Follow-up ended on October 9, 2005, with a median of 3.9 years (range = 0–7 years ). The rate of censoring was 95.0%, with 256 deaths (102 from breast cancer, 50 from other malignancies, 100 from other causes, and four from unknown causes) (). One (2%) of the 50 women classified as having died from other malignancies also had a recurrence of breast cancer. Of the 100 women who were classified as having died from other causes, two also had a local regional recurrence of breast cancer, two had contralateral breast cancer, and seven had distant metastases.
Cause-specific deaths by treatment arm and factor subgroups*
Non—breast cancer deaths accounted for 60% of known deaths (72% for those 70 years or older at study entry and 48% for those younger than 70 years). When the time of death was plotted against the type of death for women in both study arms who were younger than 70 years at study entry and for those who were 70 years or older, the time periods overlapped throughout follow-up for death from breast cancer, other malignancies, and other causes for both age groups and both trial arms (). These results thus provide evidence of substantial competing risks for both younger and older women, in that there would be a sizable risk of non—breast cancer death before breast cancer death.
Fig. 1 Time of death by type of death, age group, and therapy group. A) Age group younger than 70 years. B) Age group 70 years or older. Type of event: 1 = death from breast cancer; 2 = death from other malignancy; 3 = death other than cancer. Open circles = (more ...)
Results of the competing risks analysis are presented in for the 11 baseline trial factors. The factors age (from hypothesis H1,
< .001), cardiovascular disease (from hypothesis H1,
= .02), and lymph node status (from hypothesis H1,
< .001) were statistically significantly associated with death. There was weak evidence of an effect associated with a baseline report of osteoporosis (from hypothesis H1,
= .07). The remaining seven factors were not statistically significantly associated with breast cancer—specific death, death from other malignancies, or death from other causes: treatment (alone, without consideration of interactions with other factors), menopausal status, length of tamoxifen use, adjuvant radiotherapy, bone fracture, hormone receptor status, and adjuvant chemotherapy.
Factors associated with death by a Lagakos analysis
Age was strongly and statistically significantly associated with death (from hypothesis H1,
< .001) (). Older age was associated with statistically significantly increased mortality from all three causes of death (), with the strongest evidence of association being for death from other causes (from hypothesis H2,
= .01) (): breast cancer death (P
= .02), death from other malignancies (P
< .001), and death from other causes (P
< .001) (). These results paralleled those in a cause-specific stepwise multivariable model, with older age (in years) at trial entry being associated with increased risk of death from breast cancer (effect β = -0.02, 95% CI = -0.04 to 0.0, with the confidence interval based on the assumption that values for β have an approximately normal distribution; P
= .003, on the basis of the likelihood ratio criterion for factor effect in a stepwise model [
]), from other malignancies (effect β = -0.04, 95% CI = -0.06 to -0.02; P
< .001), and from other causes (effect β = -0.06, 95% CI = -0.08 to -0.04, P
< .001) ().
Factor effects by type of death*
Multivariable analysis of factors by type of death*
Lymph node status was also strongly and statistically significantly associated with death (from hypothesis H1,
< .001) (). Lymph node involvement was associated with an increased risk of death from breast cancer, multivariable effect (effect β = -0.37, 95% CI = -0.51 to -0.23; P
< .001) (), and was not associated with death from other malignancies or other causes (in stepwise modeling, effect β = -0.05, 95% CI = -0.19 to 0.09, P
= .50; and effect β = -0.11, 95% CI = -0.25 to 0.03, P
= .13) ().
A baseline report of osteoporosis was differentially associated with death (for hypothesis H2,
= .03) (), with a reduction in breast cancer deaths (effect β = 0.32, 95% CI = -0.06 to 0.7, P
= .07), and increase in other malignancies (effect β = -0.33, 95% CI = -0.65 to -0.01, P
= .05) (). However, a baseline report of osteoporosis was not included in any multivariable cause-specific stepwise model () because it was not statistically significantly associated with survival.
A baseline report of cardiovascular disease was differently associated with mortality (for hypothesis H2,
= .02) (), leading to greatly increased risk of death from other causes (effect β = -0.46, 95% CI = -0.76 to -0.16, P
= .002) (). The association between treatment and cardiovascular disease was included in the stepwise multivariable model for death from other causes (interaction effect β = -0.68, 95% CI = -1.06 to -0.30, P
< .001) (). Treatment with letrozole was associated with a lower risk of death from other causes if cardiovascular disease was absent at baseline; with cardiovascular disease, treatment with placebo was associated with a lower risk of death from other causes (P
< .001). The interaction effect between treatment and baseline report of cardiovascular disease was substantiated with two alternate survival analyses (P
< .001 with both Cox and Weibull survival analysis models).
There was also a statistically significant association between trial therapy and length of previous tamoxifen use for breast cancer (interaction effect β = 0.29, 95% CI = -0.01 to 0.59, with the confidence interval based on the assumption that values for β have an approximately normal distribution; P
= .05, from the likelihood ratio criterion for the interaction effect in a stepwise model [
]) (). Specifically, letrozole showed greater benefit in terms of lower risk of breast cancer mortality for those who had received more than 5 years of tamoxifen, and placebo was of greater benefit with lower risk of breast cancer mortality for those receiving 5 years or less of tamoxifen treatment.
The breast cancer model () was used to provide 5-year survival of breast cancer for a group of patients with selected characteristics that were indicated by the results and an adjuvant chemotherapy question of interest (): patients who received letrozole, were estrogen and/or progesterone receptor positive, and had received adjuvant chemotherapy. A 50-year-old woman would be expected to have a breast cancer mortality rate of 1% (95% CI = 0% to 34%) if her breast cancer was lymph node negative or 4% (95% CI = 0.01% to 5.9%) if it was lymph node positive. A 70-year-old woman would have breast cancer mortality rates of 2% (95% CI = 0% to 46%) and 8% (95% CI = 0.03% to 70%), respectively, and an 80-year-old woman would have mortality rates of 3% (95% CI = 0.01% to 52%) and 10% (95% CI = 0.06% to 75%), respectively.
Five-year breast cancer survival of patients with early breast cancer treated with letrozole by age: a log-normal model*