Neoadjuvant Trastuzumab for Locally Advanced Breast Cancer: NOAH Results

Nick Mulcahy

February 03, 2010

February 3, 2010 — In women with either HER2-positive locally advanced or inflammatory breast cancer, trastuzumab (Herceptin, Roche) should be offered as neoadjuvant treatment alongside chemotherapy and, after surgery, continued as adjuvant treatment, according to the authors of a new study published in January 30 issue of The Lancet.

The addition of 1 year of trastuzumab in this fashion improved overall response rates, almost doubled rates of pathological complete response, and reduced risk for relapse, progression, or death, compared with no trastuzumab, write the authors, led by Luca Gianni, MD, from the Istituto Nazionale Tumori in Milan, Italy.

The results of the randomized phase 3 trial, known as NOAH (Neo-Adjuvant Herceptin), were first reported at the American Society of Clinical Oncology meeting in 2008, where Dr. Gianni said that neoadjuvant trastuzumab should be a "standard treatment option."

Currently, trastuzumab is only approved for use only in the adjuvant setting.

The study's primary end point, event-free survival, was significantly improved with the addition of trastuzumab (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.38 - 0.90; = .013). Three-year event-free survival was 71% with trastuzumab and 56% without.

However, the improved survival in the trastuzumab group was not significant, note the authors, who plan to do extended follow-up.

Dr. Gianni and colleagues cast doubt as to whether a statistically significant survival advantage will be shown in the future.

We cannot conclude that the neoadjuvant component of trastuzumab treatment led to the improvement in event-free survival.

"Crossover to adjuvant trastuzumab in 17% of patients and use of trastuzumab at relapse could prevent a survival advantage being shown, despite passage of time," they write.

The authors recommend offering trastuzumab before surgery to patients, even though they are not sure if this approach is responsible for the trial's positive results.

"Importantly, we did not compare a neoadjuvant plus adjuvant approach with adjuvant treatment alone," they write. "Therefore, we cannot conclude that the neoadjuvant component of trastuzumab treatment led to the improvement in event-free survival — the same improvement might have been seen with 1 year of adjuvant trastuzumab alone."

Good News and Advice About Cardiotoxicities

In NOAH, 235 women were randomly assigned to an anthracycline-based chemotherapeutic regimen (doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil) with (n = 117) or without (n = 118) a year of trastuzumab, delivered with chemotherapy and as monotherapy after surgery.

The trial produced some good news for clinicians who are concerned about cardiotoxicities when trastuzumab is delivered concurrently with an anthracycline, suggested an accompanying editorial.

Melanie D Seal, MD, and Stephen K Chia, MD, from the British Columbia Cancer Agency in Vancouver, observe that, "somewhat surprisingly," the NOAH trial had "similar cardiotoxicity rates to those reported in the adjuvant trials (none of which delivered concurrent anthracyclines and trastuzumab)."

Only 2 patients in NOAH had clinical congestive heart failure (1.7%; 95% CI, 0.5 - 6.0); both responded to cardiac drugs, report the study authors. Another 2 patients (1.7%) had a potentially important asymptomatic fall in left ventricular function.

Still, the editorialists note, the NOAH results had "fairly short follow-up and wide confidence intervals for cardiotoxicity."

Nevertheless, to the editorialists, the cardiotoxicities reported challenge a "dogma" held by some clinicians.

The dogma became the inability to safely deliver these 2 active agents concurrently.

"After the landmark study by Slamon and colleagues showed a 27% cardiac toxicity rate in patients receiving concurrent anthracycline and trastuzumab for HER2-positive advanced breast cancer," write the editorialists, "the dogma became the inability to safely deliver these 2 active agents concurrently in clinical practice" (N Engl J Med. 2001;344:783-792).

Dr. Slamon continues to hold that opinion and favors the use of nonanthracycline-based chemotherapy in conjunction with trastuzumab, as reported by Medscape Oncology.

The editorialists, however, see advantages with anthracyclines and suggest that clinicians tailor treatment to the individual.

They write that HER2-positive breast cancers are "sensitive" to anthracyclines, and that preclinical data suggest "additive or synergistic effects" for the combination of anthracyclines and trastuzumab in patients who present with high-risk disease, such as locally advanced or inflammatory breast cancer.

"The concomitant delivery of these drugs should be considered with an apparently favorable risk-to-benefit ratio," write Drs. Seal and Chia. "Factors such as a low cumulative dose of anthracycline and high baseline left ventricular ejection fraction might contribute to a decreased rate of cardiotoxicity." They add that reduced peak doses or different formulations of anthracyclines can also lower cardiotoxicity.

F. Hoffmann-La Roche provided trastuzumab and financial support for the trial. Dr. Gianni reports serving on scientific advisory boards for Roche, Genentech, GlaxoSmithKline, Wyeth, Novartis, Millennium, Biogen Idec, and Eisai.

Lancet. 2010;375:349-350, 377-384. Abstract, Abstract

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