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Neoadjuvant endocrine treatment in primary breast cancer – Review of literature
The Breast 18 (2009) 339–344
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The Breast journal homepage: www.elsevier.com/brst
Review
Neoadjuvant endocrine treatment in primary breast cancer – Review of literature J. Mathew*, K.S. Asgeirsson, L.R. Jackson, K.L. Cheung, J.F.R. Robertson Division of Breast Surgery, Nottingham City Hospital, Nottingham, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 10 September 2009 Accepted 17 September 2009
Chemotherapeutic agents have dominated neoadjuvant treatment compared to endocrine agents in the past and have demonstrated their ability to produce tumour shrinkage to allow breast conservation. However, in the more recent setting, studies have been emerging with the use of aromatase inhibitors, especially comparing its use with tamoxifen in selected group of patients. The role of tamoxifen in its ability to achieve tumour shrinkage has been evaluated in the past, and has shown to produce slow but sustained response. Aromatase inhibitors have shown superiority over tamoxifen in adjuvant and metastatic setting, and the aim of our study was to compare their outcome with regard to response and breast conservation in the neoadjuvant setting. We also looked into optimum duration of neoadjuvant treatment and also the role of pathological complete response as a surrogate marker for clinical outcome. Our review highlights the superiority of aromatase inhibitors over tamoxifen in the neoadjuvant setting and even challenges chemotherapy with regard to response in selected group of patients. Ó 2009 Elsevier Ltd. All rights reserved.
Keywords: Neoadjuvant endocrine treatment Clinical response Breast conservation surgery
Introduction Most neoadjuvant treatment trials relate to the use of chemotherapy. However with the success of adjuvant endocrine treatment,1–3 more studies have been emerging with the use of endocrine agents in the neoadjuvant setting. In patients receiving chemotherapy, both neoadjuvant and adjuvant treatments have similar survival outcome.4 However neoadjuvant chemotherapy treatment has certain advantages over adjuvant chemotherapy. Preoperative systemic treatment could make inoperable tumours operable and also increase the breast conservation rate.5 In addition this approach provides an opportunity to study the effects of drugs on a variety of biochemical and histological features of the tumour.6,7 Neoadjuvant treatment may in itself provide prognostic information, as response to neoadjuvant chemotherapy has been shown to act as a surrogate marker of outcome.8 On the other hand neoadjuvant therapy may alter established prognostic factors such as pathological tumour size and lymph node staging. In addition, for patients who do not show a good response to therapy this carries negative prognostic information which they should be counselled about before they are asked to agree to neoadjuvant therapy. Furthermore there will
* Corresponding author. Professorial Unit of Surgery, City Hospital Campus, Nottingham University Hospitals, Hucknall Road, Nottingham, NG5 1PB, UK. E-mail address: [email protected] (J. Mathew). 0960-9776/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2009.09.012
be a minority of patients who will show progression on neoadjuvant therapy and the tumour may no longer be suitable for breast conserving surgery or mastectomy as it was pre-neoadjuvant treatment. It is also important to point out that for those patients who become suitable for and choose breast conserving surgery after neoadjuvant chemotherapy there is evidence that they have an increased risk of local recurrence.4,9 However there is an argument that the increased risk in recurrence with neoadjuvant treatment largely reflects the use of radiotherapy without surgery for patients who had apparent complete clinical response.10 Oestrogen receptor positive (ERþ) tumours are noted to be less sensitive to chemotherapy than ER negative (ER) tumours11,12 and benefit of chemotherapy in primary breast cancer is believed to decrease with age.13 Trials have shown the efficacy of tamoxifen as primary endocrine agent in locally advanced14 and operable breast cancers especially in the elderly population.15,16 With the advent of aromatase inhibitors, the role of endocrine therapy as neoadjuvant agent has been compared in postmenopausal women with operable breast cancers outside the elderly population, and we would like to explore the evidence available for aromatase inhibitors challenging tamoxifen and also even chemotherapy in ERþ tumours. The objective of endocrine therapy in the neoadjuvant setting is primarily to produce sufficient response in the tumour to allow mastectomy in inoperable tumours and potentially breast conservation in patients initially proposed to undergo mastectomy. It should
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also potentially accelerate the time required to obtain prognostic and predictive information with adjuvant studies by using surrogate markers for long-term outcome. Most of the present trials are not mature enough or powered to assess long-term outcome. The aim of our study was to review the data of various endocrine agents in neoadjuvant setting on primary breast cancers with regard to response and breast conservation surgery (BCS). We also review the studies analysing optimum duration of neoadjuvant treatment and the role of complete pathological response as a surrogate marker in neoadjuvant endocrine treatment. Selection of studies A search of Medline and Pubmed databases of studies on neoadjuvant endocrine therapy was performed. Key words used were neoadjuvant endocrine treatment in primary breast cancers, preoperative endocrine treatment in primary breast cancers, neoadjuvant endocrine treatment in locally advanced breast cancers and preoperative endocrine treatment in locally advanced breast cancers. The uses of endocrine agents as the primary modality of treatment (with no intent to perform surgery) producing tumour shrinkage and disease control which may form the basis of many of the more recent neoadjuvant endocrine treatment have been extensively evaluated in the past and were not included in the paper.17 Response to neoadjuvant endocrine treatment and the role of breast conservation There are 4 randomised controlled trials on neoadjuvant endocrine treatment and they are summarised in Table 1. Aromatase inhibitors vs tamoxifen With the superiority of aromatase inhibitors over tamoxifen in the adjuvant setting,1–3 trials have looked into early outcome in the neoadjuvant setting. Eierman et al. in a double-blinded randomised controlled trial (RCT) involved 337 postmenopausal women with ER and/or PR positive breast cancer compared the anti-tumour activity of letrozole with tamoxifen.18 At baseline, none of the patients were candidates for BCS and 14% of the patients were considered inoperable. After neoadjuvant treated for 4 months, the study showed statistically significant overall response in the letrozole group (55% vs 36%; P < 0.001) and significantly more patients in the letrozole group were candidates for BCS compared to tamoxifen arm (45% vs 35%; P ¼ 0.022). A subsequent subgroup analysis by Ellis and colleagues of same group of patients who were tested for ErbB1 and ErbB2, showed that in approximately 10% (36 patients) of patients who were ErbB1 and/or ErbB2 positive and ER positive, there were marked differences in response rates between letrozole arm and tamoxifen arm (letrozole 88% (15/17) vs
tamoxifen 21% (4/19); P ¼ 0.0004).19 Tumours that did not overexpress ErbB1 and/or ErbB2, the response rates were similar (letrozole 55% vs tamoxifen 42%; P ¼ 0.078). However the total number of patients with Erb1/2 tumours in the study was small (n ¼ 36) and there may be a danger of over interpreting small subgroups. In the adjuvant setting, although looking at different end points compared to neoadjuvant trials, showed aromatase inhibitors to be superior to tamoxifen regardless of ErbB2 status. Breast International Group (BIG) double-blinded phase 3 trial comparing letrozole vs tamoxifen (BIG 1-98) showed that letrozole was superior to tamoxifen with regard to disease free survival irrespective of ErbB2 status.20,21 Looking at the disease free survival, there was a 38% benefit in favor of letrozole over tamoxifen in ER positive HER-2 positive group and a 28% benefit in ER positive and Her-2 negative group.21 However the width of the confidence interval would suggest that the size of the study may be small and not statistically powered to address this HER-2 question. Similar data have subsequently been reported for anastrozole and tamoxifen in the ATAC study.22 Smith and Dowsett reported a double-blinded randomised controlled neoadjuvant trial (IMPACT trial – Immediate preoperative arimidex, tamoxifen, or combined with tamoxifen) which had three arms similar to the ATAC adjuvant study.23 IMPACT comprising 330 postmenopausal women with large operable/locally advanced ER and/or PR positive breast cancer undergoing endocrine treatment using anastrozole vs tamoxifen vs combination for 3 months followed by surgery. Overall, the OR was similar in all the three arms (37% in anastrozole arm, 36% in tamoxifen arm and 39% in combination arm) with no statistical difference between the different arms. However, in patients assessed as requiring mastectomy at baseline (124 patients), more patients in the anastrozole arm were eligible to undergo BCS (21/46; 46%) than tamoxifen arm (8/36; 22%) which was statistically significant (odds ratio – 2.94; 95% CI 1.11– 7.81; P ¼ 0.03). In the combination arm 26% had BCS (not significant). However not all patients accepted the recommendation of BCS and there was no statistical difference between the arms with regard to the percentage of patients actually undergoing BCS. Overall, 239 patients were assessable for HER-2 status, of which 34 patients (14%) were positive. OR was observed in 58% (7/12) patients with anastrozole, 22% (2/9) patients on tamoxifen and 31% (4/13) with combination. The differences were not statistically significant. In another neoadjuvant trial by Semiglazov et al. comparing anastrozole to tamoxifen or combination in 87 hormone receptor positive women with locally advanced breast cancer (LAPC) undergoing surgery following 3 months of endocrine treatment, showed significantly improved clinical overall response in the anastrozole arm (70%) compared to tamoxifen (44.4%) or combination (44.9%; P ¼ 0.048)24 as shown in Table 2. Proact trial is a multicenter double-blinded, double-dummy randomised controlled trial involving 451 ERþ breast cancer
Table 1 Randomized controlled trials on neoadjuvant endocrine treatment. Ref
Patients
Agents
Size (med)
Period
18
162 175
Letrozole 2.5 mg Tamoxifen 20 mg
NE for BCS
16 W
% Reduction
cOR (%) 55 36
uOR (%)
23
113 108 109
Anastrozole 1 mg Tamoxifen 20 mg Combination
3.8 cm 3.8 cm 4 cm
12 W
37 36 39
24 20 28
25
228 223
Anastrozole 1 mg Tamoxifen 20 mg
>3 cm
12 W
50 46
39 35
27
76 75
Exemestane Tamoxifen
>2 cm
12 W
76 40
61 37
Req M at b (%)
M to BCS (%)
BCS (%) 45 35
46 22 26 89 83
11 17 37 20
med – Median; NE for bcs – not eligible for breast conservation surgery; cOR – clinical objective response; uOR – ultrasound objective response; Req M at b – requiring mastectomy at baseline; M to BCS – mastectomy to breast conservation surgery.
J. Mathew et al. / The Breast 18 (2009) 339–344
patients receiving preoperative tamoxifen or anastrozole, and patients undergo surgery after 3 months of endocrine treatment.25 Chemotherapy was given in limited number of patients as required (137 patients) and adjuvant endocrine treatment for 5 years. For the overall population the OR assessed using callipers (anastrozole 50% vs tamoxifen 46.2%; P ¼ 0.37) and by ultrasound (anastrozole 39.5% vs tamoxifen 35.4%; P ¼ 0.29) did not reach statistical significance. In patients who received preoperative endocrine therapy alone with no chomotherapy and were inoperable or eligible only for mastectomy at baseline (n ¼ 262), the OR rate was significantly higher in anastrozole group both by ultrasound (anastrozole - 52/ 142–37% vs tamoxifen 29/120–24% P ¼ 0.03) and with callipers (Anastrozole 69/142–49% vs tamoxifen 43/120–36%; P ¼ 0.04). Anastrozole proved to be at least as effective as tamoxifen in neoadjuvant setting and is probably more effective in certain clinically relevant subgroups. Miller et al. carried out a prospective neoadjuvant endocrine study in postmenopausal patients with locally advanced ERþ breast cancers.26 Patients received letrozole (24 patients), anastrozole (23 patients) or tamoxifen (65 patients) preoperatively. After 3 months of treatment, both the aromatase inhibitors produced significant tumour shrinkage compared to tamoxifen (OR 88% with letrozole, OR 70% with anastrozole and OR 46% with tamoxifen; P < 0.0001). Exemestane is a steroidal aromatase inhibitor which has been investigated in the neoadjuvant setting.27–33 In an RCT by Semiglazov et al., 151 patients were randomly assigned to exemestane or tamoxifen for 3 months.27 Significantly more patients in the exemestane group had clinical objective response (exemestane 76% vs tamoxifen 40%; P ¼ 0.05) and underwent more breast conservation surgery (exemestane 37% vs tamoxifen 20%; P ¼ 0.05) compared to tamoxifen group. The superiority of exemestane over tamoxifen in the above trial has led to American College of Surgeons trial (ACOSGZ1031) comparing neoadjuvant exemestane, letrozole and anastrozole which is now almost fully recruited (340 of 375 patients). Another aromatase inhibitor vorozole has been compared to tamoxifen in the neoadjuvant setting. In this small, open label, randomised multicenter phase 2 study by Harper-Wynne et al. looking into clinical and biological effects of vorozole vs tamoxifen in ERþ postmenopausal patients with primary breast cancer
341
showed no significant difference with regard to median reduction in tumour volume (vorazole 37% vs tamoxifen 58%;P ¼ 0.11) and partial response (vorozole 22% vs 39%; NS).34 Another trial which is ongoing is the NEO-EXCEL study which is a phase 3 multicentre neoadjuvant RCT in ERþ postmenopausal patients who are to receive exemestane or letrozole þ/ selective COX 2 inhibitor. Similarly other combination of drugs is being evaluated instead of single agents so as to improve the efficacy. In advanced breast cancer a combination of anastrozole and HER-2 monoclonal antibody (trastuzumab) has recently been shown to produce increased efficacy when compared to anastrozole alone35 and trials in the neoadjuvant setting are warranted. Pure antioestrogen (fulvestrant) is another agent which is being investigated in the presurgical setting both alone and in combination with aromatase inhibitors. In summary, data from most of these trials suggest that with regard to response and breast conservation third generation aromatase inhibitors overall are better than tamoxifen in the neoadjuvant setting. This has been supported in a recent meta-analysis involving 1160 patients where preoperative aromatase inhibitors were found to be more effective compared to tamoxifen with regard to clinical objective response, ultrasound objective response and breast conservation rate.36 In HER-2 þ tumours, evidence from the RCT trials suggests superiority of aromatase inhibitors over tamoxifen especially letrozole. Duration of neoadjuvant endocrine treatment With the superiority of letrozole over tamoxifen reported in previous trials, Krainick-Strobel et al. tried to investigate whether longer treatment would further increase the response and breast conservation rate.37 Thirty-three patients were enrolled in this open clinical trial. Patients with tumours 2 cm ineligible for breast conservation surgery were given 2.5 mg of letrozole for a minimum of 4 months and a maximum of 8 months prior to surgery. Approximately 68% of the patients had breast conservation surgery and over 50% of the patients became eligible for breast conservation surgery within 4 months of preoperative letrozole. Prolonged treatment had benefit in reducing tumour volume in some patients although there was no clear optimum duration of treatment.
Table 2 Neoadjuvant endocrine phase 2 trials. Ref
Patients
Agents
40
61 60 118 87
Anastrozole 1 mg Exemestane 25 mg Doxorubicin & paclitaxel Anastrozole Tamoxifen Combination Vorozole Tamoxifen Arimidex 1 mg Arimidex 10 mg Letrozole 2.5 mg Letrozole 10 mg Exemestane Tamoxifen Exemestane þ celecoxib Exemestane Letrozole Letrozole Anastrozole 1 mg Exemestane 25 mg Exemestane 25 mg Exemestane 25 mg Exemestane 25 mg
24
34 46 47 28 29
37 50 30 31 32 33
26 27 12 12 12 12 36 37 9 4 7 33 112 13 33 29 38
Size (med)
Period
% Reduction
12 W
>2 cm
12 W
>3 cm
12 W
>3 cm
12 W
>2 cm >5 cm >3 cm
16–32 W 12 W 12 W 24 W 16 W 16–20 W
cOR (%) 62 67 63
70 44 45 37 58 81 70
91 64 100 75 89 51 62 60 55 72 84
86 50 37 71
uOR (%)
Req M at b (%)
M to BCS (%)
BCS (%)
40
33
46 44 30 32
24
83 67 69 40
71
88
92
63
100
100 39 11 83 (overall)
62
68 83 100
80 33
84 67 45
med – Median; cOR – clinical objective response; uOR – ultrasound objective response; Req M at b – requiring mastectomy at baseline; M to BCS – mastectomy to breast conservation surgery.
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Dixon et al. conducted a study in 182 consecutive postmenopausal women receiving letrozole 2.5 mg per day for 3 months or longer.38 Clinical response was assessed at 3 months and decision to proceed to surgery or continue endocrine treatment was left to surgeon following discussion at multidisciplinary meeting. Sixty-three patients continued to receive letrozole for more than 3 months and there was a progressive reduction in tumour volume even after 3 months in significant proportion of these patients and some even responding between 12 and 24 months. Continuing letrozole for more than 3 months increased eligibility for breast conservation in number of women who initially required mastectomy from 60% (81/134) at 3 months to 72% (96/134). The above studies show patients continued to experience response well after 3 months of treatment although there is no agreed optimum duration for the use of neoadjuvant treatment. There is a downside to prolonged treatment as a proportion of patients may not respond and eventually progress. In the previously mentioned study by Krainick-Strobel et al. 10% of the patients who had treatment beyond 4 months progressed.37 A recent report from our institute involving a very selected subgroup of strongly ERþ LAPC patients (n ¼ 195) who received primary endocrine therapy (PET) in our institute over a 20-year period showed a clinical benefit (CR þ PR þ SD) of 95% at 6 months and only 5% progressed at 6 months.39 The 5-year overall and breast cancer specific survival were 76% and 86% respectively. Only a minority of patients with ERþ disease progress early with endocrine treatment, and it may also be an option in selected group of patients with adequate response to continue endocrine treatment as primary therapy rather that subjecting them to immediate surgery. In summary, there is no optimum duration of treatment for neoadjuvant endocrine treatment and the decision of timing of further treatment should be based on individual patient response. Neoadjuvant endocrine treatment vs neoadjuvant chemotherapy Chemotherapy has previously been thought to produce faster response, and in the neoadjuvant setting there are not many trials comparing endocrine agents with chemotherapy. Semiglazov et al., in a phase 2 RCT looked into the efficacy of chemotherapeutic agents vs endocrine agents in neoadjuvant setting in achieving objective response and breast conservation in ERþ breast cancer patients who were ineligible for BCS from the onset.40 Eligible patients were randomly assigned 1:1 to receive endocrine therapy (anastrozole, 61 patients or exemestane, 60 patients) vs neoadjuvant chemotherapy (Doxorubicin and paclitaxel, 118 patients, 4 cycles). At 3 months assessment, there was no statistically significant difference in overall OR between the groups (anastrozole 62%, exemestane 67%, chemotherapy 63%; P > 0.5). More patients in the endocrine group were suitable for BCS compared to chemotherapy group, although not statistically significant (33% vs 24%; P ¼ 0.058). After a median follow-up of 36 months, there was no significant difference in the incidence of local recurrence between the two groups (endocrine 3.3% vs chemotherapy 3.4%). Although the outcomes were similar, the patients in both the groups were elderly (neoadjuvant endocrine, median 68 years vs neoadjuvant chemotherapy, median 67 years) and this could have impacted on the response to treatment. Previous studies have shown that incidence of hormone receptor positive breast cancer 41,42 and the ER content are known to increase with age43 and the benefit of chemotherapy in primary breast cancer is believed to decrease with age.13 Furthermore there is also evidence that neoadjuvant chemotherapy in ER positive tumours, especially lobular breast cancer, produces significantly less pCRs.44,45 In summary, in selected group of ERþ/or PgRþ breast cancer, response rate and outcome with regard to locoregional recurrence between neoadjuvant endocrine therapy and neoadjuvant chemotherapy appear similar. Considering the low toxicity associated with
endocrine treatment compared to chemotherapy, and the reported low pCR rates in ER positive tumours (especially lobular cancers) neoadjuvant endocrine approach would certainly be appropriate especially in selected group of patients. Trials on dosage of endocrine agents There are few trials, which looked into the response associated with different dosage of aromatase inhibitors. In a phase 2 doubleblind RCT by Dixon et al. involving 24 patients receiving 1 mg vs 10 mg of arimidex for 3 months, in postmenopausal women with ER rich breast cancer (>3 cm), showed an OR of 91% in 1 mg group compared to 64% in 10 mg group.46 Of the 17 patients who would have required mastectomy from the onset, 15 were suitable for BCS after anastrozole treatment. Overall 2 patients underwent mastectomy and the rest 22 had BCS. In another phase 1 study by Dixon et al., 24 consecutive postmenopausal patients with locally advanced and large operable breast cancer (tumours > 3 cm) which were ER rich received 2.5 mg (n ¼ 12) or 10 mg (n ¼ 12) of letrozole treatment for 3 months.47 There were five clinical complete response (cCR) and seven clinical partial response (cPR) in patients treated with 2.5 mg of letrozole, and nine cPR and three clinical stable disease in patients treated with 10 mg of letrozole. One patient treated with 2.5 mg of letrozole showed cCR and pCR. Fifteen patients were not suitable for BCS at initial assessment, and after neoadjuvant treatment sufficient response was produced in all of them to undergo successful BCS. Pathological complete response Pathological complete response to neoadjuvant chemotherapy has been accepted as a surrogate marker of outcome. In a recent systematic review on neoadjuvant chemotherapy, pCR ranged from 4 to 29.2%.48 However, with neoadjuvant endocrine treatment there have not been many studies reporting pathological complete response. The response pattern between neoadjuvant chemotherapy and endocrine treatment has been shown to be different. In a study by Thomas et al. looking into the patterns of response in letrozole treated group and chemotherapy treated group, showed significantly more patients in the chemotherapy group achieving complete pathological response and a scattered cell pattern was also more frequently reported.49 The neoadjuvant letrozole group produced significantly more central scars and there was a statistically significant correlation between central scarring and clinical tumour volume reduction. Milla-Santos et al. looked into 112 postmenopausal patients with large stage 111 locally advanced breast cancers undergoing neoadjuvant therapy with anastrozole 1 mg for 3 months followed by mastectomy in responders, and radiotherapy in non-responders.50 Fifty-five percent showed cCR, 29% showed cPR. Histopathology showed pathological complete response (pCR) in 12% of patients. This is one of the few studies, which has reported on pathological complete response with endocrine treatment. Summary and future directions The advent of third generation aromatase inhibitors has significantly changed adjuvant treatment of breast cancer and the superiority of aromatase inhibitors over tamoxifen seen in adjuvant trials has mirrored to a certain extent as shown in neoadjuvant randomised trials. In selected group of ERþ patients; early outcomes are comparable or even better in relation to neoadjuvant chemotherapy as evidence from phase 2 randomised controlled trials. Although more than half of the patients receiving neoadjuvant treatment would receive objective response in 3–4 months, continuing treatment even beyond this period could have incremental benefit in reducing tumour volume in some patients.
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However data with regard to duration of treatment are mostly from phase 2 studies and prospective case series. Response to neoadjuvant chemotherapy, especially pCR has been suggested to be a surrogate for clinical outcome. However in the endocrine setting the response is slow but sustained, and only very few patients will achieve complete response following short course of endocrine therapy. In patients receiving endocrine treatment as primary modality, clinical benefit at 6 months has been shown to be a prognostic indicator. However this could not be applied universally in case of neoadjuvant treatment as the preoperative endocrine treatment may not often extend to 6 months. Other prognostic indicators need to be identified, and a recent study involving over 200 breast cancers showed correlation between Ki67 labeling index and different molecular classes in breast cancer, and was suggested to be an important prognostic factor in breast carcinoma.51 Study by Dowsett et al. showed that the Ki67 after 2 weeks of treatment was a better prognostic indicator than pretreatment Ki67 (3 months).52 This is important especially in the neoadjuvant setting as a proportion of patients receiving neoadjuvant endocrine treatment may show progression after months of treatment and this could accelerate the time required to obtain prognostic and predictive information. Evaluation of these proliferation activities can give predictive information in weeks rather than months and alternative treatment approaches could be considered in those who do not show response. This would potentially save time, money and avoid ill effect of unwanted treatment. Further studies need to address and validate which parameters should be used as surrogate marker for long-term outcome with neoadjuvant endocrine treatment.
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Conflict of interest None of the authors have any financial and personal relationships with other people or organisations that could inappropriately influence this work.
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References 26. 1. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists’ Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008;9:45–53. 2. Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomized controlled trial. Lancet 2007;369:559–70. 3. Coates AS, Keshaviah A, Thu¨rlimann B, et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 2007 Feb 10;25(5):486–92. 4. Wolmark N, Wang J, Mamounas E, et al. Preoperative chemotherapy in patients with operable breast cancer: nine year results from national surgical adjuvant breast and bowel project B-18. J Natl Cancer Inst Monogr 2001;30:96–102. 5. Makris A, Powles TJ, Ashley SE, et al. A reduction in requirements for mastectomy in a randomised trial of neoadjuvant chemoendocrine therapy in breast cancer. Ann Oncol 1998;9:1179–84. 6. Markis A, Powles TJ, Kakolyris S, et al. Reduction in angiogenesis after neoadjuvant chemoendocrine therapy in patients with operable breast carcinoma. Cancer 1999;85(9):1996–2000. 7. Petit T, Wilt M, Velten M, et al. Comparative value of tumour grade, hormonal receptors, Ki-67, HER-2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. Eur J Cancer 2004;40(2):205–11. 8. Fisher B, Bryant J, Wolmark N, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998;16:2672–85. 9. van der Hage JA, van de Velde CJH, Julien JP, et al. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer Trial 10902. J Clin Oncol 2001;19:4224–37. 10. Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 2005 Feb 2;97(3):188–94. 11. Colleoni M, Gelber S, Coates AS, et al. Influence of endocrine-related factors on response to perioperative chemotherapy for patients with node negative breast cancer. J Clin Oncol 2001;19:4141–9. 12. Gianni L, Baselga J, Eiermann W, , et alEuropean Cooperative Trial in Operable Breast Cancer Study Group. Feasibility and tolerability of sequential
27.
28.
29.
30. 31.
32.
33.
34.
35.
36.
343
doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy. Clin Cancer Res 2005 Dec 15;11(24 Pt 1):8715–21. Early Breast Cancer Trialists Collaborative Group. 2000 Analysis overview results. Fifth meeting of Early Breast Cancer Trialists Collaborative Group. Oxford, UK; Sep 2000. p. 21–3. Tan SM, Cheung KL, Willsher PC, Blamey RW, Chan SY, Robertson JFR. Locally advanced primary breast tumour: medium-term results of a randomised controlled trial of multimodal therapy versus initial hormone therapy. Eur J Cancer 2001;37:2331–8. Robertson JF, Ellis IO, Alston CW. Mastectomy or tamoxifen as initial therapy for operable breast cancer in elderly patients: 5-year follow-up. Eur J Cancer 1992;28A(4–5):908–10. Mustacchi G, Ceccherini R, Milani S, et al. Italian Cooperative Group GRETA. Tamoxifen alone versus adjuvant tamoxifen for operable breast cancer of the elderly: long-term results of the phase III randomized controlled multicenter GRETA trial. Ann Oncol 2003 Mar;14(3):414–20. Hind D, Wyld L, Reed MW. Surgery, with or without tamoxifen, vs tamoxifen alone for older women with operable breast cancer. Cochrane review. Br J Cancer 2007 Apr 10;96(7):1025–9. Eiermann W, Paepke S, Appfelstaedt J, et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomised double-blind multicenter study. Ann Oncol 2001;12:1527–32. Ellis MJ, Coop A, Singh B, Mauriac L, et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB1- and /or ErbB2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase 111 randomized trial. J Clin Oncol 2001;19:3808–16. Koeberle D, Thuerlimann B. Letrozole as upfront endocrine therapy for postmenopausal women with hormone-sensitive breast cancer: BIG 1-98. Breast Cancer Res Treat 2007;105(Suppl. 1):55–66. Rasmussen BB, Regan MM, Lykkesfeldt AE, et al. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol 2008;9(1):23–8. Dowsett M, Allred C, Knox J, et al. Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or in Combination trial. J Clin Oncol 2008 Mar 1;26(7):1059–65. Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the immediate preoperative anastrozole, tamoxifen, or combined with tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 2005;23:5108–16. Semiglazov V, Semiglazov VV, Ivanov VG, et al. Anastrazole vs tamoxifen vs combination as neoadjuvant endocrine therapy of postmenopausal breast cancer patients. Proc Am Soc Clin Oncol 2003;22:880 [Abstract 3538]. Cataliotti L, Buzdar AU, Noguchi S. Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor positive breast cancer. 2006;106:2095–103 Miller WR, Dixon JM, Cameron DA. Biological and clinical effects of aromatase inhibitors in neoadjuvant therapy. J Steroid Biochem Mol Biol 2001;79:103–7. Semiglazov V, Kletsel A, Semiglazov E, et al. Exemestane (E) vs tamoxifen (T) as neoadjuvant endocrine therapy for postmenopausal women with ERþ breast cancer (T2N1-2, T3N0-1, T4N0M0) (ASCO). J Clin Oncol 2005;23:530 [Abstract]. Semiglazov V, Semiglazov VV, Ivanov VG, Ziltzova EK, et al. Neoadjuvant endocrine therapy: exemestane vs tamoxifen in postmenopausal ERþ breast cancer patients (T1-4N1-2 M0). Breast Cancer Res Treat 2003;82(Suppl. 1) [Abstract 111]. Chow LW, Yip AY, Loo WT, Lam CK, Toi M. Celecoxib anti-aromatase neoadjuvant (CAAN) trial for locally advanced breast cancer. J Steroid Biochem Mol Biol 2008 Jul;111(1–2):13–7. Dixon JM, Anderson T, Miller WR. Phase 11b study of neoadjuvant exemestane (EXE) in locally advanced breast cancer. Proc ASCO; 2001 [Abstract 1908]. Barnadas A, Gil M, Gonza´lez S, Tusquets I, et al. Exemestane as primary treatment of oestrogen receptor-positive breast cancer in postmenopausal women: a phase II trial. Br J Cancer 2009 Feb 10;100(3):442–9. Krainick U, Astner A, Jonat W, et al. Phase 11 study to define safety and efficacy of exemestane as preoperative therapy for postmenopausal patients with primary breast cancer – final results of the German Neoadjuvant Aromasin Initiative (GENARI). San Antonio; 2003 [Abstract 239] Tubiana-Hulin M, Becette V, Bieche I, et al. Exemestane as neoadjuvant hormonotherapy for locally advanced breast cancer: results of a phase II trial. Anticancer Res 2007 Jul–Aug;27(4C):2689–96. Harper-Wynne Catherine L, Sacks Nigel PM, Shenton Karyn, et al. Comparison of the systemic and intratumoral effects of tamoxifen and the aromatase inhibitor vorozole in postmenopausal patients with primary breast cancer. J Clin Oncol 2002;20(4):1026–35. Basi Sanraj K, Mackey John R. Anastrozole plus trastuzumab prolongs progression-free survival in postmenopausal patients with HER2-positive and hormone receptor-positive metastatic breast cancer: a review of the TAnDEM study. Breast Diseases: A Year Book Quarterly 2007;18:236–7. Seo JH, Kim YH, Kim JS. Meta-analysis of pre-operative aromatase inhibitor versus tamoxifen in postmenopausal woman with hormone receptor-positive breast cancer. Cancer Chemother Pharmacol 2009 Jan;63(2):261–6.
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37. Krainick-Strobel UE, Lichtenegger W, Wallwiener D, et al. Neoadjuvant letrozole in postmenopausal estrogen and/or progesterone receptor positive breast cancer: a phase IIb/III trial to investigate optimal duration of preoperative endocrine therapy. BMC Cancer 2008 Feb 26;8:62. 38. Dixon JM, Renshaw L, Macaskill EJ, et al. Increase in response rate by prolonged treatment with neoadjuvant letrozole. Breast Cancer Res Treat 2009 Jan;113(1):145–51. 39. Mathew J, Agrawal A, Asgerisson K, et al. Primary endocrine therapy in locally advanced breast cancers – Nottingham experience. Eur J Surg Oncol 2007;33: 1095–6 [Abstract]. 40. Semiglazov VF, Semiglazov VV, Dashyan GA, et al. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer 2007;110:244–54. 41. Singletary SE, Shallenberger R, Guinee VF. Breast cancer in the elderly. Ann Surg 1993;218(5):667–71. 42. Busch E, Kemeny M, Fremgen A, et al. Patterns of breast cancer care in the elderly. Cancer 1996;78(1):101–11. 43. McCarty Jr KS, Silva JS, Cox EB, et al. Relationship of age and menopausal status to estrogen receptor content in primary carcinoma of the breast. Ann Surg 1983;197:123–7. 44. Cristofanilli M, Gonzalez-Angulo A, Sneige N, et al. Invasive lobular carcinoma classic type: response to primary chemotherapy and survival outcomes. J Clin Oncol 2005 Jan 1;23(1):41–8. 45. Guarneri V, Broglio K, Kau SW, Cristofanilli M, Buzdar AU, Valero V, et al. Prognostic value of pathologic complete response after primary chemotherapy
46.
47.
48. 49.
50.
51.
52.
in relation to hormone receptor status and other factors. J Clin Oncol 2006 Mar 1;24(7):1037–44. Dixon JM, Renshaw L, Bellamy C, Stuart M, Hoctin-Boes G, Miller WR. The effects of neoadjuvant anastrozole (arimidex) on tumor volume in postmenopausal women with breast cancer: a randomized, double-blind, singlecenter study. Clin Cancer Res 2000;6(6):2229–35. Dixon JM, Love CD, Bellamy CO, Cameron DA, Leonard RC, Smith H, et al. Letrozole as primary medical therapy for locally advanced and large operable breast cancer. Breast Cancer Res Treat 2001;66(3):191–9. Mieog JSD, van der Hage JA, van de Velde CJH. Neoadjuvant chemotherapy for operable breast cancer. Br J Surg 2007;94(10):1189–200. Thomas JS, Julian HS, Green RV, Cameron DA, Dixon MJ. Histopathology of breast carcinoma following neoadjuvant systemic therapy: a common association between letrozole therapy and central scarring. Histopathology 2007 Aug;51(2):219–26. Milla-Santos A, Milla L, Calvo N, et al. Anastrozole as neoadjuvant therapy for patients with hormone-dependent, locally-advanced breast cancer. Anticancer Res 2004 Mar–Apr;24(2C):1315–8. Bharagva R, Striebel J, Onisko A, et al. Ki-67 labeling index in breast carcinoma: an immunohistochemical study with correlation to molecular subtypes. J Clin Oncol 2008;26(May 20 Suppl.) [Abstract 22107]. Dowsett M, Smith IE, Ebbs SR, et al. Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival. Clin Cancer Res 2005;11(Suppl.):951–8.
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Review
Neoadjuvant endocrine treatment in primary breast cancer – Review of literature J. Mathew*, K.S. Asgeirsson, L.R. Jackson, K.L. Cheung, J.F.R. Robertson Division of Breast Surgery, Nottingham City Hospital, Nottingham, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 10 September 2009 Accepted 17 September 2009
Chemotherapeutic agents have dominated neoadjuvant treatment compared to endocrine agents in the past and have demonstrated their ability to produce tumour shrinkage to allow breast conservation. However, in the more recent setting, studies have been emerging with the use of aromatase inhibitors, especially comparing its use with tamoxifen in selected group of patients. The role of tamoxifen in its ability to achieve tumour shrinkage has been evaluated in the past, and has shown to produce slow but sustained response. Aromatase inhibitors have shown superiority over tamoxifen in adjuvant and metastatic setting, and the aim of our study was to compare their outcome with regard to response and breast conservation in the neoadjuvant setting. We also looked into optimum duration of neoadjuvant treatment and also the role of pathological complete response as a surrogate marker for clinical outcome. Our review highlights the superiority of aromatase inhibitors over tamoxifen in the neoadjuvant setting and even challenges chemotherapy with regard to response in selected group of patients. Ó 2009 Elsevier Ltd. All rights reserved.
Keywords: Neoadjuvant endocrine treatment Clinical response Breast conservation surgery
Introduction Most neoadjuvant treatment trials relate to the use of chemotherapy. However with the success of adjuvant endocrine treatment,1–3 more studies have been emerging with the use of endocrine agents in the neoadjuvant setting. In patients receiving chemotherapy, both neoadjuvant and adjuvant treatments have similar survival outcome.4 However neoadjuvant chemotherapy treatment has certain advantages over adjuvant chemotherapy. Preoperative systemic treatment could make inoperable tumours operable and also increase the breast conservation rate.5 In addition this approach provides an opportunity to study the effects of drugs on a variety of biochemical and histological features of the tumour.6,7 Neoadjuvant treatment may in itself provide prognostic information, as response to neoadjuvant chemotherapy has been shown to act as a surrogate marker of outcome.8 On the other hand neoadjuvant therapy may alter established prognostic factors such as pathological tumour size and lymph node staging. In addition, for patients who do not show a good response to therapy this carries negative prognostic information which they should be counselled about before they are asked to agree to neoadjuvant therapy. Furthermore there will
* Corresponding author. Professorial Unit of Surgery, City Hospital Campus, Nottingham University Hospitals, Hucknall Road, Nottingham, NG5 1PB, UK. E-mail address: [email protected] (J. Mathew). 0960-9776/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2009.09.012
be a minority of patients who will show progression on neoadjuvant therapy and the tumour may no longer be suitable for breast conserving surgery or mastectomy as it was pre-neoadjuvant treatment. It is also important to point out that for those patients who become suitable for and choose breast conserving surgery after neoadjuvant chemotherapy there is evidence that they have an increased risk of local recurrence.4,9 However there is an argument that the increased risk in recurrence with neoadjuvant treatment largely reflects the use of radiotherapy without surgery for patients who had apparent complete clinical response.10 Oestrogen receptor positive (ERþ) tumours are noted to be less sensitive to chemotherapy than ER negative (ER) tumours11,12 and benefit of chemotherapy in primary breast cancer is believed to decrease with age.13 Trials have shown the efficacy of tamoxifen as primary endocrine agent in locally advanced14 and operable breast cancers especially in the elderly population.15,16 With the advent of aromatase inhibitors, the role of endocrine therapy as neoadjuvant agent has been compared in postmenopausal women with operable breast cancers outside the elderly population, and we would like to explore the evidence available for aromatase inhibitors challenging tamoxifen and also even chemotherapy in ERþ tumours. The objective of endocrine therapy in the neoadjuvant setting is primarily to produce sufficient response in the tumour to allow mastectomy in inoperable tumours and potentially breast conservation in patients initially proposed to undergo mastectomy. It should
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also potentially accelerate the time required to obtain prognostic and predictive information with adjuvant studies by using surrogate markers for long-term outcome. Most of the present trials are not mature enough or powered to assess long-term outcome. The aim of our study was to review the data of various endocrine agents in neoadjuvant setting on primary breast cancers with regard to response and breast conservation surgery (BCS). We also review the studies analysing optimum duration of neoadjuvant treatment and the role of complete pathological response as a surrogate marker in neoadjuvant endocrine treatment. Selection of studies A search of Medline and Pubmed databases of studies on neoadjuvant endocrine therapy was performed. Key words used were neoadjuvant endocrine treatment in primary breast cancers, preoperative endocrine treatment in primary breast cancers, neoadjuvant endocrine treatment in locally advanced breast cancers and preoperative endocrine treatment in locally advanced breast cancers. The uses of endocrine agents as the primary modality of treatment (with no intent to perform surgery) producing tumour shrinkage and disease control which may form the basis of many of the more recent neoadjuvant endocrine treatment have been extensively evaluated in the past and were not included in the paper.17 Response to neoadjuvant endocrine treatment and the role of breast conservation There are 4 randomised controlled trials on neoadjuvant endocrine treatment and they are summarised in Table 1. Aromatase inhibitors vs tamoxifen With the superiority of aromatase inhibitors over tamoxifen in the adjuvant setting,1–3 trials have looked into early outcome in the neoadjuvant setting. Eierman et al. in a double-blinded randomised controlled trial (RCT) involved 337 postmenopausal women with ER and/or PR positive breast cancer compared the anti-tumour activity of letrozole with tamoxifen.18 At baseline, none of the patients were candidates for BCS and 14% of the patients were considered inoperable. After neoadjuvant treated for 4 months, the study showed statistically significant overall response in the letrozole group (55% vs 36%; P < 0.001) and significantly more patients in the letrozole group were candidates for BCS compared to tamoxifen arm (45% vs 35%; P ¼ 0.022). A subsequent subgroup analysis by Ellis and colleagues of same group of patients who were tested for ErbB1 and ErbB2, showed that in approximately 10% (36 patients) of patients who were ErbB1 and/or ErbB2 positive and ER positive, there were marked differences in response rates between letrozole arm and tamoxifen arm (letrozole 88% (15/17) vs
tamoxifen 21% (4/19); P ¼ 0.0004).19 Tumours that did not overexpress ErbB1 and/or ErbB2, the response rates were similar (letrozole 55% vs tamoxifen 42%; P ¼ 0.078). However the total number of patients with Erb1/2 tumours in the study was small (n ¼ 36) and there may be a danger of over interpreting small subgroups. In the adjuvant setting, although looking at different end points compared to neoadjuvant trials, showed aromatase inhibitors to be superior to tamoxifen regardless of ErbB2 status. Breast International Group (BIG) double-blinded phase 3 trial comparing letrozole vs tamoxifen (BIG 1-98) showed that letrozole was superior to tamoxifen with regard to disease free survival irrespective of ErbB2 status.20,21 Looking at the disease free survival, there was a 38% benefit in favor of letrozole over tamoxifen in ER positive HER-2 positive group and a 28% benefit in ER positive and Her-2 negative group.21 However the width of the confidence interval would suggest that the size of the study may be small and not statistically powered to address this HER-2 question. Similar data have subsequently been reported for anastrozole and tamoxifen in the ATAC study.22 Smith and Dowsett reported a double-blinded randomised controlled neoadjuvant trial (IMPACT trial – Immediate preoperative arimidex, tamoxifen, or combined with tamoxifen) which had three arms similar to the ATAC adjuvant study.23 IMPACT comprising 330 postmenopausal women with large operable/locally advanced ER and/or PR positive breast cancer undergoing endocrine treatment using anastrozole vs tamoxifen vs combination for 3 months followed by surgery. Overall, the OR was similar in all the three arms (37% in anastrozole arm, 36% in tamoxifen arm and 39% in combination arm) with no statistical difference between the different arms. However, in patients assessed as requiring mastectomy at baseline (124 patients), more patients in the anastrozole arm were eligible to undergo BCS (21/46; 46%) than tamoxifen arm (8/36; 22%) which was statistically significant (odds ratio – 2.94; 95% CI 1.11– 7.81; P ¼ 0.03). In the combination arm 26% had BCS (not significant). However not all patients accepted the recommendation of BCS and there was no statistical difference between the arms with regard to the percentage of patients actually undergoing BCS. Overall, 239 patients were assessable for HER-2 status, of which 34 patients (14%) were positive. OR was observed in 58% (7/12) patients with anastrozole, 22% (2/9) patients on tamoxifen and 31% (4/13) with combination. The differences were not statistically significant. In another neoadjuvant trial by Semiglazov et al. comparing anastrozole to tamoxifen or combination in 87 hormone receptor positive women with locally advanced breast cancer (LAPC) undergoing surgery following 3 months of endocrine treatment, showed significantly improved clinical overall response in the anastrozole arm (70%) compared to tamoxifen (44.4%) or combination (44.9%; P ¼ 0.048)24 as shown in Table 2. Proact trial is a multicenter double-blinded, double-dummy randomised controlled trial involving 451 ERþ breast cancer
Table 1 Randomized controlled trials on neoadjuvant endocrine treatment. Ref
Patients
Agents
Size (med)
Period
18
162 175
Letrozole 2.5 mg Tamoxifen 20 mg
NE for BCS
16 W
% Reduction
cOR (%) 55 36
uOR (%)
23
113 108 109
Anastrozole 1 mg Tamoxifen 20 mg Combination
3.8 cm 3.8 cm 4 cm
12 W
37 36 39
24 20 28
25
228 223
Anastrozole 1 mg Tamoxifen 20 mg
>3 cm
12 W
50 46
39 35
27
76 75
Exemestane Tamoxifen
>2 cm
12 W
76 40
61 37
Req M at b (%)
M to BCS (%)
BCS (%) 45 35
46 22 26 89 83
11 17 37 20
med – Median; NE for bcs – not eligible for breast conservation surgery; cOR – clinical objective response; uOR – ultrasound objective response; Req M at b – requiring mastectomy at baseline; M to BCS – mastectomy to breast conservation surgery.
J. Mathew et al. / The Breast 18 (2009) 339–344
patients receiving preoperative tamoxifen or anastrozole, and patients undergo surgery after 3 months of endocrine treatment.25 Chemotherapy was given in limited number of patients as required (137 patients) and adjuvant endocrine treatment for 5 years. For the overall population the OR assessed using callipers (anastrozole 50% vs tamoxifen 46.2%; P ¼ 0.37) and by ultrasound (anastrozole 39.5% vs tamoxifen 35.4%; P ¼ 0.29) did not reach statistical significance. In patients who received preoperative endocrine therapy alone with no chomotherapy and were inoperable or eligible only for mastectomy at baseline (n ¼ 262), the OR rate was significantly higher in anastrozole group both by ultrasound (anastrozole - 52/ 142–37% vs tamoxifen 29/120–24% P ¼ 0.03) and with callipers (Anastrozole 69/142–49% vs tamoxifen 43/120–36%; P ¼ 0.04). Anastrozole proved to be at least as effective as tamoxifen in neoadjuvant setting and is probably more effective in certain clinically relevant subgroups. Miller et al. carried out a prospective neoadjuvant endocrine study in postmenopausal patients with locally advanced ERþ breast cancers.26 Patients received letrozole (24 patients), anastrozole (23 patients) or tamoxifen (65 patients) preoperatively. After 3 months of treatment, both the aromatase inhibitors produced significant tumour shrinkage compared to tamoxifen (OR 88% with letrozole, OR 70% with anastrozole and OR 46% with tamoxifen; P < 0.0001). Exemestane is a steroidal aromatase inhibitor which has been investigated in the neoadjuvant setting.27–33 In an RCT by Semiglazov et al., 151 patients were randomly assigned to exemestane or tamoxifen for 3 months.27 Significantly more patients in the exemestane group had clinical objective response (exemestane 76% vs tamoxifen 40%; P ¼ 0.05) and underwent more breast conservation surgery (exemestane 37% vs tamoxifen 20%; P ¼ 0.05) compared to tamoxifen group. The superiority of exemestane over tamoxifen in the above trial has led to American College of Surgeons trial (ACOSGZ1031) comparing neoadjuvant exemestane, letrozole and anastrozole which is now almost fully recruited (340 of 375 patients). Another aromatase inhibitor vorozole has been compared to tamoxifen in the neoadjuvant setting. In this small, open label, randomised multicenter phase 2 study by Harper-Wynne et al. looking into clinical and biological effects of vorozole vs tamoxifen in ERþ postmenopausal patients with primary breast cancer
341
showed no significant difference with regard to median reduction in tumour volume (vorazole 37% vs tamoxifen 58%;P ¼ 0.11) and partial response (vorozole 22% vs 39%; NS).34 Another trial which is ongoing is the NEO-EXCEL study which is a phase 3 multicentre neoadjuvant RCT in ERþ postmenopausal patients who are to receive exemestane or letrozole þ/ selective COX 2 inhibitor. Similarly other combination of drugs is being evaluated instead of single agents so as to improve the efficacy. In advanced breast cancer a combination of anastrozole and HER-2 monoclonal antibody (trastuzumab) has recently been shown to produce increased efficacy when compared to anastrozole alone35 and trials in the neoadjuvant setting are warranted. Pure antioestrogen (fulvestrant) is another agent which is being investigated in the presurgical setting both alone and in combination with aromatase inhibitors. In summary, data from most of these trials suggest that with regard to response and breast conservation third generation aromatase inhibitors overall are better than tamoxifen in the neoadjuvant setting. This has been supported in a recent meta-analysis involving 1160 patients where preoperative aromatase inhibitors were found to be more effective compared to tamoxifen with regard to clinical objective response, ultrasound objective response and breast conservation rate.36 In HER-2 þ tumours, evidence from the RCT trials suggests superiority of aromatase inhibitors over tamoxifen especially letrozole. Duration of neoadjuvant endocrine treatment With the superiority of letrozole over tamoxifen reported in previous trials, Krainick-Strobel et al. tried to investigate whether longer treatment would further increase the response and breast conservation rate.37 Thirty-three patients were enrolled in this open clinical trial. Patients with tumours 2 cm ineligible for breast conservation surgery were given 2.5 mg of letrozole for a minimum of 4 months and a maximum of 8 months prior to surgery. Approximately 68% of the patients had breast conservation surgery and over 50% of the patients became eligible for breast conservation surgery within 4 months of preoperative letrozole. Prolonged treatment had benefit in reducing tumour volume in some patients although there was no clear optimum duration of treatment.
Table 2 Neoadjuvant endocrine phase 2 trials. Ref
Patients
Agents
40
61 60 118 87
Anastrozole 1 mg Exemestane 25 mg Doxorubicin & paclitaxel Anastrozole Tamoxifen Combination Vorozole Tamoxifen Arimidex 1 mg Arimidex 10 mg Letrozole 2.5 mg Letrozole 10 mg Exemestane Tamoxifen Exemestane þ celecoxib Exemestane Letrozole Letrozole Anastrozole 1 mg Exemestane 25 mg Exemestane 25 mg Exemestane 25 mg Exemestane 25 mg
24
34 46 47 28 29
37 50 30 31 32 33
26 27 12 12 12 12 36 37 9 4 7 33 112 13 33 29 38
Size (med)
Period
% Reduction
12 W
>2 cm
12 W
>3 cm
12 W
>3 cm
12 W
>2 cm >5 cm >3 cm
16–32 W 12 W 12 W 24 W 16 W 16–20 W
cOR (%) 62 67 63
70 44 45 37 58 81 70
91 64 100 75 89 51 62 60 55 72 84
86 50 37 71
uOR (%)
Req M at b (%)
M to BCS (%)
BCS (%)
40
33
46 44 30 32
24
83 67 69 40
71
88
92
63
100
100 39 11 83 (overall)
62
68 83 100
80 33
84 67 45
med – Median; cOR – clinical objective response; uOR – ultrasound objective response; Req M at b – requiring mastectomy at baseline; M to BCS – mastectomy to breast conservation surgery.
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Dixon et al. conducted a study in 182 consecutive postmenopausal women receiving letrozole 2.5 mg per day for 3 months or longer.38 Clinical response was assessed at 3 months and decision to proceed to surgery or continue endocrine treatment was left to surgeon following discussion at multidisciplinary meeting. Sixty-three patients continued to receive letrozole for more than 3 months and there was a progressive reduction in tumour volume even after 3 months in significant proportion of these patients and some even responding between 12 and 24 months. Continuing letrozole for more than 3 months increased eligibility for breast conservation in number of women who initially required mastectomy from 60% (81/134) at 3 months to 72% (96/134). The above studies show patients continued to experience response well after 3 months of treatment although there is no agreed optimum duration for the use of neoadjuvant treatment. There is a downside to prolonged treatment as a proportion of patients may not respond and eventually progress. In the previously mentioned study by Krainick-Strobel et al. 10% of the patients who had treatment beyond 4 months progressed.37 A recent report from our institute involving a very selected subgroup of strongly ERþ LAPC patients (n ¼ 195) who received primary endocrine therapy (PET) in our institute over a 20-year period showed a clinical benefit (CR þ PR þ SD) of 95% at 6 months and only 5% progressed at 6 months.39 The 5-year overall and breast cancer specific survival were 76% and 86% respectively. Only a minority of patients with ERþ disease progress early with endocrine treatment, and it may also be an option in selected group of patients with adequate response to continue endocrine treatment as primary therapy rather that subjecting them to immediate surgery. In summary, there is no optimum duration of treatment for neoadjuvant endocrine treatment and the decision of timing of further treatment should be based on individual patient response. Neoadjuvant endocrine treatment vs neoadjuvant chemotherapy Chemotherapy has previously been thought to produce faster response, and in the neoadjuvant setting there are not many trials comparing endocrine agents with chemotherapy. Semiglazov et al., in a phase 2 RCT looked into the efficacy of chemotherapeutic agents vs endocrine agents in neoadjuvant setting in achieving objective response and breast conservation in ERþ breast cancer patients who were ineligible for BCS from the onset.40 Eligible patients were randomly assigned 1:1 to receive endocrine therapy (anastrozole, 61 patients or exemestane, 60 patients) vs neoadjuvant chemotherapy (Doxorubicin and paclitaxel, 118 patients, 4 cycles). At 3 months assessment, there was no statistically significant difference in overall OR between the groups (anastrozole 62%, exemestane 67%, chemotherapy 63%; P > 0.5). More patients in the endocrine group were suitable for BCS compared to chemotherapy group, although not statistically significant (33% vs 24%; P ¼ 0.058). After a median follow-up of 36 months, there was no significant difference in the incidence of local recurrence between the two groups (endocrine 3.3% vs chemotherapy 3.4%). Although the outcomes were similar, the patients in both the groups were elderly (neoadjuvant endocrine, median 68 years vs neoadjuvant chemotherapy, median 67 years) and this could have impacted on the response to treatment. Previous studies have shown that incidence of hormone receptor positive breast cancer 41,42 and the ER content are known to increase with age43 and the benefit of chemotherapy in primary breast cancer is believed to decrease with age.13 Furthermore there is also evidence that neoadjuvant chemotherapy in ER positive tumours, especially lobular breast cancer, produces significantly less pCRs.44,45 In summary, in selected group of ERþ/or PgRþ breast cancer, response rate and outcome with regard to locoregional recurrence between neoadjuvant endocrine therapy and neoadjuvant chemotherapy appear similar. Considering the low toxicity associated with
endocrine treatment compared to chemotherapy, and the reported low pCR rates in ER positive tumours (especially lobular cancers) neoadjuvant endocrine approach would certainly be appropriate especially in selected group of patients. Trials on dosage of endocrine agents There are few trials, which looked into the response associated with different dosage of aromatase inhibitors. In a phase 2 doubleblind RCT by Dixon et al. involving 24 patients receiving 1 mg vs 10 mg of arimidex for 3 months, in postmenopausal women with ER rich breast cancer (>3 cm), showed an OR of 91% in 1 mg group compared to 64% in 10 mg group.46 Of the 17 patients who would have required mastectomy from the onset, 15 were suitable for BCS after anastrozole treatment. Overall 2 patients underwent mastectomy and the rest 22 had BCS. In another phase 1 study by Dixon et al., 24 consecutive postmenopausal patients with locally advanced and large operable breast cancer (tumours > 3 cm) which were ER rich received 2.5 mg (n ¼ 12) or 10 mg (n ¼ 12) of letrozole treatment for 3 months.47 There were five clinical complete response (cCR) and seven clinical partial response (cPR) in patients treated with 2.5 mg of letrozole, and nine cPR and three clinical stable disease in patients treated with 10 mg of letrozole. One patient treated with 2.5 mg of letrozole showed cCR and pCR. Fifteen patients were not suitable for BCS at initial assessment, and after neoadjuvant treatment sufficient response was produced in all of them to undergo successful BCS. Pathological complete response Pathological complete response to neoadjuvant chemotherapy has been accepted as a surrogate marker of outcome. In a recent systematic review on neoadjuvant chemotherapy, pCR ranged from 4 to 29.2%.48 However, with neoadjuvant endocrine treatment there have not been many studies reporting pathological complete response. The response pattern between neoadjuvant chemotherapy and endocrine treatment has been shown to be different. In a study by Thomas et al. looking into the patterns of response in letrozole treated group and chemotherapy treated group, showed significantly more patients in the chemotherapy group achieving complete pathological response and a scattered cell pattern was also more frequently reported.49 The neoadjuvant letrozole group produced significantly more central scars and there was a statistically significant correlation between central scarring and clinical tumour volume reduction. Milla-Santos et al. looked into 112 postmenopausal patients with large stage 111 locally advanced breast cancers undergoing neoadjuvant therapy with anastrozole 1 mg for 3 months followed by mastectomy in responders, and radiotherapy in non-responders.50 Fifty-five percent showed cCR, 29% showed cPR. Histopathology showed pathological complete response (pCR) in 12% of patients. This is one of the few studies, which has reported on pathological complete response with endocrine treatment. Summary and future directions The advent of third generation aromatase inhibitors has significantly changed adjuvant treatment of breast cancer and the superiority of aromatase inhibitors over tamoxifen seen in adjuvant trials has mirrored to a certain extent as shown in neoadjuvant randomised trials. In selected group of ERþ patients; early outcomes are comparable or even better in relation to neoadjuvant chemotherapy as evidence from phase 2 randomised controlled trials. Although more than half of the patients receiving neoadjuvant treatment would receive objective response in 3–4 months, continuing treatment even beyond this period could have incremental benefit in reducing tumour volume in some patients.
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However data with regard to duration of treatment are mostly from phase 2 studies and prospective case series. Response to neoadjuvant chemotherapy, especially pCR has been suggested to be a surrogate for clinical outcome. However in the endocrine setting the response is slow but sustained, and only very few patients will achieve complete response following short course of endocrine therapy. In patients receiving endocrine treatment as primary modality, clinical benefit at 6 months has been shown to be a prognostic indicator. However this could not be applied universally in case of neoadjuvant treatment as the preoperative endocrine treatment may not often extend to 6 months. Other prognostic indicators need to be identified, and a recent study involving over 200 breast cancers showed correlation between Ki67 labeling index and different molecular classes in breast cancer, and was suggested to be an important prognostic factor in breast carcinoma.51 Study by Dowsett et al. showed that the Ki67 after 2 weeks of treatment was a better prognostic indicator than pretreatment Ki67 (3 months).52 This is important especially in the neoadjuvant setting as a proportion of patients receiving neoadjuvant endocrine treatment may show progression after months of treatment and this could accelerate the time required to obtain prognostic and predictive information. Evaluation of these proliferation activities can give predictive information in weeks rather than months and alternative treatment approaches could be considered in those who do not show response. This would potentially save time, money and avoid ill effect of unwanted treatment. Further studies need to address and validate which parameters should be used as surrogate marker for long-term outcome with neoadjuvant endocrine treatment.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
Conflict of interest None of the authors have any financial and personal relationships with other people or organisations that could inappropriately influence this work.
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References 26. 1. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists’ Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008;9:45–53. 2. Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomized controlled trial. Lancet 2007;369:559–70. 3. Coates AS, Keshaviah A, Thu¨rlimann B, et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 2007 Feb 10;25(5):486–92. 4. Wolmark N, Wang J, Mamounas E, et al. Preoperative chemotherapy in patients with operable breast cancer: nine year results from national surgical adjuvant breast and bowel project B-18. J Natl Cancer Inst Monogr 2001;30:96–102. 5. Makris A, Powles TJ, Ashley SE, et al. A reduction in requirements for mastectomy in a randomised trial of neoadjuvant chemoendocrine therapy in breast cancer. Ann Oncol 1998;9:1179–84. 6. Markis A, Powles TJ, Kakolyris S, et al. Reduction in angiogenesis after neoadjuvant chemoendocrine therapy in patients with operable breast carcinoma. Cancer 1999;85(9):1996–2000. 7. Petit T, Wilt M, Velten M, et al. Comparative value of tumour grade, hormonal receptors, Ki-67, HER-2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. Eur J Cancer 2004;40(2):205–11. 8. Fisher B, Bryant J, Wolmark N, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998;16:2672–85. 9. van der Hage JA, van de Velde CJH, Julien JP, et al. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer Trial 10902. J Clin Oncol 2001;19:4224–37. 10. Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 2005 Feb 2;97(3):188–94. 11. Colleoni M, Gelber S, Coates AS, et al. Influence of endocrine-related factors on response to perioperative chemotherapy for patients with node negative breast cancer. J Clin Oncol 2001;19:4141–9. 12. Gianni L, Baselga J, Eiermann W, , et alEuropean Cooperative Trial in Operable Breast Cancer Study Group. Feasibility and tolerability of sequential
27.
28.
29.
30. 31.
32.
33.
34.
35.
36.
343
doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy. Clin Cancer Res 2005 Dec 15;11(24 Pt 1):8715–21. Early Breast Cancer Trialists Collaborative Group. 2000 Analysis overview results. Fifth meeting of Early Breast Cancer Trialists Collaborative Group. Oxford, UK; Sep 2000. p. 21–3. Tan SM, Cheung KL, Willsher PC, Blamey RW, Chan SY, Robertson JFR. Locally advanced primary breast tumour: medium-term results of a randomised controlled trial of multimodal therapy versus initial hormone therapy. Eur J Cancer 2001;37:2331–8. Robertson JF, Ellis IO, Alston CW. Mastectomy or tamoxifen as initial therapy for operable breast cancer in elderly patients: 5-year follow-up. Eur J Cancer 1992;28A(4–5):908–10. Mustacchi G, Ceccherini R, Milani S, et al. Italian Cooperative Group GRETA. Tamoxifen alone versus adjuvant tamoxifen for operable breast cancer of the elderly: long-term results of the phase III randomized controlled multicenter GRETA trial. Ann Oncol 2003 Mar;14(3):414–20. Hind D, Wyld L, Reed MW. Surgery, with or without tamoxifen, vs tamoxifen alone for older women with operable breast cancer. Cochrane review. Br J Cancer 2007 Apr 10;96(7):1025–9. Eiermann W, Paepke S, Appfelstaedt J, et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomised double-blind multicenter study. Ann Oncol 2001;12:1527–32. Ellis MJ, Coop A, Singh B, Mauriac L, et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB1- and /or ErbB2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase 111 randomized trial. J Clin Oncol 2001;19:3808–16. Koeberle D, Thuerlimann B. Letrozole as upfront endocrine therapy for postmenopausal women with hormone-sensitive breast cancer: BIG 1-98. Breast Cancer Res Treat 2007;105(Suppl. 1):55–66. Rasmussen BB, Regan MM, Lykkesfeldt AE, et al. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol 2008;9(1):23–8. Dowsett M, Allred C, Knox J, et al. Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or in Combination trial. J Clin Oncol 2008 Mar 1;26(7):1059–65. Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the immediate preoperative anastrozole, tamoxifen, or combined with tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 2005;23:5108–16. Semiglazov V, Semiglazov VV, Ivanov VG, et al. Anastrazole vs tamoxifen vs combination as neoadjuvant endocrine therapy of postmenopausal breast cancer patients. Proc Am Soc Clin Oncol 2003;22:880 [Abstract 3538]. Cataliotti L, Buzdar AU, Noguchi S. Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor positive breast cancer. 2006;106:2095–103 Miller WR, Dixon JM, Cameron DA. Biological and clinical effects of aromatase inhibitors in neoadjuvant therapy. J Steroid Biochem Mol Biol 2001;79:103–7. Semiglazov V, Kletsel A, Semiglazov E, et al. Exemestane (E) vs tamoxifen (T) as neoadjuvant endocrine therapy for postmenopausal women with ERþ breast cancer (T2N1-2, T3N0-1, T4N0M0) (ASCO). J Clin Oncol 2005;23:530 [Abstract]. Semiglazov V, Semiglazov VV, Ivanov VG, Ziltzova EK, et al. Neoadjuvant endocrine therapy: exemestane vs tamoxifen in postmenopausal ERþ breast cancer patients (T1-4N1-2 M0). Breast Cancer Res Treat 2003;82(Suppl. 1) [Abstract 111]. Chow LW, Yip AY, Loo WT, Lam CK, Toi M. Celecoxib anti-aromatase neoadjuvant (CAAN) trial for locally advanced breast cancer. J Steroid Biochem Mol Biol 2008 Jul;111(1–2):13–7. Dixon JM, Anderson T, Miller WR. Phase 11b study of neoadjuvant exemestane (EXE) in locally advanced breast cancer. Proc ASCO; 2001 [Abstract 1908]. Barnadas A, Gil M, Gonza´lez S, Tusquets I, et al. Exemestane as primary treatment of oestrogen receptor-positive breast cancer in postmenopausal women: a phase II trial. Br J Cancer 2009 Feb 10;100(3):442–9. Krainick U, Astner A, Jonat W, et al. Phase 11 study to define safety and efficacy of exemestane as preoperative therapy for postmenopausal patients with primary breast cancer – final results of the German Neoadjuvant Aromasin Initiative (GENARI). San Antonio; 2003 [Abstract 239] Tubiana-Hulin M, Becette V, Bieche I, et al. Exemestane as neoadjuvant hormonotherapy for locally advanced breast cancer: results of a phase II trial. Anticancer Res 2007 Jul–Aug;27(4C):2689–96. Harper-Wynne Catherine L, Sacks Nigel PM, Shenton Karyn, et al. Comparison of the systemic and intratumoral effects of tamoxifen and the aromatase inhibitor vorozole in postmenopausal patients with primary breast cancer. J Clin Oncol 2002;20(4):1026–35. Basi Sanraj K, Mackey John R. Anastrozole plus trastuzumab prolongs progression-free survival in postmenopausal patients with HER2-positive and hormone receptor-positive metastatic breast cancer: a review of the TAnDEM study. Breast Diseases: A Year Book Quarterly 2007;18:236–7. Seo JH, Kim YH, Kim JS. Meta-analysis of pre-operative aromatase inhibitor versus tamoxifen in postmenopausal woman with hormone receptor-positive breast cancer. Cancer Chemother Pharmacol 2009 Jan;63(2):261–6.
344
J. Mathew et al. / The Breast 18 (2009) 339–344
37. Krainick-Strobel UE, Lichtenegger W, Wallwiener D, et al. Neoadjuvant letrozole in postmenopausal estrogen and/or progesterone receptor positive breast cancer: a phase IIb/III trial to investigate optimal duration of preoperative endocrine therapy. BMC Cancer 2008 Feb 26;8:62. 38. Dixon JM, Renshaw L, Macaskill EJ, et al. Increase in response rate by prolonged treatment with neoadjuvant letrozole. Breast Cancer Res Treat 2009 Jan;113(1):145–51. 39. Mathew J, Agrawal A, Asgerisson K, et al. Primary endocrine therapy in locally advanced breast cancers – Nottingham experience. Eur J Surg Oncol 2007;33: 1095–6 [Abstract]. 40. Semiglazov VF, Semiglazov VV, Dashyan GA, et al. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer 2007;110:244–54. 41. Singletary SE, Shallenberger R, Guinee VF. Breast cancer in the elderly. Ann Surg 1993;218(5):667–71. 42. Busch E, Kemeny M, Fremgen A, et al. Patterns of breast cancer care in the elderly. Cancer 1996;78(1):101–11. 43. McCarty Jr KS, Silva JS, Cox EB, et al. Relationship of age and menopausal status to estrogen receptor content in primary carcinoma of the breast. Ann Surg 1983;197:123–7. 44. Cristofanilli M, Gonzalez-Angulo A, Sneige N, et al. Invasive lobular carcinoma classic type: response to primary chemotherapy and survival outcomes. J Clin Oncol 2005 Jan 1;23(1):41–8. 45. Guarneri V, Broglio K, Kau SW, Cristofanilli M, Buzdar AU, Valero V, et al. Prognostic value of pathologic complete response after primary chemotherapy
46.
47.
48. 49.
50.
51.
52.
in relation to hormone receptor status and other factors. J Clin Oncol 2006 Mar 1;24(7):1037–44. Dixon JM, Renshaw L, Bellamy C, Stuart M, Hoctin-Boes G, Miller WR. The effects of neoadjuvant anastrozole (arimidex) on tumor volume in postmenopausal women with breast cancer: a randomized, double-blind, singlecenter study. Clin Cancer Res 2000;6(6):2229–35. Dixon JM, Love CD, Bellamy CO, Cameron DA, Leonard RC, Smith H, et al. Letrozole as primary medical therapy for locally advanced and large operable breast cancer. Breast Cancer Res Treat 2001;66(3):191–9. Mieog JSD, van der Hage JA, van de Velde CJH. Neoadjuvant chemotherapy for operable breast cancer. Br J Surg 2007;94(10):1189–200. Thomas JS, Julian HS, Green RV, Cameron DA, Dixon MJ. Histopathology of breast carcinoma following neoadjuvant systemic therapy: a common association between letrozole therapy and central scarring. Histopathology 2007 Aug;51(2):219–26. Milla-Santos A, Milla L, Calvo N, et al. Anastrozole as neoadjuvant therapy for patients with hormone-dependent, locally-advanced breast cancer. Anticancer Res 2004 Mar–Apr;24(2C):1315–8. Bharagva R, Striebel J, Onisko A, et al. Ki-67 labeling index in breast carcinoma: an immunohistochemical study with correlation to molecular subtypes. J Clin Oncol 2008;26(May 20 Suppl.) [Abstract 22107]. Dowsett M, Smith IE, Ebbs SR, et al. Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival. Clin Cancer Res 2005;11(Suppl.):951–8.