ATAC trial: Findings at 68 months

Disease-free survival and overall survival

The 68-month data from the ATAC trial indicate continued improvement in disease-free survival in patients receiving anastrozole versus tamoxifen (Howell 2005) — 3.3 percent absolute difference in recurrence rate and a 17 percent improvement in the hazard ratio for relapse in hormone receptor-positive patients. Anastrozole improves the time to distant recurrence.

The relative reduction in breast cancer mortality with anastrozole was 13 percent, and a nonsignificant improvement in time to breast cancer death was demonstrated in ATAC; however, no statistically significant difference in overall survival was demonstrated between patients receiving anastrozole versus tamoxifen.

In NSABP-B-14, which enrolled only patients with node-negative disease, we didn’t see a mortality improvement until after approximately seven years of follow-up. In the ATAC trial, 39 percent of patients had node-positive disease and the remainder had primarily node-negative disease. We’re at six years with ATAC and it may be a year or two before any mortality improvement is demonstrated. We expect it to occur because we see both a distant disease-free survival improvement and a breast cancer survival improvement, albeit not significant, with anastrozole.

Two-year recurrence rate and effects of anastrozole

A peak in recurrence occurs at two years for patients on tamoxifen, and it’s similar to the peak we see in patients who receive no treatment. We see this peak in all patients on tamoxifen, but especially in patients who have nodepositive disease. This two-year peak was blunted by anastrozole. This is important because if patients start with tamoxifen, some will relapse on tamoxifen who would not have relapsed on anastrozole, and we’ve lost those patients. In addition, we see increased toxicity with tamoxifen during those first two and a half years, so from both the efficacy and toxicity standpoints, it is probably better to begin adjuvant hormonal therapy with an aromatase inhibitor. In the ATAC trial, contralateral breast cancer was reduced by 50 percent with anastrozole, which is similar to the data from other aromatase inhibitor trials. That’s a 50 percent reduction compared to tamoxifen and an estimated 75 percent reduction compared to no treatment.

Toxicity

At the 2004 San Antonio meeting, we presented updated toxicity data including new data on the rate of hysterectomy (2.1), which was 5.1 percent in patients on tamoxifen but only 1.3 percent in patients on anastrozole (Howell 2004). The rate of endometrial cancer was 0.8 percent with tamoxifen and 0.2 percent with anastrozole, so clearly endometrial cancer doesn’t account for all of the increase seen in the hysterectomy rate. This suggests that some women are undergoing unnecessary hysterectomies. I believe this issue makes anastrozole favorable despite its higher cost.

Another issue is the joint symptoms we see with aromatase inhibitors. In the data reported, tamoxifen had approximately a 29 percent joint symptom rate compared to 36 percent with anastrozole. Matt Ellis’ group presented an interesting abstract in San Antonio indicating that women with these symptoms may have low vitamin D levels and giving them vitamin D improves some of the joint symptoms. These are early data and more studies are underway, but if we could solve this joint problem with vitamin D, it would be extraordinary.

We know from the ATAC trial that more serious adverse events are associated with tamoxifen than with anastrozole and, despite the joint symptoms, patients tend to stay on anastrozole more than they stay on tamoxifen, which is an important efficacy issue.

Bone density

In the 68-month follow-up of the ATAC trial, the fracture rates were 7.7 percent with tamoxifen versus 11 percent with anastrozole (Howell 2005). We saw no increase in hip fractures with anastrozole, which is important, but the fracture rate with anastrozole is still a concern. The other issue is fracture rate over time. I presented the data after six years, and the annual fracture rate is approximately 1.5 percent to two percent with tamoxifen and 2.5 percent with anastrozole. What surprised me was that during the fifth year of the trial, the fracture rate was lower in the anastrozole group than in the tamoxifen group, although not significantly lower. It seems that as soon as anastrozole is stopped, the fracture rate goes down.

We had a bone subprotocol in which we evaluated lumbar spine and trochanter bone mineral density over time. In the first year, an approximately 2.5 percent drop in bone mineral density occurred in patients on anastrozole. At two years, it was slightly more than a four percent drop.

This is similar to the IES data with exemestane and the MA17 data with letrozole, so the impact on bone mineral density is a class effect of aromatase inhibitors, not limited to anastrozole, and we need to learn how to manage it (Coleman 2004, Perez 2004).

In San Antonio, Michael Gnant presented the extraordinary Austrian data on using zoledronic acid to prevent bone mineral loss in premenopausal patients (Gnant 2004). Patients were randomly assigned to receive goserelin plus tamoxifen or goserelin plus anastrozole, and then a subrandomization assigned patients to zoledronic acid or not. In this study, they found that the 14 percent loss of bone mineral density on anastrozole over three years was completely abrogated by administering zoledronic acid.

Deep vein thrombosis, stroke and cardiovascular events

In the ATAC trial, 4.5 percent of patients on tamoxifen had deep vein thrombosis, whereas approximately 2.8 percent of patients on anastrozole developed this side effect. These results are comparable to similar studies and to the rate seen in women on hormone replacement therapy. We also continue to see a reduction in ischemic cerebrovascular events with anastrozole versus tamoxifen — two percent versus 2.8 percent, respectively.

In my opinion, the important data are the new and slightly worrisome findings on cardiac events in the aromatase inhibitor trials. In ATAC, the rate of events was 4.1 percent with anastrozole and 3.4 percent with tamoxifen. The increase with anastrozole was not significant — the p-value was 0.12. The IBCSG-1-98 data presented at the St Gallen’s meeting also reported on Grades III to V cardiac events. The rates were 3.6 percent in patients on letrozole compared to 2.5 percent in patients on tamoxifen, with 26 versus 13 myocardial deaths, respectively (BIG 1-98 Collaborative Group 2004). In San Antonio, Coombes reported the IES trial had a statistically significant increase — 20 myocardial infarctions in patients on exemestane and eight in patients on tamoxifen (Coombes 2004). This issue needs to be carefully monitored.

IBCSG-1-98: Letrozole versus tamoxifen up front or sequentially

The IBCSG-1-98 efficacy data at 30 months look almost identical to the ATAC data at 33 months, favoring the aromatase inhibitor over tamoxifen (BIG 1- 98 Collaborative Group 2004). There is a 21 percent reduction in disease-free survival in IBCSG-1-98 and a 22 percent reduction in ATAC. Time to recurrence is an 18 percent reduction in IBCSG-1-98 and a 17 percent reduction in ATAC. There appears to be a greater survival advantage in the BIG trial — a 14 percent reduction in death versus only a three percent reduction in ATAC, although we need to see what happens with further follow-up. The hazard ratio for overall survival was 0.97 for ATAC and 0.86 for IBCSG-1-98. The distant disease-free survival, which is possibly a surrogate for breast cancer survival, is also similar to ATAC.

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Dr Howell is a Professor of Medical Oncology at the University of Manchester in Manchester, England.