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1 Supplementary Online Content Spring LM, Gupta A, Reynolds KL, et al. Neoadjuvant endocrine therapy for estrogen receptor positive breast cancer: a systematic review and meta-analysis. JAMA Oncol. Published online June 30, doi: /jamaoncol emethods. Search Strategy etable 1. Study Quality of Eligible Trials etable 2. Summary of Toxicities efigure 1. Flowchart for Manuscript Selection efigure 2. Neoadjuvant Hormone Therapy vs Neoadjuvant Cytotoxic Chemotherapy efigure 3. Neoadjuvant Aromatase Inhibitors vs Neoadjuvant Tamoxifen efigure 4. Neoadjuvant Endocrine Therapy vs Dual Therapy efigure 5. Funnel Plots for Studies Evaluating Neoadjuvant Therapies This supplementary material has been provided by the authors to give readers additional information about their work.

2 emethods. Search Strategy Ovid MEDLINE(R) 1 exp Breast neoplasms/ or (breast adj2 cancer).ti,ab. or (breast adj2 malig*).ti,ab. or breast neoplasm*.ti,ab. 2 Tamoxifen/ or exp Selective Estrogen Receptor Modulators/ or (Femara or tamoxifen or letrozole or anastrozole or Arimidex or exemestane or Aromasin or Selective Estrogen Receptor Modulators* or serm or fulvestrant or Faslodex or endocrine therap* or endocrine treat*).ti,ab. 3 Neoadjuvant Therapy/ or Preoperative Care/ or (neo adjuvant or neoadjuvant or nat or Preoperative or presurg*4 or pre operative or pre surg*4).ti,ab. 4 Neoplasm Staging/ or (tumor stag* or tumour stag* or cancer stag* or neoplasm stag* or stage i or stage ii or stage iii or local*4 or locally advanced or LABC).ti,ab. 5 (hormone receptor positive or estrogen receptor positive or hr positive or er positive or er+ or hr+).ti,ab. 6 Disease-Free Survival/ or treatment outcome/ or Dose-Response Relationship, Drug/ or (treatment outcome* or clinical response* or drug Dose Response Relationship* or pathological* complete response* or pcr or Disease-Free Survival or surviv*).ti,ab. 7 (controlled clinical trial or meta analysis or randomized controlled trial or review).pt. or Intervention Studies/ or (intervention studies or intervention study or systematic or ebm or evidence).ti,hw. 8 exp Neoplasm Metastasis/ or (Metastasis or metastases or metastatic).ti,ab. or sc.fs. 9 1 and 2 and 3 and (4 or 5 or 6) and not 8

3 11 limit 10 to (english language and humans) PubMed ((Neoadjuvant Therapy[mesh] OR (neoadjuvant endocrine OR neoendocrine[tiab]) AND (breast cancer[tiab] or breast malignancy*[tiab] or breast tumor*[tiab] or breast tumour*[tiab] or breast neoplasms[mesh] or stage i breast[tiab] or stage ii breast[tiab] or stage iii breast[tiab] or localized breast[tiab] or localised breast[tiab] NOT (metastasis OR metastases OR secondary OR lcis OR dcis)). Limited to English

4 etable 1. Study Quality of Eligible Trials Author and trial name (if applicable) Year Study described as randomized? Randomization method described and appropriate? Study described as double blind? Method of double blinding described and appropriate? Description of withdrawals and dropouts? Jadad Score (0-5) Alba GEICAM/ Palmieri 2012 Yes Yes Not applicable Not applicable Yes Yes Yes Not applicable Not applicable Yes 3 NEOCENT Semiglazov 2007 Yes Yes Not applicable Not applicable Yes 3 Eiermann 2001 Yes Yes Yes Not described Yes 4 P024 Smith 2005 Yes Not reported Yes Yes Yes 4 IMPACT Masuda 2012 Yes Yes Yes Yes Yes 5 STAGE Cataliotti 2006 Yes Not reported Yes Yes Yes 4

5 Ellis 2001 Yes Yes Yes Yes Yes 5 Miller 2001 Yes No Not applicable Not applicable No 1 Harper- Wynne 2002 Yes Not reported Not applicable Not applicable Yes 2 Guarneri 2014 Yes Yes Yes Yes Yes 5 Baselga 2009 Yes Not reported Yes Yes Yes 4 Chow 2008 Yes Yes Not applicable Not applicable Yes 3 CAAN Smith 2007 Yes Not reported Not applicable Not applicable Yes 2 Hojo 2013 Yes Not reported Not applicable Not applicable Yes 2 PTEX46 Kuter 2012 Yes Not reported Not applicable Not applicable Yes 2 NEWEST Ellis 2011 Yes Not reported Not applicable Not applicable Yes 2 ACOSOG Z1031 Polychronis 2005 Yes Yes Yes Yes Yes 5

6 Fasching 2014 Yes Not reported Not applicable Not applicable Yes 2 FemZone Mohammadianpanah 2011 Yes Not reported Not applicable Not applicable Yes 2

7 etable 2. Summary of Toxicities Author and trial name (if applicable) Year Experimental arm agent(s) Control arm agent(s) Toxicities Alba GEICAM/ Exemestane 25 mg daily + goserelin 3.6 mg/month if premenopausal EC-T: Epirubicin 90 mg/m2 + cyclophosphamide 600 mg/m2 4 cycles q21d docetaxel 100 mg/m2 4 cycles q21d + goserelin 3.6 mg/month if premenopausal 47% of patients given CT had grade 3 4 toxicity (excluding amenorrhea) based on NCI-CTCAE 3.0, compared with 9% of patients receiving HT (P < 0.001). Patients receiving CT experienced more gastrointestinal toxicity, leukopenia, and neutropenia, with a febrile neutropenia rate of 7%. Palmieri NEOCENT 2014 Letrozole 2.5 mg daily FEC: 5-fluorouracil mg/m2 + epirubicin mg/m2 + cyclophosphamide mg/m2 x 6 cycles q21d; switched to docetaxel 100 mg/m2 after 3 cycles if SD or PD (N = 11) Statistically significant differences between treatment groups favoring letrozole were seen in relation to alopecia, nausea, vomiting, stomatitis and anemia. There were eight serious adverse reactions, all occurring in those who received CT. Six were neutropenia-related.

8 Semiglazov 2007 Anastrozole 1 mg daily or exemestane 25 mg daily Doxorubicin 60 mg/m2 + paclitaxel 200 mg/m2 x 4 cycles q21d The incidence of commonly reported adverse events was higher in patients who receiving CT. No serious adverse events were reported in patients who were receiving HT. Six patients who were receiving CT experienced febrile neutropenia that led to treatment interruption. Eiermann P Letrozole 2.5 mg daily Tamoxifen 20 mg daily The nature and frequency of commonly reported AEs was the same for the letrozole and tamoxifen groups (57% in each group). The most commonly reported AEs related to study treatment were hot flushes and nausea. Smith IMPACT 2005 Anastrozole 1 mg daily; Anastrozole 1 mg daily + Tamoxifen 20 mg daily Tamoxifen 20 mg daily All treatments were generally well tolerated. The most common adverse event in all groups was hot flashes, with a nonsignificant trend towards a lower incidence with anastrozole (18%) than with tamoxifen (26%) or the combination (28%). The only significant difference was in vaginal discharge, which was not reported in any patient on anastrozole (0%) compared with 6% of patients on tamoxifen and 8% of patients on the combination.

9 Masuda STAGE 2012 Anastrozole 1 mg daily + goserelin 3.6 mg/month Tamoxifen 20 mg daily + goserelin 3.6 mg/month Treatment-related AEs were reported by 84% patients in the anastrozole group and 77% patients in the tamoxifen group, with the majority being grade 1 or 2. 50% of patients in the anastrozole group reported musculoskeletal and connect tissue disorder AEs compared to 30% in the tamoxifen group. Cataliotti 2006 Anastrozole 1 mg daily Tamoxifen 20 mg daily Both anastrozole and tamoxifen were well tolerated. AEs considered to be study related were reported in 20.2% of patients in the anastrozole group and 18.1% of patients in the tamoxifen group. Ellis 2001 Letrozole 2.5 mg daily Tamoxifen 20 mg daily Not reported Miller 2001 Anastrozole 1 mg daily (n = 12) or 10 mg daily (n = 11) Tamoxifen 40 mg daily Not reported Harper-Wynne 2002 Vorozole 2.5 mg daily Tamoxifen 20 mg daily Not reported Guarneri 2014 Letrozole 2.5 mg daily and lapatinib 1500 mg daily Letrozole 2.5 mg daily and placebo Skin disorders, diarrhea, and liver function test abnormalities occurred more frequently in lapatinib-treated patients. One episode of grade 4 skin toxicity was reported in one patient randomly assigned to the letrozole-lapatinib arm.

10 Baselga 2009 Letrozole 2.5 mg daily and everolimus 10 mg daily Chow CAAN 2008 Examestane 25 mg daily and celecoxib 400 mg twice daily Smith 2007 Anastrozole 1 mg daily and gefitinib 250 mg daily (combined 2 arms, gefitinib 14 vs. 16 weeks) Hojo PTEX46 Kuter NEWEST 2013 Exemestane 25 mg daily 2012 Fulvestrant 500 mg/month mg on day 14 of month 1 Letrozole 2.5 mg daily and placebo Exemestane 25 mg daily; letrozole 2.5 mg daily Anastrozole 1 mg daily Exemestane 25 mg daily Fulvestrant 250 mg/month The safety profile was described as consistent with historical results of everolimus monotherapy: grades 3 to 4 AEs occurred in 22.6% of patients who received everolimus and in 3.8% of patients who received placebo. Dose reduction or interruption as a result of an AE occurred in 52.9% of the everolimus-treated patients versus 7.6% of the placebo-treated patients. One patient (4%) from the exemestane monotherapy group experienced grade 3 hot flashes. No other serious and/or severe adverse event was reported in the study. 13% of patients assigned to gefitinib and anastrozole discontinued treatment because of AEs, compared with 2% receiving anastrozole alone. Not reported Both treatments were well tolerated. Treatment-related AEs were experienced by 37.4 and 30.7% of patients and treatment-related serious AEs by 0.9 and 3.0% of patients in the fulvestrant 500 mg and fulvestrant 250 mg groups, respectively.

11 Ellis ACOSOG Z Exemestane 25 mg daily Letrozole 2.5 mg daily; anastrozole 1 mg daily No severe toxicity was reported by more than 5% of the patients. The most common grade 2 toxicity was hot flashes/flushes. Polychronis 2005 Gefitinib 250 mg daily and anastrozole 1 mg daily Gefitinib 250 mg daily and placebo Gefitinib was well tolerated as a single agent and in combination with anastrozole. Mild WHO grade 1 2 adverse events seen in both groups were felt to be consistent with the known safety profiles of gefitinib and anastrozole. Treatment was interrupted for 3 11 days in three patients in the gefitinib-alone group because of transient grade 1 diarrhea in two patients and grade 1 skin toxicity and abdominal symptoms in one patient. The addition of anastrozole did not exacerbate the adverse effects of gefitinib. Fasching FemZone 2014 Letrozole 2.5 mg daily and zoledronic acid 4mg IV q4w Letrozole 2.5 mg daily 81% of patients reported grade 1 or 2 AEs in the letrozole only arm and 87.6% in the letrozole + zoledronic acid arm. For grade 3 or 4 AEs, 8.9% were reported in the letrozole only arm and 19.1% in the letrozole + zoledronic acid arm. Most frequent side effects were musculoskeletal disorders, hot flushes, skin and gastrointestinal disorders.

12 Mohammadianpanah 2011 Letrozole 2.5 mg daily + FAC (5FU 600 mg/m2 + doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2) q21d FAC (5FU 600 mg/m2 + doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2) q21d Common treatment-related side effects such as nausea, vomiting, bone marrow suppression, and mucositis were similar in both groups, but hot flush was more prevalent in the CT/HT arm compared with the CT arm (P = 0.023). Q21d: every 21 days; q4w: every 4 weeks; CT: chemotherapy; HT: hormone therapy; NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; AEs: adverse events; WHO: World Health Organization.

13 efigure 1. Flowchart for Manuscript Selection Publications assessed for eligibility (N = 477) Excluded (N = 450) based on abstract review Duplications (N = 200) Did not meet criteria (N = 250) Full texts reviewed (N = 27) RCTs excluded (N =7) Duplicate (N = 1) Lack of data (N = 1) Incorrect outcome (N = 5) RCTs included (N = 20) CT x HT with AI (N = 3) HT plus CT x CT (N = 1) HT with tamoxifen x HT with AI (N = 6) HT with tamoxifen x HT with AI x HT with tamoxifen/ai (N = 1) HT with AI of differing durations (N = 1) HT with SERD of differing doses (N = 1) HT with 3 different AIs (N = 1) HT and other agents (N = 6) Abbreviations: RCTs, Randomized controlled trials; CT, Chemotherapy; HT, Hormone therapy; AI, Aromatase inhibitor; TAM, Tamoxifen; SERD, Selective estrogen receptor degrader.

14 efigure 2. Neoadjuvant Hormone Therapy vs Neoadjuvant Cytotoxic Chemotherapy efigure 2A. Comparison of clinical response (fixed effects model). efigure 2B. Comparison of clinical response (Peto odds ratio method). efigure 2C. Comparison of clinical response (random effects model).

15 efigure 2D. Comparison of imaging response (fixed effects model). efigure 2E. Comparison of imaging response (Peto odds ratio method). efigure 2F. Comparison of imaging response (random effects model). efigure 2G. Comparison of pathologic complete response (fixed effects model).

16 efigure 2H. Comparison of pathologic complete response (Peto odds ratio method). efigure 2I. Comparison of pathologic complete response (random effects model). efigure 2J. Comparison of rates of breast conservation surgery (fixed effects model). efigure 2K. Comparison of rates of breast conservation surgery (Peto odds ratio method).

17 efigure 2L. Comparison of rates of breast conservation surgery (random effects model). Abbreviations: M-H, Mantel-Haenzel method; CI, Confidence interval; df, Degrees of freedom

18 efigure 3. Neoadjuvant Aromatase Inhibitors vs Neoadjuvant Tamoxifen efigure 3A. Comparison of clinical response (fixed effects model). efigure 3B. Comparison of imaging response (fixed effects model).

19 efigure 3C. Comparison of pathologic complete response (fixed effects model). efigure 3D. Comparison of rates of breast conservation surgery (fixed effects model). Abbreviations: M-H, Mantel-Haenzel method; CI, Confidence interval; df, Degrees of freedom; AI, aromatase inhibitor.

20 efigure 4. Neoadjuvant Endocrine Therapy vs Dual Therapy efigure 4A. Comparison of clinical response (fixed effects model). efigure 4B. Comparison of clinical response (Peto odds ratio method). efigure 4C. Comparison of clinical response (random effects model).

21 efigure 4D. Comparison of imaging response (fixed effects model). efigure 4E. Comparison of imaging response (Peto odds ratio method). efigure 4F. Comparison of imaging response (random effects model).

22 efigure 4G. Comparison of clinical response for neoadjuvant endocrine therapy versus dual therapy with a growth factor pathway inhibitor (fixed effects model). efigure 4H. Comparison of clinical response for neoadjuvant endocrine therapy versus dual therapy with a growth factor pathway inhibitor (Peto odds ratio method). efigure 4I. Comparison of clinical response for neoadjuvant endocrine therapy versus dual therapy with a growth factor pathway inhibitor (random effects method).

23 efigure 4J. Comparison of imaging response for neoadjuvant endocrine therapy versus dual therapy with a growth factor pathway inhibitor (fixed effects model). efigure 4K. Comparison of imaging response for neoadjuvant endocrine therapy versus dual therapy with a growth factor pathway inhibitor (Peto odds ratio method). efigure 4L. Comparison of imaging response for neoadjuvant endocrine therapy versus dual therapy with a growth factor pathway inhibitor (random effects model). Abbreviations: M-H, Mantel-Haenzel method; CI, Confidence interval; df, Degrees of freedom; GFI = Growth Factor pathway Inhibitor.

24 efigure 5. Funnel Plots for Studies Evaluating Neoadjuvant Therapy Funnel Plot for Studies Evaluating Neoadjuvant Hormone Therapy vs Neoadjuvant Cytotoxic Chemotherapy efigure 5A. Studies evaluating clinical response efigure 5B. Studies evaluating imaging response

25 Funnel Plot for Studies Evaluating Neoadjuvant Aromatase Inhibitors vs Dual Therapy efigure 5C. Studies evaluating clinical response efigure 5D. Studies evaluating imaging response

Lessons Learnt from Neoadjuvant Hormone Therapy. Mike Dixon Clinical Director Breakthrough Research Unit Edinburgh

Lessons Learnt from Neoadjuvant Hormone Therapy Mike Dixon Clinical Director Breakthrough Research Unit Edinburgh 10 Lessons Learnt from Neoadjuvant Endocrine Therapy 10 Lessons Learnt from Neoadjuvant