December 2008: Updates from the 2008 San Antonio Breast Cancer Symposium

New ways to manage nausea?

Question from Diana: Are there any new ways to cope with nausea associated with chemotherapy and radiation?

Answer —Ruth Oratz, M.D., F.A.C.P.: The focus of this meeting was very much on the molecular biology of breast cancer and there were not any major presentations on managing the side effects of chemotherapy. The management of nausea and vomiting has really come a long way in the last decade and I think that most of our regimens have very good anti-nausea treatments.

HER2-positive people who may not need Herceptin?

Question from ShirleyR: What are your views on the latest findings that seem to show that HER2+ patients who also test positive for topoisomerase IIA do not require Herceptin if they have had Adriamycin as part of their chemo regimen?

Answer —Ruth Oratz, M.D., F.A.C.P.: This raises a very interesting molecular biology question in the management of HER2+ breast cancer. We know that in tumors that have high levels of the HER2/neu receptor, treatment with Herceptin (or trastuzumab, the generic name) is very beneficial. This is true in the setting of metastatic disease as well as in the early stage setting. Topoisomerase, also called topo II or TOP2A, is an enzyme that repairs abnormalities in DNA. The gene that codes for topo II is adjacent to the gene that codes for HER2/neu. There is some question about the relationship between amplifications of the HER2/neu gene and alterations or amplifications of the topo II gene. There is some data to suggest that if topo II is amplified, the tumor cell is very sensitive to treatment with Adriamycin (chemical name: doxorubicin) and it has been suggested that Adriamycin is more effective in cancers that are HER2-positive than in those that are HER2-negative. However, the consensus amongst medical oncologists is that if the tumor overexpresses HER2/neu, HER2 targeted therapies with Herceptin or Tykerb (chemical name: lapatinib) is indicated. Most medical oncologists would not recommend the use of only Adriamycin in this setting. There is more research being done on the relationship of HER2/neu and topo II, and the question of whether or not Adriamycin is required in the treatment of HER2-positive breast cancer. There are several chemotherapy regimens which do not contain Adriamycin and which do contain HER2-targeted therapy both for metastatic disease as well as early stage breast cancer. These have been shown to be equally as effective as a regimen that does contain Adriamycin. The ones that do not and the ones that do are equal in their clinical efficacy. Certainly, more work is going to be done investigating the molecular biology of HER2/neu and topo II. As of now, our clinical practice and treatment decisions are not being based on topo II levels or topo II expressions.

Research on flaxseed?

Question from Jan: A few years ago there was some encouraging research about the effect of flaxseed on breast cancer. Has any further research been done or conclusions drawn?

Answers —Ruth Oratz, M.D., F.A.C.P.: Flaxseed is a phytoestrogen, a substance derived from a plant which has estrogen-like properties. Whether or not these agents have any effect on the growth of breast cancer cells -- either to promote the growth or inhibit the growth of these cells -- is somewhat unclear. It is very difficult to do research in this area and to actually measure the biological effects of these dietary supplements or products. As far as I know, there is no new data from this new meeting regarding the dietary intake of phytoestrogen. In general, most medical oncologists recommend that patients avoid large-dose supplementations with phytoestrogen; however, small doses or small amounts taken in the diet are probably safe.

Carol Kaplan, M.D.: I agree with that, and we also often caution patients about taking high doses of other plant estrogens, such as black cohosh and soy. We often advise patients with questions about this to run their supplement list by a clinic nutritionist in order to identify supplements that they may be unaware are plant estrogens.

News regarding triple-negative breast cancer?

Question from Joan: Was there anything new presented regarding triple-negative breast cancer?

Answer —Ruth Oratz, M.D., F.A.C.P.: Yes, triple-negative breast cancer is a subset of breast cancer that is of great concern clinically. This subset of breast cancer means that the tumor cells are negative: they don't express the estrogen receptor, the progesterone receptor, or the HER2/neu receptor. They're negative for all three of these biologic markers, which can serve as targets for therapy. The implication of this is that the mainstay of treatment for triple-negative breast cancer is chemotherapy. There is a tremendous clinical need for better understanding of the biological processes that drive the growth and proliferation of triple-negative breast cancer cells. Two very interesting abstracts were presented at the meeting in San Antonio about possible molecular pathways, which may play an important role in the biology of triple-negative breast cancer. One of these described the higher expression of a gene called GRB7. Higher expression of GRB7 was associated with an increased risk of recurrence and did not correlate with any other clinical characteristics of either the tumor or the patient, except that lower expression of GRB7 was often present in women who were older than age 65. GRB7 played a critical role in signaling the molecular pathways which affect motility, migration, adhesions, and interaction between the tumor cells and its surrounding tissue. All of these factors are related to the ability of the malignant cancer cells to metastasize, and in particular to triple-negative breast cancer cells. GRB7 may present a new promising target for treatment for triple-negative breast cancer. Another interesting abstract related to triple-negative breast cancer was the presentation about a new drug called dasatinib. This is a powerful oral drug which seems to inhibit some of the pathways related to metastatic activity of triple-negative cells, perhaps including those that have to do with GRB7. In one small clinical trial, which was a Phase II study of dasatinib in 36 patients with advanced triple-negative breast cancer who had received prior chemotherapy, four patients had meaningful clinical responses, and another four patients showed some transient benefits from treatment. Although this was a small study, and activity was modest in this trial, dasatinib may be a promising agent and it deserves further study in less heavily pre-treated patients with triple-negative breast cancer. Dasatinib is a targeted biologic agent and may be more effective if given in combination with chemotherapy. Additional research will be looking at these questions.

Taking aromatase inhibitors longer than 5 years?

Question from Speechpro55: Are there any updates on the efficacy of continuing aromatase inhibitors past the 5-year mark?

Answers —Ruth Oratz, M.D., F.A.C.P.: There was a great deal of discussion at this conference about hormonal therapy of estrogen-receptor-positive breast cancer in postmenopausal women. All of the major clinical trials looking at the use of aromatase inhibitors in this population were updated at San Antonio this year in a meta-analysis of all studies, using aromatase inhibitors either as first-line hormonal therapy for 5 years or in studies in which patients received tamoxifen first and then switched to an aromatase inhibitor. In all of these trials, there was a benefit for the use of aromatase inhibitors. The benefit of aromatase inhibitors compared to tamoxifen is modest. The benefit is between a 2 and 4% decrease in breast cancer recurrence, much of which relates to a decrease in either local recurrence in the breast or in the incidence of contralateral breast cancer. There was less of an impact of aromatase inhibitor use on distant recurrence for metastases. There was no significant survival benefit to the use of aromatase inhibitors for any duration of treatment when compared to tamoxifen. The question of duration of hormonal therapy remains unanswered. In only one clinical trial do we have information about more prolonged treatments with aromatase inhibitors, that is beyond 5 years, and it is unclear if prolonged therapy has a significant benefit over 5 years of treatment. There is some concern and difficulty in interpreting the results of these clinical trials because in most of the studies, patients were able to cross over and receive treatment with aromatase inhibitors if they had been on tamoxifen alone, or to continue treatment beyond the set duration of time. So it's difficult to interpret this data. I'm not sure that we're going to have a clear-cut answer on whether or not prolonging therapy beyond 5 years of hormonal treatment truly is beneficial or not. We did not see that information emerge from any of the presentations at San Antonio this year.

Ruth Oratz, M.D., F.A.C.P.: I would also add there was a lot of discussion about aromatase inhibitors being superior to tamoxifen. I really want to emphasize (and this is my own personal viewpoint but I think shared by many others) that the benefits are modest. The side effects from these aromatase inhibitors are significant and not inconsequential. And although this was mentioned only really in one presentation, some of the difference between response to aromatase inhibitors and tamoxifen may be accounted for by the fact that perhaps between 7 and 10% of individuals taking tamoxifen do not actually derive the maximum clinical benefits from tamoxifen. The reason for this is that tamoxifen must be activated by enzymes in the liver to its active metabolite endoxifen, and perhaps up to 10% of individuals do not have the enzyme that activates tamoxifen. Also, some medications -- in particular, antidepressants -- may interfere with the activation of tamoxifen. Many patients taking tamoxifen are also on these medications, and these include Paxil (chemical name: paroxetine), Zoloft (chemical name: sertraline), Wellbutrin (chemical name: bupropion HCI), all the common anti-depressants. Perhaps some of the differences we see between aromatase inhibitors and tamoxifen are in fact related either to problems with tamoxifen metabolism or interference with tamoxifen activation by other medications. Both tamoxifen and aromatase inhibitors are effective, active hormonal therapies for women who have estrogen-receptor-positive breast cancer. The choice of which agent is best for each individual patient should be discussed by each woman and her physician, taking into account factors such as other medications that she may be on, and perhaps even the consideration of testing for the presence of the enzymes that activate tamoxifen.

Editor's Note: If you are taking tamoxifen, talk to your doctor about alternative antidepressants. For more information, please visit the Breastcancer.org Tamoxifen page.

Carol Kaplan, M.D.: It's important to note that the standard of care at this time for aromatase inhibitor therapy is an aromatase inhibitor treatment duration of no more than 5 years.

Ruth Oratz, M.D., F.A.C.P.: Either 5 years total tamoxifen plus aromatase inhibitor, or 5 years of the aromatase inhibitor, or 5 years of tamoxifen followed by 5 years of aromatase inhibitor. They're all effective; whether one is better than the other remains to be seen.

New chemotherapy for metastatic breast cancer?

Question from MLP: Dr. Kaplan, are there any new/upcoming chemotherapy drugs for metastatic breast cancer? (Any in clinical trials at this time?) We need more conferences on metastatic breast cancer! Thanks.

Answers —Carol Kaplan, M.D.: I think that at every conference that we attend we hear about exciting new drugs to be used in the metastatic setting. Some of the more notable drugs being discussed at this time include targeted therapies, specifically drugs that target patients with BRCA gene mutations, and drugs called tyrosine kinase inhibitors. An example of a tyrosine kinase inhibitor is lapatinib (brand name: Tykerb), which many of you have heard of. There was an interesting presentation at San Antonio this year about neratinib, a tyrosine kinase inhibitor, which seems to have efficacy in the treatment of metastatic HER2-positive breast cancer patients. However, this drug brings with it a significant rate of diarrhea, which is not to be minimized when treatment in the metastatic setting is often intended to improve quality of life. That is just one example of a number of agents that were discussed at the meeting. This goes back to Dr. Oratz's comment earlier about the focus of this conference being the molecular biology of breast cancer. As we learn more about the genes and protein expression involved in the biology of breast cancer, we are excited to see the introduction of a number of new targeted agents.

Ruth Oratz, M.D., F.A.C.P.: Another interesting class of drugs, again for patients with BRCA gene mutations, is the PARP inhibitors. At the conference there was an update on clinical data using these agents. Again, another promising direction for new drug discovery in the treatment of breast cancer.

Carol Kaplan, M.D.: Finally, another interesting presentation revealed a promising level of efficacy when using what are called conjugated therapies; specifically, a drug conjugated, or attached to, an antibody. In one case presented, this antibody was trastuzumab. These conjugates may allow a more direct delivery mechanism of anti-cancer drugs to tumors.

Prophylactic Zometa for hormone-positive breast cancer?

Question from MLevine: Any new research about prophylactic Zometa for hormone-positive breast cancer? Thanks!

Answer —Ruth Oratz, M.D., F.A.C.P.: Yes. To review, there was a presentation at ASCO in June of this year which demonstrated that using Zometa (or zoledronic acid) may help prevent recurrence in young women with estrogen-receptor-positive breast cancer. Historically, Zometa has been used for the treatment of bone metastases from breast and other cancers. Zometa is not a chemotherapy drug, but rather belongs to a class of drugs called bisphosphonates. These agents, including Fosamax (chemical name: alendronate sodium), Actonel (chemical name: risedronate), clodronate (brand name: Bonefos) and others, have also been shown to help improve bone density in women who have osteopenia or osteoporosis. At the San Antonio meeting, we saw an update of a clinical trial using Zometa in postmenopausal women with estrogen-receptor-positive breast cancer who were also receiving an aromatase inhibitor as hormonal therapy. In this study, similar results were now reported for the benefit of Zometa in postmenopausal women as had previously been reported for premenopausal women. So, in addition to helping maintain bone density, Zometa may help prevent recurrences of breast cancer in hormone-receptor-positive cases.

What are some upcoming clinical trials?

Question from Dorcas: Dr. Kaplan, was there any news about upcoming clinical trials at the meeting? What trials are you working on?

Answers —Carol Kaplan, M.D.: Yes, there are a multitude of clinical trials ongoing internationally meant to address many of the questions remaining in the realms of metastatic and adjuvant therapy. Some of the most exciting trials in my opinion include the use of bevacizumab (brand name: Avastin). Bevacizumab is being investigated in combination with chemotherapy in the adjuvant setting after having shown clear benefit in trials previously reported in the metastatic setting. Other notable ongoing trials include those making use of the previously mentioned PARP inhibitors, both as monotherapy and in combination with chemotherapeutic agents.

Ruth Oratz, M.D., F.A.C.P.: I think what's exciting and promising, and what we saw at this meeting, was that research was proceeding at a fast pace. There is a great deal of interest in defining not only the underlying biological mechanisms of the disease, but in identifying a variety of new therapeutic approaches.

Carol Kaplan, M.D.: For patients interested in seeking out clinical trials for which they may be eligible, www.clinicaltrials.gov is an excellent Web site that allows you to search for open clinical trials and future clinical trials that may be relevant to your care.

Long-term followup on DIEP reconstruction?

Question from NVH: Has there been any long-term follow up on the DIEP-type reconstruction? How are women faring with it?

Answer —Ruth Oratz, M.D., F.A.C.P.: I can't say that I saw anything presented at the meeting about it, but my understanding is that it's a very useful and accepted plastic surgical technique for breast reconstruction following mastectomy. The choice of which type of reconstruction is appropriate for any individual patient is a personalized decision that can really only be made by that patient in consultation with her physician. There are many alternatives for plastic surgical reconstruction of the breasts after mastectomy, including immediate reconstruction with implants, tissue expander followed by reconstruction, and a variety of flap reconstructions. The details of which surgical technique is best for any individual woman depend on her anatomy and her other medical conditions.

New research on chemo brain?

Question from Cinna: Dr. Kaplan, I am looking for more info regarding "chemo brain." Two years out from treatment with A/C, Taxol, and Herceptin I still struggle with this. Are there any new approaches? Is anyone familiar with Provigil? Thanks for your time.

Answers —Carol Kaplan, M.D.: Chemotherapy brain refers to a global cognitive deficit experienced by many women who have undergone chemotherapy treatment for breast cancer. It is, admittedly, a poorly understood phenomenon. My personal bias is that it is likely a combination of factors, rather than direct toxicity to the brain from the chemotherapy drugs. Fatigue, estrogen deficiency, sleep cycle alterations, and depression are experienced by many cancer patients, and are likely the causative factors that can be used to explain chemo brain. There have been research studies using stimulants such as Provigil (chemical name: modafinil) as well as drugs used for other neurologic conditions, such as Alzheimer's disease medications. However, I'm unaware of any definitive results proving efficacy when using these agents to treat chemo brain.

Ruth Oratz, M.D., F.A.C.P.: I agree with everything Dr. Kaplan says, and for most women this side effect is self-limited and reversible. But certainly, some patients report more prolonged effect of treatment on their cognitive functions. I would agree with Dr. Kaplan that since there are so many factors that can contribute to cognitive function, women who have long-term or persistent issues related to this should undergo a more thorough psychological -- and if it's severe even perhaps neurological -- evaluation. Other medications, other illnesses, and other circumstances (emotional and psychosocial) can contribute to the decreased cognitive functions and these should be evaluated.

Zometa for early breast cancer?

Question from RSmith: What are your thoughts on using Zometa in Stage I breast cancer? I hear there are studies showing it lowers recurrence and also helps keep bones strong. Do you think this will become standard of care for early breast cancer?

Answers —Ruth Oratz, M.D., F.A.C.P.: We addressed this question earlier directly when we talked about the updates of the use of Zometa in postmenopausal women as well as premenopausal women. Whether or not this becomes a standard of care still remains to be seen, although there is an increasing body of data to support the concept that the use of bisphosphonates in general may help reduce the incidence of breast cancer recurrence. I would like to emphasize, however, that this effect is modest and that there are potential side effects from these drugs. So the risks and benefits of using these agents for a given individual, again, should be discussed with her physician, or treatment should be conducted in a clinical trial.

Carol Kaplan, M.D.: I agree with Dr. Oratz and am excitedly awaiting results from trials designed to answer this specific question. Patients should not underestimate the potential toxicity that can come from Zometa therapy, which include bone pain, a small risk of renal insufficiency, and rare occurrences of osteonecrosis of the jaw. Zometa is a costly medication and at this time is not approved for use in the adjuvant setting, which may limit coverage by insurance companies.

Were any updates to the HERA trial presented?

Question from Mona: Were any updates to the HERA trial presented?

Answer —Ruth Oratz, M.D., F.A.C.P.: We were awaiting an important update to the HERA trial, which was an internationally conducted clinical study of the use of Herceptin (chemical name: trastuzumab) following chemotherapy for patients with HER2-positive breast cancer. In the HERA trial, women were randomized to receive either no trastuzumab or 1 year of trastuzumab therapy or 2 years of trastuzumab therapy. To date, the study has demonstrated that the use of trastuzumab was superior in efficacy to the use of chemotherapy alone without trastuzumab. However, we are still awaiting results regarding the duration of treatment, and the question of whether 2 years of trastuzumab treatment is superior to 1 year, or the same, or inferior remains unanswered. There was no update at this meeting about the duration of trastuzumab treatment in the adjuvant setting.

Anything new about lymphedema?

Question from Barbara: Anything new about lymphedema?

Answer —Carol Kaplan, M.D.: There was an abstract presented at San Antonio describing the results of a study intended to evaluate the risk of air travel and how it may relate to lymphedema. Although no definitive answer to the common patient question about whether air travel can increase their risk of lymphedema or worsen pre-existing lymphedema came from this abstract, it did demonstrate the fact that any lymphedema risk related to air travel would be minimal at most. I think it is important to note that it is common for a patient to ask breast cancer clinicians whether air travel will worsen their lymphedema, but I would caution patients against limiting their life experiences due to this concern at this time. Additionally, I would caution patients against the common use of lymphedema sleeves to prevent air travel-related lymphedema as an ill-fitting sleeve can, in fact, cause lymphedema itself or can contribute to the development of lymphedema.

Research on breast density as risk factor?

Question from JFisch: What research has there been, or might be underway, to indicate what factors might change breast density and its power as a risk factor for breast cancer?

Answer —Ruth Oratz, M.D., F.A.C.P.: I'm not sure that breast density in and of itself continues to be an important risk factor for future developments of breast cancer. However, there was an interesting abstract that stated that women who had a history of benign fibrocystic disease of the breast, particularly if atypical was present, had a higher risk of future breast cancer. This is consistent with information that has previously been reported.

Long-term research on brachytherapy?

Question from BAM: I had brachytherapy with MammoSite in 2004. Have there been any reports of any negative side effects about this form of radiation or comparisons to external radiation?

Answer —Carol Kaplan, M.D.: There were no updates on the long-term efficacy or side effects of brachytherapy at this conference.

Bioidentical hormone replacement therapy for survivors?

Question from Jan: Is there any news about bioidentical hormone replacement therapy for breast cancer survivors?

Answer —Ruth Oratz, M.D., F.A.C.P.: This conference did not present any new data about bioidentical hormone therapy. However, women should be strongly cautioned that bioidentical hormones are hormones and they carry the same increased risk of breast cancer as any other form of hormone replacement therapy.

Prognosis impacted by BRCA gene?

Question from Batemom: Are there any new studies that show how the BRCA gene impacts breast cancer prognosis?

Answer —Carol Kaplan, M.D.: I don't believe San Antonio brought any new trial results regarding this issue. However, as Dr. Oratz discussed previously, triple-negative breast cancer unfortunately brings with it a worse prognosis than certain other subsets of breast cancer, and triple-negative breast cancer is associated with the BRCA1 mutation.

Risk of leukemia after chemotherapy?

Question from SimonC: Dr. Kaplan, did anyone talk about the growing rates of leukemia and MDS following chemo for breast cancer? That's what happened to me and I'm concerned that women aren't being warned ahead of time that this is a real risk. I know my oncologist didn't talk about it.

Answer —Carol Kaplan, M.D.: Unfortunately, certain chemotherapy regimens are associated with permanent bone marrow toxicity, which can result in leukemia or a pre-leukemic diagnosis such as MDS (myelodysplastic syndrome). These risks have been well described in historical breast cancer trials, but it is important to point out that the risk is miniscule. However, unfortunately, the risk is real. I do believe that when women discuss the pros and cons of chemotherapy in the adjuvant setting with their oncologist, these toxicities should be pointed out. Having said that, if a woman is thought to be a candidate for adjuvant chemotherapy, the benefits of treatment far outweigh the risks of bone marrow toxicity. I am sorry that you have had the experience you have had, and you do well for other patients by sharing that experience.

Most promising news from San Antonio?

Question from LEN: What was the most promising news you heard this year at San Antonio?

Answer —Ruth Oratz, M.D., F.A.C.P.: There was some very exciting news this year. The two presentations that I found most provocative and encouraging were really philosophical conversations about how breast cancer grows and spreads. These were presentations by Dr. Larry Norton and Dr. Patricia Steeg about the growth and metastatic potential of breast cancer cells. Both of these scientists presented overarching and unifying fundamental concepts about what makes cancer cells malignant, and how these cells grow, divide, and spread through the body. It is this kind of clear and rational basis for building more detailed analyses of the molecular nature of cancer cells and their biological behavior that will ultimately lead to better therapies and further improvements in curing breast cancer. Once again, returning to my very initial comment about this year’s San Antonio conference, the big news this year was not so much in the details of the clinical trials reporting, but in these kinds of basic approaches to understanding the molecular biology of breast cancer.