It became readily apparent to me early on that there was a subset of women with metastatic HER2-positive disease who really did not want to receive chemotherapy up front, so I lobbied for having a first-line, single-agent trastuzumab trial. Many other investigators — including Melody Cobleigh and Debu Tripathy — were also very instrumental in moving this concept forward. So, this was really the third major initial trial to look at what trastuzumab could do in metastatic breast cancer. All of these were basically proof-ofprinciple trials.

Our trial was a Phase II study, and we accrued 114 patients. The patients were quite gratified because they were treated with a relatively nontoxic form of therapy, at least from the standpoint of subjective toxicities.

The overall, published response rate for all the patients with IHC 2+/3+, HER2-positive disease was 26 percent. We’ve subsequently learned that there is a very high false-positive rate for the patients with IHC 2+ disease. Consequently, further analyses were done using only the patients with IHC 3+ disease, and ultimately, the patients with FISH-positive disease.

Another interesting outcome measurement is prolonged stable disease, because it seemed that patients were responding to trastuzumab more like they would to hormonal therapy than to chemotherapy. We were seeing prolonged periods of disease stabilization, even though we weren’t able to objectively record definitive responses, as classically defined. So, we also evaluated the group of patients with prolonged stable disease for greater than six months. In the group of patients with FISH-positive disease, if you add the patients with prolonged stable disease to those with objective responses, about half the patients responded to first-line, single-agent trastuzumab.

I use single-agent trastuzumab in a similar manner as hormonal therapy. There are subsets of women with HER2-positive disease who don’t have horribly aggressive metastatic breast cancer. In those relatively asymptomatic patients who do not have visceral crisis or rapidly progressive disease and are not incapacitated by symptoms, I have no problem at all starting them on first-line, single-agent trastuzumab. However, the patients must be fully informed that they may be giving away something in terms of response rate, based on an analysis of crosstrial comparisons with the combination regimens.

Charles Vogel, MD, FACP

Until a few years ago, the only other option for a woman with HER2-positive indolent disease that was nonetheless progressing would have been chemotherapy. The toxicities of many chemotherapy agents would make me less enthusiastic about this approach. The availability of single-agent trastuzumab changes the playing field. In this type of patient, I would feel most justified in using single-agent trastuzumab.

Randomized trial data clearly shows a time-to-progression and survival advantage for chemotherapy plus trastuzumab compared to chemotherapy alone, and no data demonstrates that trastuzumab alone is equivalent to trastuzumab plus chemotherapy. There is indirect data, however, suggesting that trastuzumab can be initiated, and if there is disease progression, chemotherapy can subsequently be started while continuing the trastuzumab, without any real loss of apparent benefit.

From Chuck Vogel’s data there is good evidence that in patients with HER2-positive (FISH positive or IHC 3+) metastatic disease, single-agent trastuzumab before chemotherapy is comparable to conventional chemotherapy. That data provides me with the basis for using single-agent trastuzumab.

Clifford Hudis, MD

Trastuzumab monotherapy is an attractive therapeutic approach. It is analogous to the use of sequential single-agent endocrine therapy for indolent metastatic disease. HER2-positive tumors are not necessarily always aggressive. Chuck Vogel demonstrated a very acceptable response rate and clinical benefit with single-agent trastuzumab. Howard Burris and his colleagues gave trastuzumab up front and used chemotherapy in those whose disease failed to respond or progressed. This is a reasonable strategy and should be considered in appropriately chosen patients.

Nicholas Robert, MD