WEDNESDAY, December 19, 2001

"Update From the San Antonio Symposium, 2001"

San Antonio, Texas was the venue for the largest annual research meeting on breast cancer research. The Symposium not only covered areas which will affect the treatment of patients today, but also new discoveries which are sure to be important in the future. Tonight we will discuss the highlights of that meeting where much original research, (epidemiological, behavioral, basic science, etc.) is presented for the first time. The evening will be moderated jointly by Dr. Debu Tripathy and Dr. Hope Rugo, both medical oncologists at the UCSF Breast Care Center.

A breakthrough in the use of hormonal therapy in early stage breast cancer, in the new class of drugs known as aromatase inhibitors, emerged as the important finding at this year’s meeting. In the premenopausal woman, all the estrogen in the body comes from the ovaries. In the postmenopausal woman, any estrogen still circulating in the body comes from the conversion of testosterone into estrogen by the enzyme aromatase. The inhibitor interferes with (or blocks) the effect of the enzyme in converting the hormone testosterone to estrogen. The old aromatase inhibitors worked much higher in the conversion chain and caused more side effects. The new aromatase inhibitors are more selective, blocking the step to making estrogen. This has the effect of dropping the estrogen in the body to an almost unmeasurable level. All three aromatase inhibitors initially tested (Arimidex, Femara, and Aromasin) were found to be as good or better than Tamoxifen as first line therapy for metastatic breast cancer.

Anastrazole (Arimidex) was the first to be tested in early breast cancer. In this study, women who had finished their primary treatment for early stage breast cancer were randomized and double blinded to receive Arimidex (A), Tamoxifen (T), or Arimidex+Tamoxifen (A+T) for a period of five years. The results so far represent only about 2½ years of treatment. The researchers looked at recurrence from breast cancer, as well as new cancer in the contralateral breast. The 9400 subjects were postmenopausal, 85% were ER+. The results so far indicate that the women who received the A alone had less recurrences than either the T or A+T groups, which were equal. For new breast cancers, the A arm had 9, the T arm had 30 and the A+T arm had 23 new cancers. This is a highly significant reduction from what would be expected just from Tamoxifen alone. There have not been any significant differences yet for distant recurrence. Five women have died of breast cancer, while 80 have died of other problems, so the numbers are too small to make reliable statements about mortality at this point. As far as side effects, there were less hot flashes (-5.4%), vaginal bleeding and discharge (-10%) in the Arimidex group, but increases in musculoskeletal disorders such as carpal tunnel, arthritis, numbness and tingling, etc.(+15%). Fractures of the hip and spine showed no differences, but overall fractures were slightly elevated in the Arimidex group. To summarize, the encouraging but early results show that Arimidex resulted in less recurrences from breast cancer, and that the side effects are less except for muscle disorders and fractures. The absence of estrogen over five years will impact lipid profiles and may increase heart disease. The impact on bones is important long term for women who receive this treatment. Lastly, we need to explore the impact on cognitive function.

I am a postmenopausal woman currently on Tamoxifen, should I switch to an aromatase inhibitor? Women should not switch yet. This data is preliminary and emphasizes non-metastatic recurrence or the ocurrence of cancer in the contralateral breast. Currently this represents an absolute overall benefit of 2%. It is important to determine the effect on lipids because the greatest cause of death in women with early stage breast cancer is heart disease. Certainly aromatase inhibitors are a good choice for women who are intolerant of Tamoxifen. Perhaps the greatest encouragement can be gotten from the pace with which research is now moving from the metastatic to the adjuvant setting.

Does switching to an aromatase inhibitor save lives? Another large study compared the aromatase inhibitor, Letrozole to Tamoxifen for metastatic breast cancer. 90% of the patients were ER+. The response rate was found to be higher and the time to disease progression to be longer. It is harder to answer whether it saves lives because 50% of patients switch drugs after progression. Another study looked at preoperative hormone therapy. Patients were randomized to either Letrozole or Tamoxifen and then had their surgery about 4 months later. A higher rate of response was found with Letrozole. More patients were able to have breast-conserving surgery. Those patients who were HER2/neu+ showed the most benefit.

Does neoadjuvant therapy refer to chemotherapy? Usually it does, but in the case cited above it refers to hormone therapy. In Europe, neoadjuvant hormone therapy is used regularly with older women who might be at risk for more complications with surgery.

Is there any increase in uterine cancer with the aromatase inhibitors? So far there does not seem to be an increase, but uterine cancers are quite rare. You will not get that information until very large numbers of patients are studied. We were not aware of the higher risk of uterine cancer with Tamoxifen until one million women had been treated. Tamoxifen has a pro-estrogenic effect in the uterus, stimulating the uterine cells, which is probably the reason for the increase in uterine cancer. Aromatase inhibitors do not stimulate the uterus.

If aromatase inhibitors accelerate bone problems, are bisphosphonates any help? Yes, bisphosphonates like Fosamax are being studied. Three studies are looking at the possibility that bone may serve as a reservoir for micrometastatic breast cancer. Fosamax has been approved for osteoporosis, but can also lower the risk of bone complications in patients with early stage breast cancer as well as in multiple myeloma. A German study showed that giving micrometastatic patients another form of bisphosphonate, Clodronate, produced a large reduction in recurrence. The same was true in the U.K. The difference disappeared after the patients discontinued the drug. We are hoping to begin a new trial in the U.S. this year with the drug Zolendronate.

What all this research points to is our ability to incrementally lower the risk of recurrence for patients with early stage breast cancer. At this point we can lower the risk about 60%, but soon it could be as much as 90%, if the data on aromatase inhibitors and bisphosphonates hold up. The challenge is to make metastatic breast cancer very rare.

Is there any correlation between ER positivity and high bone density? That question is difficult to answer in patients with breast cancer, but looking at postmenopausal women in general, the highest 20% in bone density have the lowest risk of osteoporosis, but a higher risk of breast cancer. The reverse is true in the lowest 20% in bone density. These differences are not huge.

Where is science taking us? There is clearly an increasing understanding that every cancer is individual. This is probably due to differences in the genetic profile such that each cancer has a genetic fingerprint. Over the last five years we have developed the technology to look at over 20,000 genes in a given tumor sample. We can determine whether a gene is amplified or deleted, or whether the RNA is being expressed properly. A computer can take different patients’ tumors and cluster them by common characteristics. These profiles allow physicians to develop individual treatment options, as well as to identify new targets for therapy. Collagen is expressed differently in cancer tissue than in benign tissue. Certain collagen types are seen more often in cancers with bad prognosis than good prognosis. The prediction for the future is that we will be doing more profiling and looking at more markers. It is likely that we could get much more mileage out of the 15 or so treatment options we currently possess if we knew how to tailor treatment in a much more rational way.

Anything new on Herceptin? A Canadian study has been looking at giving Herceptin at triple the dose every three weeks instead of normal dose once a week. The findings indicate that the effect is actually greater with every-three-week dosing, but the toxicity can be greater with greater peak levels. Dr.Tripathy did a study comparing single dose to double dose Herceptin in women who were not taking chemotherapy. No difference was found in the efficacy of the drug at the two doses. The FDA has not approved Herceptin as first line therapy. The current large randomized trials using Herceptin and chemotherapy for a year are trying to avoid the combination of Herceptin and Adriamycin because that combination has been shown to cause more heart damage. Doxil is being studied and seems to have less cardiotoxicity, but it is too soon to tell. Cancer pathways are an exaggeration of cell growth and development that have not turned off as they should after embryonic development. Any pathway that you try to target which you think is specific for cancer probably is not. There is no magic bullet.

The NSABP (B27) neoadjuvant trial studied neoadjuvant chemotherapy. They studied Adriamycin/Cytoxan vs. immediate surgery. When given chemotherapy first for operable breast cancer, patients had better breast-conserving surgery and lived just as long with the same prognosis as those having surgery first. In this trial, only 13% of women had a complete response (no cancer left in breast and nodes). The next study compared AC>surgery with AC>Taxotere>surgery, and lastly AC>surgery>Taxotere. In the women who got both AC and Taxotere before their surgery 26% had a complete response.

There is also much interest in dosages. There is a trend toward giving chemotherapy weekly, although this regimen requires a lot more time in the office for patients. Lower doses given closer together may repress resistant cells and also allow for fewer side effects.

Are there any trials on microdosing? The theory on microdosing is that at low doses the effect is on the blood vessels that feed the tumor rather than on reducing the size of the tumor. This has not been proven to be the case despite much work by Judah Folkman, the father of angiogenesis. An interesting poster at ASCO last May looked at low doses of Methatrexate and Venblastine. They saw a response rate of about 25% and the medications were well tolerated. We are investigating microdosing with the COX2 inhibitors. Currently used as anti-inflammatory drugs under the names of Celebrex and Vioxx, they have been shown to prevent polyp formation, a precursor to cancer in the colon.

Anything new in metastatic disease? Apart from hormonal therapy, there aren’t any proven advances. All of the half dozen or so chemotherapeutic agents being used have about the same effectiveness. Some combination chemotherapies are felt to give a longer response time, but don’t enhance survival and tend to cause more toxicity. Our approach here is to use one regimen and then move to another when there is progression. One combination tested recently was Xeloda (activated by an enzyme that inhibits the division of DNA preferentially in tumor cells) and Taxotere (which induces cells to upregulate the enzyme which activates Xeloda) that were felt to be a synergistic combination. A study comparing these two drugs to Taxotere alone showed an increase in time to progression as well as a small survival benefit. New trials are proposing low doses of Taxotere and Xeloda as one arm of a randomized trial.

Are there any new interesting biological drugs in metastatic cancer? There are no new drugs that are very promising, but there are many new strategies: EGFR inhibitors or growth factor receptors are in trials, but no responses have been reported. Anti-angiogenic drugs have had some minimal early response. Cell cycle inhibitors are poised to enter clinical trials.