New Therapy—New Hope for Aggressive Breast Cancer--In-Depth Interview
Julie R. Gralow, MD, Director, Breast Medical Oncology, Seattle Cancer Care Alliance, talks about a new therapy for aggressive breast cancer.
When you’re diagnosed with breast cancer, one more, it’s just not one disease at all?
Dr. Gralow: Well, right now, we are thinking of breast cancer as 4 or 5 different subtypes, but the fact of the matter is the harder you look, the more you find that every single breast cancer is unique if you look at enough genes. It’s an exciting time with all the genomic profiling going on, but it’s actually getting more complicated. Breast cancer is not just one type.
Can you explain what triple negative breast cancer is?
Dr. Gralow: Triple negative is slang for a breast cancer that doesn’t stain positive for estrogen receptor, progesterone receptor and the HER2 receptor. Those are the three main things we look at when we first diagnose a breast cancer in order to help determine treatment options. With that being said, triple negative means it’s negative for all three of those things, but it’s actually really frustrating to define a subset of breast cancer by what it isn’t instead of what it is.
Does that make that harder to treat?
Dr. Gralow: Well, right now, the only treatment we have for triple negative breast cancer is chemotherapy. Estrogen receptor positive breast cancer we can treat with anti-estrogen therapies. HER2 positive breast cancer we can treat with really excellent HER2 targeted therapies, but triple negative because we don’t know what it’s positive for, is just treated with chemo right now.
Is it considered a really aggressive cancer?
Dr. Gralow: Right now it’s probably the most aggressive subtype. Interestingly, HER2 positive breast cancer used to be thought of as quite aggressive, but with better therapies, we now have much better survival, so with good treatment and better understanding that subtype of cancer. We don’t think of it as being so aggressive anymore, but triple negative breast cancer really is aggressive with limited treatment options.
What is PARP?
Dr. Gralow: PARP inhibitors or poly ADP ribose polymerase inhibitors work at preventing the cancer cell from being able to repair itself after its’ been hit by chemo. We always are repairing our own DNA in our body; our normal cells, our cancer cells are, and when cancer develops, it leaves certain subtypes like triple negative breast cancer or BRCA1 or 2 mutation breast cancers. The inherited kids of breast cancers; they already have a problem with repairing their DNA, and, so one of the major pathways in repairing their own DNA, after they get hit by DNA damaging chemotherapy is knocked out so if you add a PARP inhibitor, which is another one of the mechanisms for DNA repair, it affects the ability of the tumor cell to heal itself after getting chemotherapy and it really doesn’t affect the normal cells because they don’t have already one problem with DNA repair. We can knock out a bit of PARP in the normal cells, but they have other pathways that are still functioning, so it’s pretty nontoxic to the normal cells and pretty toxic to the cancer cells, at least those that evolved by having a DNA repair problem.
How is it given, and what are the side effects you are seeing?
Dr. Gralow: Well, many of the PARP inhibitors are oral, which is great although they can be given in other ways. Um, we generally give them with chemotherapy, so when you ask about side effects, most of the side effects are really those of the chemo. We, we make those side effects slightly worse in terms of the blood counts; the white cells that fight infection, the red cells that carry oxygen around and the platelets that help with bleeding. There might be a little bit more nausea, but really the side effects are of the chemo. We’ve done trials and the BRCA-1 and BRCA-2, inherited mutation kinds of cancer with just the PARP inhibitors alone, no chemotherapy and really we see almost no side effects when they are given by themselves.
Does it work as well when you don’t give chemo?
Dr. Gralow: In the BRCA-1 and BRCA-2 gene mutation carriers, we have some really exciting results with just the PARP inhibitors by themselves. They are so dependent. BRCA-1 and 2, the breast cancer one and two inherited genes, those proteins that come out of the BRCA-1 and 2 genes, they work, by repairing DNA. So if you inherit a mutation in BRCA-1 or 2, you’re kind of already set up to have a problem repairing DNA and the major other pathway to repair DNA is the PARP inhibitor. In that subset, it looks like we can give the PARP inhibitors all by themselves. There may be a subset of triple negative breast cancer. There is a lot of similarity in a certain subset of triple negative breast cancer with the BRCA-1 and 2 cancers. Part of the trials we have ongoing now are to try to find out if there is a subset of triple negative that you don’t even need to give chemo in; because they are so similar in their structure and their genes to the BRCA-1 and 2 cancers.
Do you have any specifics on the BRCA-1 and 2 like that trial; any percentages, any results that you could share?
Dr. Gralow: Yeah, I can find you the abstracts, but, essentially I would, as I recall around 25 to 30% had really excellent responses and a majority of other BRCA-1 and 2 carriers had stable disease.
Is PARP now part of another trial for triple negative?
Dr. Gralow: Well, many groups are looking at how to exploit these PARP inhibitors in breast cancer. We have an ongoing trial looking at giving some DNA damaging chemotherapy, two drugs Cisplatin and Vinorelbine and then adding one of the PARP inhibitors that we call Veliparib, ABT-888.
Do you guys just like to make these names up?
Dr. Gralow: We do like to make these names up. When it still has a number like that, letters and a number that usually means it’s not FDA approved yet. It’s still early. Although, we’ve been moving it along in the clinic and we would hope that if the trials stand up, that we will be able to get these drugs approved in the next couple of years.
Is there any downside to using PARP?
Dr. Gralow: I would say the major downside isn’t really side effects, but its cost. These are very expensive drugs and even a little bit of additional side effects with a lot of extra costs means we really need to study it to figure out who needs it and who benefits from it.
When you say cost, how much would a round of this cost compared to chemo?
Dr. Gralow: Until a drug is FDA approved, the company then gets to set the price. We don’t know what the cost would be, but these are expensive biologically targeted agents that we put a lot of research into in the laboratory and then moving it into patients, so history would suggest that these drugs could be on the order of $2000 to $10,000 dollars a month.
Are you excited about this drug?
Dr. Gralow: We’re really excited about this class of drugs. There are actually several drugs in this class. We’re really thrilled with the results of our trial and right now, we have been doing what we call a dose escalation trial. We weren’t quite sure that we could give full doses of the PARP inhibitor with the chemo, we needed to prove that. We are now up at our 9th dose level. We have been able to get it up, actually as high as we had intended to go and our next plan is to take it into a big national trial. We’ve got enough data now showing responses and stable disease. We’ve had patients on some combination of these drugs for years in a few cases now. Now, we are ready to take it nationally and work with a lot of other centers to, to better explore this and hopefully we can get this done quickly so that the patients who do benefit from it, will get access to it.
Should that happen in 2014, do you think?
Dr. Gralow: I think that it will probably be more like two years away.
What do you think the biggest myth, misconception is about breast cancer?
Dr. Gralow: Oh, that’s a vague, a vague question. I hear a lot of people struggle with the issue of the word cure in breast cancer, and I hear we haven’t found a cure yet. I guess that would be a big myth is that we haven’t found a cure yet. Actually survival rates in the United States from a combination of earlier detection and better treatments result in the majority of women being cured. We have found a cure, for a lot of breast cancers. We all still know women who die of breast cancer though, so we haven’t found the cure for every woman and every breast cancer, but we have found a lot of cures, and we need to work a lot harder.
How long have you been treating breast cancer patients?
Dr. Gralow: 20 years.
Is there anything you do differently in your own life that you just, you’ve changed maybe your habits?
Dr. Gralow: Because of treating breast cancer? Well yeah, actually I think the main thing I can tell you that I focus on is a healthy lifestyle. I started seeing breast cancer patients right after I was done with my training and in 1995 we formed a group called Team Survivor Northwest to help our women cancer survivors get more exercise, and I was very supportive of that. I’m the co-founder, I’m still the medical director, but I, myself, was not getting a lot of exercise. I had been in a lot of school and all, and because of Team Survivor, one of my patients, at one of our first events, we were doing a triathlon and I was there to cheer them on and my patient said to me the day before, when we were at the Expo, “Why aren’t you out there with us?” and, I said, “You’re right. I have no excuse. I’m telling you all you should do it, and I should be doing it too.” So, I drove home, got some swim goggles, and then did the triathlon the next day without any training and this is why I’m so supportive of it, is because I crossed that finish line with our team survivor and I have been working with them for two decades almost, ever since, climbing mountains, riding bikes, doing running. I’m running the New York Marathon this weekend.
END OF INTERVIEW
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