Should all HER2+ pts receive adjuvant trastuzumab?

November 1, 2007

Clinical trials have shown significant improvements in disease-free survival when trastuzumab (Herceptin) is added to standard adjuvant chemotherapy in HER2-positive breast cancer patients, but is it appropriate for all such patients, specifically low-risk patients with tumors 1 cm or smaller in size?

SAN FRANCISCO—Clinical trials have shown significant improvements in disease-free survival when trastuzumab (Herceptin) is added to standard adjuvant chemotherapy in HER2-positive breast cancer patients, but is it appropriate for all such patients, specifically low-risk patients with tumors 1 cm or smaller in size?

In a pro/con presentation at the 3rd Oncology Congress, Peter Ravdin, MD, PhD, researcher professor in biostatistics at M.D. Anderson Cancer Center, answered no to that question, maintaining that the risk-to-benefit ratio for trastuzumab is too low for such good-prognosis patients.

Taking the pro side, Edith Perez, MD, of the Mayo Clinic, Jacksonville, Florida, acknowledged that more data are needed on patients with HER2-positive tumors under 1 cm. While trastuzumab is not routinely recommended for these patients, she indicated that selected patients may benefit. "The problem is that before we didn't recommend anything for these patients," she said, "and now some are getting chemotherapy and trastuzumab."

Updated results of N9831/B-31

Two years ago at ASCO, findings from the joint analysis of N9831/B-31 were presented to a standing ovation. Updated results, presented by Dr. Perez at ASCO 2007, showed that the benefit of trastuzumab was clearly maintained.

Median 4-year DFS was 86% in the AC-T plus trastuzumab patients vs 73% for AC-T alone (HR 0.48, P < .00001). Risk of death was significantly decreased at 4 years by 35% (P = .0007), despite the fact that 21% of patients randomized to AC-T received trastuzumab after the trial was unblinded.

Trastuzumab improved DFS across the board in subgroup analyses by age, node status, hormone-receptor status, tumor size, and tumor grade, Dr. Perez said.

In patients with one to three positive nodes, she said, the difference in 4-year DFS with trastuzumab was 10% (90% vs 80.5%). In patients with 10 or more positive nodes, DFS was 73% vs only 46% for chemotherapy alone. And for patients age 60 and older, DFS with trastuzumab was 82% vs 67% with chemotherapy alone.

"This is really very dramatic," Dr. Perez commented.

Short-term outcomes

Dr. Ravdin agreed that the efficacy of trastuzumab "is truly wonderful in the HER2-positive population," but pointed out that the trials have only reported short-term outcomes. "We really don't know how good this agent is going to be over the long term, in reducing late recurrences," he said, "or how good an adjuvant agent it is in the absence of chemotherapy." He also cited studies showing that HER2 positivity is "a relatively modest independent prognostic factor."

Using Adjuvant! Online, a risk model he developed, Dr. Ravdin pointed out that a typical stage T1c node-negative breast cancer patient (60 years old, ER positive, HER2 positive, with average comorbidity) would have a baseline 10-year mortality of 19%, with a competing mortality of about 8% (the probability of dying of something other than breast cancer). For this patient, the survival benefit of adding trastuzumab to chemotherapy he calculates as 2%.

However, a similar T1ab patient (tumor of 1 cm or less) would have a lower baseline 10-year mortality (12%) and net benefit of trastuzumab of only 1%. "So these are the patients that we are justifiably concerned about whether there is a net benefit for trastuzumab," he said.

He noted that both NCCN and St. Gallen guidelines do not recommend routine use of trastuzumab for node-negative patients with tumors under 1 cm.

The wildcard

The "wildcard" in determining the risk-benefit ratio of trastuzumab, Dr. Ravdin said, is the potential for cardiotoxicity. He and Dr. Perez agreed that the short-term cardiac risk is low and the long-term risks are not yet known.

But Dr. Perez stressed that "the cardiac risk is much smaller than the benefit that can be obtained with this drug in terms of DFS," while Dr. Ravdin said that the risks of trastuzumab "are real and can be devastating for some patients," including a small risk of fatal pulmonary fibrosis.

Dr. Ravdin added that shorter duration of trastuzumab or use of chemotherapy regimens that don't include an anthracycline could help reduce cardiac risk in these patients.

Dr. Perez cited a number of ongoing prospective studies designed to determine the optimal duration and scheduling of trastuzumab. An Italian group, for example, is giving AC followed by concurrent TH for 3 months followed by either 3 or 9 additional months of trastuzumab. She also mentioned studies looking at the possibility of using the anti-HER2 agent lapatinib (Tykerb) either sequentially or concurrently with trastuzumab.

How cost-effective?

In arguing against trastuzumab for patients with tumors under 1 cm, Dr. Ravdin cited cost-effectiveness data. For the average patient on N9831/B31 with 4 to 9 positive nodes, the cost per life year saved was an acceptable $34,000. But for a poor-prognosis T1ab patient, the estimated cost was $170,000, "generally considered too high," he said.

Dr. Ravdin concluded that "there are some low-risk HER2-positive patients for whom there is little additional net benefit for trastuzumab, and they shouldn't receive this agent."

A pointed question

When asked whether trastuzumab should be used in patients with node-negative HER2-positive tumors of 0.7 to 0.8 cm in size, Dr. Perez said that it is not recommended for the majority of such patients, but that some patients of that description are receiving chemotherapy plus trastuzumab at the Mayo Clinic, especially younger patients with extremely low cardiac risk.

She suggested that the baseline 10-year risk of recurrence for these patients with small tumors could be higher than the 10% to 12% Dr. Ravdin estimates. One study showed a 10-year recurrence risk of 25% for patients with grade 3 tumors regardless of size, she commented.

Dr. Perez said that her team is currently going through files of patients at the Mayo Clinic with tumors less than 1 cm, and doing HER2 testing on specimens that lack such testing, to determine 5- and 10-year outcomes, and thus the true risk of recurrence in HER2-positive patients with these small tumors.