Extended Hormonal Therapy After Tamoxifen

DR HUDIS: One thing I notice with Figure 13 is that two percent of the clinical investigators versus 18 percent of the practicing clinicians chose “use no further therapy” when presented with this 65-year-old woman who completed five years of tamoxifen one year ago. While most of the clinical investigators would use further therapy, there appears to be a lag with this approach among the practicing oncologists.

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I don’t know on what basis the practicing oncologists choose which aromatase inhibitor to use. These data suggest that they believe what the clinical investigators frequently say, which is that there’s probably not a lot of functional difference between the aromatase inhibitors.

As clinical investigators, many of us defend ourselves, if you will, by using the drug that was specifically tested in that setting, and that’s why we are biased toward letrozole in this scenario. However, I can’t imagine, with what we know right now, that it really matters.

I believe the rationale for the increase in the use of further therapy in the clinical scenario described in Figure 13 may involve a multistep extrapolation. First, we have harped for the last few years on the natural history of ER-positive breast cancer, which has a long, chronic, relatively steady risk of recurrence.

Second, with all three types of aromatase inhibitor trials so far — whether it be up-front therapy, switching in the middle or late therapy as in the MA17 trial — we seem to nudge the risk of recurrence down from that point forward. Thus, you start to convince yourself that it’s reasonable to nudge down recurrence risk with the aromatase inhibitors, if the risk is sufficient to warrant therapy, and that the lag between the end of tamoxifen and starting treatment doesn’t matter.

I often draw in one other parallel, which sounds as if it’s from left field but it’s not — the P1 and P2 trials. The P1 study is a trial of tamoxifen for ER-positive breast cancer. That’s not how it’s spun, but that’s what it is. It’s treating “sub rosa” ER-positive breast cancers based on risk — there’s just no landmark event that brings in the patient.

Yet the lesson of P1 is that from the moment that tamoxifen is given to those patients, the hazard, their risk, is diminished. That suggests that risk may be adjusted with effective therapy. When I pull all of this together, I understand why physicians would evaluate a patient at high risk three years after finishing tamoxifen and say, “I have safety data for the aromatase inhibitors, I have this notion of long, chronic risk and I have this ability to hammer down on that risk if the patient is willing.”

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It is interesting that the number of clinical investigators who selected “start letrozole” increased from 20 percent in 2005 to 64 percent in 2006.

In December 2005, Goss presented the updated analysis of the MA17 trial at the San Antonio Breast Cancer Symposium. This was a trial of more than 4,000 postmenopausal patients with ER-positive breast cancer who within the past three months had completed four and a half to six years of adjuvant tamoxifen. The patients were randomly assigned to letrozole versus placebo.

In that trial, based on a preplanned analysis, they crossed an early-reporting boundary and presented the disease-free survival data, which clearly supported the aromatase inhibitor. I always took two lessons from the study, the narrow and the broad. The narrow lesson is that letrozole is effective, and the broad lesson is that aromatase inhibitors are effective.

The broad lesson for me is that this chronic risk of breast cancer extends fairly evenly over many years and we actually have the ability to change outcomes with active interventions relatively late in the game, so it didn’t take much for me to become comfortable recommending the extended adjuvant therapy.

Extended Adjuvant Aromatase Inhibitor Therapy

DR HUDIS: I believe that in the case of the 61-year-old patient in Figure 15 who just completed five years of anastrozole, I chose to continue the anastrozole. However, it’s important for me to stipulate that the evidence right now is not on my side. This is one of those situations in which the rationale for my decision is pulled from several places. The first is the long natural history of breast cancer and the fact that, at least with tamoxifen, there are more recurrences after the first five years than in the first five years. That motivates me to think about doing something that’s longer lasting.

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