CR REPORTS FROM THE SABCS
Something Old, Something New:
Promising treatments and strategies for metastatic breast cancer
Posted By Musa Mayer
These are exciting times. Scientific understanding of breast cancer is growing exponentially. Never have there been more cancer treatments under development. PhRMA, the professional organization of the pharmaceutical industry, lists 90 for breast cancer alone in its 2008 report (this link opens a PDF). Yet most treatments now in phase I and II clinical trials—and even some in phase III—will never be approved and reach the clinic. Either they won’t work well enough, or they’ll be too toxic, or both. In the end, few will measure up to the tough standards for safety and efficacy that testing in humans necessarily involves.
Knowing so many women with metastatic breast cancer, I always come to the San Antonio Breast Cancer Symposium with a sense of urgency, looking for possibilities—for clinical trials that might offer access to promising new therapies, for phase I and II results with minimal toxicity and great response rates, for phase III results that buy meaningful time without sacrificing quality of life, and for striking new uses of existing drugs, or new strategies, for hope. And despite the many disappointments, I always find something promising to write home about.
Let’s start with something old. Medical oncologist Matthew Ellis, of the Siteman Cancer Center in St. Louis, studied the use of two doses of estradiol (estrogen) in treating 66 patients with metastatic breast cancer who had developed resistance to an aromatase inhibitor or other hormonal treatment (see abstract 16). For inclusion in this trial, patients could have had one previous chemotherapy for metastatic disease. These were women with estrogen receptor–positive breast cancer for whom hormonal treatment was no longer working—women who were, in the research jargon, “heavily pre-treated.”
Using estrogen to treat hormone-positive breast cancer may seem paradoxical, but 30 to 40 years ago, estradiol was commonly used for treatment of hormonally responsive advanced disease. In the new study, estradiol was as effective as tamoxifen, according to Ellis, but especially on higher doses, women had side effects that mimicked pregnancy, with headaches, bloating, breast tenderness and fluid retention. In this trial, the lower dose of 6 milligrams was much more tolerable, and it was as effective as a high dose. Twenty-nine percent of the participants experienced what is termed “clinical benefit,” meaning their tumors shrank or disappeared, or their disease remained stable for more than six months. Of course the study was small, and the results should be confirmed in a larger, randomized trial. Without a pharmaceutical company to underwrite the costs of a large trial of this off-patent drug, however, it’s unclear whether the results will be subject to further trials. But an inexpensive drug treatment like this would seem particularly appealing to low-resource countries, where metastatic breast cancer patients have access to so few treatments.
The other agent in development that caught my attention was T-DM1, Genentech’s antibody-drug conjugate for patients with HER2-positive metastatic breast cancer whose cancer no longer responds to Herceptin (trastuzumab). To make this agent, Herceptin is joined with a highly potent anti-microtubule chemotherapy drug, maytansine or DM1. The antibody finds the cell surface receptor and all of the cytotoxic (cell-killing) activity is unleashed within the cell, thus widening the therapeutic window—that dose level at which a drug is effective, but not too toxic. T-DM1 is believed to have all the activity of Herceptin, and not much more toxicity because of its unique targeting mechanism.
Oncologist Svetislava Vukelja of the Tyler Cancer Center, in Texas, reported on a phase II metastatic breast cancer study that had 107 HER2-positive patients who could be assessed, 69 percent of whom had more than three sites of metastasis (see abstract 33). [Read more about Vukelja in the Summer 2007 issue of CR or listen to a podcast interview with her.] These patients had already received multiple treatments for their metastatic disease, including a median of three chemotherapy regimens, more than a year of Herceptin and, for the majority, six months of Tykerb (lapatinib). This study was able to demonstrate a response rate of nearly 40 percent as assessed by the investigator, although the median follow-up of only 4.4 months was too short to show the impact on stable disease or to look at how long the treatment helps patients. Patients who had Tykerb, approved for treatment when Herceptin fails, did as well as those who had not received the drug. In an earlier phase I study, tumors shrank in 44 percent of patients with measurable disease, allowing 9.8 months before disease progression. The company is confident enough that it is planning to launch a phase III trial of T-DM1, in which the new drug will be compared with Tykerb and Xeloda (capecitabine) in second-line metastatic patients after Herceptin and a taxane have failed. Phase II trials of T-DM1 are ongoing, and can be found by searching at ClinicalTrials.gov.
Also worth noting: The large EGF30008 study of 1,286 HER2-positive and estrogen receptor–positive metastatic breast cancer patients, which compared the combination of Tykerb and the aromatase inhibitor Femara (letrozole) with letrozole alone, improved progression-free survival from 3 months to 8.2 months, and increased clinical benefit from 29 percent to nearly 48 percent. This confirms an earlier study that showed a benefit for combining an anti-HER2 drug with an anti-estrogen for this group of patients.
Other early clinical trials of drugs presented at the San Antonio Breast Cancer Symposium that may be of interest to metastatic patients include neratinib, RAD001 (evorolimus), SAHA (vorinostat) and BSI-201, for triple-negative breast cancer. Abstracts are available for these presentations at the SABCS website. This is hardly a complete list, so browsing the abstracts and posters may well turn up other results of interest.
RETURN TO MUSA MAYER'S BLOG AND SABCS PODCASTS