First-line Herceptin plus chemotherapy: effective treatment option for HER2positive metastatic breast cancer Herceptin (trastuzumab) targets

the HER2-overexpressing breast cancer cells, which occur in about 20% of breast cancer patients, a sub-group that often has a poor prognosis. Since its approval in the USA in 1998, Herceptin has delivered impressive response rates (RRs), when administered to the right patients. It is, in fact, this very point that Dr. Brian Smith emphasized throughout his presentation, in which he discussed Herceptins efficacy and safety. Dr. Smith pointed out that first-line standard-dose (4 mg/kg loading, 2 mg/kg weekly maintenance) Herceptin therapy in combination with paclitaxel delivered an RR of 49% compared to 17% with paclitaxel alone in patients with IHC 3+ metastatic breast cancer (MBC; Table 1). Time to progression more than doubled (3.0 vs. 7.1 months) and survival increased 40% from 18 to 25 months. Upon discussing these results, Dr. Smith said, There is no question that this is a better strategy in patients who overexpress HER2 in their tumors. With ample caution not to overanalyze results across trials, he said that the reduced RRs with second-line or salvage monotherapy (35 and 18%, respectively) suggest that Herceptin should be used as first-line therapy. Call-out 1: If you are going to use Herceptin with chemotherapy, use it at first diagnosis of metastatic disease.
Table 1. Summary of pivotal first- and second/third-line Herceptin trials RR TTP Survival Therapy (%) (months) (months) First-line paclitaxel 17 3.0 18.0 Herceptin + paclitaxel 49 7.1 25.0 Second/third-line Herceptin monotherapy 35 3.5 24.4 Herceptin monotherapy as salvage 18 3.2 16.4 RR, response rate; TTP, time to progression

First-line Herceptin monotherapy RR was 35 and 34% for IHC 3+ and FISH+ patients, respectively. The clinical benefit rate, where stable disease was included in the analysis, was about 50% for these patients. Though there is no direct comparison between the efficacies of first-line monotherapy and Herceptin in combination with chemotherapy, the former is not inferior to combination therapy for IHC 3+ patients in terms of survival. Moving beyond these studies, Dr. Smith drew attention to the compounds that have demonstrated favorable activity in combination with Herceptin in pre-clinical studies. The other taxane, docetaxel, also showed promising 4483% RRs in combination with Herceptin. However, Dr. Smith pointed out that the high synergy between docetaxel and Herceptin in the lab did not simply transfer to the clinic. Dr. Smith concluded the evaluation of the efficacy of first-line Herceptin combination therapies with a summary of gemcitabine, venorelibine, and Xeloda, all with promising RRs (45% for IHC 3+, 84% for IHC 3+, and 62% for IHC 2/3+ patients, respectively). He emphasized that these therapies had favorable safety profiles with no cardiac toxicities.

Shifting to the safety of Herceptin itself, Dr. Smith said that Herceptin is generally well tolerated. Indeed, Herceptin avoids the typical chemotherapy side effects, such as alopecia and myelosuppression, instead most often causing mild-to-moderate infusionrelated fever and chills. Dr. Smith recommended that patients be observed for a while after first infusion, as about 0.3% of patients develop serious infusion reactions. Also, previous or concomitant anthracycline (e.g., doxorubicin and epirubicin) usage increases severe cardiotoxicity of Herceptin therapy, as can prior cardiac disease and increasing age. Call-out 2: Most of you will have had the experience of women saying this is much better than being on chemotherapy. To date, trials have delivered Herceptin until disease progression, some even allowing continuation past progression. Dr. Smith said, Herceptin, because of its good tolerability and lack of cumulative toxicity, is an agent where you could consider chronic treatment. He indicated that shorter-period, intermittent, or continuation-after-progression treatment designs have not been tested. At the end of his presentation, Dr. Smith reiterated that accurate HER-2 status assessment is crucial to delivering effective treatment to the right patient population. He stated that Herceptin: - - - provides a significant survival benefit as a monotherapy and in combination with chemotherapy, provides greater clinical benefit as first-line therapy, and has a favorable safety profile.

In his final remarks, Dr. Smith highlighted the fact that the optimal Herceptin combination strategy is yet to be determined. Nevertheless, Herceptin presents HER2positive MBC patients, especially those with IHC 3+ and FISH+ tumors, with a promising treatment option. Call-out 3: It is a targeted treatment. If the target is not there, then the treatment will not work.