The HER2 protein is made in high levels in about one-fifth of all cancers, and while this used to be a dangerous sign, it is now an important target, and the antibody drug Herceptin has significantly improved the outlook for these tumors. It improves the cure rate after surgery and even after cancer has spread; it can extend life but is not curative.At the San Antonio Breast Cancer Symposium, three key trials were presented that attempted to improve how well Herceptin works by combining it with other drugs. All studies were done in patients receiving preoperative (also called neoadjuvant) therapy because that is a quick way to estimate if a particular treatment will be effective in the long-term, by looking at how many patients have what is called a complete pathological response--or complete disappearance of tumor cells at the time of surgery.Chemotherapy was given in all studies. One study found a higher response rate when pertuzumab was added to Herceptin and chemotherapy. The combination of the two antibodies was also better than pertuzumab and chemotherapy. Another study looked at the addition of the oral kinase inhibitor against HER2, Tykerb (also known as lapatinib), which is also approved--but only in patients who have already gotten Herceptin. The combination of Herceptin and Tykerb was clearly better, but there were more side effects, particularly diarrhea, with Tykerb. The third study, called Neo-ALLTO had three arms, all with the chemotherapy Taxol--one with Herceptin, the other with Tykerb and the third arm with both. Again, the response rate was best with the combination. This was a very exciting validation of the fact that blocking the HER2 pathway more completely with two drugs is a more effective strategy. However, all the presenters stressed that the neoadjuvant model is only an estimate of a potential benefit, and this has to be confirmed in clinical trials that are ongoing in patients with early-stage breast cancer that are enrolling enough patients to actually compare the number of recurrences--this is the gold standard that would be required before these combinations can be approved. One of these trials is nearing completion, but will probably take two years or so to yield definitive results. But the bigger issue here is that of the many biological pathways that are being addressed in cancer are still not fully effective because tumor cells become resistant by bypassing the point at which the targeted drug works. We need to further explore how that same pathway can be blocked at different levels if this theory proves to be true.