- Email: [email protected]
Neoadjuvant Endocrine Therapy
Neoadjuvant Endocrine Therapy Ian E. Smith The modern era of neoadjuvant endocrine therapy was developed with tamoxifen in the 1980s. Trials showed useful downstaging to avoid mastectomy, but long term results showed that this could be used before but not instead of surgery. Recently neoadjuvant aromatase inhibitors have been shown to be superior to tamoxifen. Letrozole was significantly superior in terms of clinical response (55% vs. 36%) and breast conservation (45% vs. 35%). Neoadjuvant anastrozole has also been shown to be significantly superior in terms of breast conservation in the combined results from 2 trials, IMPACT and PROACT (43% vs. 31%) although a significant reduction in clinical response was not seen in the IMPACT trial. Both aromatase inhibitors have a particular gain over tamoxifen in tumours which over-express HER2. Data have emerged from the IMPACT trial suggesting that the changes in short term biological parameters such as Ki67 may predict for long term outcome in major adjuvant trials. Semin Breast Dis 7:101–107 © 2004 Elsevier Inc. All rights reserved.
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here is no new thing under the sun, and that includes neoadjuvant endocrine therapy. Almost 50 years ago, Kennedy et al reported on 27 postmenopausal women whose breast cancer was treated with hormone therapy before surgery, mainly using estrogens which were novel at the time, and their clinical description has never been bettered (Kennedy et al, 1957). “The cancers in the treated patients were altered by complete or partial softening. Many of the tumors became mobile, smaller and more difficult or impossible to palpate. Others, less extensively affected, changed from a hard to a rubbery consistency. Softening appeared to be the fundamental change observed clinically at some time in the regression of every tumor and it preceded shrinkage and diminution of mass.” There are occasional reports of premenopausal women treated with neoadjuvant oophorectomy or leuprorelin,2,3 but neoadjuvant chemotherapy is generally considered more appropriate in this context. This chapter will therefore focus on patients who are postmenopausal. There are two clinical and several research-directed reasons to use neoadjuvant endocrine therapy in women with hormone receptor–positive breast cancer. Clinically, this approach might be considered as an alternative to surgery, particuInstitute of Cancer Research and Royal Marsden Hospital, London, United Kingdom. Address reprint requests to Ian E. Smith, MD, Department of Medicine, Royal Marsden Hospital, Fulham Road, London SW3 6JJ UK. E-mail: [email protected]
1092-4450/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.sembd.2005.01.006
larly in women unfit for this procedure through age or medical infirmity. This approach has obvious short-term attractions but also important limitations, as described below. The second and currently the main clinical indication is to downstage large breast cancers, so that mastectomy might be avoided or to achieve operability in previously inoperable cancers.4 A key current research aim is to investigate neoadjuvant therapy to develop short-term surrogate clinical, pathological, or biological end points that might predict longterm outcome in adjuvant trials. Such trials are large, expensive to run, and take years to achieve their outcome. The adjuvant ATAC (Arimidex, Tamoxifen Alone, or in Combination) trial, which started in 1996, involved 9366 patients, and reported its first results 6 years later with a median follow-up of 33 months, is a good example.5 The option of a rapid neoadjuvant alternative involving a relatively small number of patients would improve dramatically the rate at which novel therapies in early breast cancer could be investigated. Furthermore, predictive shortterm end points for long-term outcome could open up the possibility of individualized adjuvant therapy rather than the current “blind” approach based on probabilities derived from adjuvant trial data. Finally, the neoadjuvant approach offers the potential of serial core biopsies to study molecular changes during treatment that might throw light on mechanisms underlying sensitivity or resistance to therapy. This chapter will review progress in these areas. 101
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102
Neoadjuvant Endocrine Therapy as an Alternative to Surgery
ceded a series of randomized comparative neoadjuvant trials, the results of which have recently emerged.
Tamoxifen was first evaluated as an alternative to surgery in early breast cancer in a series of small studies in the 1980s. In the first, it was reported to achieve tumor responses sufficient to continue treatment beyond the first follow-up visit in 73% of elderly women ⬎75 years of age.6 Eighteen percent took more than 12 months to achieve maximum response. In a subsequent small randomized trial involving 116 patients aged 70 or over comparing tamoxifen alone with surgery alone, no difference was found in either time to progression or survival between the two treatments.7 Indeed, there was a nonsignificant trend toward a decreased risk of local recurrence and a delay in the development of distant metastases in patients on primary tamoxifen. This trial had a large number of patients with T3-4 cancers. In a similar trial involving 135 patients over 70 years of age, no survival difference was found between the two groups, but here there was a 43% local failure rate in the tamoxifen alone arm at 3-year followup.8 In a larger Cancer Research Campaign UK trial comparing tamoxifen alone or surgery and tamoxifen9 in 381 women 70 years or older, no significant differences in survival or quality of life was found between the two approaches at 34 months follow-up, but a significantly higher loco-regional relapse rate was seen in the tamoxifen alone arm (23% vs 8%).9 These trials in elderly patients therefore urged caution in using neoadjuvant endocrine therapy as a substitute for surgery in most patients, but nevertheless suggested that there could be benefit in using this approach before surgery.
Neoadjuvant Versus Adjuvant Endocrine Therapy
Neoadjuvant Endocrine Therapy Before Surgery There are numerous small studies of neoadjuvant endocrine therapy before surgery in the literature, starting with the neoadjuvant estrogen report described above.1 Response rates vary and are often loosely defined, but they are generally higher than in the more rigorous randomized trials described below. In two of the tamoxifen versus surgery trials described above, reponse to tamoxifen was 55% at 6 months and 63% (best ever) in one,8 and 25% 6 months followed by 47% (best ever) in the other.9
Emergence of the Aromatase Inhibitors The most important development in the endocrine therapy of breast cancer in recent years has been the challenge to tamoxifen from the so-called third-generation aromatase inhibitors, including in particular anastrozole, letrozole, and exemestane.10 In advanced breast cancer, anastrozole and letrozole have been shown to be superior to11,12 or at least as good13 as tamoxifen. Nonrandomized studies suggested that these agents also might be more effective than tamoxifen as neoadjuvant therapy in older women with locally advanced or large operable cancers, in terms of tumor regressions and the possibility of breast-conserving surgery.14-18 These results pre-
So far, there are no published trials comparing neoadjuvant with adjuvant endocrine therapy, by analogy with the NSABP-14 and other chemotherapy trials.
Comparative Trials of Neoadjuvant Endocrine Therapy Vorozole Vorozole, a nonsteroidal third-generation inhibitor similar in structure to anastrozole and letrozole, has now been discontinued from clinical study but was the first to be compared with tamoxifen in a neoadjuvant randomized trial for 12 weeks before surgery in a small series of 53 postmenopausal patients with estrogen receptor–positive tumors.19 Nine patients (39%) had a clinical response to tamoxifen compared with 5 (22%) to vorozole (no significant difference); 3 patients had progressive disease (1 on tamoxifen and 2 on vorozole). An important aim of this small trial was to determine biological changes within the tumor during treatment; these are described below.
Letrozole There has been one multinational double-blind randomized trial (PO24) comparing neoadjuvant letrozole 2.5 mg with tamoxifen for 4 months before surgery.20 This trial involved 337 postmenopausal women with ER- and/or progesterone receptor (PgR)-positive tumors, defined by at least 10% nuclear staining and assayed locally. All patients would have otherwise required mastectomy at entry to the trial or were considered inoperable (14%). Diagnosis was established by core-needle biopsy. The median age of patients for letrozole and tamoxifen were 68 and 67 years, respectively. Overall clinical objective response rate—the primary end point— was significantly higher for letrozole than for tamoxifen (55% vs 36%, P ⬍ 0.001). The median time to response was 66 days for letrozole and 70 days for tamoxifen. Progressive disease during treatment was seen with 12% of patients treated with letrozole and 17% with tamoxifen. Letrozole was also more effective than tamoxifen when the response rate was determined by ultrasound (35% vs 25%, P ⬍ 0.0042) and by mammography (34% vs 16%, P ⬍ 0.001). The main secondary end point of the trial was breast conservation; significantly more breast-conserving surgery was achieved with letrozole than with tamoxifen (45% vs 35%, P ⬍ 0.022). Pathological complete response in the primary breast lesion was seen in only two patients treated with letrozole and three patients with tamoxifen. Only two of these five patients with pathological complete responses had no involved nodes at surgery. The nature and frequency of adverse events were very sim-
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103
Table 1 Breast Conservation Rates in Women Originally Deemed to Require Mastectomy Before Neoadjuvant Therapy Reference Eierman et al, 2001
PO24
Smith et al, 2003
IMPACT
Cataliotti et al, 2003
PROACT
Semiglazov et al, 2003 Semiglazov et al, 2004
Drugs
Patients
BCS*
P
Letrozole Tamoxifen Anastrazole Tamoxifen Combination Anastrazole Tamoxifen Exemestane Tamoxifen Chemotherapy (AP)‡ Exemestane
154 170 46 36 42 129 133 36 37 58 29 30
45% 35% 46%† 22%† 20%† 43% 31% 39% 11% 21% 33% 38%
0.022
Trial
*0.03
0.04 <0.05
0.05
*Breast-conservation surgery. †Deemed feasible by surgeon. ‡Adriamycin, paclitaxel.
ilar in both treatment groups (57% in each group). By far the commonest was hot flushing, which occurred in 20% and 24% of patients with letrozole and tamoxifen, respectively. Thromboembolic problems were described in only one patient, who had a pulmonary embolism on letrozole. In a further analysis of the same study, ER and PgR expression were reassessed in a central laboratory, and 12% of patients were found to have tumors that were both ER and PgR-negative.21 In patients whose tumors were confirmed ER- and/or PgR-positive, the response rate to letrozole was 60% compared with 41% for tamoxifen (P ⬍ 0.004) and 48% versus 36%, respectively, underwent successful breast-conserving surgery (P ⬍ 0.036) (Table 1). In this analysis, ER and PgR were quantified with the Allred scoring system, in which an intensity score (range 1-3) is added to a frequency score (range 1-5).22 Letrozole response rates were numerically superior to tamoxifen for all ER Allred scores from 3 to 8; furthermore, responses to letrozole were seen in all Allred scores between 3 to 8, whereas responses were only seen in tamoxifen per score 6 to 8. As a result, the authors suggested that letrozole might be more effective than tamoxifen in patients whose tumors show relatively low ER expression, but it is important to note that the numbers were small in each of these Allred groupings, and no definite conclusions should be drawn.
Anastrozole There have been two multinational double-blind trials comparing neoadjuvant anastrozole 1 mg daily with tamoxifen for 12 weeks before surgery in postmenopausal women with homone receptor–positive breast cancer—IMPACT (IMmediate Preoperative Anastrozole tamoxifen or Combined with Tamoxifen) and PROACT (PReOperative Anastrozole Compared with Tamoxifen). The IMPACT trial compared anastrozole with tamoxifen or with both in combination on a 1:1:1 basis23; it was designed to be the neoadjuvant equivalent of ATAC. The main clinical aim was to compare the efficacies of these treatments in terms of response and more particularly in downstaging to avoid
mastectomy. An important further aim, however, was to determine whether short-term surrogate end points of response could be identified to predict long-term outcome in the adjuvant ATAC trial; these included clinical changes after 12 weeks and/or biological change in proliferation assessed by Ki67 after 2 and 12 weeks. For this reason, postmenopausal patients with smaller breast cancers not necessarily requiring mastectomy were also included; in this important respect, the IMPACT trial differs from the neoadjuvant letrozole trial described above. Three hundred and thirty patients with confirmed invasive histology and ER positivity on core-needle biopsy were entered in the trial. Median age was 73 years, median tumor size was 4 cm for each of the 3 groups, and tumors were confirmed in a central reference laboratory as ER-positive in 98% of cases. Objective clinical response rates by caliper measurement for anastrozole, tamoxifen, and the combination were 37%, 36% and 39%, respectively, on an intent-to-treat basis, and none of these differences were significant. Ultrasound response rates were 24%, 20%, and 28%, respectively; again, none of these differences were significant. Progressive disease during treatment occurred in 9%, 5%, and 5% of patients, respectively. A subgroup of 124 patients were assessed by the surgeon as requiring mastectomy at baseline. Of these, 46%, 22%, and 26% were deemed to have achieved tumor regression sufficient to allow breast-conserving surgery after treatment with anastrozole, tamoxifen, and combination therapy, respectively (Table 1). The improvement with anastrozole compared with tamoxifen was statistically significant with an odds ratio of 2.94 and P ⫽ 0.03. There was no significant difference between the tamoxifen and combination groups. In this same subgroup requiring mastectomy, clinical responses were seen in 39% of those receiving anastrozole compared with 28% receiving tamoxifen and 36% receiving the combination. These differences were not statistically significant; the odds ratio for anastrozole versus tamoxifen was 1.67 with P ⫽ 0.28, and the odds ratio for combination therapy versus tamoxifen was 1.44 with P ⫽ 0.46.
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104 All treatments were well tolerated with only 2%, 3%, and 2% of patients withdrawing because of adverse events in the anastrozole, tamoxifen, and combination arms, respectively. The most common adverse event in all groups was hot rushes. This showed a nonsignificant trend toward a lower incidence with anastrozole (18%) than with tamoxifen (26%) or the combination (28%). The only significant difference was in vaginal discharge, which was not reported in any patients on anastrozole (0%) compared with tamoxifen (6%) or the combination (8%). Thromboembolic events including deep venous thrombosis and pulmonary embolism were recorded in the neoadjuvant period and also for 30 days’ postsurgery. No episodes were reported in patients treated with anastrozole alone compared with 2 with tamoxifen alone and 3 with the combination; 4 of these 5 events occurred during the 30 days’ postsurgery. In the second neoadjuvant anastrozole trial, PROACT— also multicenter and double-blind— 451 postmenopausal women with operable or locally advanced but potentially operable (T2-T4b) hormone receptor–positive breast cancer were randomized to anastrozole 1 mg or tamoxifen 20 mg for 3 months before surgery.24 As in the IMPACT trial, patients with small breast cancers appropriate for breast-conserving surgery were eligible for entry. In contrast to other trials, concomitant chemotherapy was also allowed and was given to 29% of patients on anastrozole and 32% on tamoxifen. Mean age was 67 in both groups and mean ultrasound tumor diameter 3.6 cm. Overall ultrasound response, the primary end point, was 40% for anastrozole and 35% for tamoxifen (P ⫽ 0.29). Clinical response by caliper measurement was 50% and 46%, respectively (P ⫽ 0.37). In the 314 patients treated with endocrine therapy alone without chemotherapy, ultrasound and clinical response rates for anastrozole and tamoxifen, respectively, were 36% versus 27% (P ⫽ 0.07) and 50% versus 40% (P ⫽ 0.08). In the 262 patients treated with endocrine therapy alone without chemotherapy who would have required mastectomy or had locally advanced disease at baseline as in the letrozole trial, ultrasound and clinical response rates were significantly better for anastrozole than tamoxifen and were, respectively, 37% versus 25% (odds ratio 1.81; P ⫽ 0.03) and 49% versus 36% (odds ratio 1.69; P ⫽ 0.04). In this subgroup, surgical improvement (inoperable to mastectomy or mastectomy to breast-conserving surgery) was deemed feasible in 47% after anastrozole compared with 38% after tamoxifen (P ⫽ 0.15) and actually occurred in 43% versus 31% (P ⫽ 0.04) (Table 1).
Combined IMPACT and PROACT Results A common population of 535 patients treated with anastrozole or tamoxifen alone was derived from the combined results of the IMPACT and PROACT trials, with respective caliper-measured response rates of 45% and 36% (P ⫽ 0.052)25; 344 of these were deemed to require mastectomy or had inoperable cancer at baseline, representing a comparable group to the letrozole trial,20 and the clinical response rate was significantly higher for anastrozole than for tamoxifen
(47% vs 35%; odds ratio 1.65; P ⫽ 0.026). In this group, improvement in feasible surgery was 47% and 35% (odds ratio 1.67; P ⫽ 0.021), and in actual surgery, 43% and 31% (odds ratio 1.70; P ⫽ 0.019), respectively.
Exemestane Only one small trial comparing neoadjuvant exemestane with tamoxifen has been reported, and so far only in abstract. Seventy-three postmenopausal women with hormone receptor–positive breast cancer were randomized to receive exemestane 25 mg or tamoxifen 20 mg daily for 3 months before surgery.26 Clinical objective response rates were reported as 89% for exemestane compared with 57% for tamoxifen (P ⬍ 0.05), including complete clinical remission rates of 14% and 11%, respectively (not significant). Ultrasound reponse rates were 70% and 41% (not significant), and breast-conservation rates were 39% versus 11%, respectively (P ⬍ 0.05) (Table 1). Two pathological complete remissions were found with exemestane and one with tamoxifen. The authors reported without details that responses were more likely with higher levels of estrogen-receptor expression.
Clinical Measurement of Smaller Cancers in Neoadjuvant Endocrine Therapy At first sight, the IMPACT and PROACT data appear paradoxical, with the suggestion in both trials of significantly greater efficacy for anastrozole over tamoxifen in larger than in smaller cancers. Biologically, this would be unlikely and, indeed, in the IMPACT trial no biological differences were detected between larger and smaller cancers as assessed by mean ER, mean PgR, mean Ki67, or in the proportion with human epidermal growth factor receptor (HER)2 3⫹ cancers (unpublished data). A more plausible explanation is that serial clinical measurements in smaller cancers during neoadjuvant endocrine therapy, where response may be slow, are likely to be exposed to larger errors; this problem could be compounded by follow-up core biopsies for biological studies after 2 weeks of treatment and the associated risk of subsequent hematoma and tissue edema. It may be that neoadjuvant endocrine therapy trials with primary clinical end points should therefore be restricted to patients with larger cancers, although patients with smaller breast cancers could still be appropriate for trials with a biological endpoint.
Neoadjuvant Endocrine Therapy Versus Chemotherapy One trial so far has directly compared neoadjuvant chemotherapy (doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2 every 3 weeks ⫻ 4 courses) with aromatase inhibitor endocrine therapy (exemestane or anastrozole for 3 months) in 117 postmenopausal women with hormone receptor–positive breast cancer.27 Results have only been expressed in abstract form. The overall clinical response rate was 76% for
Neoadjuvant endocrine therapy chemotherapy (n ⫽ 58), 80% for exemestane (n ⫽ 29), and 91% for anastrozole (n ⫽ 30). Breast-conserving surgery was achieved in 21% of patients after chemotherapy compared with 33% after exemestane and 38% after anastrozole (Table 1). The authors concluded that neoadjuvant endocrine therapy with its low toxicity was a reasonable alternative to chemotherapy in this elderly population.
Neoadjuvant Endocrine Therapy in Tumors Overexpressing HER1 and/or HER2 An important and unexpected finding within the group of patients in the letrozole neoadjuvant trial was that 15 of 17 patients whose tumors overexpressed HER1 and/or HER2 responded to letrozole (88%) compared with only 4 of 19 patients to tamoxifen (21%) (odds ratio 28; P ⫽ 0.004). In contrast, the respective response rates for the majority of patients whose tumors did not overexpress either of these receptors was 54% versus 42%, which was not statistically significant (P ⬍ 0.078).21 Likewise in the IMPACT trial, 239 patients had tumors that were assessable for HER2, of whom 34 (14%) were HER2-positive, as assessed in a central reference laboratory scoring 3⫹ by immunohistochemistry with the DAKO Hercept Test (Dakocytomation, Denmark) or greater than twofold as assessed by fluorescent in situ hybridisation (FISH). (Only two tumors overexpressed HER1, including one that also overexpressed HER2). In this small subgroup, objective responses were seen in 7 of 12 patients with anastrozole (58%), 2 of 9 patients with tamoxifen (22%), and 4 of 13 patients (31%) with the combination. This difference between anastrozole and tamoxifen was not quite significant (P ⫽ 0.09); because of small numbers the analysis was, however, very underpowered. The patient population and treatment duration differed between the two studies but their results strongly support the hypothesis that aromatase inhibitors may be more effective than tamoxifen in the treatment of ER positive early breast cancer which also over-expresses HER2. Experimental data have already suggested that HER2 over-expression may be associated with tamoxifen resistance28,29 and it now becomes important to evaluate further the significance of HER2 overexpression on long-term outcome in adjuvant trials comparing aromatase inhibitors with tamoxifen.
Biological Findings in Neoadjuvant Endocrine Therapy Trials Ki67 The nuclear nonhistone protein Ki67 is widely used as a marker of proliferation and is suppressed in hormone receptor–positive cancers with different forms of neoadjuvant endocrine therapy including tamoxifen,30-37 other selective estrogen receptor modifiers (SERMs),38,39 the so-called pure
105 antiestrogen fulvestrant,33,40 aromatase inhibitors,19,41-43 and even by withdrawal of hormone-replacement therapy.44 Some of these studies also have suggested that early changes in Ki67 following endocrine therapy correlate positively with clinical response.30,31,37,41,42 These observations provided the basis for an important secondary aim of the IMPACT trial, which was to determine whether changes in proliferation measured by Ki67 staining with MIB-1 antibody following 2 and 12 weeks of therapy might differ between the treatment groups and predict longterm outcome found in the adjuvant ATAC trial. Pretreatment, 2-week and 12-week biopsies were available on 241, 159, and 236 patients, respectively. Ki67 expression was significantly reduced by all 3 treatments after 2 and 12 weeks— anastrozole by 76% and 82%, tamoxifen by 60% and 64%, and the combination by 65% and 64%. Change after 2 weeks correlated with the change after 12 weeks. The decrease with anastrozole was significantly greater than that with tamoxifen, as assessed by geometric mean ratios of the changes in Ki67 after 2 weeks of treatment (P ⫽ 0.04) and again after 12 weeks (P ⬍ 0.001), but there were no significant differences between tamoxifen and the combination.43 Thus, changes in Ki67 after a mere 2 weeks of treatment predicted for longterm differences in relapse-free survival in the adjuvant ATAC trial. Overall, and for individual treatments, there was a trend toward a greater change in Ki67 for responders versus nonresponders at both 2 weeks (76% vs 62% reduction) and 12 weeks (75% vs 68% reduction), but these differences were not statistically significant. In the earlier and much smaller vorozole trial described above, mean falls in Ki67 treatment of 58% (P ⬍ 0.002) and 43% (P ⬍ 0.004) were seen for vorozole and tamoxifen, respectively, after 2 weeks and again after 12 weeks, but these differences were not significant between the treatments at either time point. There was also a significant fall in the Apoptotic Index for vorozole but not tamoxifen after 2 weeks.19
Changes in Lipids and Bone Resorption Markers The IMPACT trial also evaluated the comparative effects of the three treatments on serum lipids and bone resorption. The beneficial effects of tamoxifen on lipids after 3 months of treatment were as expected with a fall in total cholesterol, which was significantly different from the lack of effect after anastrozole (P ⫽ 0.005), a significant rise in high-density lipoprotein cholesterol, and a significant fall in non– highdensity lipoprotein cholesterol, which was also significantly different from the lack of effect with anastrozole (P ⫽ ⬍ 0.001). Following 3 months of treatment with anastrozole, there was a significant increase in high-density lipoprotein cholesterol but no significant effect on total cholesterol or non– high-density lipoprotein cholesterol. Anastrozole increased bone resorption as measured by serum CrossLaps, with a mean 46% increase, in contrast to tamoxifen, with a 9% reduction.45 In the vorozole trial, serum lipids did not change between
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106 the two groups. Serum levels of bone resorption marker serum CrossLaps fell significantly by a mean of 19% after 12 weeks of tamoxifen compared with a nonsignificant rise of 11% on vorozole, but the difference between the groups was not significant.
Conclusions Currently, the main clinical value of neoadjuvant endocrine therapy is in downstaging large cancers in older women to avoid mastectomy or to achieve operability in cancers deemed inoperable at presentation. Trials have demonstrated that both letrozole and anastrozole are significantly superior to tamoxifen in achieving this objective. Likewise, they are both superior to tamoxifen in achieving clinical responses in patients whose tumors are considered to require a mastectomy at baseline. No direct comparison between the two aromatase inhibitors as neoadjuvant therapy can be drawn from these results, but indirect comparisons of similar groups of patients suggest that their efficacies are broadly similar. The anastrozole trials, unlike the letrozole trial, also included some patients with smaller cancers for whom breastconserving surgery was initially feasible, and no gain for anastrozole over tamoxifen was seen in the overall analyses when these patients were included. As described above, the most likely explanation is simply that serial clinical measurements in smaller cancers during neoadjuvant endocrine therapy are likely to be exposed to errors, and such trials should perhaps therefore be restricted to patients with larger cancers, unless biological end points are used. Aromatase inhibitors appear to be more active than tamoxifen against tumors overexpressing HER2, and it is possible aromatase inhibitors may be particularly effective as adjuvant therapy for this subgroup. In the IMPACT trial, change in Ki67 after 2 weeks of treatment correlated with disease-free survival in the adjuvant ATAC trial and further work is now required to determine the extent to which this short-term surrogate marker might be a more general predictive marker for long-term outcome in trials of novel therapies for early breast cancer.
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resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat 24:85-95, 1993 Osborne CK, Bardou V, Hopp TA, et al: Role of the estrogen receptor coactivator aib1 (src-3) and her2/neu resistance in breast cancer. J Natl Cancer Inst 95:353-361, 2003 Chang J, Powles TJ, Allred DC, et al: Prediction of clinical outcome from primary tamoxifen by expression of biologic markers in breast cancer patients. Clin Cancer Res 6:616-621, 2000 Makris A, Powles TJ, Allred DC, et al: Changes in hormone receptors and proliferation markers in tamoxifen treated breast cancer patients and the relationship with response. Breast Cancer Res Treat 48:11-20, 1998 Clarke RB, Laidlaw IJ, Jones LJ, et al: Effect of tamoxifen on Ki67 labelling index in human breast tumours and its relationship to oestrogen and progesterone receptor status. Br J Cancer 67:606-611, 1993 Dowsett M, Dixon JM, Horgan K, et al: Antiproliferative effects of idoxifene in a placebo-controlled trial in primary human breast cancer. Clin Cancer Res 6:2260-2267, 2000 Dowsett M, Bundred NJ, Decensi A, et al: Effect of raloxifene on breast cancer cell Ki67 and apoptosis: a double-blind, placebo-controlled, randomized clinical trial in postmenopausal patients. Cancer Epidemiol Biomarkers Prev 10:961-966, 2001 DeFriend DJ, Howell A, Nicholson RI, et al: Investigation of a new pure antiestrogen (ICI 182780) in women with primary breast cancer. Cancer Res 54:408-414, 1994 Robertson JF, Nicholson RI, Bundred NJ, et al: Comparison of the short-term biological effects of 7alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17beta-diol (Faslodex) versus tamoxifen in post-menopausal women with primary breast cancer. Cancer Res 61:6739-6746, 2001
107 37. Bajetta E, Celio L, Di Leo A, et al: Effects of short-term pre-operative tamoxifen on steroid receptor and Ki-67 expression in primary breast cancer: an immunocytochemical study. Int J Oncol 12:853858, 1998 38. Dardes RD, Horiguchi J, Jordan VC: A pilot study of the effects of short-term tamoxifen therapy on Ki-67 labelling index in women with primary breast cancer. Int J Oncol 16:25-30, 2000 39. Decensi A, Robertson C, Viale G, et al: A randomized trial of low-dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers. J Natl Cancer Inst 95:779-790, 2003 40. Geisler J, Detre S, Berntsen H, et al: Influence of neoadjuvant anastrozole (Arimidex) on intratumoral estrogen levels and proliferation markers in patients with locally advanced breast cancer. Clin Cancer Res 7:1230-1236, 2001 41. Ellis MJ, Coop A, Singh B, et al: Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. Cancer Res 63:6523-6531, 2003 42. Kenny FS, Willsher PC, Gee JM, et al: Change in expression of ER, bcl-2 and MIB1 on primary tamoxifen and relation to response in ER positive breast cancer. Breast Cancer Res Treat 65:135-144, 2001 43. Dowsett MD, Smith IE, on behalf of the IMPACT Trialists: Ki67 response after 2 weeks neoadjuvant treatment with anastrozole, tamoxifen or anastrozole plus tamoxifen predicts relapse free survival. Clin Cancer Res 11:951S–958S, 2005 44. Prasad R, Boland GP, Cramer A, et al: Short-term biologic response to withdrawal of hormone replacement therapy in patients with invasive breast carcinoma. Cancer 98:2539-2546, 2003 45. Smith IE, Dowsett MD, et al, on behalf of the IMPACT Trialists. Assessment of lipids and bone-derived resorption products during neoadjuvant therapy with anastrozole (A), v tamoxifen (T), v combination (C) in the IMPACT trial. ASCO 2004
T
here is no new thing under the sun, and that includes neoadjuvant endocrine therapy. Almost 50 years ago, Kennedy et al reported on 27 postmenopausal women whose breast cancer was treated with hormone therapy before surgery, mainly using estrogens which were novel at the time, and their clinical description has never been bettered (Kennedy et al, 1957). “The cancers in the treated patients were altered by complete or partial softening. Many of the tumors became mobile, smaller and more difficult or impossible to palpate. Others, less extensively affected, changed from a hard to a rubbery consistency. Softening appeared to be the fundamental change observed clinically at some time in the regression of every tumor and it preceded shrinkage and diminution of mass.” There are occasional reports of premenopausal women treated with neoadjuvant oophorectomy or leuprorelin,2,3 but neoadjuvant chemotherapy is generally considered more appropriate in this context. This chapter will therefore focus on patients who are postmenopausal. There are two clinical and several research-directed reasons to use neoadjuvant endocrine therapy in women with hormone receptor–positive breast cancer. Clinically, this approach might be considered as an alternative to surgery, particuInstitute of Cancer Research and Royal Marsden Hospital, London, United Kingdom. Address reprint requests to Ian E. Smith, MD, Department of Medicine, Royal Marsden Hospital, Fulham Road, London SW3 6JJ UK. E-mail: [email protected]
1092-4450/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.sembd.2005.01.006
larly in women unfit for this procedure through age or medical infirmity. This approach has obvious short-term attractions but also important limitations, as described below. The second and currently the main clinical indication is to downstage large breast cancers, so that mastectomy might be avoided or to achieve operability in previously inoperable cancers.4 A key current research aim is to investigate neoadjuvant therapy to develop short-term surrogate clinical, pathological, or biological end points that might predict longterm outcome in adjuvant trials. Such trials are large, expensive to run, and take years to achieve their outcome. The adjuvant ATAC (Arimidex, Tamoxifen Alone, or in Combination) trial, which started in 1996, involved 9366 patients, and reported its first results 6 years later with a median follow-up of 33 months, is a good example.5 The option of a rapid neoadjuvant alternative involving a relatively small number of patients would improve dramatically the rate at which novel therapies in early breast cancer could be investigated. Furthermore, predictive shortterm end points for long-term outcome could open up the possibility of individualized adjuvant therapy rather than the current “blind” approach based on probabilities derived from adjuvant trial data. Finally, the neoadjuvant approach offers the potential of serial core biopsies to study molecular changes during treatment that might throw light on mechanisms underlying sensitivity or resistance to therapy. This chapter will review progress in these areas. 101
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Neoadjuvant Endocrine Therapy as an Alternative to Surgery
ceded a series of randomized comparative neoadjuvant trials, the results of which have recently emerged.
Tamoxifen was first evaluated as an alternative to surgery in early breast cancer in a series of small studies in the 1980s. In the first, it was reported to achieve tumor responses sufficient to continue treatment beyond the first follow-up visit in 73% of elderly women ⬎75 years of age.6 Eighteen percent took more than 12 months to achieve maximum response. In a subsequent small randomized trial involving 116 patients aged 70 or over comparing tamoxifen alone with surgery alone, no difference was found in either time to progression or survival between the two treatments.7 Indeed, there was a nonsignificant trend toward a decreased risk of local recurrence and a delay in the development of distant metastases in patients on primary tamoxifen. This trial had a large number of patients with T3-4 cancers. In a similar trial involving 135 patients over 70 years of age, no survival difference was found between the two groups, but here there was a 43% local failure rate in the tamoxifen alone arm at 3-year followup.8 In a larger Cancer Research Campaign UK trial comparing tamoxifen alone or surgery and tamoxifen9 in 381 women 70 years or older, no significant differences in survival or quality of life was found between the two approaches at 34 months follow-up, but a significantly higher loco-regional relapse rate was seen in the tamoxifen alone arm (23% vs 8%).9 These trials in elderly patients therefore urged caution in using neoadjuvant endocrine therapy as a substitute for surgery in most patients, but nevertheless suggested that there could be benefit in using this approach before surgery.
Neoadjuvant Versus Adjuvant Endocrine Therapy
Neoadjuvant Endocrine Therapy Before Surgery There are numerous small studies of neoadjuvant endocrine therapy before surgery in the literature, starting with the neoadjuvant estrogen report described above.1 Response rates vary and are often loosely defined, but they are generally higher than in the more rigorous randomized trials described below. In two of the tamoxifen versus surgery trials described above, reponse to tamoxifen was 55% at 6 months and 63% (best ever) in one,8 and 25% 6 months followed by 47% (best ever) in the other.9
Emergence of the Aromatase Inhibitors The most important development in the endocrine therapy of breast cancer in recent years has been the challenge to tamoxifen from the so-called third-generation aromatase inhibitors, including in particular anastrozole, letrozole, and exemestane.10 In advanced breast cancer, anastrozole and letrozole have been shown to be superior to11,12 or at least as good13 as tamoxifen. Nonrandomized studies suggested that these agents also might be more effective than tamoxifen as neoadjuvant therapy in older women with locally advanced or large operable cancers, in terms of tumor regressions and the possibility of breast-conserving surgery.14-18 These results pre-
So far, there are no published trials comparing neoadjuvant with adjuvant endocrine therapy, by analogy with the NSABP-14 and other chemotherapy trials.
Comparative Trials of Neoadjuvant Endocrine Therapy Vorozole Vorozole, a nonsteroidal third-generation inhibitor similar in structure to anastrozole and letrozole, has now been discontinued from clinical study but was the first to be compared with tamoxifen in a neoadjuvant randomized trial for 12 weeks before surgery in a small series of 53 postmenopausal patients with estrogen receptor–positive tumors.19 Nine patients (39%) had a clinical response to tamoxifen compared with 5 (22%) to vorozole (no significant difference); 3 patients had progressive disease (1 on tamoxifen and 2 on vorozole). An important aim of this small trial was to determine biological changes within the tumor during treatment; these are described below.
Letrozole There has been one multinational double-blind randomized trial (PO24) comparing neoadjuvant letrozole 2.5 mg with tamoxifen for 4 months before surgery.20 This trial involved 337 postmenopausal women with ER- and/or progesterone receptor (PgR)-positive tumors, defined by at least 10% nuclear staining and assayed locally. All patients would have otherwise required mastectomy at entry to the trial or were considered inoperable (14%). Diagnosis was established by core-needle biopsy. The median age of patients for letrozole and tamoxifen were 68 and 67 years, respectively. Overall clinical objective response rate—the primary end point— was significantly higher for letrozole than for tamoxifen (55% vs 36%, P ⬍ 0.001). The median time to response was 66 days for letrozole and 70 days for tamoxifen. Progressive disease during treatment was seen with 12% of patients treated with letrozole and 17% with tamoxifen. Letrozole was also more effective than tamoxifen when the response rate was determined by ultrasound (35% vs 25%, P ⬍ 0.0042) and by mammography (34% vs 16%, P ⬍ 0.001). The main secondary end point of the trial was breast conservation; significantly more breast-conserving surgery was achieved with letrozole than with tamoxifen (45% vs 35%, P ⬍ 0.022). Pathological complete response in the primary breast lesion was seen in only two patients treated with letrozole and three patients with tamoxifen. Only two of these five patients with pathological complete responses had no involved nodes at surgery. The nature and frequency of adverse events were very sim-
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103
Table 1 Breast Conservation Rates in Women Originally Deemed to Require Mastectomy Before Neoadjuvant Therapy Reference Eierman et al, 2001
PO24
Smith et al, 2003
IMPACT
Cataliotti et al, 2003
PROACT
Semiglazov et al, 2003 Semiglazov et al, 2004
Drugs
Patients
BCS*
P
Letrozole Tamoxifen Anastrazole Tamoxifen Combination Anastrazole Tamoxifen Exemestane Tamoxifen Chemotherapy (AP)‡ Exemestane
154 170 46 36 42 129 133 36 37 58 29 30
45% 35% 46%† 22%† 20%† 43% 31% 39% 11% 21% 33% 38%
0.022
Trial
*0.03
0.04 <0.05
0.05
*Breast-conservation surgery. †Deemed feasible by surgeon. ‡Adriamycin, paclitaxel.
ilar in both treatment groups (57% in each group). By far the commonest was hot flushing, which occurred in 20% and 24% of patients with letrozole and tamoxifen, respectively. Thromboembolic problems were described in only one patient, who had a pulmonary embolism on letrozole. In a further analysis of the same study, ER and PgR expression were reassessed in a central laboratory, and 12% of patients were found to have tumors that were both ER and PgR-negative.21 In patients whose tumors were confirmed ER- and/or PgR-positive, the response rate to letrozole was 60% compared with 41% for tamoxifen (P ⬍ 0.004) and 48% versus 36%, respectively, underwent successful breast-conserving surgery (P ⬍ 0.036) (Table 1). In this analysis, ER and PgR were quantified with the Allred scoring system, in which an intensity score (range 1-3) is added to a frequency score (range 1-5).22 Letrozole response rates were numerically superior to tamoxifen for all ER Allred scores from 3 to 8; furthermore, responses to letrozole were seen in all Allred scores between 3 to 8, whereas responses were only seen in tamoxifen per score 6 to 8. As a result, the authors suggested that letrozole might be more effective than tamoxifen in patients whose tumors show relatively low ER expression, but it is important to note that the numbers were small in each of these Allred groupings, and no definite conclusions should be drawn.
Anastrozole There have been two multinational double-blind trials comparing neoadjuvant anastrozole 1 mg daily with tamoxifen for 12 weeks before surgery in postmenopausal women with homone receptor–positive breast cancer—IMPACT (IMmediate Preoperative Anastrozole tamoxifen or Combined with Tamoxifen) and PROACT (PReOperative Anastrozole Compared with Tamoxifen). The IMPACT trial compared anastrozole with tamoxifen or with both in combination on a 1:1:1 basis23; it was designed to be the neoadjuvant equivalent of ATAC. The main clinical aim was to compare the efficacies of these treatments in terms of response and more particularly in downstaging to avoid
mastectomy. An important further aim, however, was to determine whether short-term surrogate end points of response could be identified to predict long-term outcome in the adjuvant ATAC trial; these included clinical changes after 12 weeks and/or biological change in proliferation assessed by Ki67 after 2 and 12 weeks. For this reason, postmenopausal patients with smaller breast cancers not necessarily requiring mastectomy were also included; in this important respect, the IMPACT trial differs from the neoadjuvant letrozole trial described above. Three hundred and thirty patients with confirmed invasive histology and ER positivity on core-needle biopsy were entered in the trial. Median age was 73 years, median tumor size was 4 cm for each of the 3 groups, and tumors were confirmed in a central reference laboratory as ER-positive in 98% of cases. Objective clinical response rates by caliper measurement for anastrozole, tamoxifen, and the combination were 37%, 36% and 39%, respectively, on an intent-to-treat basis, and none of these differences were significant. Ultrasound response rates were 24%, 20%, and 28%, respectively; again, none of these differences were significant. Progressive disease during treatment occurred in 9%, 5%, and 5% of patients, respectively. A subgroup of 124 patients were assessed by the surgeon as requiring mastectomy at baseline. Of these, 46%, 22%, and 26% were deemed to have achieved tumor regression sufficient to allow breast-conserving surgery after treatment with anastrozole, tamoxifen, and combination therapy, respectively (Table 1). The improvement with anastrozole compared with tamoxifen was statistically significant with an odds ratio of 2.94 and P ⫽ 0.03. There was no significant difference between the tamoxifen and combination groups. In this same subgroup requiring mastectomy, clinical responses were seen in 39% of those receiving anastrozole compared with 28% receiving tamoxifen and 36% receiving the combination. These differences were not statistically significant; the odds ratio for anastrozole versus tamoxifen was 1.67 with P ⫽ 0.28, and the odds ratio for combination therapy versus tamoxifen was 1.44 with P ⫽ 0.46.
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104 All treatments were well tolerated with only 2%, 3%, and 2% of patients withdrawing because of adverse events in the anastrozole, tamoxifen, and combination arms, respectively. The most common adverse event in all groups was hot rushes. This showed a nonsignificant trend toward a lower incidence with anastrozole (18%) than with tamoxifen (26%) or the combination (28%). The only significant difference was in vaginal discharge, which was not reported in any patients on anastrozole (0%) compared with tamoxifen (6%) or the combination (8%). Thromboembolic events including deep venous thrombosis and pulmonary embolism were recorded in the neoadjuvant period and also for 30 days’ postsurgery. No episodes were reported in patients treated with anastrozole alone compared with 2 with tamoxifen alone and 3 with the combination; 4 of these 5 events occurred during the 30 days’ postsurgery. In the second neoadjuvant anastrozole trial, PROACT— also multicenter and double-blind— 451 postmenopausal women with operable or locally advanced but potentially operable (T2-T4b) hormone receptor–positive breast cancer were randomized to anastrozole 1 mg or tamoxifen 20 mg for 3 months before surgery.24 As in the IMPACT trial, patients with small breast cancers appropriate for breast-conserving surgery were eligible for entry. In contrast to other trials, concomitant chemotherapy was also allowed and was given to 29% of patients on anastrozole and 32% on tamoxifen. Mean age was 67 in both groups and mean ultrasound tumor diameter 3.6 cm. Overall ultrasound response, the primary end point, was 40% for anastrozole and 35% for tamoxifen (P ⫽ 0.29). Clinical response by caliper measurement was 50% and 46%, respectively (P ⫽ 0.37). In the 314 patients treated with endocrine therapy alone without chemotherapy, ultrasound and clinical response rates for anastrozole and tamoxifen, respectively, were 36% versus 27% (P ⫽ 0.07) and 50% versus 40% (P ⫽ 0.08). In the 262 patients treated with endocrine therapy alone without chemotherapy who would have required mastectomy or had locally advanced disease at baseline as in the letrozole trial, ultrasound and clinical response rates were significantly better for anastrozole than tamoxifen and were, respectively, 37% versus 25% (odds ratio 1.81; P ⫽ 0.03) and 49% versus 36% (odds ratio 1.69; P ⫽ 0.04). In this subgroup, surgical improvement (inoperable to mastectomy or mastectomy to breast-conserving surgery) was deemed feasible in 47% after anastrozole compared with 38% after tamoxifen (P ⫽ 0.15) and actually occurred in 43% versus 31% (P ⫽ 0.04) (Table 1).
Combined IMPACT and PROACT Results A common population of 535 patients treated with anastrozole or tamoxifen alone was derived from the combined results of the IMPACT and PROACT trials, with respective caliper-measured response rates of 45% and 36% (P ⫽ 0.052)25; 344 of these were deemed to require mastectomy or had inoperable cancer at baseline, representing a comparable group to the letrozole trial,20 and the clinical response rate was significantly higher for anastrozole than for tamoxifen
(47% vs 35%; odds ratio 1.65; P ⫽ 0.026). In this group, improvement in feasible surgery was 47% and 35% (odds ratio 1.67; P ⫽ 0.021), and in actual surgery, 43% and 31% (odds ratio 1.70; P ⫽ 0.019), respectively.
Exemestane Only one small trial comparing neoadjuvant exemestane with tamoxifen has been reported, and so far only in abstract. Seventy-three postmenopausal women with hormone receptor–positive breast cancer were randomized to receive exemestane 25 mg or tamoxifen 20 mg daily for 3 months before surgery.26 Clinical objective response rates were reported as 89% for exemestane compared with 57% for tamoxifen (P ⬍ 0.05), including complete clinical remission rates of 14% and 11%, respectively (not significant). Ultrasound reponse rates were 70% and 41% (not significant), and breast-conservation rates were 39% versus 11%, respectively (P ⬍ 0.05) (Table 1). Two pathological complete remissions were found with exemestane and one with tamoxifen. The authors reported without details that responses were more likely with higher levels of estrogen-receptor expression.
Clinical Measurement of Smaller Cancers in Neoadjuvant Endocrine Therapy At first sight, the IMPACT and PROACT data appear paradoxical, with the suggestion in both trials of significantly greater efficacy for anastrozole over tamoxifen in larger than in smaller cancers. Biologically, this would be unlikely and, indeed, in the IMPACT trial no biological differences were detected between larger and smaller cancers as assessed by mean ER, mean PgR, mean Ki67, or in the proportion with human epidermal growth factor receptor (HER)2 3⫹ cancers (unpublished data). A more plausible explanation is that serial clinical measurements in smaller cancers during neoadjuvant endocrine therapy, where response may be slow, are likely to be exposed to larger errors; this problem could be compounded by follow-up core biopsies for biological studies after 2 weeks of treatment and the associated risk of subsequent hematoma and tissue edema. It may be that neoadjuvant endocrine therapy trials with primary clinical end points should therefore be restricted to patients with larger cancers, although patients with smaller breast cancers could still be appropriate for trials with a biological endpoint.
Neoadjuvant Endocrine Therapy Versus Chemotherapy One trial so far has directly compared neoadjuvant chemotherapy (doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2 every 3 weeks ⫻ 4 courses) with aromatase inhibitor endocrine therapy (exemestane or anastrozole for 3 months) in 117 postmenopausal women with hormone receptor–positive breast cancer.27 Results have only been expressed in abstract form. The overall clinical response rate was 76% for
Neoadjuvant endocrine therapy chemotherapy (n ⫽ 58), 80% for exemestane (n ⫽ 29), and 91% for anastrozole (n ⫽ 30). Breast-conserving surgery was achieved in 21% of patients after chemotherapy compared with 33% after exemestane and 38% after anastrozole (Table 1). The authors concluded that neoadjuvant endocrine therapy with its low toxicity was a reasonable alternative to chemotherapy in this elderly population.
Neoadjuvant Endocrine Therapy in Tumors Overexpressing HER1 and/or HER2 An important and unexpected finding within the group of patients in the letrozole neoadjuvant trial was that 15 of 17 patients whose tumors overexpressed HER1 and/or HER2 responded to letrozole (88%) compared with only 4 of 19 patients to tamoxifen (21%) (odds ratio 28; P ⫽ 0.004). In contrast, the respective response rates for the majority of patients whose tumors did not overexpress either of these receptors was 54% versus 42%, which was not statistically significant (P ⬍ 0.078).21 Likewise in the IMPACT trial, 239 patients had tumors that were assessable for HER2, of whom 34 (14%) were HER2-positive, as assessed in a central reference laboratory scoring 3⫹ by immunohistochemistry with the DAKO Hercept Test (Dakocytomation, Denmark) or greater than twofold as assessed by fluorescent in situ hybridisation (FISH). (Only two tumors overexpressed HER1, including one that also overexpressed HER2). In this small subgroup, objective responses were seen in 7 of 12 patients with anastrozole (58%), 2 of 9 patients with tamoxifen (22%), and 4 of 13 patients (31%) with the combination. This difference between anastrozole and tamoxifen was not quite significant (P ⫽ 0.09); because of small numbers the analysis was, however, very underpowered. The patient population and treatment duration differed between the two studies but their results strongly support the hypothesis that aromatase inhibitors may be more effective than tamoxifen in the treatment of ER positive early breast cancer which also over-expresses HER2. Experimental data have already suggested that HER2 over-expression may be associated with tamoxifen resistance28,29 and it now becomes important to evaluate further the significance of HER2 overexpression on long-term outcome in adjuvant trials comparing aromatase inhibitors with tamoxifen.
Biological Findings in Neoadjuvant Endocrine Therapy Trials Ki67 The nuclear nonhistone protein Ki67 is widely used as a marker of proliferation and is suppressed in hormone receptor–positive cancers with different forms of neoadjuvant endocrine therapy including tamoxifen,30-37 other selective estrogen receptor modifiers (SERMs),38,39 the so-called pure
105 antiestrogen fulvestrant,33,40 aromatase inhibitors,19,41-43 and even by withdrawal of hormone-replacement therapy.44 Some of these studies also have suggested that early changes in Ki67 following endocrine therapy correlate positively with clinical response.30,31,37,41,42 These observations provided the basis for an important secondary aim of the IMPACT trial, which was to determine whether changes in proliferation measured by Ki67 staining with MIB-1 antibody following 2 and 12 weeks of therapy might differ between the treatment groups and predict longterm outcome found in the adjuvant ATAC trial. Pretreatment, 2-week and 12-week biopsies were available on 241, 159, and 236 patients, respectively. Ki67 expression was significantly reduced by all 3 treatments after 2 and 12 weeks— anastrozole by 76% and 82%, tamoxifen by 60% and 64%, and the combination by 65% and 64%. Change after 2 weeks correlated with the change after 12 weeks. The decrease with anastrozole was significantly greater than that with tamoxifen, as assessed by geometric mean ratios of the changes in Ki67 after 2 weeks of treatment (P ⫽ 0.04) and again after 12 weeks (P ⬍ 0.001), but there were no significant differences between tamoxifen and the combination.43 Thus, changes in Ki67 after a mere 2 weeks of treatment predicted for longterm differences in relapse-free survival in the adjuvant ATAC trial. Overall, and for individual treatments, there was a trend toward a greater change in Ki67 for responders versus nonresponders at both 2 weeks (76% vs 62% reduction) and 12 weeks (75% vs 68% reduction), but these differences were not statistically significant. In the earlier and much smaller vorozole trial described above, mean falls in Ki67 treatment of 58% (P ⬍ 0.002) and 43% (P ⬍ 0.004) were seen for vorozole and tamoxifen, respectively, after 2 weeks and again after 12 weeks, but these differences were not significant between the treatments at either time point. There was also a significant fall in the Apoptotic Index for vorozole but not tamoxifen after 2 weeks.19
Changes in Lipids and Bone Resorption Markers The IMPACT trial also evaluated the comparative effects of the three treatments on serum lipids and bone resorption. The beneficial effects of tamoxifen on lipids after 3 months of treatment were as expected with a fall in total cholesterol, which was significantly different from the lack of effect after anastrozole (P ⫽ 0.005), a significant rise in high-density lipoprotein cholesterol, and a significant fall in non– highdensity lipoprotein cholesterol, which was also significantly different from the lack of effect with anastrozole (P ⫽ ⬍ 0.001). Following 3 months of treatment with anastrozole, there was a significant increase in high-density lipoprotein cholesterol but no significant effect on total cholesterol or non– high-density lipoprotein cholesterol. Anastrozole increased bone resorption as measured by serum CrossLaps, with a mean 46% increase, in contrast to tamoxifen, with a 9% reduction.45 In the vorozole trial, serum lipids did not change between
I.E. Smith
106 the two groups. Serum levels of bone resorption marker serum CrossLaps fell significantly by a mean of 19% after 12 weeks of tamoxifen compared with a nonsignificant rise of 11% on vorozole, but the difference between the groups was not significant.
Conclusions Currently, the main clinical value of neoadjuvant endocrine therapy is in downstaging large cancers in older women to avoid mastectomy or to achieve operability in cancers deemed inoperable at presentation. Trials have demonstrated that both letrozole and anastrozole are significantly superior to tamoxifen in achieving this objective. Likewise, they are both superior to tamoxifen in achieving clinical responses in patients whose tumors are considered to require a mastectomy at baseline. No direct comparison between the two aromatase inhibitors as neoadjuvant therapy can be drawn from these results, but indirect comparisons of similar groups of patients suggest that their efficacies are broadly similar. The anastrozole trials, unlike the letrozole trial, also included some patients with smaller cancers for whom breastconserving surgery was initially feasible, and no gain for anastrozole over tamoxifen was seen in the overall analyses when these patients were included. As described above, the most likely explanation is simply that serial clinical measurements in smaller cancers during neoadjuvant endocrine therapy are likely to be exposed to errors, and such trials should perhaps therefore be restricted to patients with larger cancers, unless biological end points are used. Aromatase inhibitors appear to be more active than tamoxifen against tumors overexpressing HER2, and it is possible aromatase inhibitors may be particularly effective as adjuvant therapy for this subgroup. In the IMPACT trial, change in Ki67 after 2 weeks of treatment correlated with disease-free survival in the adjuvant ATAC trial and further work is now required to determine the extent to which this short-term surrogate marker might be a more general predictive marker for long-term outcome in trials of novel therapies for early breast cancer.
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