are going to support you through. Because no one has a crystal ball, no one knows what the right move is. But you want to be in a place where you have a full appetizer sampler of options.

(DR)
That’s a really good point because at a lot of the places I did visit, I spoke with one physician, not a team of physicians. I really like the opportunity to speak to all of the experts on the team in the different modalities.

Carcinosarcoma management is not straightforward

(WG)
Right. Because everyone comes to it from a different perspective. For things that are straightforward, where it is sort of obvious what needs to happen and there is not a lot of controversy, you maybe don’t need a multi-disciplinary approach. They are harder to organize; it takes longer. But for things that are uncommon, that standard of care is not defined, we firmly rely on our friends. Talking, figuring out what is right for you. What types of molecular testing are we going to do? Are we going to profile? Are we not going to profile? Are we going to act on that? Are we going to try to get compassionate use? Are we going to look at clinical trials? What is the clinical trial infrastructure? What are the offerings? Where else are there offerings? These are questions that need to be asked in the setting of carcinosarcoma, for sure. And I would always want people to ask that, and we usually just bring this up.

Watch the two videos of the transcript

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5 thoughts on “Additional Research Findings on Carcinosarcoma: A Second Interview with Dr. Whitfield Growden

  1. If a woman has had a Her2+ breast cancer, snd she develops Uterine Carcinosarcoma, is it more likely to be Her2+ also?

    1. Brenda,
      I have inquired but not heard back about your question. I will let you know what I hear.
      Take care,
      Diane

  2. “Carcinosarcoma management is not straightforward”
    I’ll say! For three years we’ve pretty much been managing treatment on our own. First doctor(BIG Center) essentially wrote her off because of her age I suspect. 2nd doctor jumped in and within three days had her in surgery and on the road to chemo…then after chemo and a return in a small area…he essentially said “I got nothing”…”more chemo/radiation would destroy her body”. 3rd doctor(a different BIG Center) said “more chemo and radition”; when queried about the destructive possibilities she said: “accept the damage or die”…needless to say we walked. 4th doctor made a good case for targeted/limited radiation focused beam therapy…with the possibility of getting it all…we just finished that.
    What gets me is that the uterus is gone, the cancer is in a small area/lymph node the 2nd doctor could not get to surgically and forgot…yet everyone wants to do a pelvic exam because it STARTED as uterine.
    For some blessed reason her body is keeping it in check but not eliminating it…sure hope something real comes around to help…looks like we’re on a dead-end road right now.

    1. There is so much variation in how this cancer is treated. I continue to urge women to seek care at major cancer research centers and find treatment teams who are knowledgeable and experienced with this cancer. Don’t know where you have been but it does sound pretty discouraging. But it does sound like her immune system is protecting her for now. I believe that the cures are going to be found in scientific research and clinical trials. That is where I am focused. Best to you and your partner.

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