Endocrine Therapy - Tamoxifen
Three trials were identified that evaluated the efficacy of tamoxifen by HER2/neu status; two compared tamoxifen to observation, one compared tamoxifen plus goserelin to cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), and one compared five years versus two years of tamoxifen. In addition, two trials of aromatase inhibitors and tamoxifen reported results of interest to the question of tamoxifen interaction with HER2/neu status. The weight of the identified evidence, especially the Gruppo Universitario Napoletano (GUN) trial, suggests that the efficacy of tamoxifen is greater in HER2/neu-negative patients than in positive patients. However, while there is evidence to suggest tamoxifen is more effective in HER2/neu-negative patients, there is insufficient evidence to suggest tamoxifen is ineffective in HER2/neu-positive patients. Therefore, no definitive recommendations can be made at this time.
Endocrine Therapy - Aromatase Inhibitors
Two trials were identified that evaluated the efficacy of letrozole compared with tamoxifen according to HER2/neu status and one that evaluated anastrozole. Trials that evaluated exemestane were not identified. None of these trials reported significance testing of the interaction between HER2/neu status and treatment, although the Pennsylvania State University Hershey Medical Center (PSUHMC) trial suggests that, in the metastatic setting, letrozole benefit to objective response rate (ORR) may be more pronounced in patients with HER2/neu-negative breast cancer.
Full results regarding HER2/neu-status subgroup analysis have not yet been published from the following large trials of aromatase inhibitors: aromatase, tamoxifen, alone or in combination (ATAC), Intergroup Exemestane Study (IES), and Breast International Group (BIG) 1-98. An abstract from the 2003 San Antonio Breast Cancer Symposium (SABCS) by Dowsett et al reported on a subgroup analysis of the ATAC trial comparing time-to-recurrence by estrogen-receptor (ER) and progesterone-receptor (PR) status. The abstract reported a marginally significant difference (p=0.05) between the ER+/PR+ (hazard ration [HR] 0.82, 95% confidence interval [CI] 0.65-1.03) and ER+/PR- (HR 0.48, 95% CI 0.33 to 0.71) subgroups. As HER2/neu status and anastrozole therapy. However, an abstract from the 2005 SABCS by Viale et al, detailing the results by ER and PR status from the BIG 1-98 trial, reported no obvious difference between ER+/PR+ (HR 0.84, 95% CI 0.69 to 1.03) and the ER+/PR- (HR 0.83, 95% CI 0.62 to 1.10) subgroups comparing letrozole versus tamoxifen, and so this relationship may not hold across all aromatase inhibitors. If and when HER2/neu subgroup analyses are published from these trials, it may then be possible to make a definitive statement regarding the interaction of aromatase inhibitor therapy and HER2/neu status.
Endocrine Therapy - Ovarian Ablation
Two trials evaluated some form of ovarian ablation by HER2/neu status. Neither of these trials reported significant interaction between HER2/neu status and efficacy.
Chemotherapy - Anthracyclines
Ten trials, all conducted in the adjuvant setting, analysed the efficacy of anthracycline-based regimens versus non-anthracycline-based regimens according to HER2/neu status. While only two of these trials reported statistically significant interaction between HER2/neu status and treatment arm (anthracycline-containing regimen versus non-anthracycline-containing regimen) for an efficacy outcome, all of these trials were consistent in showing a trend for HER2/neu-positive patients experiencing greater benefit from anthracycline-based therapy than HER2/neu-negative patients. Additionally, the evidence suggests that HER2/neu-negative patients gain no benefit from anthracycline-based chemotherapy compared to CMF. This is borne out by the meta-analysis of the trials, where a significant benefit from anthracycline-based therapy in terms of disease-free and overall survival was found in HER2/neu-positive patients only.
Four trials evaluated more intensive (either higher dose or dose-dense) anthracycline-based regimens versus less intensive ones. The trials included in the meta-analysis varied in terms of the anthracycline used (doxorubicin or epirubicin), and the type of intensification (increased dosage versus shorter time frame at same dosage). The evidence from these trials and a meta-analysis of three of them support the conclusion that more intense anthracycline regimens may provide more benefit in HER2/neu-positive patients. These results are not conclusive; a significant interaction could not be established definitively in the meta-analysis, as the choice of testing method used in the Belgian trial made a considerable difference in the results. It should be noted that the testing method most similar to that used in the other two included trials, immunohistochemistry (IHC) by CB-11 antibody, yielded the least statistical heterogeneity of the three results that could have been included, and also was the only result that implied a statistically significant interaction. However, as there were fewer than 30 patients per arm in the HER2/neu-positive subgroup, this association with testing may well be simply an artefact of low numbers.
One trial examined the efficacy of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) versus FEC combined with high-dose chemotherapy. This trial found a significant interaction in terms of disease-free survival, with HER2/neu-negative patients being the only patients who received any significant benefit from the addition of high-dose chemotherapy. It is important to note that the FEC regimen received in both arms differed only by a single cycle (four cycles in the high-dose chemotherapy arm versus five cycles in the other arm), and so this interaction is likely solely due to the high-dose chemotherapy.
Chemotherapy - Taxanes
Four trials conducted in the metastatic setting and one trial in the neoadjuvant setting evaluated the efficacy of taxane-containing regimens versus non-taxane regimens according to HER2/neu status. One other trial evaluated the efficacy of three different dose levels of paclitaxel. Overall, these trials provide no evidence that taxane-base therapy, compared to non-taxane based therapy, is either more or less efficacious based on HER2/neu status.
Chemoendocrine Therapy
One trial evaluated the efficacy of tamoxifen and chemotherapy compared with tamoxifen alone according to HER2/neu status. This trial found no significant interaction between therapy and HER2/neu status, but its results were consistent with the tamoxifen trials identified above.
Radiation Therapy
There were no studies identified that evaluated the efficacy of radiation therapy compared to no radiation therapy by HER2/neu status that met the inclusion and exclusion criteria.