June 2004: Updates from ASCO 2004

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Updates on receptor-negative recurrence?

Question from San Antonio: Is there any data available for receptor-negative tumor recurrence? I have seen some on Stat5 but my searches come up with scant information. Thirty-three percent of us have these with a "poor prognosis," and all those tamoxifen studies are disheartening.

Answer —Kathy Miller, M.D.: This is a very common question and a very common cause for frustration. It's also very frustrating for oncologists because, currently, the options for treatment for women whose breast cancers are ER-negative and HER2-negative are limited to chemotherapy.

We are all looking forward to the day when we will have better options that will be more effective and less toxic. You've hit on the most important part of the problem, which is that we can't develop a therapy to target something that's not present in the tumor, so I don't have a way to target lack of the estrogen receptor.

The current efforts have focused on identifying the important factors that those ER-negative tumors do express. That will make it possible to develop specific therapies for those tumors. We've already identified some of those factors. One is the Stat5 protein that you've found in your reading. Treatments aimed at Stat5 are now being tested in the laboratory, but they have not yet been used in patients.

There is one piece of good news for women whose tumors are ER-negative. We know that chemotherapy is more effective in the tumors that are ER-negative compared to the tumors that are ER-positive.

Trials on hormonal therapies objective?

Question from glenna: What is the relationship between the clinical studies and the study sponsors? In other words, how objective are the clinical studies, particularly the studies on hormonal therapies such as tamoxifen and Arimidex?

Answers —Kathy Miller, M.D.: You're right to think very carefully and critically about the results of any study. It's important both to make certain that that study is relevant to your situation, and to think carefully if the study was well-conducted and reliable.

Because many of our new therapies were developed by the pharmaceutical companies, the companies play a critical role in many of the clinical trials. For most of those trials, the company sponsors the study and pays for all of the costs associated with doing the study, but does not influence the results or control the publication or data management of those results.

Marisa Weiss, M.D., president and founder: Any reliable study is usually evaluated intermittently by a group of objective clinical scientists without any interest or other connections to the drug or drug company. They serve as an "honest broker" for the validity of the results.

Kathy Miller, M.D.: It's important to remember that we would rarely recommend a major change in treatment based only on the results of one study.

Marisa Weiss, M.D., president and founder: One of the key guidelines to clinical research is the importance of "reproducibility." This means that we usually wait for more than one study group to confirm similar results before accepting them as worthy for a change in clinical practice recommendations.

Difference between Femara, Aromasin?

Question from Marsha: What is the difference between Femara and Aromasin? I have been on Femara/Zometa for bone mets to spine, shoulder and hip since May '03 with a clean bone scan in December '03. Two friends have been placed on Aromasin, one for third-line treatment for bone mets and the other for first-line treatment following surgery, no mets. Thank you very much.

Answer —Kathy Miller, M.D.: Femara and Aromasin are very closely related. They both inhibit or block the actions of the aromatase enzyme. This is the enzyme that converts other hormones to estrogen and accounts for the majority of estrogen in post-menopausal women. That's why both Femara and Aromasin and a third related drug called Arimidex are only used in post-menopausal women.

The differences between Femara and Aromasin are subtle. Aromasin is called a steroidal inhibitor and Femara is a non-steroidal inhibitor. This means they have a different chemical backbone and some slight differences in function. In mice, Aromasin has less effect on the bones and may have less associated risk of osteoporosis. What we don't yet know is if this difference is also seen in women.

We do know that all of the aromatase inhibitors may increase bone loss and increase osteoporosis, but they may not do this to the same extent. All of the aromatase inhibitors can be effective in post-menopausal women with estrogen-receptor positive tumors who have had previous therapy with tamoxifen because their chemical structures are different. Some women whose disease has progressed on a non-steroidal aromatase inhibitor like Femara or Arimidex may still respond or have prolonged stable disease on a steroidal inhibitor like Aromasin.

Research on long-term quality of life?

Question from Lorraine: What research is being done on long-term quality of life issues as these relate to the aftermath of chemo and hormonal therapies?

Answers —Kathy Miller, M.D.: This is a very important question and a very active area of research. Many of the recently completed adjuvant therapy studies included careful assessment of the quality of life of women who've received those treatments. There are also some studies just starting that will ask women who were treated for their breast cancer more than 10 years ago about their quality of life now and other health problems that may have developed over this time.

I think it's representative of the improvements that we have made in our treatment. With so many more women surviving their breast cancer for long periods of time, these issues will become much more important.

A recent example was presented at the American Society of Clinical Oncology (ASCO) conference. The MA-17 study, which looked at the effects of taking Femara in women who were completing five years of tamoxifen, included a detailed analysis of overall quality of life and menopausal symptoms. In that study, women who were randomized to Femara had very small increases in some menopausal symptoms and bodily pain, most commonly joint stiffness. With such a large study, these small differences (generally 1%–2%) were statistically significant but rarely were severe enough that women stopped therapy.

Marisa Weiss, M.D., president and founder: There was another study that looked at quality of life in women who stayed on tamoxifen compared to women who switched over to Aromasin. They looked at menopausal symptoms in 7,000 patients using questionnaire studies every three months.

They found that muscle aches were somewhat more common in the Aromasin group, vaginal discharge was more common in the tamoxifen group, and vaginal dryness was equally similar in both groups. Hot flashes were slightly increased in the tamoxifen group. Once again, these differences and the annoyance of these symptoms were not usually significant enough for women to decide to stop treatment.

There was a study that looked at sexual function over time in women who received adjuvant treatment after surgery for early breast cancer. In general, they found that women's sexual function seemed to recover substantially by one year. Women who had chemotherapy took somewhat longer to reach a more normal level again, as well as women who had tamoxifen. The chemotherapy effect was more significant than the tamoxifen effect, however.

The rate at which recovery occurred also depended on the amount of treatment given. But, once again, at the one-year mark, many women felt that they had recovered a significant amount of what they had lost.

There's another study that looked at the chance of continuing to menstruate after chemotherapy. The important question that was looked at was: "Does the addition of a taxane chemotherapy (such as Taxol, Taxotere) beyond an Adriamycin-containing regimen, increase the risk of going into menopause early?" This study of about 160 pre-menopausal women did not show an increased risk of going into menopause when a taxane was added to the initial Adriamycin-based chemotherapy.

Kathy Miller, M.D.: These studies are very important for women to know all the effects of chemotherapy, both good and bad, when making decisions about their treatment.

What next after five years on Arimidex?

Question from Marietta: What do you think women will be able to take after being on Arimidex for five years?

Answers —Kathy Miller, M.D.: That's a question we are all wondering. There are many things we don't know about the optimal use of the aromatase inhibitors like Arimidex in the adjuvant setting. The initial studies used a five-year duration of treatment, since that's how long women take tamoxifen. We wanted to make certain that any difference in the effectiveness was due to the difference in the drugs, not just the difference in the duration of therapy.

What we don't yet know is the optimal duration of Arimidex therapy. The women enrolled in that first Arimidex adjuvant trial, called the ATAC Trial, are just now coming to that five-year point. Two subsequent studies are being discussed and planned. One would compare five years of Arimidex to ten years of Arimidex. A separate study is considering switching from Arimidex to tamoxifen after five years on Arimidex.

In this situation, it's important for women to remember that we are all learning this information at the same time. So I often remind my patients that five years of Arimidex is our current plan today, but that may change based on new information between now and when they come to that five-year point.

Marisa Weiss, M.D., president and founder: There was an interesting paper presented at ASCO that looked at women who had just finished five years of tamoxifen and were free of disease upon "graduation." This study then looked at the next five years of follow-up to see if these women are still at significant risk for breast cancer recurrence.

This study did show that there is still a measurable risk of recurrence after five years, particularly in women whose cancers were originally node-positive. This study does raise the question about the potential role of extended adjuvant hormonal therapy after five years of tamoxifen. The MA-17 study, which adds Femara after tamoxifen, does address this issue. Again, as Kathy has said, we don't have these similar data in women who graduated from five years of Arimidex or any other aromatase inhibitor, but we know that your question is very important and highly relevant to many women in your same situation.

Herceptin in post-surgical, non-metastatic?

Question from Angela: Are there any new announcements regarding the role of Herceptin in the post-surgical setting with non-metastatic cancers (those that have not spread from where they started)?

Answers —Kathy Miller, M.D.: The large studies evaluating the role of Herceptin in women who have just been diagnosed and completed surgery are still ongoing. We do have some other important information about the use of Herceptin in earlier stages of breast cancer.

One is the importance of accurate HER2 testing. In one of those large adjuvant studies, women initially joined the study based on the HER2 test results done in their local hospital. A sample of their tumor was then sent to a central laboratory for additional HER2 testing. In up to one quarter of women, the HER2 test results from their local hospital were incorrect.

This is clearly important both for those trials and the use of Herceptin in early-stage breast cancer, as well as for the treatment of metastatic (advanced) breast cancer. We know that the HER2 testing can be difficult and complicated. The results from large laboratories that do many of these tests each day are much more accurate.

There was also one very small study using Herceptin in combination with chemotherapy in women with large tumors. In this study, some women had chemotherapy alone, and other women were treated with chemotherapy plus Herceptin before surgery. The women randomized to receive Herceptin in addition to chemotherapy were more likely to have complete elimination of the tumor at the time of surgery. Unfortunately, this was a very small study with less than 40 patients total, so these results certainly should not change practice at this time.

Marisa Weiss, M.D., president and founder: This study was originally supposed to have more women in it, but they stopped the study early because enrollment to the study was so slow.

Kathy Miller, M.D.: Despite the very small number of patients, the results are encouraging.

Lupron increases survival rates?

Question from Julie: Are there any studies that show that Lupron, in conjunction with tamoxifen, increases survival rates in pre-menopausal, hormone-receptor positive women?

Answers —Kathy Miller, M.D.: This is a very important question. Lupron suppresses the function of the ovaries and decreases estrogen levels in pre-menopausal women. Removal of the ovaries or suppression of the ovary function was one of the first effective treatments for breast cancer. What we still don't know is if ovarian suppression with a drug like Lupron adds to the benefits of chemotherapy and tamoxifen.

Several studies have tried to answer this important question in the past, and they all had the same problem: namely, those early studies did not take into account the fact that many pre-menopausal women will have premature loss of ovarian function from the chemotherapy. As a result, those studies included many women who became menopausal with the chemotherapy, and, therefore, would not benefit from a specific treatment to decrease ovarian function.

There is an ongoing international trial called the SOFT (Suppression of Ovarian Function Trial) that will answer this question. In that trial, pre-menopausal women with estrogen-receptor positive breast cancer are randomized to either tamoxifen as the standard treatment, ovarian suppression with tamoxifen, or ovarian suppression with an aromatase inhibitor. If women had chemotherapy, they are eligible for this trial only if they continue to menstruate after chemotherapy.

Marisa Weiss, M.D., president and founder: Reports of studies that looked at the effectiveness of Lupron compared to CMF chemotherapy in pre-menopausal women showed that these two options produce essentially the same results. This confirms prior studies that show essentially similar outcomes for pre-menopausal women who have hormone-receptor positive disease.

The weakness of these findings relates to the choice of chemotherapy offered, CMF. This chemotherapy regimen, while considered an effective option, may not represent the most effective option for pre-menopausal women choosing chemotherapy today.

Kathy Miller, M.D.: Another important flaw in those studies is that none of those women received tamoxifen.

Evista okay after tamoxifen?

Question from EricaT: Is it advisable to take Evista (chemical name: raloxifene, a drug for building bone strength that may help prevent cancer) after having taken tamoxifen? I participated in the B1 Cancer Prevention Trial and took tamoxifen for five years ending in 1998.

Answers —Kathy Miller, M.D.: This is a very important question and one that many doctors don't understand. This specific question—that is, finishing five years of tamoxifen and then switching to Evista—has not been studied. But we do know that taking tamoxifen for 10 years was not better than taking tamoxifen for just five years, and, in fact, 10 years of tamoxifen was slightly less effective in node-negative women.

The effects of Evista and tamoxifen on the breast are the same. That makes us very concerned that taking tamoxifen and then switching to Evista is the same as continuing tamoxifen as far as your breasts would know. Many women who have been treated for breast cancer are rightly concerned about osteoporosis, and they are frequently advised to use Evista rather than considering estrogen.

In women who have had tamoxifen, I would suggest other options, such as Fosamax or Actonel, as a better option for treating or preventing osteoporosis. Of course, it's also important to remember that taking adequate amounts of calcium and vitamin D and getting regular weight-bearing exercise are critical for healthy bones as well.

Marisa Weiss, M.D., president and founder: If you're looking for more extended anti-estrogen protection beyond your five years of tamoxifen, and if you are post-menopausal, you can talk to your doctor about the possible role of Femara.

Dose-dense chemo vs. conventional?

Question from Website Question: How does dose-dense chemotherapy compare to conventional?

Answer —Kathy Miller, M.D.: Dose-dense chemotherapy means giving the same dose of chemotherapy with shorter intervals. There is one large study reported at the San Antonio Breast Cancer Meeting that compared Adriamycin and Cytoxan followed by Taxol given either every three weeks or every two weeks (at the dose-dense schedule). Giving the chemotherapy every two weeks requires the support of growth factors like Neupogen or Neulasta so the blood counts will be high enough for treatment every two weeks.

In that study, the women who received the dose-dense chemotherapy had fewer recurrences of their breast cancer and a slightly greater chance of surviving their breast cancer than women treated with the every-three-week schedule. Because everyone who got dose-dense chemotherapy was treated with growth factors, there were also fewer infections. Of course, one obvious advantage of the dose-dense schedule is that patients finish all their chemotherapy faster.

Dose-dense therapy is certainly not appropriate for everyone. This study was only in node-positive patients. It's also important to remember that this is only one study. Other studies evaluating the dose-dense regimen are needed to confirm these results, and an ongoing trial coordinated by the National Cancer Institute of Canada is studying the dose-dense schedule as well. If this trial finds similar results, I think you will see the dose-dense regimen much more commonly used.

Are aromatase inhibitors safe?

Question from Website Question: How safe are aromatase inhibitors without long-term studies having been done? I am skeptical after being on HRT (hormone replacement therapy) for ten years only to find out it contributes to breast cancer.

Answer —Kathy Miller, M.D.: I think you're right to be skeptical. Certainly, it is impossible to have long-term results from such early studies. The women in those early aromatase inhibitor studies will continue to be followed so we will gather that longer-term safety information over a longer period of time.

Of course, that doesn't help you and other women who need to make decisions about their treatment today. This requires a long conversation with your doctor and balancing the risk of your breast cancer and the potential long-term complications of the aromatase inhibitors—specifically, the risks of osteoporosis and increased cholesterol levels.

Chemo options after Herceptin combo?

Question from Jean: With lung mets after failure on Taxotere/Herceptin, what is the option after using a Navelbine/Herceptin combination?

Answer —Kathy Miller, M.D.: There are many other chemotherapy options, either alone or with Herceptin that can be helpful in your situation. Specifically, we know that Xeloda or gemcitabine (brand name: Gemzar) can be effective in women who have had previous chemotherapy regimens or previous treatment with Herceptin. If you are interested in clinical trials, this is also a good time to talk to your doctor about clinical trials testing new agents that might be appropriate for you.

Herceptin combined with Iressa or Avastin?

Question from Liza: Are there any results from trials of combining Herceptin with Iressa or Avastin?

Answer —Kathy Miller, M.D.: Not yet. There are ongoing trials combining Herceptin with Iressa or Tarceva as well as Avastin. These trials are still enrolling patients, so we don't have the results yet. We do know from studies in the laboratory and in mice that inhibiting more than one growth factor pathway at the same time is more effective than inhibiting just one factor.

Iressa and Tarceva inhibit the epidermal growth factor receptor (EGFR) which often cooperates with HER2 to make breast cancers grow more rapidly. (These are like sister receptors who like to talk to each other.) Avastin inhibits the vascular endothelial growth factor (VEGF). VEGF stimulates the growth of blood vessels that feed the tumor. Breast cancers that express HER2 commonly produce lots of VEGFs. The interaction between these factors is what has prompted those ongoing clinical trials.

There are also several new drugs in clinical trials that inhibit several factors with one drug. For example, reported at ASCO were early results with a new drug Lapatinib (GW572016; some people refer to it as "016"). This drug inhibits both EGFR and HER2. It is currently being studied in women with HER2-positive breast cancer who have had previous treatment with Herceptin. In those early results, some of those patients had decreases in their tumors.

Ongoing studies will help us understand how well this drug works and how to best use it. Your local oncologist can help you identify a clinical trial with this drug or others that might be right for you. You can also find links to many websites listing clinical trials on www.breastcancer.org.

Switching aromatase inhibitors?

Question from Victoria: Is there any research being conducted where another aromatase inhibitor is given after five years of Arimidex in post-menopausal women? I know that aromatase inhibitors given after tamoxifen have been researched with good results.

Answer —Kathy Miller, M.D.: I don't know of any studies looking at switching from one aromatase inhibitor to another after five years. Instead, new studies will look at the duration of therapy using the same aromatase inhibitor.

Osteoporosis prevention and breast cancer?

Question from Alan: In prostate cancer treatment, leading oncologists recommend osteoporosis prevention by taking things such as Fosamax concurrent with anti-hormonal treatment, vs. as an add-on (following) treatment. What is currently in vogue for osteoporosis prevention/treatment during the anti-hormonal phase in the breast cancer world?

Answers —Kathy Miller, M.D.: Excellent question!

Marisa Weiss, M.D., president and founder: As we grow older, our bones tend to lose some of their strength. What happens upon a diagnosis of breast cancer and with consideration for hormonal therapy is the simultaneous look at bone health since all these treatments can have an impact on the health of your bone.

So even if you haven't looked at your bone health before, at the same time you're trying to make these other decisions, you might find out you've lost some bone strength and you may have partial thinning of the bone, partial osteopenia, or significant loss of bone strength (osteoporosis). Your doctor will need to look at these two issues, both separately as well as together.

Kathy Miller, M.D.: Rather than treat every woman the same and give every woman a medicine like Fosamax for osteoporosis, it's better to evaluate your bone strength and determine if you need additional therapy.

There is another reason that we are studying medicine used for osteoporosis in women with breast cancer. We know that medicines like Zometa or Aredia (these are related to Fosamax) can delay the progression and prevent complications in women with metastatic disease involving the bones. This has made us wonder if using these medicines after an initial diagnosis, in addition to chemotherapy or hormonal therapy, might prevent or significantly delay the development of recurrent disease in the bones. Several small studies have looked at this question, adding a related drug called clodronate to the initial treatment of women with early-stage breast cancer.

Marisa Weiss, M.D., president and founder: This drug is not yet available in the United States.

Kathy Miller, M.D.: These studies found a consistent decrease in osteoporosis but the impact on recurrence of breast cancer was inconsistent. Inconsistent results in several small studies are very common. We have completed a large study to definitively answer this question. This study has completed enrolling patients, but we don't yet have the results.

Procrit during chemo worsens outcome?

Question from Liza: What is your opinion of the recently published studies showing that using Procrit during chemo can result in a worse outcome?

Answer —Kathy Miller, M.D.: This is a very complicated issue. We know that using Procrit in patients with cancer who are anemic improves the anemia and improves the quality of life of those patients. In those studies, there was no suggestion that adding Procrit decreased the effectiveness of chemotherapy or radiation.

Two more recent studies looked at using Procrit in patients who were not anemic. The goal was to prevent anemia and the fatigue and decreased quality of life that can accompany severe anemia.

In those two studies, there was a suggestion that Procrit decreased the effectiveness of chemotherapy and radiation. Those results were not expected and the studies did not collect much of the information that we would need to really evaluate and understand these results. For instance, the patients randomized to receive Procrit had slightly worse prognostic features at the time they entered the study, so this slightly lower response to the chemotherapy may not have been related to the Procrit.

Unfortunately, right now we just aren't sure. I would not be concerned about using Procrit in patients who are anemic, but I would be cautious about using Procrit to prevent anemia until we have more information. This is most likely to come up in using the dose-dense chemotherapy regimen. The dose-dense therapy is more likely to cause anemia than giving the chemotherapy every three weeks.

Effects of Theratope vaccine?

Question from Website Question: What is the latest report on the effects of the Theratope vaccine, and what is the present clinical trial using the vaccine?

Answer —Kathy Miller, M.D.: The Theratope Trial evaluated the effectiveness of a breast cancer vaccine in patients with metastatic breast cancer who remained stable or responded to initial chemotherapy. The results were presented at the San Antonio Breast Cancer Meeting last December and were disappointing. Patients who received the vaccine did not have any greater response or duration of disease control than patients treated without the vaccine. There was some suggestion that the vaccine may benefit women with estrogen-receptor positive breast cancer. Future studies with the vaccine are likely to focus on those patients.

Tamoxifen doesn't work for HER2-positive?

Question from Faye-from-Australia: I am HER2 and hormone positive. I have started on tamoxifen. I am 37. I have read that being HER2-positive might mean that tamoxifen might not work for me. Do you have anything further on that?

Answer —Kathy Miller, M.D.: There are some studies that have suggested that tamoxifen might be less effective in women with HER2-positive breast cancer. It's important to recognize that other studies have not found a difference in the effectiveness of tamoxifen in HER2-positive vs. HER2-negative tumors.

It's also important to remember that none of the studies found no benefit to tamoxifen in the HER2-positive patients, merely a question that the benefit of tamoxifen might be less. For post-menopausal women, the aromatase inhibitors would provide another option for hormonal therapy that might be more effective in HER2-positive tumors. For pre-menopausal women, tamoxifen is still the best choice.

Ductal lavage as screening tool?

Question from Sunflower: What is your opinion of ductal lavage (testing fluid from breast milk ducts) as a screening tool—is it able to pick up suspicious lesions that would not yet be detected by mammography?

Answers —Kathy Miller, M.D.: Ductal lavage is not designed as a screening tool. Each breast has at least eight and potentially up to 40 different ducts. In a typical ductal lavage procedure, only one or two ducts are sampled. This makes it impossible for ductal lavage to screen or sample all the ducts. Ductal lavage may be helpful to evaluate nipple discharge but is not a good screening tool.

Marisa Weiss, M.D., president and founder: There were a number of reports of the potential value of MRI scanning in women with breast cancer, which we will present in the next breastcancer.org research newsletter. This does represent a promising screening tool for women at high risk for breast cancer (meaning women who have a strong family history, women with a proven breast cancer gene abnormality, and possibly also women with a personal history of breast cancer).

These studies also looked at the value of MRI upon a diagnosis of breast cancer to help evaluate the extent of disease, and to select the most appropriate forms of local therapy, as well as to help measure response to therapy. Stay tuned for this coverage.