Stage I, II, IIIA, and Operable IIIC Breast Cancer
The AVENTIS-TAX-GMA-302 study was a three-arm large trial containing two anthracycline arms (AC-D: doxorubicin, cyclophosphamide, docetaxel or AC-DH: doxorubicin, cyclophosphamide, docetaxel, and trastuzumab) and a nonanthracycline one (DCbH: docetaxel, carboplatin, trastuzumab). In its second interim efficacy analysis with a median follow-up of 36 months, there were 462 DFS events and 185 deaths. For DFS, the HR was 0.61 for patients in the AC-DH arm (95%CI, 0.48-0.76; P < .001) and 0.67 for patients in the DCbH arm (95%CI, 0.54-0.83; P =.003), compared with the AC-D. This translated to absolute benefits (from years 2 to 4) of 6% and 5%, respectively with the addition of trastuzumab. Nevertheless, longer follow-up is needed in patients in the DCbH arm to warrant the omission of anthracyclines in these patients.
The Finland Herceptin (FINHER) study assessed the impact of a much shorter course of trastuzumab. In this trial, 232 women younger than 67 years with node-positive or high-risk (>2 cm tumor size) node-negative HER2 -overexpressing breast cancer were given nine weekly infusions of trastuzumab concurrently with docetaxel or vinorelbine followed by FEC. At a 3-year median follow-up, the risk of recurrence and/or death was significantly reduced in patients receiving trastuzumab (HR = 0.41; P = .01; 95% CI, 0.21-0.83; 3 year DFS = 89% vs. 78%). The difference in OS (HR = 0.41) was not statistically significant (P = .07; 95% CI, 0.16-1.08).[Level of evidence: 1iiA]
In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (ALTTO [NCT00553358]), the role of lapatinib (in combination with, in sequence to, in comparison to, or as an alternative to trastuzumab) in the adjuvant setting is being investigated. Lapatinib is a small molecule tyrosine kinase inhibitor that is capable of dual-receptor inhibition of both EGFR and HER2 and seems to be less cardiotoxic than trastuzumab. In phase I/II studies as a single agent, lapatinib has resulted in objective responses between 4.3% and 7.8% in ER2-positive patients who had progressed on multiple trastuzumab-containing regimens with a substantial number having stable disease at 4 months (34%-41%) and 6 months (18%-21%). In a phase III trial (GSK-EGF100151), lapatinib plus capecitabine was superior to capecitabine alone in women with HER2 -positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. The hazard ratio for time to progression was 0.49 (95% CI, 0.34-0.71; P < .001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group.
The combination of lapatinib and trastuzumab in the ALTTO trial is further supported by a demonstration that lapatinib combined with trastuzumab confers a significantly improved progression-free survival in patients with metastatic breast cancer who experience progression on prior trastuzumab-containing treatment when compared to lapatinib alone.