The NSABP B-35 schema is shown here and this was a study in postmenopausal patients with hormone receptor positive DCIS that was treated with lumpectomy with plan for radiotherapy, so all of these women had lumpectomy and radiation therapy. This was a double blind placebo-controlled trial, women got two pills, they got an active anastrozole pill and a placebo tamoxifen or an active tamoxifen and a placebo anastrozole. They took this medication for five years and we followed them up.

This was the primary outcome for our trial, it’s a composite outcome, as you can see here. It was timed to any breast cancer event such as a local recurrence, a regional recurrence, distant disease or a breast second primary that could be either invasive or DCIS. So many, many things combined together to look at a sample that’s powered to detect this difference.

These were the results that were presented last year at ASCO and, as you can see, there is a 27% reduction in hazard of recurrence in this composite complex endpoint but just pointing out the anastrozole arm here out at ten years had a 93.5% event free survival and for the tamoxifen group it was 89.2%. So this shows you the extraordinarily high quality long-term disease free survival for these women.

Now, we stratified our trial by women being less than 60 or over 60, these were all again postmenopausal women, but we actually had specific a priori hypotheses specifically related to the quality of life study that the toxicities of these two drugs might differ according to how close you were to having gone through menopause. If you look at this here there is no significant benefit when you compare tamoxifen to anastrozole on the right in the women over age 60, so it’s dealer’s choice there, they’re equivalent. But if you look at the left, the benefit is primarily in women who were less than 60 and there’s about a 5-6% difference there between the two curves that is statistically significant and there was a statistically significant interaction between age. So the benefit in this trial that we saw clinically was really only in the younger women.

For the quality of life study that was embedded in this trial and it was a secondary outcome among others, our primary hypothesis was that there would be no difference between quality of life between the two treatments and that they would be equally well tolerated. We had a hypothesis that anastrozole might have a higher rate of hot flashes, particularly in the women less than 60 years of age. At that time we had very little data to go on about what the quality of life impact would be; the results of the ATAC trial in invasive breast cancer didn’t have its quality of life results come out until several years later so we had made this hypothesis. Our secondary aims for the quality of life trial, again based on some early data from ATAC, were that there would be greater vaginal dryness and pain with intercourse with anastrozole and poorer sexual functioning with the anastrozole group compared to tamoxifen.

We used a battery of instruments that really built on our prior breast cancer prevention trials, the BCPTP-1 trial and the P-2 STAR trial, where we had learned a lot about the biology of tamoxifen and, in the case of STAR tamoxifen and raloxifene, these are validated scales that we had a lot of information on. We used an intention to treat analysis and we compared the two arms using mixed models for repeated measures with adjustment for baseline scores, time point and age category and, again, looked in this case through 60 months, the questionnaires were administered every 6 months from baseline on. We also have data in the year afterwards but we have not analysed that as yet.

This is the contour diagram and schema for the trial, you can see there were over 3,100 patients randomised to the trial. We had 1,223 patients in the quality of life sub-study. We basically continuously accrued until we reached what had been our target of 1,150 patients which was an adequate sample size for the trial. We over-recruited a bit but we needed a total of 500 patients in each arm who would be evaluable to be able to answer this in a statistically well-powered design.

I’m just showing a few of the patient characteristics here. You can see more of the women were over age 60 years but it’s pretty closely divided and we had about 12% non-white women who participated in this trial. The medical characteristics were also equally divided and this sample represents the population that was in the full trial so it’s not a selected group.

Here are the first results. You can see on the left with the SF12 physical component scale there’s absolutely no difference between the two treatment groups over the five years of the study and on the right the mental component scale. The mean or median for the population in the US is 50, the physical function gets worse as we get older so there’s a little bit of a decrement there but what you see is there is no change in physical functioning or mental functioning as women took either of these two drugs.

Here what you can see is the frequency with which women reported hot flashes at least a little bit bothersome, and I’m going to show you the severity scores in more detail. When we originally looked at the design of the trial we were interested in both frequency and severity and to make our data a bit more comparable to what’s reported in terms of the toxicity from the IBIS trial if you look on the left, and again the yellow is the tamoxifen patients, the aqua are the anastrozole patients, and if we look at the first column for hot flashes in women less than 60 you can see they have a higher rate, it’s in the low thirties, for the women over 60 it’s in the high twenties. If we look at vaginal dryness that’s a little bit more common in women with tamoxifen and anastrozole at baseline, it’s in the thirties. And if we look at joint pain over 60% of the women just entering the trial had musculoskeletal complaints and joint pain. So this is very common in postmenopausal women. What I want to call your attention to is what happens at six months and what we see in terms of the frequency of hot flashes it goes up with both drugs in the younger and older women, a tad worse in the tamoxifen group. If we look at vaginal dryness that also goes up in both groups but it’s more significant in the anastrozole for vaginal dryness. Joint pain goes up about 10% for the women who were on tamoxifen and 20% for women who were on anastrozole.

So in the next slides I’m going to talk more about severity which I think gives you a better picture of what women experience with both of these drugs. The questionnaire that we used rated the groups of symptoms on a score of 1 being slightly, 2 being moderate, 3 being quite a bit and 4 being extremely. The thing to note here is these scores are between 1 and 2 on average in terms of severity. So we’re talking about modest severity of symptoms, even though they may be frequent they’re not that severe. On the left if we look at vasomotor symptoms the yellow curve is for tamoxifen, the aqua curve is for anastrozole, and what you see is that shortly after starting either one of these drugs, hot flashes, this was a composite of hot flashes and night sweats, go up in both groups but nicely actually diminish over time in both groups. If you look on the right, the composite musculoskeletal pains which is joint pains, muscle aches and general aches and pains, three items on that scale, we see that both of them go up but much more significantly in the anastrozole treated group and they do not really subside significantly, they stay up over time.

If we look at sexual functioning again, which had been one of our hypothesised scales, this is the MOS sexual functioning scale that has four items that look at various aspects of sexual functioning. Contrary to what we had hypothesised there was no difference between the two groups, and just to give you a sense, the higher score means more sexual problems. A normal for the general population might be around 20, so this is an increase in sexual difficulties but no difference between the two groups.

Now, I want to talk about the stratified analysis because this gets back to the choice of how are we going to decide what drug is best for which group of people. We looked at women who were over 68 years of age and those are the actual lower curves here and the higher curves are for the women who were over age 60 for vasomotor symptoms. So not only are vasomotor symptoms worse in women treated with tamoxifen but they’re significantly greater in younger women. Again, we had hypothesised that anastrozole might be worse, we were wrong on this, clearly tamoxifen is worse. So again this might be a symptom that would be important to think about in younger women with tamoxifen. We also looked at the items on weight problems where we saw that younger women, again no difference between the two groups on the right, between either of the two drugs, but younger women significantly reported greater difficulties with weight gain and being unhappy with their appearance.

For vaginal symptoms, this is vaginal dryness and pain with intercourse, we see significantly greater problems for women, again not high severity, we’ve got a severity up there around 1 but if you have it it’s a problem. We see this again much more significant for younger women and worse with anastrozole. On the right, very low symptomatology but this is vaginal discharge and itching, those are those items, and again younger women having more difficulties. But again low severity, it’s close down there to zero.

So, in conclusion, both anastrozole and tamoxifen are well tolerated in patients with DCIS with greater severity of some symptoms in women less than 60 years of age. The symptom profiles actually differ in the expected directions and now, 12-13 years after we designed this trial, we know a lot more about these two drugs and it’s very consistent. But this is the patient report of the experience. I think with this kind of information on patient reported outcomes, as well as the breast cancer free interval which I showed you to begin with, which again reminding you no difference in breast cancer free interval in women over 60 but a significant reduction in women less than 60, physicians and patients can now make much more personalised decisions about which of these two effective agents they should select.