The Breast 24 (2015) 406e412

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Original article

Neoadjuvant endocrine therapy for resectable breast cancer: A systematic review and meta-analysis Frederico Leal, Vitor Teixeira Liutti, Vivian Castro Antunes dos Santos,  Augusto Rinck Junior, Maximiliano Augusto Novis de Figueiredo, Ligia Traldi Macedo, Jose Andre Deeke Sasse* Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas (UNICAMP), Vital Brasil 251, 13083-888 Campinas, Brazil

a r t i c l e i n f o

a b s t r a c t

Article history: Received 15 August 2014 Received in revised form 8 March 2015 Accepted 13 March 2015 Available online 7 April 2015

Introduction: The role of neoadjuvant endocrine therapy for resectable breast cancer is not well established, despite encouraging results obtained in the metastatic and adjuvant settings. This systematic review aims to examine existing medical literature on neoadjuvant hormone therapy (HT). Methods: Data from prospective, randomized trials was included if comparing neoadjuvant HT versus surgery alone without adjuvant treatment, or neoadjuvant HT versus chemotherapy (CT), or HT plus CT versus CT alone, or HT plus CT versus HT alone, or two distinct HT. Odds Ratios (OR) were calculated from pooled data. Results: Five studies compared HT with tamoxifen versus HT with aromatase inhibitors (AI). A metaanalysis of their results demonstrated superiority of AIs in overall response rate (ORR) (OR 1.9; 95% CI 1.17e3.08). Two trials compared HT against CT, and pooled data from them demonstrated a trend favoring CT (OR for ORR 0.75; 95% CI 0.35e1.6). That trend disappeared when only postmenopausal women were considered (OR 1.01; 95% CI 0.62e1.63). One trial compared HT plus CT with no neoadjuvant treatment, and obtained an 83% ORR. One trial compared HT plus CT versus CT alone and found a non-significant increase in ORR for adding HT to CT (OR 1.48; 95% CI 0.58e3.77). No trial compared HT plus CT versus HT alone. Conclusions: Neoadjuvant HT is a safe and feasible option, but it cannot be considered equivalent to CT. If neoadjuvant HT is performed, AIs are preferable over tamoxifen due to higher response rates. © 2015 Elsevier Ltd. All rights reserved.

Keywords: Endocrine therapy Breast cancer Neoadjuvant Preoperative Tamoxifen Aromatase inhibitor

Introduction Breast cancer is a heterogeneous disease, with different histological and molecular subtypes bearing distinct clinical presentations, responses to treatment, and prognosis [1]. In the process of better understanding the biology of breast neoplasms, it was established that the subgroup of tumors that express hormone-receptors are sensitive to estrogen blockade and present better survival for metastatic disease, as well as a reduction of the risk of recurrence or death for patients with resected localized disease [1]. Estrogen receptor (ER) positivity has also been shown to be an independent prognostic factor, for patients with hormone receptor positive tumors tend to have better survival both in the

* Corresponding author. Fax: þ55 19 35218345. E-mail address: [email protected] (A.D. Sasse). http://dx.doi.org/10.1016/j.breast.2015.03.004 0960-9776/© 2015 Elsevier Ltd. All rights reserved.

early and advanced disease when compared to an ER negative disease of the same stage [1,2]. Systemic treatment for early breast cancer may be delivered before or after local curative treatment. Several randomized trials and a systematic review have demonstrated that the benefit provided by chemotherapy is similar regardless of the treatment being delivered in the adjuvant or neoadjuvant setting [3]. Possible advantages of the preoperative treatment are: a tumor shrinkage favoring surgical resection and better cosmetic results; the possibility of performing conservative surgery when radical mastectomy was originally required, and the possibility of better evaluating the neoplasm's biological behavior and its response to systemic treatment [4]. The latter has been suggested to be a reason of preference for neoadjuvant treatment, given the opportunity to maintain or change therapy according to tumor response. However, the benefit of this response-guided strategy has not been proven by prospective randomized trials [5].

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Neoadjuvant treatment with cytotoxic chemotherapy has become a standard option for localized or locally advanced breast cancer, but the role of preoperative hormonal therapy is much less established. Concerns involving the delayed time to achieve response in comparison to neoadjuvant chemotherapy have limited the use of such approach to patients who are unfit to receive cytotoxic drugs [6]. Large, prospective randomized trials testing the efficacy and safety of pre-operatory endocrine therapy are still lacking. There is, however, some evidence supporting the use of neoadjuvant hormone deprivation. Studies performed with post-menopausal patients who were unfit or refused chemotherapy have shown encouraging response rates and surgical results [6e8]. Also, estrogen-receptor positive tumors are less likely to show a pathologic complete response when treated with neoadjuvant chemotherapy despite their better overall prognosis [9], warranting a rationale to consider different systemic treatment strategies. If the role of neoadjuvant estrogen blockade is unclear, there is more uncertainty about the optimal agent of choice. There is some evidence that aromatase inhibitors (AI) are superior to tamoxifen in this setting, but the magnitude of this difference is still uncertain [7,8]. Combinations of endocrine and cytotoxic therapy, or the combination of two different anti-estrogenic drugs have been proposed, but their benefit has not been established [7,10]. This systematic review aimed to extract from medical literature the existing data regarding efficacy and safety of neoadjuvant

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endocrine therapy. It also sought potential differences between hormonal treatment (HT) strategies. Methods This systematic review was performed according to the principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [11]. A systematic search, with no language restrictions, was performed in electronic databases including PubMed/MEDLINE, EMBASE, LILACS, ClinicalTrials.gov, the Cochrane Library, ASCO Meeting abstracts, ESMO Meeting abstracts, and San Antonio Breast Cancer Symposium abstracts. The search was performed in January 2014. Only articles reporting results from prospective, randomized clinical trials were to be included in the meta-analysis. We searched for studies comparing neoadjuvant hormone therapy (HT) followed by surgery versus surgery alone, or comparing two different neoadjuvant HT strategies (including combination of two or more antiestrogenic agents), or comparing neoadjuvant HT versus neoadjuvant chemotherapy, or comparing neoadjuvant HT plus chemotherapy versus neoadjuvant chemotherapy alone, or comparing neoadjuvant HT plus chemotherapy versus neoadjuvant HT alone. Trials with premenopausal women, postmenopausal women, or both were equally allowed. Studies including patients with any neoplasm other than female breast cancer were excluded, as well as

Fig. 1. Flow Chart. RCT: Randomized controlled trial, CT: Chemotherapy, HT Hormone therapy, AI: Aromatase inhibitor.

ORR ORR ORR ORR ORR or PD or PD

Exp.: experimental, Q21d: each 21 days, ORR: overall response rate, CR: complete response, pCR: pathological complete response, PD: progressive disease, ORR: overall response rate.

or PD or PD

Yes Yes No Yes Yes or PD or PD

months months months months months 4 3 3 3 6 daily daily daily daily daily þ goserelin Tamoxifen 20 mg Tamoxifen 20 mg Tamoxifen 20 mg Tamoxifen 20 mg Tamoxifen 20 mg 3.6 mg/month or PD or PD

months months months months months 4 3 3 3 6 Hormone therapy versus other hormone therapy Eiermann 2001 Letrozole 2.5 mg daily Smith 2005 Anastrozole 1 mg/Anastrozole 1 mg þ Tamoxifen 20 mg daily Semiglazov 2005 Exemestane 25 mg daily Cataliotti 2006 Anastrozole 1mgdaily Masuda 2012 Anastrozole 1 mg daily þ goserelin 3.6 mg/month

Clinical CR and pCR Yes 9-13 weeks 5FU 600 mg/m2 þ Doxorubicin 60 mg/m2 þ cyclophosphamide 600 mg/m2 q21d 9-13 weeks Hormone therapy plus chemotherapy versus chemotherapy alone Mohammadianpanah 2012 Letrozole 2.5 mg daily þ 5FU 600 mg/m2 þ Doxorubicin 60 mg/m2 þ cyclophosphamide 600 mg/m2 q21d

ORR Yes 24 weeks 24 weeks 2012

Examestane 25 mg daily(þ/ goserelin) Alba

ORR No 12 weeks

Doxorubicin 60 mg/m2 þ Paclitaxel 200 mg/m2 q21d Epirubicin 90 mg/m2 þ cyclophosphamide 600 mg/m2 q21d then docetaxel 100 mg/m2 q21d 3 months

No x No neoadjuvant treatment 3 months

Table 1 Study characteristics.

From 758 potential studies identified by the systematic search, 36 initially met the inclusion criteria. From these, 18 were excluded for reporting duplicated data, 4 for being protocols without published results, and 5 for reporting results from studies testing treatment strategies different from the ones of our interest (trials testing targeted therapies or non-surgical approach). After the exclusion of these articles, nine studies were included in the systematic review [10,15e22]. A flow chart explaining inclusion is shown in Fig. 1. The selected trials consisted of one study comparing neoadjuvant HT plus chemotherapy versus no neoadjuvant treatment; two studies testing HT against cytotoxic chemotherapy; one study comparing neoadjuvant cytotoxic chemotherapy plus HT versus neoadjuvant chemotherapy alone; and five studies comparing different neoadjuvant HT. No prospective, randomized

Year

Results

Hormone therapy versus no neoadjuvant treatment Makris 1998 Tamoxifen 20 mg daily þ (Mitomycin 7 mg/m2 þ Mitoxantrone 7 mg/m2 þ Methotrexate 35 mg/m2 q21d) Hormone therapy versus chemotherapy Semiglazov 2007 Anastrozole 1 mg or Examestane 25 mg daily

Experimental arm drug(s)

Exp. arm treatment duration

Control arm drug(s)

Control arm treatment duration

Multicentre study

Primary endpoint

studies analyzing unresectable or metastatic breast cancer. Articles reporting results from trials held in the adjuvant setting were also excluded. Papers reporting only subgroup analysis on neoadjuvant HT were not included unless those analyses were preplanned and their data reported separately from the remaining patients. Data extraction was performed independently by two authors. Disagreements were solved by consensual decision by all authors. Overall response rate (ORR), pathologic complete response rate (pCR), rate of conservative surgery (CSR), and toxicity were the end-points of interest. ORR was defined as the probability of achieving a clinical complete response (no clinically measurable lesions) or a partial response (reduction by at least 30% in the maximum diameter of measurable lesions). pCR was defined as the probability of no residual lesion to be detected by pathological examination of the resected tissue. ORR, pCR, CSR, and toxicity were expressed by odds ratio (OR). When the measures of benefit were not reported in the articles, estimates for those values were calculated [12]. All studies selected were evaluated by the authors for characteristics linked to potential bias. Information about randomization, blinding, allocation concealment, dropouts, intention-totreat (ITT) analysis, and funding source was especially evaluated. Eligibility criteria for the studies were also assessed for differences in patient populations among the trials. Meta-analyses for this systematic review were conducted with RevMan 5.0 software (Cochrane Collaboration's Information Management System). Analyses of data consisted of pooled OR for dichotomous endpoints, using the Mantel-Haenzel method and considering a random effect model [12]. The 95% confidence intervals (CI) were calculated and presented in forest plots. The diamond at the bottom of the plot summarizes the best estimate pooled results (with the width representing its corresponding 95% CI). A diamond placed right of the central line in the forest plot indicates a pooled ratio greater than 1.0 (meaning an increased chance for events in the research arm), while a diamond placed to the left means a ratio smaller than 1.0 (meaning a reduction in event probability in the research arm). Statistical heterogeneity was evaluated with the chi-squared test, and expressed using the I2 index [13]. If significant heterogeneity (defined as an I2 index > 50%) was identified, a possible explanation was investigated. Differences between studies regarding eligibility criteria, patient population, and treatment delivered arms were assessed and discussed. The risk of publication bias was evaluated through visual appraisal of funnel plots [14]. The risk of selective reporting within trials was assessed by searching trials' original design at the website clinicaltrials.gov.

Conservative Surgery

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Fig. 2. Neoadjuvant hormone therapy versus neoadjuvant cytotoxic chemotherapy. MeH: Mantel-Haenzel method, CI: Confidence interval, df: Degrees of freedom.

trial comparing neoadjuvant HT with chemotherapy versus HT alone was identified. Details on the studies' design are shown in Table 1. Neoadjuvant hormone therapy versus no neoadjuvant treatment Only one randomized trial testing the benefit of preoperative endocrine therapy compared to surgery alone was identified [10]. In fact, this study tested neoadjuvant HT combined with chemotherapy, but there was consensual decision among authors to include it in this review. ORR in this trial was 83% for the neoadjuvant treatment arm. pCR occurred in 10% of the patients. The rate of conservative surgery was 89% in the neoadjuvant arm versus 78% in the control arm (OR 2.31; 95% CI 1.22e4.37). Toxicity was low in both arms. Neoadjuvant hormone therapy versus neoadjuvant cytotoxic chemotherapy Two randomized trials tested pre-operatory endocrine treatment against neoadjuvant chemotherapy [15,16]. Pooled data from their results has shown a non-significant benefit for chemotherapy, with a OR 0.75 for ORR (95% CI 0.35e1.6). However there was important heterogeneity (I2 ¼ 59%). Details of this pooled analysis are shown in Fig. 2. The trials used different methods for response assessment: while Semiglazov and colleagues measured the ORR by caliper, mammography and ultrasonography, Alba et al. assessed response exclusively by magnetic resonance imaging (MRI). This difference in response evaluation could partially explain the difference in results. Another important difference between these trials is that while Semiglazov included only postmenopausal women, the trial by Alba recruited patients regardless of menopausal status. Considering only postmenopausal women from both trials, we obtain a pooled OR of 1.01 (95% CI 0.62e1.63) with no heterogeneity (I2 ¼ 0%). Details of this analysis for postmenopausal women only are shown in Fig. 3. Breast conservation rate was higher for HT than chemotherapy in these trials, with a pooled OR 1.54 (95% CI 0.97e2.46) but the

difference was not statistically significant (p ¼ 0.07). There was no heterogeneity for this end-point (I2 ¼ 0%). Toxicity was higher in the chemotherapy arm in both arms. Alba and colleagues reported a reduction in any Grade 3e4 adverse events (OR 0.109; 95% CI 0.03e0.35) favoring the HT arm; while Semiglazov et al. reported increased rates of neutropenia, febrile neutropenia and cardiotoxicity in the chemotherapy arm. Hormone therapy plus chemotherapy versus chemotherapy alone Only one trial comparing combined treatment with neoadjuvant chemotherapy was identified [17]. Including both estrogen receptor positive (ERþ) and estrogen receptor negative (ER-) patients, this trial found a non-significant increase in ORR for adding hormone blockade to neoadjuvant chemotherapy (OR 1.48; 95% CI 0.58e3.77). When only ERþ patients were considered, however, the benefit became statistically significant (OR 7.5; 95% CI 1.48e37.91). A marginally significant benefit in terms of pCR was also observed in the ERþ population (OR 4.09; 95% CI 1.0e16.72) but not in the total study population (OR 3.01; 95% CI 0.97e9.38). The addition of endocrine therapy to standard neoadjuvant chemotherapy did not increase toxicity in this study. Comparisons of different types of neoadjuvant hormone therapy Five trials were identified, all of them comparing neoadjuvant therapy with AIs versus tamoxifen [18e22](both associated with central hormonal blockade with goserelin in the only study that did include premenopausal women [22]). Pooled analysis demonstrated a significant benefit favoring the AI arm in terms of ORR evaluated by caliper (OR 1.9; 95% CI 1.17e3.08); however with important heterogeneity (I2 ¼ 78%). These results are shown in Fig. 4. When ORR was evaluated by ultrasonography, there was also a significant benefit for the AI arm (OR 1.54; 95% CI 1.18e2.00) and by this criterion heterogeneity among trials was low (I2 ¼ 22%). Detailed results for this pooled analysis are shown in Fig. 5. Three studies have reported data on pCR, and demonstrated no statistically significant difference between treatment arms for this

Fig. 3. Neoadjuvant hormone therapy versus neoadjuvant cytotoxic chemotherapy (for post-menopausal women only). MeH: Mantel-Haenzel method, CI: Confidence interval, df: Degrees of freedom.

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Fig. 4. Aromatase Inhibitors versus Tamoxifen (assessed by caliper). MeH: Mantel-Haenzel method, CI: Confidence interval, df: Degrees of freedom, AI: Aromatase inhibitor.

Fig. 5. Aromatase Inhibitors versus Tamoxifen (assessed by ultrasonography). MeH: Mantel-Haenzel method, CI: Confidence interval, df: Degrees of freedom, AI: Aromatase inhibitor.

end-point (OR 0.97; 95% CI 0.28e3.33) with no heterogeneity (I2 ¼ 0%). pCR was low in both arms, ranging from 0 to 15%. The study by Smith et al. compared a third treatment arm, in which patients received a combination of tamoxifen and letrozole, against the tamoxifen alone control arm. There was no significant difference between the combination treatment and tamoxifen alone (OR 1.11; 95% CI 0.64e1.92). Toxicity was low with both treatment strategies, with only one treatment-related death for each arm considering data from all studies. Hot flushes, fatigue, and vaginal discharge were more frequent in the tamoxifen arm, but the difference did not achieve statistical significance for any of these adverse events. Headache and nausea were more frequent with AIs than tamoxifen, also with no statistical significance. Arthralgia was the only adverse event that occurred most frequently in the AI arm, with statistical significance (p ¼ 0.005) while constipation was more common with tamoxifen (p ¼ 0.02). Conclusions In contrast to the metastatic or adjuvant context, the role of endocrine therapy in the neoadjuvant setting has not been exhaustively tested. Most of the data comes from small trials, with limited statistical power. However, with ORR ranging from 20% to 76%, and considering the low toxicity observed, neoadjuvant HT can be considered a safe and efficient treatment option [10,15e22]. One of the possible advantages of neoadjuvant treatment is the possibility to observe the disease's biological behavior in response to systemic therapy. This feature is of particular importance in the context of clinical trials, since a potential benefit can be detected by an increase in response rates in the pre-operatory setting long

before any survival advantage could be observed [4,23,24]. Specially, pCR is known to correlate with disease-free and overall survival on patient-level. That means achieving a pCR can be considered a favorable prognostic marker. However, this correlation is much weaker on the clinical trials level, therefore pCR cannot be considered a surrogate endpoint for survival [23,25]. Also, ERþ neoplasms tend to have low pCR when treated with chemotherapy [9], and our systematic review found low pCR with neoadjuvant endocrine therapy as well. Our pooled analysis did not show statistical difference between chemotherapy and endocrine therapy in terms of ORR, but there was a trend toward a benefit for chemotherapy from the pooled data of two small randomized studies, thus a significant benefit favoring chemotherapy arms could have been demonstrated with larger samples. It is therefore not safe to consider neoadjuvant HT equivalent to neoadjuvant chemotherapy, and the latter should remain the standard treatment option for fit patients. However, as some patients are not candidates for chemotherapy, neoadjuvant HT can be considered an effective alternative. Hormone blockade has a favorable toxicity profile [26], with hot flushes being the most commonly reported adverse event, and the trials identified in this systematic review have reported a very small number of treatment-related deaths [19,22,26]. Also, when only postmenopausal women were considered, the trend toward a benefit for chemotherapy disappeared from our pooled analysis, suggesting that this specific subgroup might benefit from endocrine therapy as much as from cytotoxic treatment [15,16]. This hypothesis should, in fact, be investigated in a large prospective trial. Adding HT to standard neoadjuvant chemotherapy has been investigated, although the efficacy of concurrent treatment has not

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yet been established in any clinical setting. It has been proposed that, by arresting cell cycle in G0 phase, hormone blockade may limit the cancer cells sensibility to cytotoxic drugs [27]. Some clinical data suggest a negative interaction between chemotherapy and endocrine therapy [28], and one clinical trial has shown a greater benefit for endocrine therapy following adjuvant chemotherapy than for concurrent treatment [28]. On the other hand, some studies performed in the metastatic setting have shown encouraging results for combined therapy [29]. The unique randomized study included in this systematic review did show a nonsignificant benefit favoring the combination arm [17]. Our meta-analysis has confirmed the superiority of AIs over tamoxifen. Treatment with AIs demonstrated better clinical response rates, a larger frequency of pCR (though small in both arms) and better chance of breast-conserving surgery. Side effects were different between the two modalities of HT, but manageable in both. Treatment-related deaths were uncommon with either option. AIs have demonstrated superior response rates in the advanced disease context, and also some benefit in progression-free survival [30,31]. In the adjuvant setting, AIs provide a better disease-free survival over tamoxifen, though no difference in overall survival has been reported to this point [32]. Therefore, results from our systematic review are consistent if the ones observed in trials concerning adjuvant or palliative HT for breast cancer. The unique study that tested a third arm consisting of tamoxifen and letrozole combination did not show significant benefit with combination treatment [19]. Such results are consistent with what has been observed the adjuvant treatment trial ATAC, in which no additional benefit was obtained from the combination of anastrozole and tamoxifen when compared to tamoxifen alone [33]. Despite the importance of response rate, and particularly pCR, as good prognostic marker for patients treated with neoadjuvant chemotherapy, there is no evidence that the same correlation occurs with neoadjuvant HT and pCR are rare in hormone-receptor positive tumors, regardless of treatment strategy. Therefore, longer follow-up and mature survival data from these trials comparing both treatments are needed before one could affirm that neoadjuvant treatment with AIs provides a survival benefit when compared to preoperative tamoxifen. However, once higher clinical responses provide better surgical outcomes and chance for breastconserving surgery, AI should be preferred over tamoxifen due to better response rates, independently of survival data. In summary, our systematic review is not sufficient to establish neoadjuvant endocrine therapy as a standard treatment for hormone-receptor positive breast cancer, but it does confirm this approach as a safe and feasible option. If this strategy is chosen, AIs should be preferred over tamoxifen due to higher response rates. Conflict of interest statement We have no conflicts to declare. We received no funding for this research. Acknowledgments We thank Deborah Salerno for her kind support with grammar and style. References [1] Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thürlimann B, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2013. Ann Oncol 2013;24(9):2206e23.

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