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¹ The M.S. Hershey Medical Center, Hershey, PA
² VA Medical Center, Lebanon, PA
³ Novartis Pharma AG, Basel, Switzerland
⁴ Novartis Pharmaceutical Corp, East Hanover, NJ
⁵ Bayer Corporation, Tarrytown, NY

In response to the letter by Drs K. Altundag and O. Altundag on our recent report,¹ we have completed a new analysis of time-to-progression (TTP) looking at prior adjuvant tamoxifen or not in the subset of patients with serum HER-2/neu levels. Most patients who had received prior adjuvant tamoxifen were in the normal serum HER-2 group (letrozole, 37 patients; tamoxifen, 43 patients), with small numbers in the elevated HER-2 group (letrozole, 14 patients; tamoxifen, 12 patients).

In the unadjusted analysis by treatment only, median TTP was 9.5 months for letrozole (95% CI, 8.8 to 12.2 months) and 6.2 months for tamoxifen (95% CI, 5.8 to 8.8 months), with an overall P value of .0005. In the analysis adjusted by serum HER-2 status and prior adjuvant tamoxifen, the P value was lowered to .0002 for the comparison of letrozole with tamoxifen. HER-2 was significant (P < .0001) but prior adjuvant tamoxifen was not (P = .2837). In the analysis of TTP stratified by prior adjuvant tamoxifen, the treatment difference was significant (in favor of letrozole) regardless of whether adjuvant tamoxifen was given (P = .0016 for treatment difference) or not (P < .0001) in normal HER-2 patients (results below). In the elevated HER-2 group, numbers were too small and power too low for the treatment differences to be significant. When the analysis was stratified by treatment, prior adjuvant anti-estrogen therapy and HER-2 status, the overall significance level was P < .0001 for the treatment difference (in favor of letrozole).

The results are presented for this analysis:

Letrozole: Normal HER-2 with no prior adjuvant tamoxifen: median TTP was 12.0 months (95% CI, 9.4 to 15.3 months), and progression occurred in 118 of 157 patients (75%); normal HER-2 with prior adjuvant tamoxifen: median TTP was 13.0 months (95% CI, 9.0 to 26.8 months), and progression occurred in 27 of 37 patients (73%); elevated HER-2 with no prior adjuvant tamoxifen: median TTP was 6.1 months (95% CI, 3.9 to 9.1 months), and progression occurred in 59 of 65 patients (91%); elevated HER-2 with prior adjuvant tamoxifen: median TTP was 6.2 months (95% CI, 3.7 to 8.2 months), and progression occurred in 12 of 14 patients (86%).

Tamoxifen: Normal HER-2 with no prior adjuvant tamoxifen: median TTP was 8.9 months (95% CI, 6.2 to 10.1 months), and progression occurred in 131 of 157 patients (83%); normal HER-2 with prior adjuvant tamoxifen: median TTP was 6.0 months (95% CI, 3.3 to 9.3 months), and progression occurred in 38 of 43 patients (88%); elevated HER-2 with no prior adjuvant tamoxifen: median TTP was 3.3 months (95% CI, 3.0 to 5.8 months), and progression occurred in 58 of 63 patients (92%); elevated HER-2 with prior adjuvant tamoxifen: median TTP was 3.2 months (95% CI, 2.8 to 8.9 months), and progression occurred in 12 of 12 patients (100%).

From these results, it can be seen that, for the letrozole arm, serum HER-2 status but not adjuvant tamoxifen influences median TTP. For the tamoxifen arm, clearly serum HER-2 status also influences median TTP. In the elevated serum HER-2 group, there is little difference whether or not adjuvant tamoxifen was given. In the normal serum HER-2 group, the difference in TTP between patients given adjuvant tamoxifen and those not given adjuvant tamoxifen is statistically significant (P = .0316).

When the effects of treatment-free interval and duration of adjuvant tamoxifen in this subset of patients were investigated, the significance disappeared when either treatment-free interval from tamoxifen and/or duration of adjuvant tamoxifen were entered in the model. Neither treatment-free interval nor duration of adjuvant tamoxifen was significant.

When adjuvant tamoxifen was a factor in the model for the entire population with serum HER-2/neu levels, it was not statistically significant. Tamoxifen resistance may play a role in response to subsequently given tamoxifen, but simple modeling in the current study does not identify patients who may have become resistant to tamoxifen. The source factors leading to the poor response rate in patients in the tamoxifen arm previously exposed to tamoxifen would appear to be complex, and not directly related to the length of previous exposure to tamoxifen or to the treatment-free interval following adjuvant tamoxifen. Elevated serum HER-2/neu level remained an independent predictive factor for shorter TTP, regardless of whether any prior adjuvant tamoxifen therapy was received.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): A. Lipton, Novartis; H.A. Chaudri-Ross, Novartis. Acted as a consultant within the last 2 years: A. Lipton, Novartis; H.A. Harvey, Novartis. Performed contract work within the last 2 years: A. Lipton, Bayer Diagnostics; Kim Leitzel, Bayer Diagnostics.

REFERENCE

1. Lipton A, Ali SM, Leitzel K, et al: Serum HER-2/neu and response to the aromatase inhibitor letrozole versus tamoxifen. J Clin Oncol 21:1967–1972, 2003[Abstract/Free Full Text]

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