Adjuvant Systemic Therapy


Oncotype DX™ assay

Breast Cancer Update for Surgeons 2005 (1)

DR NORMAN WOLMARK: We wanted to determine whether the Oncotype DX assay could predict the benefit of chemotherapy, so we examined the data from NSABP-B-20, which randomly assigned patients with receptor-positive, node-negative disease to tamoxifen versus tamoxifen plus CMF chemotherapy versus tamoxifen plus MF chemotherapy. We found that patients who were at high risk based on their recurrence scores derived benefit from chemotherapy, but patients at low risk, who comprised 50 percent of the cohort, did not appear to derive substantial benefit from the addition of chemotherapy to tamoxifen. The intermediate group comprised only 20 to 25 percent of the cohort, and we didn’t have the power to determine if they benefit from the addition of chemotherapy.

We were surprised to find that the relative risk reduction was not uniform — different risk groups did not have the same relative risk reduction. The greatest relative risk reduction was seen in patients at highest risk.

Computerized models and the Oncotype DX assay

Breast Cancer Update for Surgeons 2005 (3)

DR ELEFTHERIOS P MAMOUNAS: John Bryant presented data at the last St Gallen meeting evaluating the recurrence score and Adjuvant! Online, and they seem to perform independently to a certain extent. Adjuvant! Online will add to the recurrence score, and the recurrence will add to Adjuvant! Online. Peter Ravdin is working with us to modify Adjuvant! Online to introduce the recurrence score; they provide complementary information, which is important for the patient. However, Adjuvant! Online doesn’t provide any prediction on benefit from therapy, whereas the recurrence score adds prognostic and predictive value.

The role of adjuvant aromatase inhibitors in postmenopausal women

Breast Cancer Update 2005 (2)

DR I CRAIG HENDERSON: Based on data from various adjuvant endocrine therapy trials, I believe it is unreasonab le to withhold aromatase inhibitors from postmenopausal women with hormone receptor-positive disease. ATAC is still the definitive adjuvant trial in terms of comparing tamoxifen to an aromatase inhibitor, and the data are very compelling. An aromatase inhibitor is now my drug of choice, and that changed in just the past few years.

As for switching patients from tamoxifen to an aromatase inhibitor, I discuss this with every postmenopausal patient on tamoxifen. We don’t know know the optimal duration of various endocrine therapies. While we know that five years of tamoxifen is as good as or better than 10 years, the optimal duration of aromatase inhibitors is unknown at this time.

Breast Cancer Update 2005 (7)

DR ROWAN T CHLEBOWSKI: If you start with tamoxifen, after two and a half, three or five years, more patients will have relapsed than on an aromatase inhibitor. A substantial number of those patients will be irretrievable — they have incurable disease — and so you’re banking on the fact that you’ll be able to capture more patients later, but we don’t have any data for that. That’s just speculation.

While I believe that sequencing therapy may be better, ultimately, I still don’t see any reason not to start with the most effective therapy. An aromatase inhibitor followed by tamoxifen or a nonsteroidal aromatase inhibitor alone makes more sense to me. We have to wait to see the data from the BIG FEMTA trial, which includes an arm with letrozole as initial treatment followed by tamoxifen.

Breast Cancer Update 2005 (5)

DR DEBU TRIPATHY: I believe a clear, consistent story is emerging without a lot of conflicts and conundrums: Adjuvant aromatase inhibitors are better than tamoxifen. Whether the aromatase inhibitors are used at the time of initial diagnosis, after two to three years or five years of tamoxifen, there is a favorable impact on local, distant and even contralateral breast cancer recurrences.

The unresolved questions are: Should you use a little tamoxifen, maybe two years and then cross over? Should you only use an aromatase inhibitor right off the bat and maybe even think of continuing beyond five years? The trial that will provide the most information in this regard is the BIG FEMTA/BIG 1-98 trial.

Breast Cancer Update 2005 (4)

DR WILLIAM J GRADISHAR: I sit on the NCCN guidelines breast cancer committee, and if you evaluate the next rendition of the guidelines, you’ll find we have not dismissed the use of tamoxifen but rather moved the use of aromatase inhibitors up front. Within the NCCN guidelines, we’re trying to select the aromatase inhibitor to be used based on the design of the study. For firstline therapy, we would use anastrozole. If a patient has been on tamoxifen for a period of time, exemestane is now a legitimate choice, and after five years of tamoxifen, letrozole is an option. We view all of these agents as active and well tolerated.

Effects of aromatase inhibitors on bone

Breast Cancer Update 2005 (7)

DR CHLEBOWSKI: The five-year toxicity data are very favorable for anastrozole compared to tamoxifen because the three life-threatening toxicities — endometrial cancer, arterial and venous vascular events — were all significantly less with anastrozole. Many oncologists have a lot of concern regarding bones, but I believe it’s going to be not only a preventable, treatable situation but also something that is likely to go away completely in the near future. There is no difference in hip fractures after 68 months with anastrozole and tamoxifen. This is for a group of patients who had no prescreening when they entered the study and no ongoing protocol-defined follow-up for bone. If you’re going to actually do any screening, any treating, you’re going to have lower numbers than that.

Breast Cancer Update 2005 (1)

DR MICHAEL BAUM: The fracture rate incidence is becoming a little more reassuring. An excess fracture rate occurs in the first two or three years, but then the lines are beginning to come together. As patients stop taking anastrozole, the fracture rate returns to that of the patients randomly assigned to tamoxifen. Furthermore, so far, no difference has occurred in fractures of the neck or femur, which are of particular concern. I think the issue of bone is easy to manage. We should be alert to it, monitor bone mineral density, perhaps exclude patients who have established osteoporosis, and then be ready to intervene with a bisphosphonate when the patient becomes osteopenic.

Aromatase inhibitors and arthralgias

Lynn Sage Breast Cancer Symposium 2005

In the Arimidex or Tamoxifen Alone or in Combination (ATAC) trial, arthralgia was reported by 35.6% vs 29.4% of patients on anastrozole and tamoxifen, respectively, at the 68-month followup. While the incidence was significantly higher in the anastrozole arm (p < 0.0001), it is noteworthy that the incidence of arthralgia with tamoxifen was also high (29.4%), with an absolute difference of 6.2%. Most arthralgia incidences occurred early in both treatment arms (75% in the first 33 months) and were primarily mild to moderate in intensity.

— Paul Plourde et al. Poster. Lynn Sage
Breast Cancer Symposium 2005.

Breast Cancer Update 2005 (4)

DR ANTHONY HOWELL: Matt Ellis’ group presented an interesting abstract at San Antonio indicating that women with these joint symptoms may have lowered vitamin D levels and that giving them vitamin D improved some of the joint symptoms. The data are very early, and they are conducting more studies, 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 that despite the joint symptoms, patients tend to stay on anastrozole more than they stay on tamoxifen, which is an important efficacy issue.

Adjuvant endocrine therapy in premenopausal women

Patterns of Care 2004 (2)

DR JOYCE O’SHAUGHNESSY: I have combined an LHRH agonist with an aromatase inhibitor in premenopausal women, but it’s rare because for women who are at high enough risk for that therapy — multiple positive nodes or even node-positive, HER2-positive breast cancer — I generally recommend oophorectomy, and then I’m comfortable with an aromatase inhibitor.

Meet The Professors 2005 (3)

DR ROBERT W CARLSON: The data today are quite convincing that the aromatase inhibitors should play a role as adjuvant hormonal therapy for postmenopausal women with ER-positive breast cancer. Precisely how to sequence or incorporate those data into the premenopausal subset is much less clear. We do know that the aromatase inhibitors do not suppress circulating estrogen levels adequately in women with functioning ovaries, whether or not they have menstrual function. Therefore, if you’re going to use an AI for a young woman, you have to be certain that she is postmenopausal, or I think she should be enrolled in one of the prospective trials evaluating the use of ovarian suppression and an AI in premenopausal women. We do know that a number of women stop having menstrual function or periods subsequent to cytotoxic chemotherapy, yet their ovaries continue to cycle. A substantial proportion of women also stop having ovarian function with cytotoxic chemotherapy, at least over the short term, but on further follow-up, their ovarian function returns.

ASCO 2004 Technology Report

Cessation of menses does not necessarily mean absence of ovarian function, as premenopausal estradiol levels may be found in women experiencing chemotherapy- related amenorrhea. There is widespread agreement that aromatase inhibitors should not be employed as monotherapy in premenopausal women. This view stems from the lack of evidence for adequate estrogen suppression and potential for stimulation of the ovaries via increased gonadotropin release.

— Eric P Winer, MD et al.
J Clin Oncol 2005;23(3):619-29.

Breast Cancer Update 2005 (4)

DR MICHAEL GNANT: We were particularly interested in younger patients because they are physiologically used to higher levels of estrogen from their functioning ovaries. We undertook ABCSG- 12 to first establish the severity of that treatment-induced bone loss and, second, to see whether it can be prevented or treated. We found out that a significant loss occurs — on average close to 15 percent — in these premenopausal women treated with endocrine therapy with goserelin and with tamoxifen or anastrozole. We also discovered that it could be prevented with zoledronic acid given twice a year.

Breast Cancer Update 2005 (4)

DR HOWELL: Three important randomized trials are enrolling premenopausal women with hormone-receptive disease — SOFT, TEXT and PERCHE. The ABCSG-AU12 trial randomly assigned approximately 2,000 patients to goserelin plus tamoxifen versus goserelin plus anastrozole, with a second randomization to zoledronic acid or not. That study will tell us whether tamoxifen or an aromatase inhibitor is superior when combined with goserelin in premenopausal women. We expect that goserelin with anastrozole will be better, which is why so many patients are already being treated off protocol.

Sequencing aromatase inhibitors after adjuvant tamoxifen

Breast Cancer Update 2005 (2)

DR BAUM: I am now absolutely confident that women who have been on tamoxifen for two or three years should switch to an aromatase inhibitor. We have excellent data for both exemestane and anastrozole from three trials. Boccardo’s small ITA trial with anastrozole was the first to report, followed by the large IES study with exemestane and the joint Austrian-German study of anastrozole presented in San Antonio. Overwhelming evidence indicates that a switch to an aromatase inhibitor is beneficial.

I recommend the switch regardless of whether the patient has been on tamoxifen for one year or four years. You can wait forever for refinements, but no one is ever going to do a trial of a switch at one year or a switch at four years. We just have to stretch the available evidence and be sensible about it, and I think it would be reasonab le to switch.

The MA17 trial is a well-conducted trial in women who have already received five years of tamoxifen. It shows proof of the principle that you can influence the natural history of breast cancer after five years of tamoxifen.

Breast Cancer Update 2005 (2)

DR MAURA N DICKLER: The aromatase inhibitors add benefit immediately after surgery, after two to three years of tamoxifen or as extended adjuvant therapy. In breast cancer, the highest risk of recurrence is typically within the first two to three years after surgery. In women who participated in the ATAC trial, you can see a difference in the disease-free survival curves well before the two and a half year mark. Not only do you lose patients to an early breast cancer recurrence in the first two to three years, but you also lose some women to adverse events on the tamoxifen arm.

The IES study and MA17 do not really take those facts into consideration because those patients have already dropped out prior to randomization. I typically offer anastrozole to the majority of postmenopausal patients with receptor-positive tumors after surgery and chemotherapy. When patients come in after two to three years of tamoxifen, I discuss switching them to an aromatase inhibitor. At the end of five years of tamoxifen, I discuss letrozole.

Breast Cancer Update 2005 (4)

DR HOWELL: I use exemestane after two to three years of tamoxifen based on the IES data. However, if you compare the IES exemestane data to the data from the combined ARNO 95 and ABCSG-8 trials, in which the patients were switched to anastrozole, the agents appear to be similar in terms of efficacy. The hazard ratio for relapse-free survival was 0.73 in the IES study and 0.60 in the ARNO study, so I believe these two agents are equivalent in this situation.

We now have data to support the use of either anastrozole or exemestane after two or three years of tamoxifen. After five years of tamoxifen, we have only the MA17 trial data, so I use letrozole in this setting.

Breast Cancer Update 2005 (3)

DR RAIMUND V JAKESZ: In the combined trials of ABCSG-8 and ARNO 95, more than 3,200 postmenopausal patients, all with receptor-positive disease, were exposed to two years of adjuvant tamoxifen after surgery. We then randomly assigned them to tamoxifen or anastrozole for three years. The data were clean and informative. In the IES trial, exemestane resulted in a risk reduction of approximately 35 percent, whereas in the combined trials the risk of an event was reduced by 40 percent with anastrozole. Most of the difference in event rate with anastrozole was due to a huge reduction in distant metastases.

Breast Cancer Update 2005 (Special CME Meeting Edition)

DR C KENT OSBORNE: Several groups have looked at statistical modeling of the optimal long-term sequencing of an AI after tamoxifen versus immediate use of an AI — Jack Cuzick’s group in London, the Dana-Farber group with Hal Burstein, and our own group in Houston with our statistician, Sue Hilsenbeck. All of these models suggested similar findings, and they could not rule out a moderate benefit from sequencing compared to immediate use if one looks at the longterm results after 10 years in the large subgroup of ER/PR-positive tumors. Although there is a peak in recurrence at two to three years, ultimately more patients recur after year five than in the first five years, and the sequence of tamoxifen followed by an AI could turn out to be a better strategy. While it is true that we can’t necessarily go by the results of mathematical models, they do provide some evidence of what the possibilities of these different strategies might be over the long term.

Breast Cancer Update 2005 (9)

DR MAMOUNAS: It is important to study the duration of aromatase inhibitor therapy. The NSABP will take patients who complete five years of an aromatase inhibitor or took tamoxifen for two to three years and then switched to an aromatase inhibitor and randomly assign them to either continue an aromatase inhibitor — letrozole — versus placebo for five years. We will essentially do what we did in the NSABP-B-14 extension trial but with aromatase inhibitors.

68-month follow-up of the ATAC Trial

Lancet 2005

The present data suggest that it is not appropriate to wait five years to start an aromatase inhibitor. Furthermore, the higher rates of recurrence (especially in years 1–3) and the increased numbers of adverse events and treatment withdrawals associated with tamoxifen lend support to the approach of offering the most effective and well-tolerated therapy at the earliest opportunity. Five years of anastrozole should now be considered as the preferred initial adjuvant endocrine treatment for postmenopausal women with hormone receptor-positive localized breast cancer.

— ATAC Trialists’ Group.
Lancet 2005;365(9453):60-2.

Breast Cancer Update 2005 (1)

DR BAUM: The ATAC trial has reached an important point in its evolution with a median follow-up of 68 months. Almost all of the patients are now off therapy, and we have one year of follow-up after the therapy was completed. I believe this is probably the most important of the three analyses, and this latest analysis allows me, as a practicing clinician, to change my mind and my practice. I now would say that anastrozole is the preferred initial treatment for postmenopausal women with hormone receptorpositive disease.

The simplest interpretation of the results is that anastrozole prevents one in four of the relapses we see in patients on tamoxifen. That translates into highly significant improvements in disease-free survival, recurrence-free survival and distant disease-free survival.

In the hazard rate analysis plot from the ATAC trial, we’re seeing two peaks with tamoxifen. The first peak is lowered with tamoxifen, but a peak still occurs. In the anastrozole arm, the initial peak is lost and the second peak is flatter. I believe this is the most profoundly important observation in this trial, not only to help make therapeutic decisions but also to give a fascinating biological insight. The strongest argument for starting adjuvant endocrine therapy with an aromatase inhibitor is that anastrozole almost ablates that first peak. If you wait two to three years, as some of the trials are reporting, the effects are wonderful, but meanwhile, you’ve lost those patients who will relapse and ultimately die in those first two years.

Letrozole versus tamoxifen up front or sequentially

Breast Cancer Update 2005 (6)

DR JACK CUZICK: The efficacy results in BIG FEMTA were essentially the same as those in the ATAC trial at the 30-month point. The hazard reduction was similar, and the side-effect profile was, by and large, the same, although it was reported differently. A few differences were seen. They found a benefit for letrozole only in patients with node-positive disease, which is difficult to understand. It’s probably a chance finding, but we need to follow that.

At this stage, they’ve found no difference in efficacy between the patients with PR-positive and PR-negative disease. We have to acknowledge that the data are different from what’s been observed in other trials.

The third and most worrying finding is the substantial excess in cardiovascular deaths for letrozole compared to tamoxifen, which hasn’t been observed in the trials with anastrozole. Whether this is due to chance or differences in cardiovascular mortality is important to know. Letrozole is a slightly more potent aromatase inhibitor, and it is not clear whether that has an impact.

Breast Cancer Update 2005 (5)

J MICHAEL DIXON: The BIG 1-98 data are a short-term analysis — follow-up is only 25.8 months, whereas for the ATAC trial the follow-up is five years — and some concerns exist as to how the BIG 1-98 data are being analyzed. The trial has four arms, and patients who switched therapy after two years were included in the analysis, but only up until the time when they were switched. That’s a bit unusual because one would expect some of the benefit from the first two years of tamoxifen and letrozole to continue.

BCIRG 001: Adjuvant TAC versus TAC

Breast Cancer Update 2005 (1)

DR JOHN R MACKEY: In our first study, BCIRG 001, 1,500 women from 21 countries were randomly assigned to six cycles of adjuvant TAC or FAC. The women enrolled in the trial had nodepositive disease. We now have mature results with five years of follow-up.

The trial demonstrated that adjuvant TAC significantly improved disease-free survival by 28 percent in relative terms (p = 0.001). Overall survival was also strikingly improved; the trial demonstrated a 30 percent relative reduction in mortality with adjuvant TAC, which was an absolute six percent improvement in overall survival.

This would be a perfect story if an increase in side effects did not occur. In fact, TAC was associated with a high rate of febrile neutropenia. Approximately 25 percent of the women receiving TAC experienced an episode of febrile neutropenia, which was not unexpected because primary prophylaxis with G-CSF was not allowed. We now know that if we were to do the study again and administer TAC with G-CSF, we would see a febrile neutropenia rate, on a per-patient basis, of about three to six percent.

NSABP trial B-38

Breast Cancer Update 2004 (3)

DR CHARLES E GEYER JR: Two key adjuvant trials have been BCIRG 001, evaluating TAC versus FAC, and the CALGB dose-dense trial 9741 of AC paclitaxel. Currently, our view is that TAC appears to be the optimal way to administer an anthracycline/docetaxel regimen, and dose-dense AC/paclitaxel is the optimal way to administer those agents.

Which is better? It’s impossible to answer that question without performing a clinical trial, which is why we developed trial NSABP-B-38. It’s a pragmatic design in which we regard TAC as our control arm. A clear advantage of dosedense therapy is that it is so well tolerated, and it clearly affords the opportunity to add a fourth drug to the paclitaxel. TAC is a maximally tolerated regimen. You really can’t push it much more, so we sought a candidate drug to combine with paclitaxel.

Adjuvant clinical trials incorporating capecitabine

Breast Cancer Update 2005 (3)

DR O’SHAUGHNESSY: The vinorelbine/ capecitabine combination is one of numerous capecitabine combinations being evaluated in European adjuvant trials. I’m not aware of any adjuvant or neoadjuvant studies evaluating capecitabine/ paclitaxel; however, a number of neoadjuvant and adjuvant trials are evaluating capecitabine/docetaxel.

Even if I had data with capecitabine/ paclitaxel, I probably would not have considered evaluating that combination — as opposed to capecitabine/docetaxel — in our adjuvant trial. In metastatic disease, docetaxel 75 mg/m2 in combination with capecitabine has a clear survival advantage compared to docetaxel 100 mg/m2. Usually, we try to take that advantage in survival in metastatic disease and immediately move it into the adjuvant setting.

Inclusion of older patients in trials of adjuvant chemotherapy

JAMA 2005

Our study adds to the increasing number of trials that suggest that older patients in fair to good health tolerate standard chemotherapy regimens, and even more intensive regimens, almost as well as younger patients. Moreover, and more importantly, this study suggests that the added value gained from more intensive chemotherapy regimens commonly used in the adjuvant setting might be shared by older patients and not limited to younger age groups.

— Hyman B Muss, MD et al.

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