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HER2 status as predictive marker for aromatase inhibitor versus tamoxifen use in early breast cancer

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Dr Bartlett talks to ecancertv at SABCS 2015 about using HER2 status as a predictive marker for benefiting from treatment with an aromatase inhibitor (AI) versus tamoxifen based on data from a meta-analysis of more than 12,000 patients who participated in three landmark AI trials: ATAC (Arimidex, Tamoxifen, Alone or in Combination), BIG (Breast International Group) 1-98 and the TEAM (Tamoxifen Exemestane Adjuvant Multinational) studies.

You’ve been looking here at her to status very interestingly you’re also concerned with aroma taste inhibition and tamoxifen can you tell me what was the big issue that you were investigating here what did you set out to do and so her too has long been recognized as a driver of endocrine resistance patients who are her2-positive tend to relax earlier on

Endocrine therapy than patients who are not and the question we were addressing was whether or not patients who should receive endocrine therapy are better treated with aromatase inhibitor from day 0 if they are her2 positive or whether they could delay and use a switching strategy for two or three years and potentially extend their endocrine therapy for maybe

Five or seven years so explain what you did in the study please yeah so what we perform was a patient level meta-analysis of three trials in each trial her two had been tested in one of three central laboratories we were able to recruit 12,000 patients with data to the study and to test whether or not her two acted as a predictive biomarker for benefit from a is

Versus tamoxifen in the first three years of treatment which is what informs that treatments which should i start now or should i wait now from a quick reading it seems to me this is not completely straightforward though is it no it isn’t completely straightforward i mean we satisfied the criteria for our primary endpoint we had a significant treatment by marker

Interaction the benefit meaning what meaning the benefit from ii’s over the first three years represented a 30-percent risk reduction in her2 negative patients but actually there was minimal evidence of a risk reduction and her2 positive patients in fact they were the hazard ratio was 1.1 suggesting they might even have some deleterious effect however as you said

It wasn’t straightforward the challenge was that the her2 population is a small population of the overall test subjects so we only had a thousand her2 positive patients and in that population we only had 111 events that affects the tiss tiss t’kul power of that interaction term and analyzing three trials we also saw a degree of heterogeneity a different effect in

Some of the different trials again formally that wasn’t statistically significant reinforcing our primary conclusion but it concerned us that we couldn’t necessarily recommend a change in practice because of that jannetty there was a second issue that prevented us from recommending a change in practice and that is at the time the trial was performed monotherapy

With herceptin for her2-positive cases who had not received chemotherapy was not available so in the modern era it’s possible perhaps recommend these patients for herceptin treatment that may change our results of course some people switch from tamoxifen to aroma taste inhibition is that included in your calculation this was a primary goal of our calculation

Was looking at the priests which period so we haven’t yet looked at what happens after the switch that’s going to be a further analysis in the future but it seems that patients with 0 to negative disease certain category of patients do better with an ai that seems to be the implication again insofar as the treatment by market interaction tests that we can make a

Fairly robust conclusion in that space we’re less able to conclude that the her2 positive patients do not benefit although there’s a question mark about that so could you sum up the the conclusions of this i think the conclusions we have drawn is that that there remains a question mark about the benefit for a is in the her2 positive population that further research

Is needed before we can make any recommendations to change clinical practice in that group but we will be going away to do that research over the next year or so so as a predictive marker hurt who does what in this role as a predictive marker statistically her to would select those patients who should get up front ai and they would be the her2 negative population

But with the caveats that i’ve explained around the study we would not regard that as sufficient at this stage to drive a change in clinical practice so your recommendations to doctor right now would be what continue as you have been doing so the straightforward strategy normally would be the straightforward strategy normally will depend on clinic to clinic some

Clinicians will use a switching strategy for her2 positive or her2 negative patients some patients will go up clinicians we’ve got up front that’s based on other meta analyses of the aromatase inhibitor trials and clinicians will look at their individual patients and make those decisions and i guess the take-home messages don’t change the way you do that from last

Week to this week and it’s a bit disappointing that there isn’t predictive biomarker what hopes do you hold out for finding one thanks a challenging space i think that the the problem we have is that the biomarker positive groups tend to be small i think there is there is still hope that we could do this i think we have evidence that other drivers of this pathway

May increase the population that we can test and it may be that in the next year or two we come up with a better analysis but it’s a very challenging space predictive biomarkers so what’s the bottom line for doctors deciding on a i versus tamoxifen i’m go back to the aromatase inhibitor overview groups evidence on the on the trials most of those suggests that

Upfront a eyes would appear to be more beneficial the the p value for the switch versus upfront a eyes is 0 point 0 for 5 it’s very modest change at present i would say watch this space for further evidence emerging in that particular setting but certainly every patient probably requires an ai at some point in their endocrine therapy you

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HER2 status as predictive marker for aromatase inhibitor versus tamoxifen use in early breast cancer By ecancer