Friday, December 12, 2008

Jane Zones, Board Member

Dr. Patricia Steeg’s Excellent Presentation and Flying Pigs

Patricia Steeg, a molecular biologist who heads the Women’s Cancers Section of the National Cancer Institute, was recognized with the Komen Foundation’s Brinker Award at the SABCS meeting this year. She gave an excellent presentation on “Molecular insights into breast cancer metastasis”. Dr. Steeg has studied tumor metastasis for nearly two decades, and identified the first metastasis suppressor gene. She brought this work to clinical trial, and has focused particularly on brain metastasis of breast cancer.

Dr. Steeg’s take-away message was that therapies targeting metastatic tumors are worthy of much more attention than they currently receive. (When Barbara ran into Dr. Steeg earlier in the meeting and congratulated her on her award, Dr. Steeg noted her amazement that work on metastasis was being recognized at this meeting, and suggested that now we can expect pigs to fly.) Most breast cancer researchers, she stated, consider intervening at the metastatic stage too late—“the horse is already out of the barn.” Steeg states that growth in the primary tumor site is not equivalent to distant growth, and that overexpression of Nm23-HI (the first metastasis suppressor gene, which she discovered) suppresses metastases with no effect upon primary tumor size. “Primary tumors and metastatic tumors are not hardwired identically.”

Over 25 metastasis suppressor genes have now been identified, which allows a tremendous range of information and sites for developing therapeutic agents. Because drugs affect primary tumor growth and metastasis differently, we need to develop new types of agents than are already being used in breast cancer treatment.

Dr. Steeg’s particular interest in brain cancer has led her to study the “blood-brain barrier.” Most drugs cannot reach brain targets through the circulatory system, and much of the remainder of her talk dealt with various drugs that have more capacity to permeate the blood-brain barrier. Her talk set the stage for a variety of presentations on breast cancer metastasis on Friday morning.

Larry Norton Speaks Challenging Traditional Views of Cancer

Another distinguished cancer researcher receiving an award was Larry Norton, of Sloan-Kettering, who gave a broad-ranging talk titled “What is Cancer? How Modern Molecular Science is Challenging Traditional Views.” Norton is the co-creator of the Norton-Simon hypothesis, with Richard Simon, that proposes that providing maximally effective chemotherapy in as short a time as possible, reducing the volume of the primary tumor, followed by a complementary systemic therapy to eradicate remaining slower-growing cancer cells, will be the most effective form of treatment. He is a known advocate of high-dose treatment and concentrated administration of treatment.

In his talk, Dr. Norton acknowledge that most of what he had known to be true about breast cancer in the many years he’s worked in this field has proved to be wrong. He listed what is currently “known” about breast cancer:

  • it progresses in an orderly fashion
  • it is systemic, not local
  • histologic grading is prognostic
  • molecular profiling works
  • in treatment, 1 + 1 ≥ 2
  • molecular profiling works

He then went about citing evidence that supported these “knowns”, and evidence that challenged them, showing that we are all still operating (as if we didn’t know that) in a very uncertain universe.

Dr. Norton then laid out a new hypothesis for us all to consider, argue about, and study. He posits that the genes that predict metastasis do not have anything to do with mitosis (cell division), but rather with a cell’s relationship with surrounding cells. “Self-seeding” tumors (those which contain cells that circulate and then return to the primary tumor) are those which are metastatic. He noted that self-contained tumors, which do not self-seed, are evenly shaped, and that in mammographic images of aggressive primary breast tumors, the shape is ragged and uneven—as if there is a cluster of small tumors concentrating near one another.

A math whiz, according to the man who introduced him, Dr. Norton came up with a differential equation to describe the process graphically, which he hopes will help to provide more effective treatment schedules.

Dr. Norton has been an ally of BCA since ASCO met in San Francisco a number of years ago. He was the incoming president of the organization, and intervened on our behalf when we were barred from the ASCP meeting, while the pharmaceutical industry-friendly non-profits had retained their presence. Because of his going to bat for us, we developed a better relationship with ASCO.

The Genentech Luncheon

The three BCAers, Barbara, Allison, and Jane, attended a lunch sponsored by Genentech for breast cancer advocates. They do this every year at SABCS, and it gives them an opportunity to make a progress report on their latest trials and to do a little public relations. The post-lunch meeting began with a brief video on Genentech’s relationships with breast cancer advocates. Ironically, this relationship began over a dozen years ago with a confrontation involving members of BCA who were demanding compassionate access to Herceptin for women who were HER2+. Following months of negotiations, one woman chained herself to the Genentech gate, which changed the situation rapidly. Margi Stuart, a BCA board member, was one of the first to gain compassionate access to Herceptin after that action, and she claimed it extended her life considerably, allowing her to live to see her younger daughter graduate from high school. Margi died in 1997.

Of course none of this confrontational activism was depicted in the video—the several people who were interviewed lauded the cooperative relationships between Genentech and the advocates. Although BCA has had a long, continuing relationship with the company since that early struggle, no representative from our organization was interviewed for the video.

One of the trials described was on Avastin, which was recently approved by the FDA for first line treatment of metastatic breast cancer, despite BCA’s opposition. Data from the Ribbon-1 trial has never been published or released, though BCA has been asking for it for weeks since the “top line” results (i.e, the fact that the trial achieved its primary endpoint of progression free survival) were released by the company. Meanwhile, doctors are offering it to women without our being able to assess the strength of the evidence of effectiveness or safety. In response to Barbara’s question about data release at the conclusion of the talk, company representatives said they have been withholding it until they could present it at a formal conference.

Response to a further question from Barbara, about whether they had a large enough sample in their study to assess overall survival effects of Avastin, was evasive, but a spokesperson for Genentech told her later in the day that the answer to that question was “no.” The primary endpoint of Ribbon-1 was “progression-free survival”—an outcome that allows fewer participants and a much shorter trial. The speaker said that they consider this a “meaningful” endpoint, although their defense of it was convenience and expense.