Friday December 15, Day 2 of the San Antonio Breast Cancer Symposium

Key Quotes of the Day:

* Best treatment for the average woman is not the best treatment for the individual woman.

* Dumb tumors usually outwit smart oncologists.

*These cells are constantly stimulated….like drinking espresso all day!

Today there were several presentations on hormonal therapies followed by a lot of translational and basic science on targeted therapies and treatment combinations

Clinical
1. One study that was mentioned in a press release and therefore likely to make the news was underwhelming. This study found that using exemestane (brand name Aromasin) after five years of tamoxifen resulted in a 2% overall improvement in relapse free survival. The side effects were not insignificant, and included an increase in fractures, joint pain, and bone pain.

A second study compared fulvestrant (brand name Faslodex) with exemestane as a second hormone treatment after a relapse. This study showed no difference. Bottom-line: These drugs are all about the same.

2. A more provocative study was a meta-analysis of LHRH agonists--like goserelin (brand name Zoladex) and lupron--in premenopausal women with ER-positive breast cancer. LHRH agonists are drugs that put premenopausal women into temporary menopause. A number of studied have been conducted on these drugs, mostly in Europe. In these studies the LHRH agonist has been combined with chemotherapy with or without tamoxifen or with tamoxifen alone. This meta-analysis combined the results of all of these studies. It found that LHRH agonists are as effective as the chemotherapy regimens in ER-positive women. There was a small additional benefit seen when the LHRH agonist was used after chemotherapy and/or tamoxifen.

This suggests that the main way that chemotherapy works in premenopausal ER- positive breast cancer is by causing menopause to occur. We do not know yet if adding an aromatase inhibitor to an LHRH inhibitor is better; those studies are now being done.

The chemotherapy believers will undoubtedly point out that these studies were typically done with the chemotherapy regimen CMF and not with what we currently use (AC followed by T). This may be true. However, another study presented showed that women who are put into menopause with chemotherapy do better than women who are not, especially if they are younger than 40 and Her 2- negative.


Big Picture:
Several big messages today, but I think the biggest is that using targeted therapies, whether with hormone blockers, growth factor, or angiogenesis inhibitors, to stop breast cancer is more complicated than we thought. In several cases studies have found that blocking one path--i.e. angiogenesis with VEGF inhibitors--is either not enough to stop cancer or only stops it temporarily because either the body has alternative routes to accomplish the same thing or because tumors have different mechanisms than normal tissue.

Two approaches were discussed for overcoming this problem: using combinations of different types of targeted therapies or determining which therapy can best take advantage of the weakness of the cancer. It is important to point out that most of the studies talked about below are being done on cancer cells in Petri dishes as well as mice and rats.

1. In the first category, Dr. Ashworth presented data on women with BRCA1 or BRCA2 mutations. BRCA is a DNA repair gene. Women who have inherited a BRCA mutation have one damaged gene and one that is okay. If the second gene becomes mutated they cannot repair DNA in the usual way. But they have an alternative approach that is not quite as good but works as a backup. Dr. Ashworth’s group used a drug (carboplatinum) that causes DNA damage that requires the main pathway for repair. Since there was no way to do the repair, the cells died. They also developed another approach, which was to use a drug that blocked the back-up path. This left the cell with no method of repair, which led to cell death. This approach is now being studied in women with BRCA mutations.


2. Dr. Santen presented a review of hormone control of breast cancer. He pointed out that cancer cells that have been deprived of estrogen for a long time (as with an aromatase inhibitor) become more sensitive to very low levels of estrogen. This leads to two potential approaches. Either further eliminating estrogen if possible or--even more interesting--giving estrogen at a high level. The latter actually causes cells to die and can be used to purge the resistant cells. After taking this high-dose estrogen, a woman could then, theoretically, go back to the aromatase inhibitor. This hypothetical approach appeals to me since it confirms the approach we used to use in the 1970s--changing the hormonal milieu. When the tumor becomes used to low estrogen you raise it; when it starts liking high levels you lower it, etc. More studies will be done on this approach.

3. The third example of combing two targeted therapies came from a UCLA study presented yesterday, where they used Herceptin and a VEG-F inhibitor together in a small group of women with metastatic disease to assess the safety of the combination. Another study found that combinations of angiogenesis inhibitors seem to work better than only one type. One interesting observation was that tumors with blocked angiogenesis seem to have more metastasis, while those with lots of angiogenesis have less.