December 2005: Updates from the 2005 San Antonio Breast Cancer Symposium

Effectiveness of dose-dense chemo?

Question from DeborahL: Is there any news about the effectiveness of dose-dense chemo?

Answer —Generosa Grana, M.D., F.A.C.P.: There was news presented looking at dose-dense chemotherapy showing that it is still very effective chemotherapy, but that in certain subsets it may not be as effective as we originally had thought. Particularly in the hormone-receptor-positive subsets, the impact is less. In my mind, that doesn't mean we shouldn't use this regimen. I think it's still a very good regimen and the subject of a very important study that's being done across the country right now, so further research will shed light on its true role. But again, it is still a very active regimen.

NSABP B38 is ongoing, comparing dose-dense AC followed by Taxol to a regimen known as TAC. A third arm in that study is the dose-dense regimen with the addition of Gemzar (chemical name: gemcitabine).

Why does chemo cause fatigue?

Question from Praisejoy: Why does chemotherapy rob us of energy?

Answers —Generosa Grana, M.D., F.A.C.P.: Chemotherapy has traditionally been associated with fatigue. Some of that may be due to the fact that it can cause anemia and lowering of the white blood count. Some is probably the direct effect of the drug on rapidly dividing cells in the body such as the gut, etc. Again, the specific reason why chemotherapy causes fatigue is not necessarily well understood. Sometimes the fatigue can be handled by reducing the dose, sometimes by using other drugs to raise the red blood cell count and correct anemia, and sometimes we use drugs such as Ritalin (chemical name: methylphenidate) or Provigil (chemical name: modafinil) to help alleviate some of the fatigue.

Marisa Weiss, M.D., president and founder: You can read more about managing fatigue in our special section of Breastcancer.org.

How many A/C cycles are appropriate?

Question from Carol: The typical AC treatment is four—why not three or five? What if I only do three? I am stage I, node-negative, hormone-positive and 41 years old.

Answer —Generosa Grana, M.D., F.A.C.P.: The choice of four cycles of AC, you're right, is rather empiric. Studies were originally done with two years of chemotherapy, then one year, then six months, and somehow we came to four cycles of AC. There's some concern that that may not be sufficient. There is a study ongoing right now looking at women like yourself, women who have node-negative disease, where we are comparing four cycles of AC to six cycles of AC, or four doses of Taxol to six doses of Taxol. So the study is addressing the question of Taxol vs. AC, and the number of doses, four vs. six. Three or five is unknown, as we have never done studies. You should get benefit, but I can't say how much.

Some people who have breast cancers that are lymph-node negative and hormone-receptor-positive could use the Oncotype DX test to get a better handle on prognosis and to help in the decision making about chemotherapy vs. hormone therapy, although that test cannot help in making a decision about three vs. four vs. five of AC.

What's next after radiation, Femara?

Question from ADJO: I have taken tamoxifen for five years after a radical mastectomy and chemotherapy. My cancer came back last year and I received radiation and now I am on Femara. My oncologist said that I could take this medication for three years. What is next as far as treatment goes?

Answer —Generosa Grana, M.D., F.A.C.P.: I believe you should sit down and readdress the duration question with your oncologist. Femara is a very good drug after a five-year course of tamoxifen. The data that's available would suggest a five-year course of Femara after completion of a five-year course of tamoxifen. There is research ongoing to ask the question as to whether it might be better to take the Femara for ten years rather than five.

Women in the MA-17 study who received five years of tamoxifen followed by five years of Femara are now being randomized again to receive another five years of Femara or nothing [placebo]. Ultimately the study will help us determine the true duration of Femara after tamoxifen.

Candidate for hormone blocker, not chemo?

Question from SCU: I had a modified radical mastectomy and lymph node removal and am now in chemotherapy. I just finished four rounds of AC and am due to start Taxol in two weeks. Considering this information as well as new guidelines coming out of San Antonio recently stating that hormone-receptor status is THE most important criterion for treatment, am I a candidate for a hormone blocker now, instead of more chemo? Also, what about radiation?

Answers —Generosa Grana, M.D., F.A.C.P.: I don't believe that the presentations at San Antonio suggested that hormone-receptor status was the most important factor in determining outcome. What they suggested was that outcomes from cancer depend on many things, among which are hormone status and HER2/neu status, along with age and other factors. The decision to use four cycles of AC followed by four cycles of Taxol has to depend on an assessment of risk—how big is the cancer, are there lymph nodes involved and if so, how many, how old are you, and then part of that decision will encompass hormone-receptor status.

So it's a much more complex question, and one you should address with your oncologist. I believe that in a woman who has positive lymph nodes, there continues to be a role for regimens such as AC followed by Taxol.

Marisa Weiss, M.D., president and founder: The traditional indications for radiation after mastectomy include having a cancer that's 5cm (about 2 inches) or larger, having four or more positive lymph nodes, and having a positive (involved) margin of recession. There are other certain circumstances where radiation may be indicated depending on your individual situation, such as a woman who has a small lump but with a lot of lymphatic or vascular invasion (breast cancer cells found in the blood and fluid channels of the breast) because that type of situation is associated with a higher risk of recurrence after mastectomy. It's helpful to get an opinion regarding the role of radiation and consider this carefully in your situation.

New treatments following Arimidex?

Question from Tweeti: Are there any new treatments on the horizon for those who have completed five years of Arimidex?

Answer —Generosa Grana, M.D., F.A.C.P.: At this point, we don't have any clinical trial information to support use of Arimidex beyond five years. There is a study, as I mentioned, looking at 10 years vs. five of Femara, but it will be some years before data from that trial become available. So in my current clinical practice, I discontinue the aromatase inhibitor in early-stage breast cancer at five years. The issue is different for women who have advanced or metastatic breast cancer, in which case most oncologists would leave them on hormonal therapy indefinitely or as long as that therapy is working.

Data was presented at San Antonio focusing on two to three years of tamoxifen vs. 10 years of tamoxifen, and although in women with lymph-node-positive breast cancer there was a slight benefit to longer vs. shorter tamoxifen, that benefit was really seen in the first four to five years of tamoxifen rather than in years five to 10. So even with drugs such as tamoxifen, there is no data to support longer use of tamoxifen.

There are two studies currently being done in Europe—ATLAS and ATOM—that will give us data on longer tamoxifen, 10 vs. five years, but until that data becomes available, the standard of care is five years of tamoxifen or five years of an aromatase inhibitor. For the woman who got five years of tamoxifen if she is post-menopausal, one could consider using five years of an aromatase inhibitor after the tamoxifen, i.e. five years of Femara.

Avastin with Aromasin for bone metastases?

Question from Lin: Can Avastin be combined with Aromasin in a case of breast cancer with metastases to the bones?

Answer —Generosa Grana, M.D., F.A.C.P.: The only data that has been presented to date on Avastin is in combination with chemotherapy, in particular in combination with Taxol. Dr. Kathy Miller from Indiana University updated a trial that had been presented at the ASCO meeting in May, which compared Taxol alone to Avastin plus Taxol, with the Avastin given every two weeks intravenously, demonstrating a significant benefit in reducing risk of recurrence and improved survival when Avastin was added to Taxol.

Avastin is being studied in a variety of combinations—with chemotherapy, with Herceptin, with hormone therapy—but as of yet, there is no data on any of those combinations to show either effectiveness or toxicity.

What feeds receptor-negative breast cancer?

Question from Tahoe Nancy: Any new information about what feeds receptor-negative breast cancer tumors?

Answer —Generosa Grana, M.D., F.A.C.P.: I think there is a lot of interest in studying the cancer that is hormone-receptor-negative to get a better handle on the pathways involved in those tumors. As of yet, we don't have a great understanding of what drives those tumors or what pathways we can block to effectively interfere with those tumors. What we do know about women who have hormone-receptor-negative cancers is that they tend to benefit more from the typical regimens such as dose-dense chemotherapy (AC followed by Taxol given at two week intervals). The woman who is hormone-receptor-negative tends to benefit more. Those women don't benefit from hormonal agents, but again there are some very interesting compounds being developed that may be perfect for those women, such as Avastin [a humanized monoclonal antibody], such as lapatinib, and some of the other compounds in development will target these cancers.

Femara vs. Arimidex?

Question from Lee: What is the difference in the aromatase inhibitors? Why would one doctor choose Femara over Arimidex?

Answer —Generosa Grana, M.D., F.A.C.P.: A lot has been made about differences in chemical structure, differences in whether a compound is steroidal, such as Aromasin, or non-steroidal such as Femara. Much has been made about how much these compounds suppress estrogen production, and whether they block the enzyme in the reversible or irreversible fashion.

But the reality is that there is no direct clinical evidence demonstrating in a head-to-head comparison (a study that directly compares one drug to the other) that any one of these drugs is superior to any other. Most oncologists tend to select the aromatase inhibitor that has been studied in a particular setting. It may also be affected by whether those clinicians have been involved in some of those studies.

For example, in newly diagnosed breast cancer patients who are post-menopausal, people tend to choose either tamoxifen or Arimidex or Femara because Arimidex and Femara have been studied in post-menopausal women and shown to be better than tamoxifen and with a better safety profile. If a woman has been on tamoxifen for two to three years and she and her oncologist are considering switching, most would switch to either Aromasin or Arimidex because clinical trials with these two drugs did exactly that.

Women going on an aromatase inhibitor after five years of tamoxifen tend to be recommended Femara because the MA-17 trial did exactly that. So most people tend to be clinical trial based and use the results of clinical trials to make decisions in their practice. But there is no direct comparison between these three drugs.

Long-term results for lumpectomy, radiation?

Question from Teresa: What are the 10-year results of combining radiation after lumpectomy for DCIS and other low-risk breast cancers?

Answer —Marisa Weiss, M.D., president and founder: Long-term follow-up was presented on the addition of radiation after lumpectomy compared to lumpectomy alone for women with DCIS (non-invasive breast cancer). This study showed that radiation was able to reduce the risk of developing recurrent invasive as well as non-invasive breast cancer by 60%. There was no survival advantage from that, however, at the end of the review period. But radiation, by dropping the risk of recurrence by 50%, gave more women the opportunity to keep their breast as an alternative to mastectomy.

New research on BRCA1, BRCA2?

Question from Flashdif: Is there any new research or knowledge about the ramifications of BRCA 1 or 2?

Answers —Generosa Grana, M.D., F.A.C.P.: The information presented showed nothing that dramatically changed our understanding of the implications of BRCA 1. One of the leading symposia was presented by Dr. Kenneth Offit from Memorial Sloan-Kettering Cancer Center where he reviewed issues inherent in genetic counseling and testing for BRCA 1 and 2. He reiterated the goals of testing, which are to inform and help make decisions, and confirmed the fact that although there is concern about genetic discrimination, as yet there has not been documented discrimination.

We showed some small data showing that DCIS (non-invasive breast cancer) can be seen in women who are BRCA 1 and 2-positive and should be considered part of the spectrum of hereditary breast cancer, and others have shown the same with larger numbers. So the important thing is that things haven't changed regarding the risk these mutations impart, but we are more attuned to the individuals needing testing for these mutations.

Marisa Weiss, M.D., president and founder: One study looked at the role of breast preservation therapy (lumpectomy and radiation) compared to mastectomy in women with a breast cancer gene abnormality diagnosed with early- stage breast cancer. This study found that breast preservation therapy was just as effective in these women compared to women without a breast cancer gene abnormality relative to the diagnosed cancer. But, the women with a breast cancer gene abnormality are at higher risk of developing a new and unrelated cancer in the same breast or the other breast over the years, relative to someone without a gene abnormality.

Blood tests, tumor markers indicators?

Question from Teddy: Is there any progress in the area of blood tests for breast cancer or in the area of tumor markers and recurrence?

Answers —Generosa Grana, M.D., F.A.C.P.: There was a lot of work presented, not in identifying a blood test to help diagnose breast cancer, but rather to use blood tests or bone marrow biopsy results to assess prognosis and treatment effects. Bone marrow biopsies were shown in early-stage breast cancer to allow one to identify cancer cells in the bone marrow at the time of diagnosis in some women with early-stage disease. Whether this will be a test that is of value above and beyond lymph nodes and other tumor features is yet to be determined by ongoing studies.

Marisa Weiss, M.D., president and founder: Do you use this information in your practice?

Generosa Grana, M.D., F.A.C.P.: I do not use bone marrow biopsy testing in early-stage breast cancer patients.

Another area that was looked at is the concept of measuring circulating tumor cells in the blood as a way of predicting outcome and predicting effectiveness of chemotherapy in the women with metastatic or advanced breast cancer. This may give an early measure of ineffectiveness of treatment much sooner than one can achieve by looking at CT scans or similar imaging modalities. Currently I am not using this in clinical practice, but these are interesting tools that may have a role in the next few years.

Why not use treatments in Phase III?

Question from ZH: I keep reading about all the latest findings from Phase III clinical trials, but my doctors don't feel comfortable using any of them, for example, Abraxane rather than paclitaxel. When can I expect new treatments to be offered without entering a clinical trial?

Answer —Generosa Grana, M.D., F.A.C.P.: It very much gets at the question of whether you have early-stage or advanced breast cancer. In early-stage breast cancer, we tend to be very dogmatic about sticking with regimens that have been studied extensively in clinical trials, are FDA approved (with the exception of Herceptin which is not yet, but soon to be approved) and whose toxicity we understand.

So no one would use the results of the phase III trial with Abraxane to use Abraxane in early-stage breast cancer. There, the role is for Taxol or Taxotere. Abraxane is otherwise known as nanoparticle Taxol, or albumin-bound Taxol, and it was shown in clinical trials to be somewhat better than Taxol and to avoid some of the toxicities of Taxol. It is FDA-approved for breast cancer. Again, it is up to the physician and patient when Abraxane is used and whether it's used instead of Taxol in metastatic breast cancer, but it is not a drug that has data for early stage disease. A Phase III clinical trial is a study that is being done in a specific population of cancer patients where a standard treatment is compared to a newer treatment that has shown promise in that area, i.e. comparing Abraxane to Taxol.

Info on HERA project with Herceptin?

Question from Vicky: I'm taking part in the HERA project in Barcelona (Spain) with Herceptin for two years. I'm in the second year. My oncologist mentioned good results. Can you please tell me more news?

Answer —Generosa Grana, M.D., F.A.C.P.: The most important thing is that you are to be congratulated for being part of such an important clinical trial. This trial has already shed light on the role of Herceptin for early-stage breast cancer and is the only trial of the four that were done in early-stage breast cancer that is addressing the question of longer vs. shorter Herceptin.

Patients in the HERA trial received treatment for their breast cancer with surgery and chemotherapy plus radiation, and only after their treatment was completed did they get assigned to either observation, Herceptin for one year, or Herceptin for two years. The data that was presented at San Antonio was an update on what had previously been presented at ASCO, and it focused only on the results for patients in the observation arm or the one-year arm; there are no data yet for patients on the two-year arm. We have to assume the study has not been stopped early and those patients have not been unblinded (the study has not been closed). So we have to assume the two-year results are not adding much to the toxicity, but how much more beneficial those two years will be over one year we don't know at all.

Right now we know that one year of Herceptin reduces risk of recurrence by 50% and improves those outcomes in women who have both lymph-node-negative and lymph-node-positive disease. We don't yet have much data on survival because it is a young trial and we need more follow-up on those patients. But again, it is a very exciting trial and I would encourage you to continue on it because this trial will help determine how we treat women with early-stage breast cancer.

FinHer study and adjuvant Herceptin?

Question from MM: Could you comment on the FinHer study presented at SABCS and shorter periods of adjuvant Herceptin?

Answer —Generosa Grana, M.D., F.A.C.P.: The FinHer study was a study of approximately 1000 women who were treated with chemotherapy in the form of Taxotere (chemical name: docetaxel) or Navelbine (chemical name: vinorelbine), given with or without Herceptin. So patients received Taxotere plus or minus Herceptin, or Navelbine plus or minus Herceptin for nine weeks, then everyone completed three cycles of chemotherapy with a regimen called FEC where E is epirubicin.

The study showed that if we're looking just at the chemotherapy itself, Taxotere was slightly better than Navelbine. When we look at the patients who received Herceptin, those patients did significantly better than those who did not receive Herceptin and when Herceptin was added, it did not seem to matter too much which chemotherapy was utilized, whether Navelbine or Taxotere. The importance of this trial is that the Herceptin was given for only nine weeks as opposed to the 52-week schedule the other trials have looked at. This has not changed clinical practice for women who are HER2/neu positive, but this sets the stage for studies that will now be addressing the issue of shorter courses of Herceptin.

Which is the next best treatment step?

Question from SandyW: I had a mastectomy five years ago, did four cycles AC, four cycles Taxol, 35 rads, three years of tamoxifen. This year, the cancer recurred with metastases to lymph nodes, lungs, and liver. I started Aromasin in August, but there has been no change in PET in four months. My oncologist said I could either stay on Aromasin or go to chemo with Taxotere or Abraxane. I don't know how to make this decision myself. Help!

Answer —Generosa Grana, M.D., F.A.C.P.: This is a situation where you need to sit down with your oncologist and have more of a discussion. In metastatic breast cancer, no growth is an acceptable thing. We don't always look for shrinkage and disappearance. We call your situation "clinically stable disease" and this is a very meaningful response. So oftentimes we don't change the chemotherapy but rather continue the hormone therapy until there is progression of disease. But again, your specific case should be discussed with your oncologist.

In women with metastatic disease, our goal is to slow the pace of the disease and if we're lucky to eradicate the disease, but you use your least toxic drug first. In a women who is hormone-positive, most people will use hormonal therapy as long as it works, then consider changing to another hormonal agent and really not rush into giving up on these agents and moving to chemotherapy because of the added toxicity of chemotherapy.

Other possible BRCA genes?

Question from Lee: I have a strong family history of breast cancer: me at 36, mom and grandmother in their 40's. I tested negative for BRCA but was told that it was a BRCA gene not discovered yet. Is there another BRCA gene in study?

Answer —Generosa Grana, M.D., F.A.C.P.: In women who have a very strong family history (and that may mean three or more women with breast cancer in the family, young age at diagnosis, etc.), testing negative is not as reassuring as it might be because we consider these families to be hereditary and we approach them as if they are hereditary.

We believe there may be other genes involved in these families, maybe a BRCA 3 or 4, or maybe other genes. But in answer to your question, these genes have not been identified and there are no tests either in a commercial lab or a research center. So stay tuned—more research will be done. We've come a long way since BRCA was identified 10 years ago, so we have high hopes the genetic link in families such as yours will be unraveled, but it's going to take additional time. By hereditary, I mean a trait or condition that is transmitted in the family from generation to generation.

Future of breast cancer research?

Question from JS: Considering the updates from this year's conference, what might we hope to see announced next year? Or in five years?

Answers —Generosa Grana, M.D., F.A.C.P.: I'm not so hopeful we will have exciting things next year, because it will take a while for this to percolate, but the next five years will be fruitful in showing us new ways to treat a woman with early-stage breast cancer. We will move beyond tumor size or HER2-positive to this gene-array-based technology. These technologies depend on sampling a tiny area of the tumor and testing that tumor for expression of anywhere from 30 to 70 genes and their specific pattern in that cancer. That is the whole technology behind Oncotype DX testing and a similar test called the Amsterdam-4.

So five years from now we may be using different tools to assess risk. I'm hopeful that five years from now we will be doing much more in the way of targeted therapy where we will choose drugs such as Herceptin, Avastin, lapatinib, and others that will target specific pathways in the cancer cell rather than randomly attacking cells in a non-specific way, which is what chemotherapy traditionally does.

Marisa Weiss, M.D., president and founder: Many of these new types of medicine will help the woman who has hormone-receptor-negative disease.

Generosa Grana, M.D., F.A.C.P.: The Amsterdam-4 is much like the Oncotype DX, but it looks at 72 genes and their expression in the tumor and it labels the cancer "good risk" and "poor risk," much as Oncotype does. Currently Oncotype is useful in the woman who is hormone-receptor-positive and lymph-node-negative.

We need tools like Oncotype that will be of use in all patients, hormone-receptor-negative and positive, lymph-node-negative and positive. These tests might be able to help us determine, first of all, what the woman's prognosis is from her cancer; secondly who needs chemotherapy and who needs hormone therapy and who needs both; and ideally, who might benefit from a particular type of chemotherapy so that we could target our drugs better.

In addition to targeting the tumor and finding more effective less toxic drugs, it would be ideal to also have better ways of managing the toxicities of our treatment.

Antibiotics during entire chemo standard?

Question from Gafdotcalm: Is it standard to be on antibiotics during the entire duration of chemotherapy?

Answer —Generosa Grana, M.D., F.A.C.P.: Some people use what are known as prophylactic antibiotics during certain periods of the chemotherapy cycle. It is sometimes done from days five to 15 of a chemotherapy cycle with the goal of preventing infectious complications. The jury is still out on how effective this approach is, and with better use of growth factor support (Neulasta [chemical name: pegfilgrastim] and Neupogen [chemical name: filgrastim]) there may be less need for these antibiotics. In my practice, I don't traditionally use suppressive antibiotics, although every case has to be individualized.

What kind of exercise while on Herceptin?

Question from JHA: I am taking Herceptin and my heart muscle is sufficient to continue treatment, but not optimum (53% by MUGA test). Can I continue exercising, and if so, how vigorous and what type is best to avoid congestive heart failure?

Answer —Generosa Grana, M.D., F.A.C.P.: You are alluding to the fact that Herceptin can cause cardiac toxicity, in particular damage to the muscle of the heart. This can lead to congestive heart failure, which is weakening of the muscle of the heart and subsequent accumulation of fluid, fatigue, and other symptoms. There is no good data on what the outcome is for women who do have damage from Herceptin. There is a feeling that this damage is not as severe as what we have seen in the past with Adriamycin, and that it might improve when the Herceptin is discontinued, but the reality is that we don't have much information on which to base that.

As to how to avoid the cardiac toxicity, once you are on Herceptin we don't have anything we can do that we know will improve that. The role of exercise is completely unknown, and I would discuss that, if at all, with a cardiologist who might be able to give you some guidance on exercise and its role and safety.

What I do tend to do in women who have a heart test (a MUGA scan) in the low normal range (50-55%) is to often repeat it in a month or two, rather than traditionally waiting three months. That way, we make sure if there is a decline, the Herceptin can be stopped before irreversible damage is done.

In early-stage breast cancer, most people would not be comfortable restarting Herceptin unless the ejection fraction goes up to the normal range again. (Ejection fraction is the pumping capacity of the heart. Normal is above 50%.) The clinical trials have built in hold points for Herceptin so that if it drops below a certain point, the drug has to be held and if it improves, it can be resumed but there are certain criteria that led to complete discontinuation of the drug. These included a drop by more than 15% in the ejection fraction, or clinical symptoms of congestive heart failure.

Next steps after positive sentinel node?

Question from MiasMom: I thought I was having a sentinel node biopsy, but after doing it, my doctor found positive lymph nodes and did a standard lymph node dissection. Was this necessary?

Answers —Generosa Grana, M.D., F.A.C.P.: The traditional approach to a woman who has a positive sentinel node is to remove additional nodes so that one can determine the true extent of disease, get a better handle on prognosis, determine what kind of chemotherapy to use, and determine whether the axilla [underarm] and supraclavicular [over the collarbone] area need to be irradiated.

Data was presented that if you have a microscopically positive sentinel node, dissecting the axilla was helpful in making decisions about outcome and treatment. Studies are being done to ask whether the best way to manage the axilla in a woman with a positive sentinel node is to remove it or irradiate it.

Marisa Weiss, M.D., president and founder: At this time, if you have a positive sentinel lymph node, additional surgery is recommended in order to determine outlook/prognosis as well as to guide appropriate effective therapies. One study showed that for women who had only a few cells in the sentinel lymph node that were detected only by special stains and the traditional lymph nodes were free and clear, that woman's outlook proved to be the same as the woman who had no lymph node involvement. But if a woman was found to have collections of cells in her sentinel lymph nodes that were discovered by traditional testing methods (H&E staining), that finding did have an impact on prognosis. That type of situation is considered more serious than women without lymph node involvement.

Hormonal therapy dose based on weight?

Question from Zanhummer: Recently, research showed that women who were overweight may not receive the correct dosing of chemo for their weight and had worse outcomes. Has any research been done on hormone therapies like Femara to see if dosing for overweight women is effective?

Answer —Generosa Grana, M.D., F.A.C.P.: There has been no work done on dosing of hormonal therapy and its effectiveness based on weight, so we traditionally use the same doses in all women. There is one standard dose of all the aromatase inhibitors. That may not be correct, but that is the status of our understanding of these agents today.