Stopping Copper To Stop Cancer
NEW YORK CITY (Ivanhoe Newswire) - Aggressive breast cancer can be hard to beat. Even if women do overcome it, there's a good chance it could come back. Now, doctors believe depleting the body of a well-known metal could be the key to keeping it away.
These days Martha Bruehl always takes time to stop and smell the roses. She was diagnosed with stage four breast cancer nine years ago.
"I was not as scared until I found out it was in my liver," Martha Bruehl told Ivanhoe.
She's had chemo, radiation, and surgery but Martha's cancer has come back twice.
Now, she's taking part in a study investigating if depleting the body of copper will keep aggressive breast cancer at bay. Researchers studied 40 women with tumors that were likely to recur. When given the copper-depleting drug, known as TM, patients had a reduction in cells that promote tumor growth.
"For the vast majority of them, their tumor didn't come back. Even in those that we would really 100-percent expect their tumors to come back," Dr. Linda Vahdat, Director of the Breast Cancer Research Program at Weill Cornell Medical College, told Ivanhoe.
In fact, two patients with stage four triple-negative breast cancer are disease-free at four and five years. Most triple-negative patients with advanced cancer die within ten months and 85 percent of patients with stage three or four breast cancers were disease-free at ten months.
Martha is one of them. Her cancer is still in remission and she's hoping it will stay that way!
"I can fight it," Martha said.
Doctors don't know exactly why copper levels go up in cancer patients. They tell us you really can't control or deplete copper levels by monitoring your diet. Patients in the study start by taking nine of the anti-copper pills a day. The only side effects are the risk of low white blood counts and sulfur burps.
BACKGROUND: Breast cancer is the second most common cancer diagnosed in women, and while treatment of the cancer has drastically improved over the years, it is not uncommon for the cancer to recur. Recurrent breast cancer is breast cancer that comes back after initial treatment. This recurrence could be because the original treatment did not completely destroy or remove all of the cancer cells, or the breast cancer is so aggressive that it survived chemotherapy, hormone therapy, or radiation. Breast cancer can take months or even years after treatment to return. (Source: www.mayoclinic.com)
TYPES: Recurrent breast cancer can take three different forms:
Local recurrence is when the cancer comes back in the same area as the initial tumor, which is often the breast, chest wall, or skin in the chest area of women who underwent a double mastectomy. Signs of local recurrence are a lump or thickening in the breast area, redness or inflammation of the skin, or any strange nipple changes.
Regional recurrence refers to breast cancer that comes back in the lymph nodes in the armpit or collarbone area. Swollen lymph nodes, pain in the arm or shoulder, or a loss of feeling in the arm or hand can all indicate a potential regional recurrence.
Distant recurrence can be the most severe form of recurrent breast cancer. A distant recurrence is when the breast cancer has spread and comes back in a different part of the body. The most common areas the cancer spreads to are the liver, bones, and lungs. (Source:www.mayoclinic.com)
TREATMENT: Treatment for recurrent breast cancer depends on how aggressive the cancer is as well as where it reappeared. Sometimes surgery or targeted radiation is enough to rid the person of the cancer cells, but other times chemotherapy, hormone therapy, and targeted therapies are needed. If the cancer is too aggressive to be cured, patients may want to treat the symptoms so they are comfortable. (Source: www.breastcancer.org)
NEW TECHNOLOGY: For high-risk triple-negative breast cancer, researchers at Weill Cornell Medical College discovered that an anti-copper drug compound disables the ability of bone marrow cells from setting up a "home" in organs to receive and nurture migrating cancer tumor cells. The average survival for this type of breast cancer is historically nine months, but results from the phase II clinical trial shows if patients at high-risk of relapse with no current visible breast cancer are copper depleted, it results in a prolonged period of time with no cancer recurrence. Only two of the 11 study participants with a history of advanced triple-negative breast cancer relapsed within ten months after using the anti-copper drug, tetrathiomolybdate. Four of the study participants with a history of metastatic triple-negative breast cancer have had long-term benefit remaining disease free for between three and five and a half years. Also, study participants with other forms of high-risk for relapse breast cancer, either in stage three or four, without evidence of disease after treatment have also done well in the study. The progression-free survival rate among the 29 patients has been 85 percent. (Source:http://weill.cornell.edu/news/releases)
Dr. Linda Vahdat, Director of the Breast Cancer Research Program, Chief of the Solid Tumor Service, and Professor of Medicine at Weill Cornell Medical College, talks about a new treatment option for breast cancer.
What's the difference between triple negative breast cancer and what people generally think of breast cancer?
Dr. Vahdat: Because of the sequencing of the human genome project, we really have a lot of insight into breast cancer. One of the things that we know is that triple negative breast cancer is a particularly challenging type of breast cancer to take care of. Specifically in that it grows in a very different way than regular breast cancer. Because of that, we need to come up with new strategies in order to cure people who have triple negative breast cancer.
What do you mean it grows in a different way?
Dr. Vahdat: Well, we know that regular breast cancer has what we call receptors. So, you have hormone receptors. If someone has a hormone receptor, we can use anti-hormonal therapy. Some breast cancers have the HER2 receptor or amplification of the HER2. So, we have a drug that can totally neutralize the cold reception. Triple negative breast cancers don't have those receptors; therefore, we are searching for new ways in order to keep it from growing.
We hear so much about people surviving breast cancer, but is this one of the cases where you would probably have less survivors?
Dr. Vahdat: Patients who are diagnosed with triple negative breast cancer have a worse prognosis. They have a higher risk of the tumor coming back and when the tumor comes back, it's very difficult to treat.
Is prognosis usually 10 months out?
Dr. Vahdat: Yes. If you were to look at statistics, the average lifespan of a woman diagnosed with metastatic triple negative breast cancer is less than a year.
Before this new drug, how were you treating triple negative breast cancer?
Dr. Vahdat: There isn't really a special to treat triple negative breast cancer. Even though we have a lot of research going on to try to understand how it grows, we haven't come up with new strategies to shrink it or to keep it at bay.
So, now there's a new drug. Can you tell me about the new drug?
Dr. Vahdat: So, this whole anti-copper approach is really interesting. It certainly would be something that some people might consider "out there." Based on a lot of laboratory work that was done at the University Michigan, there were a lot of tips that perhaps you could decrease the progression of breast cancer in patients who were given a copper depletion approach. We weren't really sure why, but we started our trial back in 2007. We were taking women who we thought were at really high risk of tumors coming back. Our goal was to decrease some of the cells that we thought were critical to tumor progression. We subsequently have proven in another trial that those cells, the EPC's, were critical for tumor progression. However, in our trial we gave a copper depletion compound, called TM, to our patients who are at a high risk of the tumor coming back. Basically we saw that we could decrease these cells that we thought were important, but what was even most striking is that for the vast majority of patients there tumor didn't come back.
Would you say copper in a woman's body almost feeds a cancers growth?
Dr. Vahdat: I would say that excess copper can certainly promote tumor progression.
How do you get excess copper?
Dr. Vahdat: I am not one 100 percent sure how you get excess copper. I know that by modulating your diet you can't decrease the amount of copper, which is absorbed into your system. For some reason excess copper is mobilized and it can certainly facilitate tumor progression. There's no doubt about that.
Is that a key factor in this triple negative breast cancer? Do all the women with triple negative breast cancer have high copper levels?
Dr. Vahdat: If you were actually to measure their copper levels, which we do by measuring something called cirillo plasma, or CP level, most copper levels are within the normal range. So there's certainly some sort of "fine line" that is crossed in patients who have tumor progression. We've had a couple of people whose tumors have come back while on the trial. One of the things that we've seen is that all the sudden, for no apparent reason, their CP level goes up, even though they are taking their pills as they should. So, for some reason there's a spike in the normal range of copper and then they relapse.
Can you explain what happens in this trial?
Dr. Vahdat: We are giving our patients a drug called tetrathiomolybdate which is a short acting oral drug. They have to take it several times a day. By doing so, they stably deplete serum copper level to where normal cell function can take place. However, we have hypothesized tumor angiogenesis cannot. Angiogenesis is a process where blood vessels are put down.
Now when you say several times, exactly how many times is that?
Dr. Vahdat: When a patient starts taking TMA, they take the pills four times a day. They eventually end up having to take nine pills a day. So, it's a real commitment. It takes about a month to stably copper deplete them and then they go down to five pills a day. Then we sort of fine tune it to where they'll have to take anywhere from two pills a day to nine pills a day, depending on how their body processes the drug.
So is there any risk?
Dr. Vahdat: Well, everything has risk. I would say the two side effects that we've seen is that if we over copper deplete patients there is a risk of them having a low white blood count, we do that three percent of the time, and the other thing that patients can get is a sulfur burp. Sulfur burps actually smell like rotten eggs. My patients will always tell me that it bothers other people more than it bothers the patient, but we give them what we call a PPI, a proton pump inhibitor, to decrease the acid level in their stomach and it gets rid of the sulfur burp. So, really the only risk that we've seen so far, and we have patients who are on trial for more than six years, is that if we over copper deplete them their white blood count can be lowered.
You said that you have patients on trial for 6 years?
Dr. Vahdat: Yes, it is pretty amazing. The second person we put on our clinical trial was someone with a triple negative breast cancer, who is what we call a stage four NED. She had a triple negative breast cancer that had come back and then she had gotten rid of it by surgery. It had spread to her liver. She came on the trial about two months after her liver resection. Now she's taking her pills and she's doing fine. Originally the trial was supposed to be for two years. People would be on it for two years. This was based on what was happening in the field at the time, but at two years her cancer still had not come back. We did not expect this, so thought we should extend the study. So, we got some more funding and extended the study for another two years. At four years, the cancer still hadn't come back. We felt committed that we could not stop the trial. We believed that we were helping her. So, we extended it a third time. Now, we're about to go into our fourth extension of the study because she's still fine.
How many people were originally in the study?
Dr. Vahdat: We had forty people in it. Well actually, the report that we published was for the first forty patients on the study. Now, we have sixty patients on the study. About a year ago we had done our analysis and we really saw how we were able to most efficiently copper deplete the triple negative. We decided that we wanted to recruit patients with triple negative breast cancer. So, we probably have about twenty patients with triple negative currently on our trial.
What are you seeing with the results of that?
Dr. Vahdat: Well, we see that we're able to efficiently copper deplete the triple negatives. We are able to drive down the endothelial progenitor cells, which we believe are a critical component of the microenvironment.
So, there is really no downside?
Dr. Vahdat: Well, no. There everything has a downside. I guess the downside is that our patients need to come and visit us once a month, every four weeks. They're a very committed group of wonderful patients.
Now do you have a number; like eighty percent of the women are past their 10 months?
Dr. Vahdat: Yes. I would say we saw two patterns of relapse. We saw a couple of people who relapsed within three months of starting TM. Based on how the mechanism of metastasis works, they were actually in the process of relapsing when they came into the study. We could have copper depleted them, but it wouldn't have made a difference. The machinery had already started. Out of all of our stage four NED's who were triple negative, we've only had one relapse. That's about five percent.
This only works for people who have not had cancer?
Dr. Vahdat: We're testing it in people who have no cancer that you can see. Giving TM to patients with cancer is not a new idea. There has been quite a bit of work done at other places. However, the population they chose to test it in was people who had overt cancer and they were looking for shrinkage of the cancer. So pretty much across those trials, about a third of the patients had what we call stable disease and then the rest progressed. That is consistent with how we think it works. That's actually why we wanted to go into a group of patients who had no cancer that you could see, thinking that perhaps we could keep that angiogenic switch in the off position.
Can you tell me a little bit about Martha?
Dr. Vahdat: Martha actually is what we call a stage four NED. She is not a triple negative, but she's a hormone receptor positive patient. We have the same prognosis for stage four NEDs; they live longer because they have more options. She's been on trial for several years. Martha actually had liver metastasis and she's fine.
Does this give you hope?
Dr. Vahdat: I really think that we are probably on to something. However, the scientist in me says that yes this looks great, but we need to move it forward and we need to test it in a formal way. I'm hoping that we'll sufficiently identify our enriched population, which I believe will be triple negative and that we'll be able to do a randomized trial. I think that if the effects are as large as we think they are, it won't take too long to figure it out. So, there are a lot of logistical issues. Once we started to observe this we really began to think we're making a big difference.
I have a fabulous laboratory collaborator, Dr. Mctal, who has really taken the lead on really understanding what we are doing to the tumor micro environment past affecting the EPC's. He's done terrific work. He's worked out mechanistically; about eighty percent of how we believe it's working. I believe that will help us figure out which patients will get the most benefit out of it. It is sort of a personalized medicine, not a shotgun approach. We measure these cells, these EPC's, and this other cell called HPC's. We think that that's an important end point, at least so far. I mean this may change as we get more information, but there's a lot of work that goes in to measuring those cells, lot of variability. It's labor intensive. We have our bioengineers at Ithaca developing an automated test for us so that we would just take one vile of blood, throw it on a silica chip, and then we have the number. I think that's going to be very important too. So, there are all these different pieces of the puzzle. Now, the other thing is the drug supply. Because there isn't a pharmaceutical company behind this, I mean this is really a project supported by philanthropy here at Cornell. We're very lucky that we have so many generous people who help support our projects. It's been funded by the Komen Foundation early on, the Breast Cancer Alliance of Greenwich, as well as New York Community Trust and Cancer Research and Treatment, which is a philanthropic Institution with very close Cornell ties. So that's pretty much how we funded ourselves. There's not a pharmaceutical company, although we would love to have big pockets of a pharmaceutical company to help us. We've identified a long acting TM compound and we are in discussion with the people who own the patents for that so we can partner with them to further develop this drug and bring it to the people who need it most. It's just very exciting for us because it's an example of transitional medicine. So, I feel like we're one step closer.
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Weill Cornell Medical Center