June 2005: Updates from ASCO 2005

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Herceptin okay to take alone after chemo?

Question from Gina: I heard about Herceptin for early stage HER2-positive disease with chemotherapy. What about for those who are early stage HER2-positive who have completed chemotherapy? Is Herceptin now being recommended to be taken alone and if yes, for how long?

Answer —Hope Rugo, M.D.: That's a very good question. However, I think it's a short term question, as women who are starting treatment today or are currently on treatment will get Herceptin. Women who have completed treatment within six to 12 months can reasonably be offered Herceptin. I would not give more chemotherapy in order to give the Herceptin with chemotherapy.

I think a reasonable approach would be to give Herceptin every three weeks for one year. The only exception would be a patient who had very early or low risk disease. If a woman has a very small tumor that is hormone-receptor positive, they would not have qualified for any of the adjuvant trials. We don't know if the addition of Herceptin is helpful because the risk of recurrence is very low and there are side effects from Herceptin. When you balance it out, the risk vs. benefit ratio may not be towards benefit.

MUGA tests show heart damage from Herceptin?

Question from KathyM: I am in a Herceptin clinical study and have had a number of MUGA tests. I was at 58% at the start and after three treatments at 49% and now five months later at 50%. I'm not having any negative side effects and want to continue for the second year. Do you think that this percentage may continue to go up, or does it show that my heart is being damaged and I should pull out of the study?

Answer —Hope Rugo, M.D.: It sounds like your ejection fraction is relatively stable, but it depends on the clinical trial and the stage of your disease. It appears that most, but not all of Herceptin heart toxicity is reversible.

Updates on vaccine trials for HER2-positive?

Question from NitaZ: Do you have any information about the ongoing clinical trial for the past five years that is using a vaccine to stop recurrence of HER2-positive breast cancer? You must have a HLA-2A blood type for this vaccine to work. I heard that the Joyce Murtha Breast Care Center in Pennsylvania is running this trial. Thank you.

Answers —Hope Rugo, M.D.: There are a number of vaccine trials going on. Many of these trials are focusing on patients who have either specific kinds of breast cancer, like HER2-positive breast cancer and/or patients who have an immune type that can be used to target the vaccine, like HLA-2A. To date, there are not any efficacy results from these studies. It would be reasonable for a patient with a very high risk or with advanced breast cancer to consider participating in one of these trials. Overall, vaccine studies to date have been disappointing in the treatment of cancer, but it may be that by better understanding the immune response, we will improve these results.

Jennifer Armstrong, M.D.: Dr. Rugo's points are quite well made. For anyone interested in how to access trials anywhere in the country, there is an excellent website at NCI.

Hope Rugo, M.D.: This is a very important resource for patients - www.cancer.gov. The clinical trials home page is www.cancer.gov/clinicaltrials That website also has information about cancer and clinical trials in general. One other helpful website is the National Comprehensive Cancer Network at www.nccn.org.

AIs and chemical ovarian ablation?

Question from Jastafford: Can you talk about the use of aromatase inhibitors in premenopausal women who have received chemical ovarian ablation?

Answers —Hope Rugo, M.D.: There are two settings where this could be discussed and considered for treatment - one is for the treatment of metastatic breast cancer and there have been data published that suggest if patients receive chemical ovarian ablation (ovary shutdown) and truly have suppression of estrogen production, that aromatase inhibitors can be very effective. In premenopausal women who have early stage breast cancer, this is a research question.

There are three large international trials looking at ovarian suppression with either tamoxifen or an aromatase inhibitor or in one trial, tamoxifen alone. At the moment, the standard of treatment in terms of hormone therapy for premenopausal women with early stage breast cancer is tamoxifen. However, these trials are very important and will help us answer the question about how much additional benefit might be gained when ovarian suppression is added to standard chemotherapy and hormone therapy.

There is a trial ongoing in Austria that is looking at ovarian suppression for three years with either an aromatase inhibitor or tamoxifen. They're also following bone density to look for osteoporosis. They have already shown that ovarian suppression with either tamoxifen or an aromatase inhibitor causes significant loss of bone mineral density. However, this can be prevented with the use of the bisphosphonates or medication that helps to preserve bone density. For an individual woman who is on ovarian suppression, the choice of tamoxifen or an aromatase inhibitor should be made in discussion with her oncologist.

It is very important that ovarian suppression is confirmed by serial testing of the blood for estrogen as, in particular for young women, even monthly injections may fail to sufficiently suppress the ovaries or it may take more time than expected to suppress the ovaries.

Jennifer Armstrong, M.D.: I just want to review some of the terminology we're discussing. As Dr. Rugo just elegantly described, premenopausal women with hormone receptor positive breast cancer are candidates for one type of hormonal therapy now, and that is tamoxifen. Postmenopausal women with hormone receptor positive breast cancer can benefit from several different types of hormonal therapy which includes either tamoxifen or aromatase inhibitors.

There are ongoing investigations to see if premenopausal women are made postmenopausal by suppressing their ovarian function, whether these women receive similar benefit with aromatase inhibitors as women who have gone through menopause naturally. This is what is called “chemical ovarian ablation.”

Developments on prevention for BRCA2?

Question from Lhz: Are there any new developments in cancer prevention for women with the BRCA2 mutation?

Answers —Hope Rugo, M.D.: There is a fair amount of work being done looking at specific pathways for women with the BRCA2 mutation. The first studies in this area will probably involve treatment as opposed to prevention. The prevention areas are really still looking at hormone therapy and in particular considering the use of aromatase inhibitors.

One study called the APRIS study is looking at postmenopausal women with no previous breast cancer history who have the BRCA mutation, studying the use of aromatase inhibitors in that population of patients. In addition, there is a body of literature that shows that ovarian suppression usually in the form of prophylactic oophorectomy (ovary removal) reduces the risk of subsequent breast cancer by 50%.

There is interest in causing ovarian suppression, then adding back a low level of hormones to avoid the side effects of early menopause in younger women. Even women with the BRCA mutation will still benefit from an oophorectomy by the age of 35 with a 50% reduction in their risk of developing breast cancer.

In terms of scanning, MRIs have been very interesting. The problem with these tests is the high incidence of false positives. However, for women with the BRCA mutation who have breasts, screening MRIs have slightly more benefit than risk. The first MRI scan is most likely to be positive, so the number of scans necessary is not at all clear. Yearly scans are likely too frequent, but that remains to be seen. The field of statins is also interesting in prevention. This is an area of interest for BRCA carriers as well.

Jennifer Armstrong, M.D.: That's a great point in that most of the preventive measures have been relative to BRCA1 and 2 carriers. To my knowledge, there have not yet been specific recommendations for carriers of one mutation as opposed to the other.

Low-fat diet, statins have impact on DCIS?

Question from Kdg: Do the low-fat diet and statins have any impact on DCIS?

Answers —Hope Rugo, M.D.: There are two streams of data available now. First, the low-fat diet that was studied in the WINS trial where just the initial data were presented. This suggested that low-fat diets or weight loss reduced the risk of recurrence from early stage breast cancer when appropriate systemic therapy was also given. In other words, women on the WINS trial were required to have received standard adjuvant therapy for their cancer. The WINS study showed a greater effect from a low-fat diet in women who are estrogen receptor negative. This data and information remains to be clarified with further follow-up from women on the trial.

Other studies have looked at low-fat diets and suggested similar results. And a recent study showed that moderate exercise also appears to reduce the risk of recurrence from early stage breast cancer.

There haven't been any studies yet, though, looking at statins as a treatment for women with invasive cancer. They just looked at women who took statins by prescription, and did not look at family history or hormone replacement therapy. It was suggested from that data that taking statins for at least four years reduced the risk of recurrence in a population of women who had a low incidence anyway. It would be expected that exercising and keeping one's weight controlled would likely be a net positive benefit, not just for DCIS but for general health as well. In terms of statins, this is being investigated. We don't have any data where we've given statins to some women and placebos to the others.

At my institution, Dr. Laura Esserman is studying the biologic effects of statins in women with DCIS. Women receive two weeks of statin therapy before their surgery for DCIS and then the biologic changes in the DCIS are studied in the tumor that is removed. Hopefully this data will be used on a national basis to look at the effect of statins on women with DCIS.

Jennifer Armstrong, M.D.: As one of my patients said to me in the office yesterday, “You mean now I really do have to renew my membership to my gym?”

Tamoxifen vs. raloxifene? Effects of folic acid?

Question from Abiola: Here in Nigeria we are given blanket treatment due to lack of facilities. Can you tell me first, should cancer survivors take folic acid? Second, what are the research findings comparing tamoxifen and raloxifene (Evista)? No doctor here is able to give me an answer.

Answer —Hope Rugo, M.D.: Folic acid is an important vitamin, but as far as we know, has no impact on survival or recurrence after a diagnosis of cancer. It is occasionally used to offset the effects of cancer chemotherapy. Tamoxifen has been shown to have significant impact on recurrence, reducing recurrence by up to 50% and the effects can last for up to 15 years after treatment. Raloxifene (Evista) has never been used in clinical trials and should not be used to treat breast cancer. The only usage is in the field of prevention. Prevention is a very different effect than treating early stage breast cancer. Tamoxifen is the standard of care, and, in postmenopausal women, an aromatase inhibitor is also used.

Does exercise have impact on recurrence?

Question from Roxanne: The Nurses' Health Study found that breast cancer patients who do other kinds of moderate exercise for 3 to 5 hours a week are about 50 percent less likely to die from the disease than sedentary women (especially if their tumors were hormone sensitive). Is this because physical activity lowers hormone levels? If I am on tamoxifen and am postmenopausal, how much of an impact on cancer recurrence would moderate exercise have?

Answers —Hope Rugo, M.D.: Women who are on the Nurses' Health Study received standard therapy. In fact, the answer to your question is not known definitively, but the theory is that women who exercise have a lower body mass index—in other words, they're thinner, and may have lower circulating insulin levels. We know that fat stores estrogen, so it may be that the effect is to reduce estrogen stored in tissues and the amount of estrogen that's produced. Or it may be several different effects that we don't yet fully understand.

I believe that moderate exercise is an important part of any person's life. But now, based on this data, it's clearly important for women who have had early stage breast cancer, regardless of their use or not of hormone therapy. So one would expect that moderate exercise would reduce risk of recurrence along with use of standard therapies like tamoxifen.

Jennifer Armstrong, M.D.: I totally agree. I've been talking with my patients about the increasing evidence for a regular exercise program for further risk reduction in recurrent breast cancer.

Saturated fats related to breast cancer?

Question from Blittle: Regarding the benefits of the low-fat diet: First, was there a distinction between animal (saturated) fat and fats like olive oil and oils from nuts, and second, how much of the benefit might be related to eliminating the hormones, antibiotics, and pesticides that may be concentrated in animal fats?

Answers —Hope Rugo, M.D.: The diet that was used in the WINS trial specified the daily caloric intake from fat. The goal was to get down to 15%, but they only achieved about 25%. They did not specify which type of fat to use. If hormones and pesticides in food play a part in developing breast cancer, I would expect the latency period (the time it would take for effects to show in the body) would be quite long. So although that may contribute to reducing risk, I don't think it would have been the primary factor in reducing hormone receptor negative cancer in the WINS trial.

Jennifer Armstrong, M.D.: Everyone is asking really great questions that are pushing the envelope of what we know. Many of these issues remain unanswered, and are exciting areas for future investigations.

Dose-dense adjuvant therapy benefits?

Question from RoseB: My doctor told me that dose dense therapy in the adjuvant setting was discussed at ASCO and that no true clinical benefit was observed. Can you comment? Thank you.

Answers —Hope Rugo, M.D.: Dose dense chemotherapy was tested in a randomized trial, and these patients are still being followed. There was a significant benefit in disease-free survival in women treated with dose dense therapy and that is still seen now. Disease-free survival was the primary goal, and dose dense therapy is the treatment given and superior to standard dosing. Data presented at ASCO suggested that dose dense therapy has its greatest effect in patients with hormone receptor negative disease. This is true of all chemotherapy regimens.

There was very preliminary survival data presented at ASCO as well. It suggests that although the degree of benefit of dose dense therapy is the same now as when initially presented, there's a difference due to the way events are calculated by statistics. The statistical significance is just below par. This does not mean that the regimen is not effective, nor does it change the data originally presented. In addition, longer term follow-up has approved the safety of dose dense treatment and allows chemotherapy to be given over four months instead of six months.

In the future, we will be able to choose therapies based on biologic characteristics of the tumor, as it is clear that some cancers will benefit more from either dose dense therapies or more aggressive regimens than others, but we do not yet have the ability to make those decisions. Therefore, I think dose dense therapy is still a very reasonable and well tolerated adjuvant therapy for women and is superior to every three week dosing when using Adriamycin and Cytoxan, followed by Taxol. (chemical names: doxorubicin, cyclophosphamide, paclitaxel)

Jennifer Armstrong, M.D.: I completely agree.

Taxotere and Xeloda effective together?

Question from Jamie: What are the indicators Taxotere and Xeloda are working for Stage IV breast cancer?

Answers —Hope Rugo, M.D.: Taxotere and Xeloda (chemical names: docetaxel and capecitabine) is a combination that is very effective treatment for metastatic breast cancer. We don't yet know what the best combination therapy is, or in what situation combination therapy would be better than sequential single agent chemotherapy. This particular combination has to be used with caution because of the risk of skin toxicity from Xeloda, but it is very effective treatment with a higher response than single agent treatments with Taxotere.

For some people, the higher response is worth the side effects of the combination. For other patients, survival is identical when given Taxotere first or Xeloda first followed by the next chemotherapy when their cancer progresses. I use combination therapy only for more resistant disease. Another very effective combination is Taxotere and gemcitabine (Gemzar) for early stage breast cancer to see whether potentially improved response might translate to improved outcome for women with curable disease. For treatment of women with advanced breast cancer, toxicity always needs to be a consideration and if it is not clear that a treatment that is more toxic will improve survival, the treatment needs to be used very judiciously.

Jennifer Armstrong, M.D.: I'm so glad that Dr. Rugo brought up the issue of combination chemotherapy vs. sequential single agent chemotherapy. I too tend to favor sequential single agent chemotherapy in the metastatic setting to minimize toxicity while still optimizing benefits. And in another situation in which combination chemotherapy is considered not only in resistant disease but when there is a need for a rapid response, Dr. Rugo's comments on specific toxicity profiles are quite important.

Trials prove Avastin effective?

Question from Clazz: Has Avastin proved effective for liver metastases? Is it in a trial phase? Who is administering the trial?

Answers —Hope Rugo, M.D.: Avastin (chemical name: bevacizumab) was studied in combination with Taxol and treatment for metastatic breast cancer in women who had not yet received chemotherapy for metastatic disease. In that trial, it appears that the response to Taxol was doubled by adding Avastin. The response lasted twice as long in the patients who got Avastin compared to those who got Taxol alone.

There is a suggestion from that study that the patients who got Avastin might also be living longer, but the data is still very early. Patients on this trial had the disease in various places, and many had disease in the liver. So it would be expected that some patients with disease in their liver would have a response to Avastin given in combination with Taxol.

Whether or not this combination is effective in women who have already received treatments for metastatic breast cancer remains to be seen, and there are a number of trials that will be started in the near future because of the excitement over the data you have mentioned.

Jennifer Armstrong, M.D.: One of the discussions at ASCO was while we do not yet know how much Avastin might add to other regimens (and as Dr. Rugo mentioned, we don't yet know how it might add to second or third line regimens), it was suggested that the data is persuasive for patients with newly diagnosed metastatic breast cancer initiating first line therapy. To my knowledge, Avastin is not yet FDA approved in this use. May I ask, Dr. Rugo, if you had a patient with metastatic breast cancer in whom you were starting first line therapy with a taxane, are you currently using Avastin?

Hope Rugo, M.D.: I have used Avastin where women are not eligible for treatment on a clinical trial, or have had a poor response to initial therapy. The problem at present is that Avastin is very expensive, and until we have more data telling us exactly how to use this agent in breast cancer, it will be hard to use the drug routinely in all women as first line treatment of metastatic breast cancer.

However, I have had some patients on trial with Avastin who have had good and long-term response so I already had experience in using the agent, which helps. Oncologists specializing in breast cancer in the U.S. are talking continuously about how we are designing the next line of studies that will expand on the use of Avastin for both early and late stage breast cancer. This will help us to understand which patients are most likely to benefit from this treatment.

Jennifer Armstrong, M.D.: It really is a very exciting time. One thing we didn't mention above was that in addition to relying on evidence-based medicine, FDA approval is needed to reform reimbursement. So there can be problems with payment and reimbursement when using Avastin off-protocol for breast cancer. These are important issues to identify.

How long to take aromatase inhibitors?

Question from Wizzy: Any research results on how long to take aromatase inhibitors?

Answers —Hope Rugo, M.D.: The standard length of treatment with hormone therapy (tamoxifen in the past) was five years. The aromatase inhibitor trials in the adjuvant setting have looked at 5 years of hormone therapy. This is a total of five years whether patients start with an aromatase inhibitor or whether they switch after two or three years of tamoxifen.

There is one study that looked at continuing hormone therapy with an aromatase inhibitor after 5 years of tamoxifen and showed very striking results in reducing recurrence. However, we don't have data on women who took five years of aromatase inhibitor after diagnosis.

Until we have better information on length of therapy, aromatase inhibitors should be stopped after five years, as we don't have evidence on possible risks or benefits to their cancer after this length of time. The story is different if you start with tamoxifen. A women who has taken five years of tamoxifen who is going to Letrozole (Femara) as extended therapy could continue this therapy anywhere from three to five years. But only about 1,200 women made it to four years before the study closed.

Jennifer Armstrong, M.D.: So if a woman starts with tamoxifen for two years, you would discontinue the aromatase inhibitor after five years?

Hope Rugo, M.D.: Yes, this is different than a woman who received tamoxifen for five years and then is switched to an aromatase inhibitor. In this latter situation, an aromatase inhibitor may be considered for anywhere from two to five years.

Long-term use of Xeloda effective for metastases?

Question from VickiG: I have just been diagnosed with metastatic breast cancer in my lungs, liver, and bones. I have just started Xeloda. This is the third time I have had cancer in three and a half years. I did chemo, radiation, removed my ovaries and was on tamoxifen until recently. I am 45 years old. I am not a candidate for Herceptin. Can you tell me about long-term use of Xeloda? Are they seeing good results?

Answers —Jennifer Armstrong, M.D.: Let me say, Vicki, it sounds like you've been through quite a lot. It is also important to note how many treatment options we and you now have. I think Xeloda is a great drug, and have seen wonderful results. Dr. Rugo talked earlier about some of the side effects of Xeloda among which most notably to patients are often the “hand-foot syndrome” (tenderness and peeling of the palms and soles).

That being said, there are some excellent treatments to help manage that side effect, including things as simple as good emollients or hand creams for both the palms and soles. Your doctor may have talked to you about Bag Balm, and I've had patients rave to me about Kiehl's cream as well as wearing comfortable, loose-fitting shoes, etc. I of course would have to know the details of what you have received in the past to know what else remains available to you in the future, but I am optimistic that Xeloda might be an excellent option for you for quite some time.

Hope Rugo, M.D.: I use a lot of Xeloda - it's a great agent, and hair doesn't fall out. I've had patients on it for long durations in some cases. Sometimes the side effects can be reduced by giving the drug in a one-week-on, one-week-off schedule as opposed to the usual two-weeks-on, two-weeks-off schedule.

We're getting a study going that will look at nicotine patches to reduce the toxicity seen with Xeloda because making the small blood vessels smaller might help. But even with that, this is a great agent to use for treatment of cancer. I would suggest for a woman in your situation that you discuss available clinical trials with your oncologist at every change of treatment. Participation in the right trials for you may expand your treatment options. The number of treatment options that are available have improved the life and quality of life for women with metastatic breast cancer.

Future of targeting genes?

Question from Lynn: Are there any other oncogenes that will likely become targets for treatment in the near future?

Answers —Hope Rugo, M.D.: Oncogenes are genes, so you're talking about targeting genes. We often target the product of the gene, rather than the gene itself; for example, the gene product targeted by Herceptin is HER2. A gene product targeted by Avastin is VGFR.

In terms of the genes themselves, there has been a lot of interest in blocking genes from being able to make a product. So far, that work has been complicated by the ability to reach and block the gene. More work is going on in that area, but we don't have any clinical results yet. We need to understand what the right genes are to block in breast cancer. The way we're going to find that is by understanding the genetics of tumors. The way we're doing that is by getting biopsies during treatment in women who are getting chemotherapy before surgery, which is known as neo-adjuvant therapy.

Jennifer Armstrong, M.D.: There will surely be other targets revealed that we will learn to manipulate to better control and/or prevent cancer in general and breast cancer in particular. It's an exciting time, and we look forward to these future revelations.

Clinical trials for IBC specifically?

Question from Peggy: Are there any clinical trials going on that look at only inflammatory breast cancer?

Answers —Hope Rugo, M.D.: Yes, there are trials in the US looking at inflammatory breast cancer at a variety of different sites. Some information on those studies can be accessed at the NCI website mentioned earlier.

For women with inflammatory breast cancer that has metastasized or recurred, there are no clinical trials focusing on the history of inflammatory breast cancer. It falls under the category of women who have recurrent disease in general. We are recognizing that many women with inflammatory breast cancer have disease that is HER2-positive and there is interest in trying to treat the HER2- negative inflammatory breast cancer as well. We are designing a study with many collaborators including the University of North Carolina that will focus on women with hormone receptor negative and HER2-negative breast cancer and I suspect many of these women will have had inflammatory breast cancer.

Jennifer Armstrong, M.D.: The issue of treating inflammatory breast cancer distinctly touches upon an evolving understanding that we are gaining of breast cancer. In fact, we are beginning to understand that there are probably many different types of breast cancer. As we gain more insight into the different patterns of expression and behavior of these distinct entities, we hope to gain better insight into more effective treatment options. This will be particularly important in tumor types that behave aggressively.

Soy safe even with phytoestrogens?

Question from Miriam: I am concerned about phytoestrogens and have been eating a lot of soy prior to my diagnosis in December. I know that soy has a lot of health benefits and was wondering if it is still safe to eat even though it has the phytoestrogens.

Answers —Hope Rugo, M.D.: Yes. You'd have to eat a truckload of it to make any difference. There are nations that eat soy along with rice as a staple, and the incidence of breast cancer is lower in those populations than in us with Western diets. It's obviously due to many factors besides soy, but I believe the amount that we eat cannot possibly have an impact on breast cancer. We have done a trial looking at prevention by the surrogate marker of breast density, and it was very hard for women to take enough soy to get a pharmaceutical dose of phytoestrogens.

Jennifer Armstrong, M.D.: That's very reassuring to hear. I will confess I've been more of a “nervous Nellie” and have advised my patients that they may want to avoid soy. But having heard your perspective, I think I'll be quite a bit more lenient on this one. May I ask your opinion on alcohol intake in patients with breast cancer?

Hope Rugo, M.D.: The alcohol data is much, much, much more robust than data with soy. Drinking more alcohol—and the amounts are not well-defined—clearly increases the risk of breast cancer. So given the recent data on exercise and fat intake in women who have had a diagnosis of breast cancer, I think women should drink less alcohol. Having alcohol every day doesn't appear to be good for you. I think drinking more than two alcoholic drinks per day has a detrimental effect on health.

Jennifer Armstrong, M.D.: Sounds like we agree on this one. I often tell my patients that while alcohol intake in moderation, especially red wine, has been shown to be beneficial to cardiovascular health in the general population, the potential risks of alcohol in women with breast cancer may outweigh the potential benefits.

Any less cardio-toxic, Herceptin-like drugs?

Question from Linda: Are there any new Herceptin-like drugs that are less cardio-toxic (causing cardiac side effects)?

Answers —Hope Rugo, M.D.: There are new Herceptin-like drugs, but we don't have cardiotoxicity results yet. There is a new antibody being tested called pertuzumab, or 2C4. The drug that has had the most testing is an agent that is actually a pill, and the class of drug is called kinase inhibitors. That drug is called lapatinib. There is data that it is effective in HER2-positive breast cancer that has continued to grow despite Herceptin treatment. Clinical trials are evaluating lapatinib in combination with Herceptin, as well as other agents.

Jennifer Armstrong, M.D.: It's great to have Dr. Rugo's cutting-edge knowledge on all of these options. It really is an exciting time and we look forward to adding treatment options for women with breast cancer.

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