OR WAIT null SECS
As part of its coverage of SABCS, the cancernetwork.com spoke with C. Kent Osborne, MD, who is the director of both the Lester and Sue Smith Breast Center and the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston.
As part of its coverage of SABCS, thecancernetwork.comspoke with C. Kent Osborne, MD, who is the director of both the Lester and Sue Smith Breast Center and the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston. He is also professor of medicine in cellular and structural biology at Baylor. Dr. Osborne sat on the executive committee for SABCS this year, and discusses not only his own research, but also the year in breast cancer and what were the most exciting advances we've seen in 2011. To listen to a podcast of the complete interview, go tocancernetwork.com.
CANCERNETWORK: Dr. Osborne, what, in your opinion, is one of the most exciting results that we will hear about at the meeting?
C. KENT OSBORNE, MD
DR. OSBORNE: First of all, the results of a large randomized trial known as the CLEOPATRA trial in patients with metastatic breast cancer. This trial, along with several others reported earlier this year, looks at a combination of drugs that block HER2. HER2 is a cause of the cancer in about 20% to 25% of breast cancer patients. We have made excellent progress in blocking that pathway, but still, some patients are resistant. What we're discovering based on studies presented earlier this year and those presented at the San Antonio meeting; we're going to find that a combination of drugs to more completely block the pathway is superior to the old standby, which is Herceptin [trastuzumab]-which has, itself, made a big impact in survival for breast cancer in patients with this kind of breast cancer. We're seeing a more effective regimen with the combination of other drugs that also block the pathway, and we will see the results of the CLEOPATRA study that hopefully will continue to show this result.
CANCERNETWORK: Can you give us a sense of how many patients become resistant to Herceptin?
DR. OSBORNE:Let's look at the adjuvant setting-that is, getting chemotherapy or other hormonal therapy or Herceptin after surgery-in patients where there is no evidence of disease. These are aggressive tumors; they metastasize early and patients recur soon. Chemotherapy itself is quite effective in these tumors, and the use of chemotherapy reduced the risk of recurrence by about half in these patients.
Let's say a woman presented with a HER2-positive breast cancer and had several positive lymph nodes. That person's chance of recurrence in 10 years might be 60% to 70%, but chemotherapy lowered that by half, down to 30% or 35%. Well, the addition of trastuzumab to the chemotherapy lowered it by another half, so with trastuzumab plus chemotherapy, we have converted what is normally thought of as a more aggressive kind of breast cancer into a “relatively good” kind of breast cancer. Still, however, about half of the patients who are treated with trastuzumab develop resistance and will have a recurrence despite its use, so we're now trying to discover why that is. And we have some pretty good ideas-one of which is that HER2-targeted therapy with Herceptin only partially blocks the HER2 pathway and that more complete blockade with multiple drugs seems to be a better way of doing it.
CANCERNETWORK: Do you think combination therapy, across the cancers, will result in better outcomes? Do you feel that combination therapy of Herceptin added with another drug with be the standard of care for all HER2-positive patients in the future?
DR. OSBORNE: Yes. But the question is: which combination? There are several that people are looking at. The CLEOPATRA study is using Herceptin combined with a drug called pertuzumab. There are other combinations reported that are very exciting, such as Herceptin combined with lapatinib, and there is a very large adjuvant trial going on now, and accrual to the trial has just been completed. It's known as the ALTTO trial and it's comparing lapatinib by itself, trastuzumab by itself, and the combination of lapatinib plus trastuzumab. When that result comes out, if I had to guess I would say that the combination of lapatinib and Herceptin plus chemotherapy will prove to be a lot better. I'm going to guess that it's also going to be better when it's used in the adjuvant setting, but that remains to be seen.
I think that when that study comes out, if it's positive, yes, lapatinib and Herceptin will become the standard, but then there's the issue of whether some of these other combinations might be just as good or better, or less toxic, and that's what people are trying to work on now.
CANCERNETWORK: Thinking about the continuing challenge of detecting and treating breast cancer, what has been one of the biggest successes in your mind in 2011, in either detection or treatment?
DR. OSBORNE: I would say that there are two things. First, another trial has been presented, but I don't think it's been published yet, and that trial looked at another way of preventing breast cancer with the use of a drug called exemestane (Aromasin). Of course, tamoxifen is an anti-estrogen that has been shown to reduce the risk of breast cancer in high-risk individuals by about half. Well, this exemestane drug works by lowering the amount of estrogen in the body in postmenopausal women, so that's another way of treating breast cancer. In this trial, they compared exemestane vs placebo, and exemestane was also highly effective, so this demonstrates how important estrogen is in causing breast cancer or contributing to it. In this study, I think there was a 70% reduction in the risk of acquiring breast cancer.
The biggest problem we're having in the area of breast cancer prevention is in getting high-risk individuals to use drugs like tamoxifen or exemestane. I think the second big thing is the clear demonstration now, in multiple studies, that combining drugs to block HER2 works better than any drug alone, for example trastuzumab or lapatinib. The next question of course is, do we really need chemotherapy in these patients? In a study that our group presented at ASCO this year, we didn't use chemotherapy. It was a neoadjuvant study, so we could detect how much the tumor shrank, and 12 weeks of lapatinib plus Herceptin resulted in 40% total eradication of the invasive breast cancer from the breast without any chemotherapy at all. So there is probably a group of patients with HER2-positive breast cancer-maybe as many as 40% to 50% of them-who don't need chemotherapy. This remains to be proven in large trials, but the data seem to indicate that we're getting almost as good a result just with the combined HER2 blockade as we are with our combined HER2 blockade plus chemotherapy. I'm certain that there is a group of patients who can be treated with this targeted therapy alone. Now the question is, how can we identify them ahead of time and spare them the toxicities and costs of chemotherapy?
CANCERNETWORK: Not using chemotherapy-is this something that is going to be part of a session at the San Antonio meeting?
DR. OSBORNE: Not much, but I'm going to mention it briefly in my discussion of three papers that will be presented at the meeting on HER2-targeted therapy. On Friday, there is a study looking at a new HER pathway inhibitor called neratinib, and then there is the CLEOPATRA study. There's also another study looking at the combination of Herceptin plus pertuzumab and at different chemotherapy regimens to determine how tolerable the regimens are. I'll be discussing that, and one of the questions I will raise is, do we really need chemotherapy in all patients or is there a subset who may not need it? But because those studies were presented at either ASCO or last year at this meeting, it's not going to be a major discussion point until additional data come out.
CANCERNETWORK: We know that it takes an understanding of both the biology and the pathways involved in breast cancer to effectively diagnose and treat the disease-and the SABCS puts an emphasis on allowing communication between clinicians and basic researchers. Could you describe how this came to be a critical aspect of the symposium?
DR. OSBORNE: Yes. The story involves Bill McGuire and Charles Coltman, who are the co-directors of the division where I first started my career in 1977 at the University of Texas Health Science Center at San Antonio. The three of us started this symposium way back then, and initially it was just a symposium for the local cancer doctors, a sort of educational meeting, but then we decided that we should bring in some science and requested that people submit abstracts and asked them to present their research data at the meeting. It was Bill's philosophy back then, and I guess I inherited it when I began to take over the meeting as director in 1992-it was the idea of translational research, which is doing research in the laboratory that can be directly translated to improving patient care. Bill might have been one of the first translational researchers for any disease, before the term was even coined.
Bill always believed that the meeting should include basic science and clinical science, and that these two different types of research should all be presented in the same room, not in separate rooms, so that the clinicians would have a greater understanding of the biology of the disease and the basic scientists would have a greater understanding of the challenges in the clinic. I think that's been a very successful approach, and in fact, although there is an occasional clinician who says, “Gee, I'm bored by the basic science,” or a basic scientist who says, “Gee, the clinical stuff doesn't have any relevance to me,” the great majority of the people have liked this format. You sit in one room and you hear about biology and you hear about the results of clinical trials. I think that cross-fertilization has been very good. We were probably doing that earlier in many ways, but now it's mandatory because now our treatments are all based on knowing the biology of the disease and knowing what pathways are driving the cancer and what could be the escape pathways, when the tumor outsmarts us, to get around the drug that we're using. One has to know the biology of the disease now, so we're going to keep this format of having biology and clinical medicine presented at the meeting together.
As part of its coverage of the ASH meeting this year, thecancernetwork.comspoke with Andrew Evens. Dr. Evens presented an oral abstract at ASH entitled “Lymphoma in Pregnancy: Excellent Fetal Outcomes and Maternal Survival in a Large Multicenter Analysis.” We discussed his research with him, and the issue of fertility preservation across the cancers.
Andrew Evens, DO, MSc, is the deputy director for clinical and translational research, and medical director of the Clinical Research Office at the University of Massachusetts Memorial Health Care Cancer Center of Excellence. He is also associate professor of medicine and leads the lymphoma program at the University of Massachusetts Medical School. To listen to a podcast of the complete interview, go tocancernetwork.com.
CANCERNETWORK: Can you start by telling our audience a little about the study?
ANDREW EVENS, DO, MSc
DR. EVENS: Yes. It was a retrospective study, as this is somewhat of a rare entity-not that lymphoma is rare, it's approximately the sixth most common cancer, but its actual occurrance during a pregnancy is relatively uncommon. Cancer of any type occurs in approximately 1 in every 1,000 gestations, or pregnancies, but of course there are many thousands of pregnancies that occur every year in the US. This means that, each year in the US, approximately 3,000 to 3,500 pregnant women will have some form of a cancer diagnosed. The most commonly diagnosed cancer is breast, but the second most common are hematologic malignancies, of which lymphoma is the most common.
When you distill it down to just lymphoma, there are probably a couple hundred cases diagnosed during pregnancy in a year. I'm a lymphoma specialist at U Mass; we're a relatively tight-knit community across the US and we all deal with this. We might have a handful of these in total-a couple of cases a year. However, when it's a rare entity, there's not as much published data in the literature to guide even us specialists, much less for physicians out in the community when they see these cases. For these reasons, there were 10 different centers that came together at the same time and said, “Can we put together our collective experiences and try to help guide, not only ourselves, but treating oncologists across the world?”
CANCERNETWORK: Can you tell us a little about the methods and the results of the study?
DR. EVENS: Again, it was a retrospective analysis but we had a definite design to the study: we collected different information that we wanted to identify and we all worked from the same template of questions to be asked. The study only included cases where a lymphoma occurred during the pregnancy-but at any time during the pregnancy. Then we wanted to determine, what type of lymphoma was diagnosed, how the patient did, and were they treated or were they not. The study included multiple centers: Stanford University, Miami, Fred Hutchinson, University of Nebraska, Roswell Park, Northwestern University, Mayo Clinic, and Washington University-and lymphoma leaders from each. Across all of these institutions, we were able to come up with 90 total cases, which is pretty remarkable because if you look at the data that're published right now-cases of actual lymphoma during a pregnancy-the largest was Hodgkin's disease (HL), with 10 cases, and the number is about the same for non-Hodgkin's lymphoma (NHL), so we're really pleased in a way that we were able to come up with that many cases.
It was mainly a descriptive analysis, describing the different types of lymphoma, but by extension we also looked at outcomes. Everyone was IRB [Institutional Review Board]–approved, throughout the institutions. Initially we put all our data together and we had 90 cases-but we had to exclude 8 because either there was insufficient information for them or the actual diagnosis did not fit our pre-defined definition for them. Obviously the diagnosis had to occur during a pregnancy, and a couple of these had occurred after or before. The final data set was 82 cases. The median age of patients was 31, but the range of patients was 18 through 40. We then looked at the median time of diagnosis, in terms of weeks of gestation-gestation is usually 40 weeks-and diagnosis occurred at a median of 24 weeks, and the range was anywhere from 5 weeks, up until the 40th week of pregnancy.
The majority, 46%, were in the second trimester of pregnancy, with the next most common time of diagnosis in the third trimester. In this pool of patients, there were 43 cases of NHL and 39 cases of HL. Then we distilled it down even further, because within NHL there are many different subtypes, so of those 43 cases of NHL the majority were the more aggressive lymphomas-most notably, diffuse large B-cell lymphoma-but there were some T-cell lymphomas, which are also aggressive. For HL, there aren't as many subtypes, but the most common subtype was nodular sclerosis.
Obviously this was a retrospective report, so therapy had happened in the past-everything was at the discretion of the treating physicians at the time. There were questions like, should everyone have a bone marrow biopsy, what kind of scanning should we do-because certainly you have to be more sensitive to what kinds of radiation you use, and even the CT scanning is controversial. The most common imaging modality in these patients was an MRI, because that doesn't have classic radiation used with it; however, there are still some concerns, in particular with the contrast. We found that two-thirds of the NHL patients had advanced-stage, and half of the HL patients had advanced-stage-the rest had early-stage disease.
One other interesting thing that we found: obviously when women are pregnant they should gain weight, but in the study we found that the median weight gain was only 3%. The common presentation of lymphoma is weight loss (weight loss is classified as a B symptom), so obviously the weight gain in this group was relatively low compared to that of the healthy population. They didn't lose weight, but they didn't gain much, and that was an interesting finding.
Now I'll move on to the treatment of the patients. There were a few cases that occurred very early in the pregnancy, during embyrogenesis, when all the organs of the human body are being formed. I think most people would agree that it's pretty tricky to give chemotherapy during the first trimester, and there would be a risk of malformations and other problems. In total, there were five patients in the first trimester, and one patient very early on, who had termination of the pregnancy because they had aggressive lymphomas and needed to start immediate chemotherapy. That left us with 76 patients, and of course treatment was dependent on what was actually going on at the time, but therapy was actually deferred in 28 of the patients who were diagnosed at a median of 34 weeks. For these patients (who were asymptomatic) the therapy was deferred, then they delivered and then started therapy. But 63% of patients (48 patients) did start chemotherapy during pregnancy. When we look at these 48 patients, they were diagnosed at a median of 25 weeks, so understandably the treating physicians said “we cannot wait 2 months, the lymphoma could progress, it could be fatal, so we have to start treatment.”
There are data in the literature (albeit, as I mentioned, really only in case reports) that it is relatively safe for certain chemotherapies to be given-ones that are not antimetabolites, like methotrexate. Therapy was given in these 48 patients and it was really the classic, standard therapy. In Hodgkin's disease, it was often a common regimen known as ABVD [doxorubicin, bleomycin, vinblastine, dacarbazine], and for diffuse large B-cell, it was rituximab [Rituxan] with CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone].
Our hypothesis was that chemotherapy would be tolerable for the patient and that fetal outcomes would be good-and it was tolerated really well: we saw no differences in toxicity or side effects in the women themselves. I should say that every single case was co-managed with high-risk maternal fetal medicine, and the goal in working together, even in cases where chemotherapy was started early, was to carry the baby to term, to try to get it beyond 36 weeks because you want lung maturation to be able to take place. In 85% of cases, the pregnancy did last beyond 36 weeks. We also analyzed any perinatal complications, and we saw a relatively low risk of pre-eclampsia and other complications, relative to pregnancies that were not associated with lymphoma.
When we looked at birth weights of the infants, from the cases that received chemotherapy vs cases that did not receive chemotherapy, they were the same, and in all the cases, there were no malformations that were detected.
Finally, what we saw was that the outcomes were pretty good. The outcomes for diffuse large B-cell and Hodgkin's disease were similar to those that might occur if the patients were not pregnant. We divided it between B-cell lymphoma, in which the 3-year overall survival was over 80%, while in HL the 3-year overall survival was over 90%. For T-cell lymphoma, which is a more aggressive entity, it was a little bit lower, but the main point is that these outcomes appeared pretty consistent with non–pregnancy-associated lymphoma outcomes.
CANCERNETWORK: Thanks. You actually answered many of my questions within your description of the results.
DR. EVENS: That was my goal-to give a long-winded answer so there would be very few follow-up questions!
CANCERNETWORK: Well I do have one more! I know that fertility preservation is becoming a bigger issue across the cancers, after treatment. Can you talk a little about how lymphoma survivors fare in terms of preservation of fertility?
DR. EVENS: At least in the context of this study, that was a very tricky issue because they were all actively pregnant. But with more of a 30,000-foot view, it definitely is an issue in cancer survivors, both men and women. Especially for anyone who is at a child-bearing age, we absolutely want to have that discussion.
The risk of infertility is based on a couple of things; first, the age of the patients and especially women. Obviously, the greater the age of a woman, the greater the risk of infertility even without chemotherapy. The other variable for determining risk of infertility is the type of chemotherapy used. There are certain chemotherapy regimens, for example the one I mentioned for HL, ABVD, where the resulting risk of infertility in women younger than age 30 or 35 is in the single digits-probably in the range of 1% to 3%. But there might be a more aggressive chemotherapy regimen, say hyperCVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone in course A; methotrexate, cytarabine in course B], or the MCGRATH chemotherapy, or a regimen called BEACOPP [bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone], and these are the more aggressive chemotherapies where the risk of infertility-both in men and women-might be anywhere from 30% to 80%.
So there are some lymphomas where there's really a “grade A” standard therapy regimen, and we know that if we vary from that regimen, the survival will drop. So we usually don't vary, and instead we say “what can we do to preserve fertility?” For men, there's obviously sperm banking, and for women there certainly is ovarian harvest, but that usually has to be in the context of in vitro fertilization. In other words, they need to have a partner to immediately fertilize the egg. Outside of that context, unfortunately ova cannot be frozen alone, like sperm can. However, there are experimental protocols, clinical trials that are looking at how to preserve them-there are active fertility programs that are analyzing breakthrough techniques to try to make this possible.
So as you can see, fertility preservation is dependent on both patient and disease type, but it's definitely an important discussion to have.