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WEDNESDAY, November 13, 2002 "Update from the San Antonio Meeting on Breast Cancer, December, 2002" The most important feature of this yearly meeting is to see that which is new and innovative, but really changes practice. The report of the findings of the NSABP clinical study in which women were randomized to receive radiation plus tamoxifen or to radiation alone after lumpectomy for DCIS is one of these studies. Study showed that about a third of the women benefited from tamoxifen and the benefit was largely restricted to the women who were estrogen receptor positive. According to Craig Allred, we should now consider it definitive to do estrogen receptors on all DCIS patients. The other aspect of interest in this trial was that central labs read about 80% of the stains and about 20% were done in outside labs. In these outside labs, some benefit was found in the ER- patients, but when the staining was redone, it was found that these patients actually were ER+ to a small degree. The error rate was 20 to 30%. It is worth repeating negative results because even with a small number of cells staining, there will be a benefit from therapy. Another important finding was that we might be over-treating many women who have a small chance of recurrence. We are beginning to look at changing the order of therapy. Instead of surgery it may be more practical to treat women with DCIS with hormone therapy. The results from a trial featuring the aromatase inhibitors like Arimidex were not very different from last year. They are a little more effective than tamoxifen, especially in reducing breast cancer in the contralateral breast. The toxicity profile is probably also a little improved with the aromatase inhibitors. There may be a significant bone loss potential with these drugs. It is something that will have to be watched as we go forward with adjuvant trials. The meeting also talked a lot about diagnostic and prognostic factors. We want to know what is going to be the outcome for an individual patient with an individual tumor. We also want to know about predictive factors, whether or not an individual cancer will respond to hormone therapy, chemotherapy or both. Another area of research is in the field of micro arrays, looking at the DNA and RNA to see what signals might be different and how that corresponds to prognosis. This has already moved into the clinic here through a neoadjuvant trial whereby the patient is given chemotherapy prior to surgery, and then given serial biopsies to look at genetic changes. Another promising field is proteomics, looking at proteins that are made as a way of assessing cancer, seeing if cancer could have been predicted (after the fact) by blood tests. Blood tests in the future may help us predict recurrences or early cancers. Another possible breakthrough may be the use of enzymes like UPA or PAI-1, which appear to be important in the ability of cancer cells to invade blood vessels, which lead to metastasis. They are being looked at as a predictive factor to determine the type of treatment cancer patients should have. Early studies have shown that the levels of these enzymes were important in patients with node negative breast cancer. They found that those with low levels did well, those with high levels got recurrences. These patients were randomized based on their enzyme levels to receive either no treatment or CMF chemotherapy. This may be a good way to differentiate which patients should receive treatment and which patients are being over-treated. Harback looked at women with four or more positive nodes, and found that those with high levels of the enzyme had a good response to chemotherapy. This procedure is not yet being used in the U.S. because it requires freezing the tissue and then squeezing it to get the enzymes out of the cytoplasm of the cells. Some laboratories are looking at using fixed tissue. The last thing that was looked at was developing different combinations of markers to assess prognosis and response to therapy: combining serum HER2/neu with COX II over-expression (blocked by Celebrex and Vioxx). This may be a marker for poor prognosis, and may be soon ready to move into the clinic setting. Something very interesting work is being done in the area of in novel diagnostics. Treatment requires blocking the phosphates on the receptor that make the cell multiply. One way to stop cancer growth is by blocking the estrogen receptor. Tamoxifen works to block the effect of estrogen by mimicking it. Aromatase inhibitors block the production of estrogen. Estrogen receptor antagonists block the estrogen receptor but don’t have any estrogen-like activity. The estrogen receptor can even be signaled in the absence of estrogen. Some of the agents, which block EGFR (epidural growth factor receptor), can be used to restore the responsiveness of the estrogen receptor. They include Iressa and Tarceva. Measuring EGFR may tell us how resistance develops. Do tumors change? Approximately 13% of ER+ tumors can become estrogen receptor negative when they recur. HER2 generally doesn’t change. One of the issues may be the testing and the preservation of the tissue; tissue must go into fixative right away to maintain the markers. Can you reduce the recurrence of DCIS by adding tamoxifen to radiation? This question has not been answered yet. We know that mortality from DCIS is in the 2% or less range after 10 years. The current trial looked at hormone receptor positivity to see if it made a difference. Patients received either placebo or tamoxifen. All of the impact in reducing events was in patients with ER+ DCIS. An update of the ATAC trial was presented. It continues to show that anastrazole is superior to tamoxifen in the adjuvant setting. Aromatase inhibitors are also having an impact in the prevention of new contralateral cancers. The conclusion is that aromatase inhibitors are superior to tamoxifen and will replace tamoxifen in the future. We still need to wait for longer-term data on side effects. We know the side effects of tamoxifen (uterine cancer, cardiovascular disease, etc.). Aromatase inhibitors have problems too. They cause joint pain (which usually goes away over time), may cause changes in lipid profiles (which can cause heart disease), and block estrogen so that osteoporosis may be worse. In a study of 1250 premenopausal women looking at bone mineral density, they studied bisphosphonates (including zoledronate) as well as tamoxifen and anastrazole. There was a 10% decrease in bone density with anastrozole, but if it was given with zoledronate every six months, there was no decrease. We are also interested in what zoledronate can do in the marrow to prevent the growth of cancer cells. Any increase in cerebral mets while preventing peripheral mets? There is no evidence of this. In fact women with brain metastases are living longer than ever before. Herceptin, for example, does not cross the blood/brain barrier. What agents are available today to prevent demineralization (loss of bone)? For non-cancer treatment, there are two drugs: aledronate and risedronate. Both are available in single dose weekly. Why wouldn’t you have an oophrectomy instead of using these drugs? In young women who might still be considering children, your ovaries will recover from the use of these drugs; also there are the concerns of menopause. At what age should you not consider chemotherapy? 60 seems to be a magic number in some ways because at about that time you are certain to be in menopause. There are competing medical problems and complications from treatment. It is harder to show benefits from treatment. Women under the age of 40 should always consider chemotherapy because hormone therapy may not be as effective. It is not clear whether postmenopausal node negative women need chemotherapy. What type of chemotherapy is best? In Canada they did an MA5 trial which saw very little long-term problems of chemotherapy after 10 years. They randomized patients to a regimen of CEF. It was found to be better than CMF. Another study from France compared FEC with 100-mg./m sq. of epirubicin to FEC with 50-mg/m sq. of epirubicin. They found that FEC 100 was better. It was concluded that epirubicin has less cardiotoxicity than AC. CALGB 9741 has been testing the concept that giving the same dose of chemotherapy closer together gives better results. Patients were first randomized to receive either concurrent or sequential chemotherapy. The second randomization was dose dense (every two weeks) or standard (every three weeks). Sequential chemotherapy was adriamycin followed by taxol followed by cytoxan. Concurrent was AC followed by taxol. The results showed that there was no difference between concurrent or sequential dosing, but there was a big difference between dose dense and standard administration. Dose dense had a significant benefit in disease free and overall survival after three years. It was also less toxic. Patients are also finished with therapy much sooner. Both ER+ and ER negative patients benefited from the two-week regimen. The problem is cost: it is double: $17,000 versus $34,000. Another interesting trial presented involving metastatic disease compared taxol + herceptin with taxol + carboplatin + herceptin. The addition of carboplatin showed a doubling of time to progression (6.9 months without carboplatin versus 11.2 months with carboplatin) although it is a more toxic regimen. Are any novel agents being used? New taxanes are promising in breast cancer. APO 007, a nanotaxane, appears to work in taxane resistant patients. Novel taxanes, which appear to cross the blood/brain barrier seem to work in taxane-resistant cancers. Pegylated taxanes try to avoid toxicity and hair loss. How often would you suggest bone mineral density testing? It is really important to have a baseline BMD, and then to have it checked every 1-2 years. What about ductal lavage? This does not detect invasive cancer, only those cancers which are in the ducts. We need to find out how this can best be used. Possibly it can be used to instill agents into the cancer cell and reduce the conversion of testosterone to estrogen locally. Next meeting will be
Wednesday, January 15, 2003. The topic is “Coping with Breast Cancer: A
Psychosocial Perspective for You and Your Family”. |
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