Dr. Slamon's 10-6-11 NEJM review on Herceptin

[Hopeful]

http://www.nejm.org/doi/full/10.1056...TOC#t=abstract

From the full article:

"The emerging further understanding of longterm and life-altering toxic effects associated with adjuvant anthracyclines may provide the most compelling support for nonanthracycline regimens. The well-known, long-term side effects of anthracyclines include significantly increased risks of congestive heart failure, myelodysplasia, and acute leukemia. However, recent analyses
of the National Cancer Institute Surveillance, Epidemiology,and End Results (SEER) database indicate that we may be underestimating the full effect of anthracycline use on long-term cardiac and hematologic health in patients treated for breast cancer with these agents, possibly because the majority of adjuvant studies have been designed primarily to evaluate differences in efficacy and have used follow-up periods of 7 to 10 years for both efficacy and safety analyses. Attempts to obtain longer-term safety data, including cardiac outcomes, are systematically biased by loss of later follow-up.

In addition, the SEER database is derived from information on women 65 years of age or older. The mean age of women in the HER2-positive adjuvant studies was 51 to 52 years, whereas the
mean age of the overall breast-cancer population is approximately 62 years. Given that data from our study and other trials show that trastuzumab augments the incidence of anthracycline-associated congestive heart failure and subclinical loss of LVEF, the full effect of any nonsymptomatic damage induced by the combination of trastuzumab with anthracycline-based regimens may not be apparent until much later as these younger women have additional, age-related cardiac insults. Our findings on long-term, subclinical LVEF losses, as well as the published results from the SEER database analyses, involving some 42,000 women, support this concern.

Furthermore, although myeloid growth factors permit delivery of full-dose, accelerated- schedule adjuvant anthracycline cyclophosphamide treatments, registry data suggest a doubling of the incidences of acute leukemia and myelodysplasia associated with these regimens, though the absolute risk remains low. Of note, all cases of acute leukemia in our study occurred in patients who had previously been exposed to an anthracycline. Some observers have argued that these major toxic effects are rare and are offset by significant efficacy gains obtained with anthracyclines. However, our data do not fully support this argument. We did not find any significant incremental therapeutic benefits of combined trastuzumab–anthracycline treatment as compared with TCH, yet we did see significant increases in both acute and chronic toxic effects with the trastuzumab–anthracycline regimen. Consequently, we believe that TCH offers an effective alternative to the anthracycline-based regimens and their associated risks."

Hopeful

[Lani]

more--article about and abstract


Survival Significantly Increased in Early Breast Cancer after Treatment with Herceptin and Chemotherapy
[UCLA's Jonsson Comprehensive Cancer Center]
Treating women with early stage breast cancer with a combination of chemotherapy and the molecularly targeted drug Herceptin significantly increases survival in patients with a specific genetic mutation that results in very aggressive disease, a researcher with UCLA's Jonsson Comprehensive Cancer Center reported Wednesday.

The study also found that a regimen without the drug Adriamycin, an anthracycline commonly used as a mainstay to treat breast cancer but one that, especially when paired with Herceptin, can cause permanent heart damage, was comparable to a regimen with Adriamycin. The data shows that anthracyclines aren't necessary to treat early stage breast cancer effectively, and that the cardiac and other associated toxicities can and should be avoided, said study lead author Dr. Dennis Slamon, whose basic laboratory and clinical research led to the development of Herceptin.

"We're encouraged that the survival advantages found in this study have been maintained and continue to be significant," said Slamon, director of clinical/translational research at UCLA's Jonsson Comprehensive Cancer Center. "I believe there's room for even further improvement."

The study appears Oct. 6, 2011 in the peer-reviewed New England Journal of Medicine.

The three-armed study compared the standard therapy of Adriamycin and Carboplatin followed by Taxotere (ACT), the same regimen plus one year of Herceptin (ACTH), and a regimen of Taxotere and Carboplatin with one year of Herceptin (TCH).

Slamon said this is the first time that overall survival has been measured this far out—a little more than five years—in this population of breast cancer patients.

The study shows a survival advantage for patients in the Herceptin-containing arms, with 92 percent of patients on ACTH and 91 percent of patients on TCH still alive at five years, compared to 87 percent in the ACT arm. Estimated disease-free survival, or the time from treatment to recurrence, was 75 percent the ACT arm, 84 percent among those receiving ACTH and 81 percent in the TCH arm.

The study set out to specifically test Herceptin with and without anthracylines to determine whether oncologists could provide a therapy as effective as ACTH without the resulting toxicities, including congestive heart failure and other cardiac problems. The study, Slamon said, showed that the women who did not receive Adriamycin had outcomes similar to those who did, but had much less heart toxicity.

The women who did receive Adriamycin and Herceptin had a five-fold greater increase of experiencing congestive heart failure and a two-fold increase of sustained cardiac dysfunction without symptoms. The women getting Adriamycin and Herceptin also experienced worse "acute" toxicities, such as nausea, diarrhea, vomiting, neuropathy, fatigue and falling white blood counts, Slamon said. Additionally, seven women in the anthracycline arms developed acute leukemia, a rare and deadly side effect of Adriamycin. One woman in the non-Adriamycin arm did develop an acute leukemia after receiving an anthracyline outside the study, Slamon said.

"Given the data in this study, it makes one really question what role Adriamycin should play in the treatment of HER-2 positive early breast cancer, or in the treatment of early breast cancer at all," Slamon said. "This trial should impact the way these breast cancers are treated, with a non-anthracycline regimen being our preferred option. I think this is a change that is going to be slow in coming, unfortunately, as many of our adjuvant treatments for breast cancer are built on the backbone of anthracyclines. While they're effective, whatever gain patients may receive is more than made up for in the serious and chronic long-term side effects."

Herceptin is effective in women with HER-2 positive breast cancer, about 20 to 25 percent of those diagnosed with the disease every year or 200,000 to 250,000 women annually worldwide. HER-2 positive breast cancer is more aggressive and results in a poorer prognosis and shorter survival times, said Slamon, who discovered the link between HER-2 positivity and aggressive breast cancer in 1987.

Conducted by the Breast Cancer International Research Group (BCIRG), the study enrolled 3,222 women with early stage breast cancer between April 2001 and March 2004. Patients were randomized to one of the three arms.

The study's primary endpoint was disease-free survival, but it also measured overall survival, safety, including cardiac toxicities, pathologic and molecular markers and quality of life.

"An improved understanding of the molecular basis of malignant disease is allowing the development of rational treatment strategies that are more effective and less toxic than traditional empiric regimens," the study states. "The identification and characterization of the HER-2 alteration in a subset of human breast cancers and the subsequent development of Herceptin represent the practical realization of this translational ideal. Our findings show that we can further exploit this new and translational knowledge to optimize efficacy while simultaneously minimizing acute and chronic toxic effects."

An editorial that accompanies the article states that the data in the study "suggest that a non-anthracycline regimen is an acceptable standard of care. The present is clearly brighter for patients with HER-2 positive breast cancer and the future promises to shine even more."

The study was sponsored by Sanofi-Aventis and Genentech and was funded in part by the Department of Defense, the Revlon/UCLA Women's Cancer Program, the U.S. Army Medical Research and Development Command, the National Cancer Institute, the California Breast Cancer Research Program and the Peter and Denise Wittich Family Project for Emerging Therapies in Breast Cancer.

EARLY VIEW: ABSTRACT: Adjuvant Trastuzumab in HER2-Positive Breast Cancer
[New England Journal of Medicine]
Background: Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab.

Methods: We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety.

Results: At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study.

Conclusions: The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk-benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia.

[chrisy]

Ha!
Now they can stop putting this on the SABCS fight night debate since the main argument made last time opposing Dr. Slamon's point was that the only evidence was a "non published study!".

[Hopeful]

Some letters to the NEJM editor on the article, and Dr. Slamon's response, just published in the current issue:

http://www.nejm.org/doi/full/10.1056...2823?query=TOC

Hopeful

[her2 newBEE]

Hi Chrisy...really curious what your onc thinks about this with regard to MM-302. I can only guess that an anthracyline attached to Trastuzumab/Her2 targeted agent would have less systemic toxicity than a standard anthracycline regimen???