Friday, December 15, 2006

Barbara Brenner, Former Executive Director

I’ve been to this meeting enough times to know that there are some things that just aren’t talked about here. Environmental causes of breast cancer that are outside of our control is one of those things. But while I’m here—talking to people at the exhibit booths, listening to presentations, chatting with folks while we wait in the bathroom line—I also hear about things that are not discussed from the presentation podium but should be. Here’s the list so far:

1. Drug Interactions

Someone mentioned to me that they were starting to hear about women treated with Abraxane who developed liver problems that appeared to be associated with the drug. I asked the medical people at the Abraxis booth about this. While the company has no data on liver problems with their drug, the rep speculated that it was possible that liver problems could result if patients where also on drugs that inhibit the liver metabolism pathways through which the drug passes. She told me that the company has not looked at drug interactions like this, and it didn’t seem that the company planned to do so. This issue—of how drugs are processed through the body and how other drugs we are on might affect that process—seems very important to patients who are on multiple therapies.

2. The Sky is Falling—Patients Won’t Enroll in Trials

At least one scientific presentation I heard, along with several advocate statements bemoaned the plan by the NCI to cut funding to the clinical oncology groups that run breast cancer clinical trials. The concern expressed is that cutting funding will undermine progress in research on treatments. At the same time, people bemoan the difficulty in recruiting patients into the thousands of clinical trails that are underway. If patients aren’t enrolling, it doesn’t matter that there may be fewer trials. When funding is being cut, it seems to me to be an ideal time to see what opportunities exist for fixing a system that is clearly facing major problems. At the same time, the FDA has proposed new guidelines for providing early access to experimental therapies, raising concerns among some advocates that doing so will deter people from enrolling in trials. Maybe it’s time to take a serious look at the structure of the clinical trial system, rather than struggling to protect one that doesn’t seem to be working all that well.

3. Access to Treatment

After the presentation today of Abstract 12, comparing Faslodex to Aromasin in metastatic breast cancer patients previously treated with a non-steroidal AI (Arimidex or Femara), I asked whether there was any reason that a patient should chose one drug over the other. The presenter said that the answer was no—the results of the trial simply give patients an option. My unspoken reaction was that this was basically a drug marketing study, paid for by AstraZeneca, the maker of Faslodex. But, as I learned from Dr. Francine Halberg, there may be more to it than that, at least from the patient’s perspective. It seems that coverage of co-pay amounts or availability of some drugs under some insurance programs may indeed affect what patients can afford or even get. This is precisely the kind of thing that needs to be discussed at this meeting, and from the podium. Shouldn’t oncologists know whether their patients can get drugs they may need?

4. Tidbits Hiding in the Poster Presentations

My assigned task for this morning’s poster sessions was to look at the posters on adjuvant therapy. I learned some interesting tidbits looking at the posters and talking to the poster presenters:

  1. Optimal duration of adjuvant Herceptin is still unknown, but we know from a pilot study (Abstract 2075) that prolonged administration (52 weeks in this trial) does not confer a significant advantage.
  2. While the US is just starting a long-term study (TailoRx) to look at whether patients with early stage breast cancer that is ER+ can skip chemotherapy, a British study has already found that women with ER+ and HER2+ breast cancer is found on mammogram can skip chemotherapy and Herceptin, and be treated effectively with hormonal therapies alone. (Abstract 2090)
  3. A Canadian study (Abstract 2098) of Herceptin found that 21.6% of patients had a cardiac event while takingthe drug, though many of the patients recovered sufficiently to go back on Herceptin after a break from treatment.
  4. Women with ER negative breast cancer who are treated with tamoxifen are more likely to die from breast cancer than women with ER negative breast cancer not treated with the drug. According to Abstract 2083, “prescription of tamoxifen to women with ER negative breast cancer should be avoided.” I would have thought we knew that already, so it’s interesting to see it reported here.

Aromatase Inhibitors and Other Hormonal Therapies

Most of this morning’s oral presentations concerned aromatase inhibitors. We learned that:

Aromasin (exemestane) as adjuvant therapy is as effective as Femara (letrozole) when given after 5 years of tamoxifen in the adjuvant setting. Abstract 49 showed that the absolute benefit in terms of disease free survival (DFS) from adding Aromasin is 2%, and is “borderline” statistically significant. There was no difference in overall survival in this trial, which was cut short when the Femara vs. tamoxifen trial was ended early because of the superiority of Femara.

Faslodex (fulvestrant) is no better—and no worse—than Aromasin (exemestane) in terms of time to progression of disease for post-menopausal women with hormone positive breast cancer that has progressed after taking a non-steroidal aromatase inhibitor (AI). (Abstract 12)

Researchers are trying to identify molecular predictors of response to AIs for women with metastatic breast cancer, and some women who are ER negative on traditional assays may be eligible for AIs using appropriate molecular assays. (Abstract 14)

LHRH (luteinising hormone-releasing hormone) agonists have been used in a number of trials in the treatment of pre-menopausal, hormone positive, breast cancer. Jack Cuzick reported on a review of these trials (Abstract 15). The only trials that showed statistically significant results in reducing recurrence and mortality were those involved adding LHRH agonists to chemotherapy.

The honor of giving the McGuire Lecture this year was handed to Richard Santern, who spoke in the topic of “Aromastase Inhibitors: Where Do We Go From Here.” His talk tracked the history of the development of AIs, the evidence (quite recent, and not very strong statistically yet) that AIs improve overall survival, and the questions of whether AIs can be combined and whether resistance can be overcome. He speculated that, in the future, AIs will be combined with drugs that regulate growth factors (like Herceptin. He also believes that research needs to pursue the idea that giving the hormone estradiol can be used to address resistance to AIs, and that a breast-specific AI will be developed in the future for breast cancer prevention.

Antiangiogenic Therapy in Breast Cancer

George Sledge gave this talk, appropriate since his research group is running the E2100 trial that is the basis for Genentech’s now delayed application for approval of Avastin (bevacizumab) for treatment of metastatic breast cancer. Antiangiogenic drugs are designed to inhibit the development of blood vessels that enable cancer to spread.

His talk started with a description of E2100, which randomized patients with metastatic disease to receive either Taxol alone or Taxol plus Avastin as first line therapy, noting that the trial establishes proof of principal that antiangiogenic treatment can work. In this trial, patients had improved progression free survival (PFS)—11 months on Avastin, compared to 6 months on Taxol alone.

Sledge talked about how antiangiogenic therapy works, who it works for, and how it can be made better. Currently, antiangiogenic therapy inhibits VEGF, the vascular endothelial growth factor. As of yet, it is not possible to predict who will benefit, so women can avoid useless therapy as well as the toxicity and expense. He noted that, in the clinic, all patients progress on the therapy, and that there are many possible mechanisms of drug resistance. He did not address how to approach overcoming antiangiogenic resistance.

To see whether Avastin can be made to work better, a pilot trial is underway in the adjuvant setting, evaluating the safety of AC alone versus AC plus Avastin. If safety is established, another trial will start testing Avastin in two different durations against a control chemotherapy regimen. A Phase III trial combining Avastin and Herceptin is also being planned, since over-expression of HER2 and VEGF are correlated in breast cancer. Other angiogenic growth factors will be targeted, with one—PDGF (platelet derived growth factor)—already the subject of an early phase trial using Sutent (sunitinib or SU11248) in breast cancer.

Sledge noted what he called his mechanism-based adjuvant paranoia—what he worries about with antiangiogenic therapies:

  • Is one year of treatment long enough to inhibit revascularization? (This question prompted a “wow” from a doctor behind me.)
  • Micro-metastases may persist
  • Toxicity of chronic angiogenesis suppression

And there are other research questions with antiangiogenic drugs:

  • What’s the role of hormonal therapies with antiangiogenic drugs?
  • What would the effect be in a neoadjuvant setting?
  • Would metronomic therapy—the chronic administration of treatment at relatively low, minimally toxic doses on a frequent schedule of administration at close regular intervals, with no prolonged drug-free breaks—work?
  • Will combinations of these drugs work?

Sledge concluded that anti-VEGF therapy works in the clinic, though we don’t know why or in whom. He asserted that researchers can do better and they will. He didn’t promise when.

Genentech Advocacy Briefing

At lunch time, I attend a “by invitation” advocacy briefing by Genentech. We heard company representatives bemoan the lack of U.S. enrollment in clinical trials and the need for industry and advocates to work together to address the problem. We heard that the company believes that industry (which discovers drugs), the FDA (which protects patient safety), and the NCI (which moves clinical research forward to improve standards of care) all work best when they work together. We learned that the company believes that observational trials are necessary to understand the best use of approved drugs, since off-label use makes standard clinical trials impossible. And we heard that Genentech is committed to evaluating endpoints that are most meaningful to patients, such as survival rather than tumor response.

We were given an overview of both Herceptin and Avastin from the company’s perspective, reviewing the current uses and on-going trials.

There was a question—from me—about the release of the FDA Complete Response Letter issued in connection with the company’s effort to obtain agency approval to market Avastin for breast cancer. (Presumably Genentech won’t release it because the company is focused on getting the approval as fast as it can.) There was a question about the FDA’s proposed new guidelines on access to experimental therapies. (The company will not comply.) There was a question about the effect of the funding cut for the NCI clinical oncology groups. (Genentech is outraged—these groups need more funding, not less.)

At least they served lunch.