June 2006: Updates from ASCO 2006

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Latest news on Tykerb for metastases?

Question from KF: What is the latest news about Tykerb for metastatic breast cancer treatment, especially for brain metastasis? Will it likely be given in addition to Herceptin (especially if Herceptin is still working in the rest of the patient's body) or instead of Herceptin (if/when brain metastasis occurs)? Is there other info or online references about this new drug now?

Answers —Nicholas Robert, M.D.: One of the big news items that came out of the American Society of Clinical Oncology meeting was Tykerb (chemical name: lapatinib). This is a new oral drug, still not commercially available, which is different from Herceptin (chemical name: trastuzumab) and works a bit differently. Trastuzumab attaches to part of the HER2 molecule, whereas lapatinib inhibits an enzyme called tyrosine kinase and inhibits both the HER2 molecule and other molecules called HER1.

At the ASCO meeting it was reported that patients who had metastatic HER2-positive cancer and who had the tumor progress after being treated with trastuzumab in chemotherapy were randomized to be either treated with chemotherapy or chemotherapy plus lapatinib. The patients who got the combination did better with a higher response rate and longer time before their cancer progressed. These results were so impressive that the trials were closed early and what's exciting is that we now have another drug that has targeted tumors that are HER2-positive. The fact that it's oral is also attractive. That's the good news.

In another trial, the patients with brain metastasis were treated and the hope was this would get into the brain. The small number of patients that were treated, less than 40, showed some responses but only in a few patients, raising the issue as to whether this drug will really be useful for brain metastasis. Lastly, the idea of using the combination of Herceptin and Tykerb is interesting, but we'll need more information before we know whether it's a good idea. There is a compassionate expanded access program through the drug sponsor, which is GlaxoSmithKline, but I think the bigger question is, "Where is it going to fit?" I think that question will not be really answered adequately until we do another randomized trial comparing that population at the trial, treating them with either chemotherapy and Tykerb versus chemotherapy and Herceptin, and learn which is the better treatment. In the meantime, some of us will have the opportunity to do another trial, now in the adjuvant setting where patients who've had a history of HER2-positive breast cancer and completed their chemotherapy will be randomized to receive Tykerb or a placebo. These will be patients who were diagnosed before we learned about the positive role of Herceptin. There's certainly a discussion of Tykerb versus Herceptin in the adjuvant setting.

Jennifer Griggs, M.D., M.P.H.: Like all good studies, we have more questions than answers. We see this over and over again when we have a new drug: we ask ourselves how we use the drug, for whom and how long, and where in the treatment course.

Receptor-negative adjuvant treatment news?

Question from Adrian: Any news regarding adjuvant treatment for receptor-negative breast cancer? Anything expected in near future?

Answer —Jennifer Griggs, M.D., M.P.H.: We've pointed out before on this Web site that most of the treatments with chemotherapy and most of the changes in how we give chemotherapy benefit people with estrogen-negative tumors than those who have had tumors that are estrogen-positive. That's just because of the biology of the tumor—chemotherapy works better when cells are dividing more rapidly, which in general negative-receptor tumors are. One of the things that we do in breast cancer care is move drugs or combinations of drugs from the treatment of metastatic disease into the adjuvant setting into people who do not have any evidence of disease following surgery. So we take drugs and combinations that are exciting in people where we can watch the disease respond and then start using those drugs or combinations in people who might fare very well in surgery alone. There are several very good clinical trials going on right now that are doing just that, and we are anxiously awaiting the results.

Any other gene mutations for breast cancer?

Question from Lmtin: I recently underwent genetic testing for BRCA1 and BRCA2. I have a strong history of breast cancer on my paternal side and was diagnosed Stage II at the age of 40. I was surprised to get negative results and was told that BRCA1 and BRCA2 account for 80% of genetic breast cancers, but the rest, they feel, have not been discovered. Are we any closer to discovering any other gene mutations for breast cancer?

Answers —Nicholas Robert, M.D.: We know that a percentage of women (probably around 10%) have a genetic disposition for developing breast cancer. Although the discovery of BRCA1 and BRCA2 was a great step forward in identifying women who have a genetic disposition, there's a percentage of women with a strong family history that when tested are BRCA-negative. We think that these women do have a gene that's abnormal that we have not identified, the so-called BRCA3. At this point, we aren't aware of any good candidates for the next gene abnormality.

Jennifer Griggs, M.D., M.P.H.: There are quite a few recent papers looking at enzymes that help get rid of toxins that we're exposed to and repair DNA that are not the BRCA genes. That may explain some of the interactions between a genetic makeup and what we're exposed to, including our own diet and other behavior. So for example, some people have one form of an enzyme that means that they benefit from a diet rich in fruits and vegetables. Other people have a different form of an enzyme that basically means that they don't benefit from a diet rich in fruits and vegetables. This is exciting for two reasons. First, it can help make sense of why some studies show a benefit with a plant-based diet and others don't. And even more exciting, it can help us with interventions or measures that can be targeted for people most likely to benefit. So these are genes that can explain the interaction between genes and the environment. Understanding how these genes are inherited is a little more complicated than BRCA1 and BRCA2, but we're getting there. Write your Congressmen for more money to go to research.

Nicholas Robert, M.D.: It's important for people with a strong family history of breast cancer regardless of their BRCA status (or as you just heard, their appetite for fruit and vegetables), that monitoring for these patients has changed dramatically for the good. The role of breast MRI, an expensive diagnostic test, in women with a high risk for developing breast cancer does diagnose earlier cancer than standard mammography. So it's important that women who are concerned about their family history of cancer seek out advice not only about BRCA testing but how to use these newer detection methods.

Jennifer Griggs, M.D., M.P.H.: Many centers are offering digital mammography, which is particularly helpful in places with radiologists that do more than breast imaging, and may increase the accuracies of mammography.

Diet to help prevent recurrence?

Question from MarilynC: What is the current advice on diet to help prevent recurrence? I'm three years out of treatment. Thanks. I need a definitive answer!

Answers —Nicholas Robert, M.D.: Again, there's good news. People have been talking about diet and breast cancer for many years. Last year there was a presentation of the Women's Intervention Nutrition Study (WINS), discussed again at this year's meeting. Hopefully, there will be an opportunity to review this data in greater detail. The bottom line is that a low fat diet (which translated to weight loss) reduced the risk of recurrence for women with breast cancer. The trial is a little bit complicated to understand in that the benefits appear to be in the patients who had tumors that were estrogen receptor-negative. Nonetheless, many of us are very excited about this study because it addresses a concern and a need that many of our patients have about doing something themselves in reducing their risk of cancer recurrence. This trial supports the idea that weight control through diet and exercise is important and we may see in the future that the oncologist will need to be more proactive about giving advice and suggestions on how women who've had breast cancer can use diet and exercise to do better.

Jennifer Griggs, M.D., M.P.H.: I'd add a caution that women not feel from this discussion that they caused their breast cancer from something they did or did not do. It's important that women with a recurrence should not have the added burden that they did something wrong. Many women with recurrences are very thin.

Nicholas Robert, M.D.: I think the point has been made that it's a double-edged sword. On one hand people want to be able to do something and if they don't they created a problem by omission. The reality is that breast cancer is very complicated because there are many factors involved. But this trial on nutrition is encouraging because there may be benefits comparable to some of our drugs that can be achieved by diet and exercise. This is a story that is just starting and by no means are we at the end of the story. There will for sure be more information about this approach in the future.

New info on ATAC study and Arimidex?

Question from Miki: Is the ATAC study still going on? Are the results pointing to a recommendation of taking Arimidex for five years for estrogen-receptor positive cancers? Any recommendations for after the five years of Arimidex? Are any serious side effects showing up in women who have taken Arimidex for several years?

Answers —Jennifer Griggs, M.D., M.P.H.: Last year, Dr. Robert and I were at a breastcancer.org conference together talking about the fact that there are just as many facts as there are questions, as with any good study. Decisions about hormonal treatment after breast cancer surgery offer many choices for women and their doctors. There are some tumors in which the aromatase inhibitors are clearly superior. For example, tumors that have the estrogen receptor but do not have the progesterone receptor appear to be better treated with the aromatase inhibitors than with tamoxifen. Medical experts are fairly passionate about this decision and several different treatment strategies have been proposed. For example, starting somebody on tamoxifen and then changing to an aromatase inhibitor is a strategy some doctors prefer. Other doctors choose the aromatase inhibitors in all postmenopausal women. Some people give five years of tamoxifen followed by five years of an aromatase inhibitor. The biggest problem I'm having is in my patients who've had five years of an aromatase inhibitor after surgery and then want to know what to do. Do they continue on the aromatase inhibitor for another five years? Would switching to tamoxifen in that case make sense? Or are they all done with hormonal treatments? Fortunately, we have studies of these questions going on right now. In the meantime, you and your doctor need to balance the benefits and risk of tamoxifen and the aromatase inhibitors and make a decision in your specific case.

Nicholas Robert, M.D.: In terms of the question of the duration of Arimidex (chemical name: anastrozole) after five years, there will be a study soon available to try to address that question. It's a trial that already is opened in which patients after five years of tamoxifen took another aromatase inhibitor called letrozole, also known as Femara. After five years of letrozole, patients are being randomized to continue letrozole or stop. This clinical trial will also be open to patients who've been on an aromatase inhibitor for five years. These patients will be eligible for this trial as well. This will give us some information about the duration of aromatase inhibitors. In terms of side effects, it's become clear that women on aromatase inhibitors lose bone and they need to be monitored closely for bone loss. Also, there continues to be some controversy about increased lipids like cholesterol in patients who are on aromatase inhibitors, so this is another health factor that needs to be monitored.

When to switch from tamoxifen to AI?

Question from EFitzpatrick: Is there any firm data yet on the right time to switch from tamoxifen to an aromatase inhibitor?

Answers —Nicholas Robert, M.D.: In patients who start with tamoxifen with the plan to switch, switching is usually done around two and a half years of being on tamoxifen. The bigger question some feel is whether people should start tamoxifen and switch, or start an aromatase inhibitor. There is an ongoing trial testing that approach which should shed some light. It should be noted that there is a subset of women where tamoxifen is probably the best choice and that is in a group of women who go into menopause after chemotherapy. These are women who were premenopausal, went into chemotherapy and then had the cessation of their period. Some of these patients over a length of time, a few months or longer, can have return of their periods. In those patients some feel that tamoxifen is a good choice as the initial hormonal treatment.

Jennifer Griggs, M.D., M.P.H.: I've had quite a few patients go through what we think is menopause on chemotherapy. I put them on tamoxifen, they come off tamoxifen and they get their periods, indicating that they never really had the complete stopping of ovarian function. They had something called "chemopause."

Difference between aromatase inhibitors?

Question from Kala: How do the aromatase inhibitors differ from each other?

Answers —Nicholas Robert, M.D.: At this point there are three aromatase inhibitors: Arimidex (chemical name: anastrozole), Femara (chemical name: letrozole) and Aromasin (chemical name: exemestame). All are available and could be used in the adjuvant study. At this point there is no clear-cut advantage of one aromatase inhibitor over the other. There are some biochemical studies suggesting that Femara suppresses estrogen better than Arimidex, but it is unclear whether this has any clinical significance. All three drugs are associated with bone loss.

Jennifer Griggs, M.D., M.P.H.: If you have a hard time with one drug, don't give up on them. Talk to your doctor about trying another aromatase inhibitor before giving up. The joint aches and pains that some women get on the aromatase inhibitors seem to be the worst at about six months. So if your doctor switches your medication and you get better, they may say, "Aren't we clever to change!" when your symptoms may have gotten better on their own. In my experience, they may not get better.

Side effects of aromatase inhibitors?

Question from CPNR: I would like to know more about taking aromatase inhibitors instead of tamoxifen after surgery and radiation treatment. How long have they been in use? What are the short and long-term side effects? Have they been approved in South America? The doctor suggested tamoxifen but the patient is looking for another drug with fewer side effects.

Answer —Nicholas Robert, M.D.: They've been in use for many years. Short-term side effects are potential hot flashes and joint and muscle aches. In postmenopausal women, in my mind clearly the aromatase inhibitors present an option to tamoxifen especially when there's a concern about blood clots and to a lesser extent concern about uterine cancer, both of which are associated with tamoxifen, although rare.

Herceptin recommended for HER2-positive?

Question from PS: Have there been any recommendations for those who are HER2-positive but did not receive Herceptin during their initial treatment and are two or more years out of chemo? If Herceptin is not recommended, why not? Thank you.

Answer —Nicholas Robert, M.D.: This is an excellent question. Of course there's some frustration by individuals who've seen the positive results in using Herceptin in the adjuvant trials. The critical issue is the question about timing of Herceptin treatment. In clinical trials patients received Herceptin no longer than six months after completing their chemotherapy. Just as it's standard to give chemotherapy within one or two months of diagnosis of breast cancer, where we don't think about giving chemotherapy one or two years later after the diagnosis of breast cancer, we use that same approach with Herceptin because we don't know if there's any benefit. There are concerns about side effects like damage to the heart. There is going to be a clinical trial available in this country in which the new HER2 drug, lapatinib (Tykerb), will be available for such women. It is important to emphasize in this trial there will be a placebo offered because currently standard treatment is no treatment because they're years away from their diagnosis.

Future of immune therapy?

Question from Adrian: Dr. Robert, there seem to be a few trials at this time looking at immune therapy for breast cancer and other cancers. What might be expected within the next few years in terms of immune therapy, such as the recent approval of the vaccine against HPV as prevention for cervical cancer? Is there data to suggest that the body can be trained to recognize breast cancer cells and eliminate or kill them?

Answer —Nicholas Robert, M.D.: The idea of using the immune system to fight cancer is very attractive. Our immune system helps us fight infections, so why can't it help us fight cancer? Unfortunately, after decades of trying to use an immune approach in breast cancer, this has still not been a successful strategy. Nonetheless, people are still exploring this approach with vaccines. The major challenge is that cancer cells, although different from our normal cells, from an immune point of view are really not that different, making it very challenging to develop a successful immune approach. There are a number of vaccine studies in breast cancer, including vaccine for HER2-positive tumors. I think we will need to wait for the results of these before we can say much more. Lastly, a very positive story in vaccines in HPV, a cause of cervical cancer. The vaccine was directed against the virus, not against human cells.

Treatment after tamoxifen, still menstruating?

Question from DeeC: Are there any updates on treatment for a woman still getting her period after five years of tamoxifen?

Answer —Jennifer Griggs, M.D., M.P.H.: In the very high-risk woman, for example, somebody with a lot of positive nodes, many doctors are considering suppression of the ovaries so an aromatase inhibitor could be used. In a woman who is considered to be at lower risk, we generally discuss living the healthiest life that you can and continuing to recover from what can often be long-term effects of treatment.

Hormonal therapy for metastatic ER+?

Question from Robin: Are there any significant research developments for women with metastatic ER+ breast cancer with respect to hormonal therapy?

Answer —Nicholas Robert, M.D.: In terms of options for treatment in this group of patients, there's some exciting laboratory work suggesting that a drug called Faslodex (chemical name: fulvestrant), which eliminates the estrogen receptor when combined with certain aromatase inhibitors, may produce a better outcome. This approach will be evaluated in clinical trials to see if it's actually true. In addition, some women who have estrogen receptor-positive tumors may develop an enhanced response if a drug interacts with other targets such as HER1 and HER2. This again represents some strategies that will need to be evaluated in clinical trials. As you can see, there are a lot of good ideas. We have learned that you cannot clarify these good ideas with mice in the laboratory. It's important for women with breast cancer and their doctors and nurses to explore clinical trials and see if there's a trial that fits your situation. When you participate in a clinical trial you're not only getting a state-of-the-art treatment, but also personally contributing to the advancement in care of breast cancer—not only for yourself but also for others. In this way, you can directly make a difference.

Two-year dosage Herceptin clinical trial?

Question from Nana: Is there any information available regarding the two-year dosage Herceptin clinical trial? I was told results would be published in 2006.

Answers —Nicholas Robert, M.D.: It may take two more years before we get an answer.

Jennifer Griggs, M.D., M.P.H.: That's a good thing because it shows that not enough women have had a recurrence to show a difference between the different treatment groups.

Survival statistics for mets treated with Avastin?

Question from KBreen: What are the latest survival figures in women with metastatic breast cancer who are being treated with Avastin in combination with Xeloda or IV taxanes?

Answers —Nicholas Robert, M.D.: There have been two trials in patients treated with Avastin (chemical name: bevacizumab) who have breast cancers. The first trial was in patients who had multiple prior chemotherapy treatments who then received Avastin and Xeloda (chemical name: capecitabine) versus Xeloda. Unfortunately, in those patients Avastin did not make a difference in outcome. More recently, there has been a trial with weekly Taxol (chemical name: paclitaxel) and Avastin, and in those patients there's been an improvement in response as well as delaying recurrence. But to date there has not been any survival improvement. That may change. The role of Avastin in breast cancer remains unclear. There are two current clinical trials that are evaluating Avastin in both first-line and second-line settings, looking at different chemotherapy regimens with or without Avastin. These trials are critical in terms of learning how to best use this very expensive drug.

Jennifer Griggs, M.D., M.P.H.: The statistics in breast cancer are grouped together in lots of groups of people. You might get information on average length of survival or you may get information on how many patients are alive at one year or two years. Some people may want a crystal ball, and obviously you deserve an honest answer from your doctor so you can prepare for things that you might want to do. On the other hand, everybody's story is different and you have to be very careful not to take an estimate of survival as gospel. If you live with metastatic breast cancer, it's helpful to us as oncologists to tell us how much information you want about your prognosis so that we know how best to work with you.

Developments in triple-negative treatment?

Question from Roger: What are the latest developments and strategies to treat triple-negative advanced disease?

Answers —Nicholas Robert, M.D.: Triple-negative breast cancer refers to tumors that are negative for estrogen and progesterone as well as negative for the HER2 receptor. This represents about 15% of patients. Fortunately, this group of patients appears to respond better to chemotherapy than women who are estrogen receptor-positive. Also there are now a number of drugs that are available for this group of patients. How best to use these drugs, and maybe others, remains a question. In addition, we know this group of patients is positive for something on a molecular level. There is research being done looking for genes and proteins to better understand the biology of this group of patients. It is expected that in the future we will have targets to shoot for like we have in other breast tumor groups.

Jennifer Griggs, M.D., M.P.H.: One of the most exciting things in breast oncology is the recognition that just like individuals are different, breast cancers are different. So we're getting smarter in our treatment. A couple years ago, we didn't know or refer too commonly to "triple-negative" tumors. The new categories that we have for breast cancer offer promise for more intelligent treatment.

Advances in treatment for premenopausal women?

Question from Naomime: Almost every day I read of advances in breast cancer research, but they always seem to be for postmenopausal women. What is being done for premenopausal women, like my daughter who was diagnosed at 36 years old, and suffers severe side effects from the drugs available to her?

Answer —Jennifer Griggs, M.D., M.P.H.: The tumor biology in premenopausal women is often the ER-negative cancer. So much of what we talked about earlier applies to a discussion of advances in premenopausal women. It sounds as if your daughter is experiencing a lot of side effects with treatment and we know that younger women can often have a harder treatment; for example, nausea. It's hard sometimes for patients to speak up to their doctors and let them know just how uncomfortable they are on treatment, but I suspect that your daughter's doctor could work with her to make her treatment better in her case. So I would encourage her to be very clear about her symptoms.

Shorter, more intense radiation for DCIS?

Question from Scarlettsmom: What are the advances in shorter-term yet more intensive radiation affecting treatment in patients with DCIS? What about balloon radiation or other ideas for shortening the time?

Answer —Nicholas Robert, M.D.: This question addresses the role of so-called partial radiation: the idea of giving high-dose radiation to the tumor site and sparing the rest of the breast. This approach also shortens the time for radiation. There is a current ongoing national clinical trial addressing partial radiation and standard radiation in women with breast cancer. This important question should attract patients who are interested in this approach. There is a concern that this approach of partial radiation may not offer the same advantage as whole breast radiation in terms of reducing a second breast cancer. Also the type of breast cancer that can be treated with this approach appears to be limited. It's important before we assume something new is better to demonstrate in a controlled setting whether the treatment is actually better.

New studies for BRCA gene repair?

Question from RKF: Are there any new studies for BRCA gene repair?

Answer —Jennifer Griggs, M.D., M.P.H.: This is an emerging field. Certainly gene directed therapies are exciting and worth further study.

Preventive treatments for BRCA1 mutation?

Question from DeWanda: I'm 31 and I have the BRCA1 mutation, although I have never had breast cancer. Were there any new findings this year about preventive treatments for people with BRCA1 mutations?

Answers —Jennifer Griggs, M.D., M.P.H.: What we know at this point is that a risk-reducing surgery to remove the ovaries and fallopian tubes in selected women can help reduce the risk of breast and ovarian cancer. At your age this may be too early a time to go through such a surgery, especially if you still plan on having children. One thing that's come out in the last year or two is that after removal of the ovaries women can have hormone replacement therapy without "undoing" the risk-reducing effects of the surgery to remove the ovaries. In other words, one doesn't need to live without estrogen to benefit from this surgery. Other prevention measures that have been proposed include ovarian suppression with an injection of medication that can be given either shorter-acting (every month) or longer-acting (every three months) to temporarily reduce the exposure of the breast tissue to estrogen. This is investigational and would not be considered standard of care, but could be a compromise for a woman who does not yet want to have her ovaries removed, but would like to do something that might reduce her risk of breast cancer. Ovarian suppression can also act as a form of contraception, so for some women it offers a double advantage.

Nicholas Robert, M.D.: In terms of detection it's become clear that someone at 31 should be having regular breast MRIs on an annual basis which should complement a mammogram, which should be a digital.