Select Excerpts from the Discussion

Track 1

DR LOVE: Kathy, would you recommend delayed endocrine therapy in this situation?

DR PRITCHARD: For reasons I don’t understand, data from MA17 are now showing that the women who were initially on placebo and crossed over to letrozole after the trial stopped have actually done better than the women who were originally assigned to placebo. That’s not a randomized comparison, but I believe it gives us a clear signal that starting an aromatase inhibitor even one, two or three years after finishing tamoxifen still has an effect.

I believe using an aromatase inhibitor for either of these patients is logical, and I probably would recommend one in both cases. The question with the older patient is, how long does the average 81-year-old live? Still, she’s at high risk and Muss’s paper suggests that older women don’t experience many quality-of-life problems on aromatase inhibitors, at least in the short term (Muss 2006).

DR GOSS: I feel strongly that we have a large, prevalent pool of women in the world with hormone receptor-positive breast cancer and that many of them have been incompletely treated. We’re seeing a benefit across a huge spectrum of time for the application of endocrine therapy, and I believe clinicians should ask, “Why shouldn’t I use it?” rather than, “Why should I use it?”

I see patients being excluded unnecessarily based on age, preexisting osteoarthritis and other trivial reasons. Clinicians are dismissing the application of a treatment that’s highly effective, and I believe this problem must be addressed by the oncology community worldwide.

DR LOVE: Is there an upper limit, in terms of the number of years since completing tamoxifen, at which you feel it’s been too long to consider additional adjuvant endocrine therapy?

DR GOSS: The data are confined to a range of one to seven years, from our postunblinding analysis. It was previously shown, biologically, that if you initiate tamoxifen at any time in the pathway of this follow-up, you can effect benefit, and I believe that’s true here.

Tracks 2, 5

DR LOVE: Matt, when you see a postmenopausal patient who was diagnosed 10 or 15 years ago and never received adjuvant endocrine therapy, do you consider therapy now?

DR ELLIS: That presents a conundrum. I’m certain Paul would agree that a point exists at which offering endocrine therapy is inappropriate. One would imagine that it could be as far out as 15 to 20 years. Certainly the idea that patients with ER-positive disease have a poorer prognosis beyond five years underscores the fact that intervention could be beneficial.

DR WINER: I don’t object to administering an aromatase inhibitor to the elderly woman eight years after tamoxifen, and I would agree that her median survival is probably in the range of six to seven years.

However, it’s extremely unlikely that a modeling approach or clinical trial would demonstrate a survival advantage here. I expect the disease-free survival advantage will be modest for an 81-year-old patient, depending on her competing morbidities, so I’m not going to push her to receive an aromatase inhibitor at this point.

DR LOVE: Aman, how much of a delay are you comfortable with?

DR BUZDAR: I’m comfortable within the MA17 period, which was approximately six months. Although our gut reaction is that we should be prescribing endocrine therapy to these patients, currently we don’t have strong evidence to support that, except for the MA17 data, which came after code breaking and the patients were given a choice — they were not randomly assigned.

I believe we need to wait until we have prospectively randomized studies before we offer all patients delayed therapy.

DR GOSS: Although I agree that a randomized trial would be preferable, it’ll be many years before we have such data, and it’s difficult to imagine that with the strong biological effect we’re seeing in MA17 — albeit not Level 1 evidence — there’s no likelihood of affecting events for patients with hormone receptor-positive disease in follow-up.

Tracks 6-7

DR LOVE: In the clinical setting, how do you approach the patient who has completed five years of an adjuvant aromatase inhibitor?

DR SPARANO: I try to clarify for the patient which of the recommendations that we are making are data driven, with unequivocal proof that this is the appropriate choice, and which of our recommendations are not supported by clear data but are based on our intuition, and then work with the patient to devise a plan that best suits the situation.

For a patient who’s completed five years of up-front aromatase inhibitor therapy, we don’t have the data, so my approach is to consider the patient’s risk of recurrence as it was estimated at baseline and take into account how well the patient tolerated the aromatase inhibitor, her age, comorbidities, et cetera.

DR MACKEY: In the clinical setting, I believe the continuation of an aromatase inhibitor beyond five years is purely speculative. We have a good grasp regarding the toxicities with five years of an aromatase inhibitor — some of the best data come from the ATAC trial — but some of the side effects could be cumulative over time (ATAC Trialists’ Group 2006).

For example, we probably expect higher degrees of bone toxicity with extended aromatase inhibitor therapy, but I believe one of the biggest worries would be neuropsychiatric complications of long-term estrogen deprivation. A lot of data from epidemiologic studies show that lower serum estrogens are associated with a higher risk of dementia.

In my practice, I don’t continue patients beyond five years of an aromatase inhibitor because of the lack of data and the potential for long-term effects.

DR LOVE: Rowan, could you address this issue of cognitive functioning?

DR CHLEBOWSKI: Evidence from a number of preclinical, observational studies suggested that estrogen, especially exogenous estrogen, was associated with favorable effects on cognition. Then the data from the Women’s Health Initiative (WHI) randomized trial, with more than 16,000 otherwise healthy postmenopausal women, demonstrated an increase in strokes associated with estrogen use, and among women 65 years of age or older, dementia was increased (Chlebowski 2006).

Therefore, we have to worry that anything that increases arterial vascular events will have an unfavorable effect on cognition, and in the ATAC trial, we see that anastrozole carries a significantly reduced risk of arterial vascular effects compared to tamoxifen (ATAC Trialists’ Group 2006).

Thus, I’m less concerned about this issue. We don’t know what the effect of aromatase inhibitors is on cognition, but I would need a new signal to become concerned about that side effect with the long-term use of aromatase inhibitors.

DR LOVE: MJ, one of the major options for patients completing five years of an AI is participation in NSABP-B-42, which is evaluating an additional five years of AI therapy. However, in a nonprotocol setting, how do you approach women who are reaching five years on an aromatase inhibitor in your practice?

DR JAHANZEB: I tell patients that emerging evidence shows that their risk of recurrence persists and we don’t know whether it’s more beneficial to continue or stop the aromatase inhibitor. Then, if they choose to continue, it’s informed consent, and I find that approximately a third of my patients continue the aromatase inhibitor, whereas the other two thirds don’t.

Tracks 8-9

DR LOVE: Mark, do you consider the tumor’s PR or HER2 status when selecting adjuvant endocrine therapy?

DR PEGRAM: At UCLA, we feel strongly that HER2 is a broad marker for endocrine resistance independent of the type of antiestrogen therapy used, and that’s what the data are bearing out, so I don’t see how that could be useful in decision-making. Also, the data indicate benefit from an aromatase inhibitor in HER2-positive and in HER2-negative disease, and it appears that aromatase inhibitors, as a class, are generally more active than tamoxifen regardless of HER2 status.

DR GOSS: I believe the data are showing that although HER2 positivity is a relative endocrine-resistance marker, both tamoxifen and aromatase inhibitors are effective — it’s just that aromatase inhibitors, as in every other clinical setting, are more effective. In my opinion, a higher relapse risk, such as a HER2-positive or PR-negative tumor, more strongly justifies the use of an up-front aromatase inhibitor over tamoxifen.

DR LOVE: Eric, how do you view the value of PR and HER2 in selecting an adjuvant endocrine agent?

DR WINER: I believe that both PR and HER2 are perhaps not predictive factors but prognostic factors, and for a patient at higher risk of relapse in the first few years, I am more inclined to use the aromatase inhibitor up front.

DR BUZDAR: If you examine BIG 1-98 or Dowsett’s data, on patients with PR-negative and HER2-positive tumors, the benefit of aromatase inhibitors over tamoxifen is modest, but it is still in the same direction (BIG 1-98 Collaborative Group 2005; Dowsett 2005).

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