Thursday, December 14, 2006

Barbara Brenner, Former Executive Director

The days are long here. Mine started this morning with breakfast with a Stefanie Jeffrey, a surgeon and researcher at Stanford who is a member of BCA’s Scientific Advisory Board. We talked about many things, but what most intrigued me was what Stefanie is thinking about how there are probably lots of women with breast cancer who don’t need any treatment other than surgery. Of course, that’s not an idea that anyone will explore at this meeting. Here, the reports are largely about giving more kinds of treatment to get what, at this stage anyway, are pretty meaningless results from the patient’s perspective. As you’ll notice if you read on.

Epigenetics: Beyond the Genome

The day started with a presentation by Manel Esteller from the Spanish National Cancer Center on the breast cancer epigenome. He gave the best description of epigenetics I’ve heard: gene activity that doesn’t depend on gene sequences. Folks in this field are looking for how the environment talks to DNA as a way of understanding breast cancer. What Dr. Esteller means by “environment” is not what we at BCA usually mean by the word. He’s looking at modifications that happen to proteins and to DNA that are outside of the gene sequence. So he’s looking beyond genes to biological and internal chemical processes that affect breast cancer. It’s about more than genes, as we know from the fact that identical twins—who have the same genes—don’t always both develop breast cancer when one of the pair does. People working in epigenetics are trying to find drugs that will address the epigenetic processes. We’ll need to stay tuned for what comes out of this work.

Targeted Therapies: Little Trials, Wrong Endpoints, Wrong Design?

We first heard about Tykerb (lapatinib) earlier this year at ASCO. Today we heard about two trials looking at the drug, one in inflammatory breast cancer, and the other in metastatic breast cancer patients.

The first abstract presented involved neo-adjuvant treatment of 34 patients with inflammatory breast cancer. The primary objective of the trial was pathological complete response (pCR) in the breast and lymph nodes. The first preliminary analysis showed that 20 of 21 patients had clinical response, and 3 had pCR within the first two weeks of treatment. Researchers found significant clinical activity compared to usual chemo regimes for inflammatory breast cancer, with a 30% clinical response rate on Tykerb alone, and a 77% rate when Tykerb was combined with Taxol (paclitaxel). The presenter, Dr. Cristofanilli, was excited by these results for inflammatory breast cancer patients, though he noted that a prospective trial (and presumably a larger one) will be needed to prove that the treatment works. This is, according to Dr. Cristofanilli, the first targeted therapy tested in a multi-centered trial in inflammatory breast cancer patients.

Abstract 2 looked at Tykerb plus capecitabine (Xeloda) versus capecitabine alone in patients with HER2 positive advanced or metastatic breast cancer. The primary objective of this trial involving 321 patients was time to progression (TTP). TTP was 36.9 weeks on Tykerb plus capecitabine compared to 19.7 weeks on capecitabine alone. Presumably based on these results, the trial was stopped early. There was loss of LVEF (heart function) in 2.5% of the patients who got Tykerb. The researchers are looking for a subgroup of patients who might benefit from Tykerb from the point of view of progression free survival (PFS), but so far have found only that level of HER2/neu over-expression is predictive of benefit.

The third abstract presented today also looked 207 HER2 positive breast cancer patients with hormone-dependant metastatic disease, evaluating whether Herceptin (trastuzumab) prolongs progression free survival (PFS). Overall survival (OS) was a secondary endpoint of the trial. Half of the patients were treated with Arimidex (anastrozole) alone, half were treated with Arimidex plus Herceptin. Patients on Arimidex plus Herceptin had 4.8 months of PFS, compared to 2.4 months for patients who received Arimidex alone, and the difference was statistically significant. Overall survival was prolonged in the patients on the combination therapy, but the data on OS were not statistically significant. Side effects were worse on patients who were treated with Herceptin plus Arimidex. In both arms of this trial, time to treatment response was 2 months, and median duration of treatment response was 10 months.

None of these trials was large enough to generate truly meaningful results. In addition, all three of these trials had worthless endpoints. Time to progression (TTP) and progression free survival (PFS) are pretty much meaningless markers for patients. What patients need to know is whether the drug will improve their chances of survival, and for how long. And TTP or PFS don’t necessarily tell patients anything meaningful about survival data. This is pretty clearly from information that Dr. Mackey presented in the Herceptin trial described in Abstract 3. In an unplanned subgroup analysis, patients without liver metastases had better OS on combined therapy (41.3 months) than on Arimidex alone (32.1 months). But the TTP for this group of patients was twice as good (7.7 months) on combined therapy than on Arimidex alone (3.8 months). There are currently 9 trials of Tykerb (which is not yet approved by the FDA) underway. None of them has a primary endpoint of overall survival.

And one doctor asserted that neither of the last two trials was structured in a way that permits us to truly say that the combination therapies are better than either treatment alone, when both drugs in the trials haven’t been tired alone in these patients before combining them.

HER2/neu Vaccine in Development

Abstract 4 presented clinical trials results from two trials of a HER2/neu vaccine labeled E75, which the presenter described as an intervention designed to be used in community setting in patients at high risk of recurrence. While the trials were small and not randomized, the 101 patients who received the vaccine had a clinical recurrence rate of 7%, compared to a recurrence rate of 16% in the control group after 24 months. A large, randomized Phase III trial was called for by the presenter.

Breast Cancer Incidence Declined in 2003

The report on Abstract 5 was prepared by Jane Zones, BCA Board Member who is attending her first San Antonio meeting.

Miscellaneous Research Musings

It’s not easy to characterize the common themes in the information presented in the general afternoon session. We heard a presentation (Abstract 6) arguing that a human mammary tumor virus is responsible for much of the breast cancer in the United States in Western Europe. And we heard a presentation (Abstract 7) on proliferating macrophages and their association with worse prognosis and worse outcomes. Macrophages, according to Wikipedia, are cells that that originate from specific white blood cells called monocytes. Monocytes and macrophages are phagocytes, acting in both nonspecific defense (or innate immunity) as well as specific defense (or cell-mediated immunity) of vertebrate animals. Their role is to phagocytize (engulf and then digest) cellular debris and pathogens either as stationary or mobile cells, and to stimulate lymphocytes and other immune cells to respond to the pathogen.

We also heard updates on two trials. Abstract 10 looked at the impact of a radiation “boost” on local control of breast cancer, fibrosis and overall survival after 10 years. The boost improved local control (local recurrence rate in the “no boost” group was 12%, and 7% in the “boost” group), but made no difference in overall survival. The local control benefit was greatest in younger patients, and decreased with age. The boost group did experience more fibrosis.

Abstract 11 presented further follow up, at 8.2 years, of a trial looking at whether women 70 or older with early stage, ER+ breast cancer benefited from adding radiation therapy to tamoxifen. The only difference between the two groups of patients was that those who had radiation had a lower incidence of local recurrence. The absolute benefit from the radiation in local recurrence rate was 5.9%. Dr. Hughes, in presenting the data, concluded that tamoxifen without radiation is a reasonable option for women 70 and older with early, ER+ breast cancer. He did not address – and apparently didn’t study – whether women would do as well with surgery alone.

Adjuvant Herceptin Redux

Dennis Slamon presented Abstract 52 the second interim analysis of the BCIRG 006 trial of Herceptin as adjuvant therapy. The three-armed trial involves 3222 HER2 positive patients receiving either a) Adriamycin plus cytoxan, followed by taxotere, b) adriamycin plus cytoxan, followed by taxotere and Herceptin for 1 year, or c) taxotere and carboplatin, followed by Herceptin. Primary endpoint is disease free survival. Secondary endpoints are overall survival and toxicity.

The first efficacy results were released in April 2005, and cross-over to Herceptin was permitted at that time. As of now, only 17 of the 1073 patients eligible to crossover have done so, meaning that 98.4% of the control arm enrollment can be followed for comparative analysis. This is good news, given the impossibility of ever knowing exactly how effective and safe drugs are in the long term when trials are cut short and people are allowed to take the drug that was being evaluated. This happened in the tamoxifen prevention trial (NSABP 1), and is becoming a common problem in many drug trials.

Disease free survival and overall survival benefits from Herceptin persist at 36 months in this trial. Cardiotoxicity from Herceptin also persists, and does not appear to resolve as some have speculated that it would. In the anthracyline (Adriamycin) based arms, there 4 patients have developed leukemia. While leukemias are expected with anthracyclines, Dr. Slamon noted that these cases had occurred early. With the updated analysis presented, the difference in number of DFS events and breast cancer deaths in favor of Adriamycin plus cytoxan followed by taxotere and Herceptin, neither of which is statistically significant, is now exceeded by the number of critical adverse events. He closed his talk with the provocative question of whether anthracyclines should continue to be used in treating breast cancer.