Adjuvant Endocrine Therapy in Pre- and Postmenopausal Patients

Transcription

1 Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version Adjuvant Endocrine Therapy in Pre- and Postmenopausal Patients

2 Adjuvant Endocrine Therapy AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version Versions : Bauerfeind / Dall / Diel / Fersis / Friedrichs / Gerber / Göring / Harbeck / Huober / Jackisch / Lisboa / Lück / Maass / von Minckwitz / Möbus / Müller / Oberhoff / Schaller / Scharl / Schneeweiss / Schütz / Solomeyer / Stickeler / Thomssen / Untch Version 2016: Jackisch / Schneeweiss

3 Assessment of Steroid Hormone Receptor Status AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version Oxford LoE: 1 GR: A AGO: ++ Endocrine responsiveness: Immunohistochemistry (ER and / or PgR) 0% pos. cells: endocrine non responsive 1-9% pos. cells: endocrine low responsive 10% pos. cells: endocrine responsive Status unknown: endocrine responsive

4 Adjuvant Endocrine Therapy Assessment of Menopausal Status AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version Oxford / AGO LoE / GR Assessment of menopausal status Menstruation history + FSH, E2 ++

5 Adjuvant Endocrine Therapy AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version Standard therapy in endocrine responsive tumors: Oxford / AGO LoE / GR Endocrine therapy 1a A ++ Chemotherapy followed by endocrine therapy 1a A ++ (dependent on individual risk and tumor biology)

6 Adjuvant Endocrine Therapy AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version Oxford / AGO LoE / GR Endocrine responsive & doubtful: Endocrine therapy 1a A ++ Endocrine therapy sequentially after CT 2b C ++ Non-responsive: No endocrine therapy 1a A ++

7 AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version General Principles in Adjuvant Endocrine Therapy AGO ++ Standard treatment duration 5 years Treatment up to 10 years may be considered based on the individual risk of relapse (e.g., N+ status at presentation) Duration, choice & sequence of AI or Tam mainly rely on menopausal status and side effects Switch to another endocrine treatment (Tam or AI) is better than to stop AI as first treatment preferably in postmenopausal patients at high risk and lobular cancers So far no evidence for AI > 5 yrs

8 Premenopausal Patients Adjuvant Endocrine Therapy AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version Oxford / AGO LoE / GR Tamoxifen* 5-10 yrs. 1a A ++ GnRHa alone 1a B + (only if relevant contraindications for Tam) In patients with ovarian function (within 8 mo.) after adjuvant chemotherapy (exploratory retrospective analysis suggests higher benefit in younger age)**: # OFS (ovarian function suppression) 5 yrs. + TAM 5 yrs. 1b B +/- # OFS 5 yrs. + AI 5 yrs. 1b B +/- * Treat as long as tolerable and premenopausal * Switch to AI optional when patient turned postmenopausal # Increased side effects may impair compliance. High compliance to TAM ist more effective, than addition of GNRH or treatment with GNRH+AI with impaired compliance. ** Duration of treatment may be prolonged to up to 10 yrs using TAM

9 Premenopausal Patients Adjuvant Endocrine Therapy AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version Oxford / AGO LoE / GR AI alone 1c A - - AI after GnRHa (induced amenorrhea) 5 D - - Upfront AI in patients with chemotherapyinduced amenorrhea (CIA, TIA) 4 C EAT in perimenopausal pts. with validated postmenopausal status after 5 yrs. of Tam 2b B + Reduction of POF* caused by adjuvant 1b B +/- chemotherapy *POF: Premature ovarian failure

10 Postmenopausal Patients Adjuvant Endocrine Therapy AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version Oxford / AGO LoE / GR AI for 5 yrs. 1a A + Preference in lobular inv. cancers 2b B ++ Sequential therapy for 5-10 yrs. ++ Tam followed by AI (2-5 yrs.)* 1a A AI (2-5 yrs.)* followed by Tam 1b C Preference in N+ Tamoxifen 20 mg/d for 5-10 yrs. 1a A ++ *Duration of AI 5 yrs.

11 Ovarian Protection and Fertility Preservation in Premenopausal Patients Receiving Adjuvant Chemotherapy (CT) AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version Ovarian function protection Oxford / AGO LoE / GR CT + GnRHa 1a B +/- (GnRHa application > 2 weeks prior to chemotherapy) Impairment of CT effect cannot be excluded! Fertility preservation counselling 4 C + Fertility preservation with assisted reproduction therapy (further information 4 C +

12 Testing Ovarian Reserve AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version Assessment of ovarian reserve in infertile patients (>6-12 mths without conception)* 5 C + Tests for fertility assessment Oxford / AGO LoE / GR Anti-Müllerian Factor 3b B + Antral follicle count 3b B + * Tests are suggested for women > 35 yrs and infertility for 6-12 months; the tests do not predict failure to conceive, but they allow to counsel that the window of opportunity to conceive may be shorter than anticipated and infertility treatment may be considered.

13 Contraceptive Options for Women after Diagnosis of Breast Cancer AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version Oxford / AGO LoE / GR Barrier methods 5 D + Sterilization (tubal ligation / vasectomy) 5 D + Non-hormonal intrauterine devices (IUDs) 3b D + Levonorgestrel-releasing IUDs 2b C - Removal in newly diagnosed patients 4 D +/- Timing methods 5 D - Injectable progestin-only contraceptives 5 D - Progestin-only oral contraceptives 5 D - Combined oral contraceptives 5 D -

14 Emergency Contraception after Diagnosis of Breast Cancer AGO e.v. AGO e. V. in der DGGG e.v. sowie in der DGGG e.v. in sowie der DKG e.v. in der DKG e.v. Guidelines Breast Version Guidelines Breast Version Oxford / AGO LoE / GR Copper intrauterine devices (Cu-IUD) 5 D + Levonorgestrel, Ulipristal 5 D +

15 Ovarian Function Preservation Comparison of Randomized Trials AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version ZORO PROMISE Munster et al. - US POEMS Patient number 60 (60 HR-) 281 (50 HR-) 49 (13 HR-) of (218 HR-) Age median 38 years 39 years 39 years Premenop. < 50 years Treatment goserelin triptorelin triptorelin goserelin Start of treatment >2 weeks prior to cht >1 week prior to cht > 1 week prior to cht > 1 week prior to cht Primary Endpoint menstruation at month 6 after chemotherapy Primary objective to detect 30% absolute increase of menstruation rate Multivar. analysis age as only independent predictive factor Resumption of menses at month 12 in HR- cohort Median time to restoration of menses (months) 83% with LHRH vs. 80% w/o 6.1 with LHRHa vs. 6.8 w/o; p=0.30 rate of early menopause at month 12 after chemotherapy to detect at least 20% absolute reduction in early menopause treatment as only independent predictive factor 93% with LHRHa vs. 74% w/o not reached with LHRH vs. 6.7 w/o; p=0.07 menstruation rate within 2 years after cht to detect 20% difference in amenorrhea rate - from 10% to 30% n.d. 74% with LHRH vs. 68% w/o 5.8 with LHRH vs. 5.0 w/o; p=0.58 Ovarian failure at 2 yrs after cht Treatment as only Independent predicitve factor 78% with LHRH vs. 75% w/o; at 2 years; 22% with LHRH vs. 8% n.d. Cyclophosph. dose 4600 vs. 4700mg 4080 vs mg n.r. n.a.

16 Metaanalysis of GnRHa for Prevention of Premature Ovarian Failure AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Autor Jahr Odds Ratio Ereignisse Ereignisse (95%CI) GnRHa Kontrolle Guidelines Breast Version Vorteil GnRHa / Vorteil Kontrolle nach Del Mastro et al. Cancer Treat Rev 2014

17 TEXT /SOFT Joint Analysis AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version TEXT Premenopausal Patients with HR+ BC 12 wks after surgery (N = 2672) Tamoxifen 20 mg/day + OFS* (n = 1328) Exemestane 25 mg/day + OFS* (n = 1332) 5 yrs Joint Analysis Tamoxifen + OFS* (n = 2344) SOFT Premenopausal patients with HR+ BC 12 wks after surgery (if no chemo) or 8 mos after chemo (N = 3066) Tamoxifen 20 mg/day + OFS* (n = 1016) Exemestane 25 mg/day + OFS* (n = 1014) Tamoxifen 20 mg/day Median follow-up: 5.7 yrs Exemestane + OFS* (n = 2346) *OFS TEXT: triptorelin 3.75 mg IM every 28 days for 6 mos, then optional bilateral oophorectomy or irradiation SOFT: choice of method Nach Pagani O, et al. N Eng J Med, 371(2) 2014

18 Aromatase Inhibitors in Adjuvant Therapy AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version Overview over Published Trials: Upfront and Extended Therapy Trial Source AI Indication Pts ATAC BIG 1-98 NCIC CTG MA.27 ATAC Trialists Group 2010 BIG 1-98 Collaborative Group 2011 A L F/U mo upfront vs T upfront 2 vs T 4922 Goss 2010 E upfront vs A Extended Adjuvant Therapy MA 17 Goss 2005 L ABSCG6a Jakesz 2007 A NSABP- B33 Mamounas 2008 E 97 extended after 5y T vs P DFS/BCFS/TTR/ TTDR/CBC HR + patients: DFS HR 0 86, p=0 003 TTR 0,79, p= TTDR 0 85, p=0 02 OS Side Effects Remarks HR 0.87 p=0 4 DFS = 0 86 P = 0,007 P = 0,048 EFS HR 1,02 DDFS HR 0,95 DFS HR 0.58, p<0.01 TTDR HR 0.60, p<0.01 CBC HR 0.63, p=0.13 extended after 5y T vs Nil DFS HR p=0.031 ns Extended after 5y T Vs P DFS HR 0,68 p=0,07 RFS HR 0,44 p= 0,004 ns HR 0,61 in N+, p=0,04 ns SAE T>A gyn AE T>A VE T>A SE A>T SAE T=L gyn AE T>L TE T>L CE L>T SE L>T Osteoporosis A>E El. liver enzymes E>A Hyperlypidaemia A>E CE L=P SE L>P SE E=P after 6 Mo only anastrozole vs tamoxifen, combination arm stopped after first analysis; ER+PR-=ER+PR+ (Cuzick 2010) QoL (Cella 2006) L>T in particular in case of N+ Randomization for Celecoxib cancelled QoL (Whelan 2005) Lipids (Wasan 2005) Grad 3 AE E>P 9%vs3%, p=0,03 Profit from E particular in N+ A anstrozole; gyn AE, gynecological adverse event; BCFS, breast cancer-free survival; CBC, contralateral breast cancer; CE, cardiac events; CVE, cardiovascular events; Cx, chemotherapy; DFS, disease-free survival; RFS relapse-free survival; E, exemestane; ER, estrogen receptor; HR, hazard ratio; L, letrozole; OS, overall survival; P, placebo; PR, progesterone receptor; Qol, quality of life; Rx, radiotherapy; SAE, serious advesrse event; SE, skeletal event; T, tamoxifen; TE, thromboembolism; TTR, time-to-recurrence; TTDR, time-to-distant-recurrence; VE, vascular event; (?) according to retrospective analysis. * only HR positive population

19 Aromatase Inhibitors in Adjuvant Therapy Overview over Published Trials: Switching/Sequential trials AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version Trial Source AI Indication Pts IES Bliss JM E ITA Boccardo 2006 A ABCSG - 08 ARNO95 Jakesz 2005 ABCSG -08 Jakesz 2005 A ARNO 95 BIG 1-98 TEAM N-SAS BC03 A Kaufmann 2007 A Regan et al 2011 L Van de Velde 2011 E Aus Japan 2010 A F/U mo switch after 2-3y T vs T switch after 2-3y T vs T switch after 2y T vs T switch after 2y T vs T DFS/BCFS/TTR/ TTDR/CBC DFS HR 0.76, ITT p<0.01 DFS HR 0,75, ER+/u BCFS HR 0.76, ITT, s BCFS HR 0,75, ER+/u TTDR HR 0.83, ITT, s TTDR HR 0,82 ER+/u, s EFS HR 0.57, p<0.01 RFS HR 0.56, p=0.01 DFS HR 0.59, p<0.01 TTR HR 0.60, p<0.01 TTDR HR 0.61, p<0.01 DFS HR 0.61, p=0.01 TTDR HR 0.68, p=0.11 CBC HR 0.45, p=0.07 switch after 2y T vs T DFS HR 0.66, p=0.049 switch after 2y T vs. Let swtch after 2y L vs. Let. TEAM: E alone vs Tam switch after 2 3 y to E Tam 5 y vs Tam A switch after 1 4 y Tam disease-free survival; 87 5%, 87 7%, 85 9% ns hazard ratio 0 97, 95% CI ; p=0 60) DFS: 0.69 P = 0.14 RFS 0.54 P = 0.06 OS HR, 0.86; 95% CI, 0.75 to 0.99; P =.04). ns ns ns HR 0,53, p= %, 88 7%, 88 1% ns n.a. n.a. Side Effects gyn AE T>A TE T>E SE E>T diarrhea E>T SAE T>A TE T>A SE A>T TE T>A SE A>T SAE T>A 30,8 vs 22,7 % SE L>T VE L = T DVT; endometrial > switch Musculoskeleta l problems hyperlipidaemi a > E mono dito Remarks Random after 2-3y T, only pts. relapse-free after 2-3 y T were included Random after 2-3y T, only pts. relapse-free after 2-3 y T were included Analysis of switch data only, random upfront No chemotherapy, random after 2 y T; only pts relapse-free after 2 y T were included Comparison of switch L/T or T/L vs. L Metaanalysis ARNO95 ABSCG8 ITA Jonat 2006 A switch (2-3y T) 4006 DFS HR 0.59, p<0.01 HR 0.71, p=0.04 with heterogeneity A, anastrozole; gyn AE, gynecological adverse event; BCFS, breast cancer-free survival; CBC, contralateral breast cancer; CE, cardiac events; Cx, chemotherapy; DFS, disease-free survival; E, exemestane; ER, estrogen receptor; HR, hazard ratio; ITT, intent to treat; L, letrozole; OS, overall survival; P, placebo; PR, progesterone receptor; Qol, quality of life; Rx, radiotherapy; s, significant; SAE serious advesrse event; SE, skeletal event; T tamoxifen; TE, thromboembolism; TTR, time-to-recurrence; TTDR, time-to-distant-recurrence; u, unknown; VE, vascular event; (?) according to retrospective analysis.

20 Assessment of Ovarian Reserve AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version Tests recommended to assess ovarian reserved (according to ACOG Committee Opinion No. 618: Ovarian Reserve Testing. Obstetrics & Gynecology 2015 ;125 : Test FSH (follicle stimulating hormone) plus estradiol Anti Müllerian Hormone (AMH) Antral follicle count (AFC) Details Serum level on cycle day 2 3 Variation between cycles possible High FSH value is associated with poor response to ovarian stimulation No specific timing for the test Stable value within and between menstrual cycles Low AMH value is associated with poor response to ovarian stimulation Number of visible follicles (2 10 mm) during transvaginal ultrasound Performed on cycle days 2 5 Number of antral follicles correlates with ovarian response to stimulation All the tests do not predict failure to conceive, but they allow to counsel that the window of opportunity to conceive may be shorter than anticipated.

21 10 yrs versus 5 yrs Breast Cancer Mortality in ER+ Rate ratio per period in attom and ATLAS 5 yrs. vs. 10 yrs Tamoxifen AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version yrs. vs. 5 yrs. Tam attom Trial (n=6934 ER+) 10 yrs. vs. 5 yrs. Tam Atlas Trial (n=10543 ER+) 10 yrs. vs. 5 yrs. Tam attom + Atlas combined (n=17477 ER+) Years ( ) 0.92 ( ) 0.97 ( ) Years ( ) p = ( ) p = ( ) p = All years 0.88 ( ) p = ( ) p = ( ) P= nach Grey et al ASCO 2013 J Clin Oncol 31, 2013 (suppl. Abstr 5)

22 Adjuvant Endocrine Therapy in Pre- and Postmenopausal Patients (2/21) No further information No references

23 Assessment of Steroid Hormone Receptor Status (3/21) No further information References: Statement 1 1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG).: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365 (9472): , Colleoni M et al.: Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial J Clin Oncol 24 (9): , Harvey JM, Clark GM, Osborne CK, et al.: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17 (5): , 1999.

24 Adjuvant Endocrine Therapy Assessment of Menopausal Status (4/21) No further information References: 1. Ortmann O, et al: Adjuvant endocrine therapy for perimenopausal women with early breast cancer. Breast Feb;18(1): Clemons M, et al: Identifying menopause in breast cancer patients: considerations and implications. Breast Cancer Res Treat Aug;104(2): Su HI, Sammel MD, Green J, Velders L, Stankiewicz C, Matro J, Freeman EW, Gracia CR, DeMichele A. Antimullerian hormone and inhibin B are hormone measures of ovarian function in late reproductive-aged breast cancer survivors. Cancer Feb 1;116(3): Partridge AH, Ruddy KJ, Gelber S, Schapira L, Abusief M, Meyer M, Ginsburg E. Ovarian reserve in women who remain premenopausal after chemotherapy for early stage breast cancer. Fertil Steril Jul;94(2): Anders C, Marcom PK, Peterson B, Gu L, Unruhe S, Welch R, Lyons P, Behera M, Copland S, Kimmick G, Shaw H, Snyder S, Antenos M, Woodruff T, Blackwell K. A pilot study of predictive markers of chemotherapy-related amenorrhea among premenopausal women with early stage breast cancer. Cancer Invest Apr-May;26(3): Anderson RA, Cameron DA. Pretreatment serum anti-müllerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer. J Clin Endocrinol Metab May; 96(5): Su HI, Chung K, Sammel MD, Gracia CR, DeMichele A. Antral follicle count provides additive information to hormone measures for determining ovarian function in breast cancer survivors. Fertil Steril Apr;95(5):1857-9

25 Adjuvant Endocrine Therapy (5/21) No further information References: 1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet Aug 27;378(9793): doi: /S (11) Epub 2011 Jul Thürliman B et al: Is chemotherapy necessary for premenopausal women with lower-risk node-positive, endocrine responsive breast cancer? 10-year update of International Breast Cancer Study Group Trial Breast Cancer Res Treat. 2009; 113: Goldhirsch A, Winer EP, Coates AS 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: Hackshaw A1, Roughton M, Forsyth S, Monson K, Reczko K, Sainsbury R, Baum M. Long-term benefits of 5 years of tamoxifen: 10-year follow-up of a large randomized trial in women at least 50 years of age with early breast cancer.j Clin Oncol May 1;29(13): doi: /JCO Epub 2011 Mar Pagani O1,et al.adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med Jul 10;371(2): doi: /NEJMoa Epub 2014 Jun Albain KS, Green SJ, Ravdin PM, et al. Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from Intergroup trial 0100 (SWOG-8814). Proc Am Soc Clin Oncol 2002;21:37a (abst 143

26 Adjuvant Endocrine Therapy (6/21) No further information References: 1. Early Breast Cancer Trialists' Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of randomised trials. Lancet 2005;365: Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the effi cacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet Aug 27;378(9793): doi: /S (11) Epub 2011 Jul Fisher B, Anderson S, Tan-Chiu E, et al. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptornegative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol 2001;19: Jaenicke F, Prechtl A, Thomssen C, et al. Randomized adjuvant chemotherapy trial in high-risk, lymph nodenegative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1. J Natl Cancer Inst ;93: Hutchins L, Green S, Ravdin P, et al. CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node-negative patients: first results of Intergroup Trial INT 0102; Proc Am Soc Clin Oncol 1998;17:1a (abstr. 2). 6. Hackshaw A1, Roughton M, Forsyth S, Monson K, Reczko K, Sainsbury R, Baum M. Long-term benefits of 5 years of tamoxifen: 10-year follow-up of a large randomized trial in women at least 50 years of age with early breast cancer.j Clin Oncol May 1;29(13): doi: /JCO Epub 2011 Mar 21.

27 General Principles of Adjuvant Endocrine Therapy AGO ++ (7/21) Further information: Voting: 18/7 References: 1. Metzger O, Giobbie-Hurder A, Mallon E et al. Relative effectiveness of letrozole compared with tamoxifen for patients with lobular carcinoma in the BIG 1-98 trial. SABCS 2012, S Davies C, Hongchao P, Godwin J et al. Long-term eff ects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381: Hackshaw A1, Roughton M, Forsyth S, Monson K, Reczko K, Sainsbury R, Baum M. Long-term benefits of 5 years of tamoxifen: 10-year follow-up of a large randomized trial in women at least 50 years of age with early breast cancer.j Clin Oncol May 1;29(13): doi: /JCO Epub 2011 Mar Cuzick J1, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, Forbes JF; ATAC/LATTE investigators. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol Dec;11(12): doi: /S (10) Epub 2010 Nov Higgins MJ1, Liedke PE, Goss PE.Extended adjuvant endocrine therapy in hormone dependent breast cancer: the paradigm of the NCIC-CTG MA.17/BIG 1-97 trial. Crit Rev Oncol Hematol Apr;86(1): doi: /j.critrevonc Epub 2012 Oct Regan MM1, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, Forbes JF, Smith I, Láng I, Wardley A, Rabaglio M, Price KN, Gelber RD, Coates AS, Thürlimann B; BIG 1-98 Collaborative Group; International Breast Cancer Study Group (IBCSG). Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial

28 at 8 1 years median follow-up. Lancet Oncol Nov;12(12): doi: /S (11) Epub 2011 Oct Ingle JN. Overview of adjuvant trials of aromatase inhibitors in early breast cancer. Steroids Jul;76(8): doi: /j.steroids Epub 2011 Mar van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel JM, Paridaens R, Markopoulos C, Hozumi Y, Hille ET, Kieback DG, Asmar L, Smeets J, Nortier JW, Hadji P, Bartlett JM, Jones SE. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet Jan 22;377(9762): doi: /S (10) Baum M et al.. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet Jun 22;359: Erratum in: Lancet 2002;360: Coates AS 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, pub ahead January Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 2005;97: Jakesz R1, Greil R, Gnant M, Schmid M, Kwasny W, Kubista E, Mlineritsch B, Tausch C, Stierer M, Hofbauer F, Renner K, Dadak C, Rücklinger E, Samonigg H; Austrian Breast and Colorectal Cancer Study Group.Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. J Natl Cancer Inst Dec 19;99(24): Epub 2007 Dec Mamounas EP1, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, Eisen A, Fehrenbacher L, Farrar WB, Atkins JN, Pajon ER, Vogel VG, Kroener JF, Hutchins LF, Robidoux A, Hoehn JL, Ingle JN, Geyer CE Jr, Costantino JP, Wolmark N. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin Oncol Apr 20;26(12): doi: /JCO Epub 2008 Mar Whelan TJ, Goss PE, Ingle JN, et al. Assessment of quality of life in MA.17: A randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 2005;23:

29 15. Wasan KM, Goss PE, Pritchard PH, et al. The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L). Ann Oncol 2005;16:

30 Premenopausal Patients - Adjuvant endocrine therapy (8/21) Further information and references: Tamoxifen* 5-10 yrs. 1a A ++ Voting: 100% acceptance 1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365 (9472): , Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the effi cacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet Aug 27;378(9793): doi: /S (11) Epub 2011 Jul Davies C, Hongchao P, Godwin J et al. Long-term eff ects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381: Tormey DC, Gray R, Falkson HC: Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. Eastern Cooperative Oncology Group. J Natl Cancer Inst 88 (24): , GnRHa alone 1a B + Voting: 100% acceptance 1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365 (9472): , Walshe JM et al: Amenorrhea in premenopausal women after adjuvant chemotherapy for breast cancer. J Clin Oncol 24: , Swain SM, Jeong JH, Wolmark N. Amenorrhea from breast cancer therapy--not a matter of dose. N Engl J Med Dec 2;363(23):

31 4. Goel S et al: LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women. Cochrane Database Syst Rev Oct 7;(4):CD Cuzick J et al: Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet 2007; 369: in patients with ovarian function (within 8 mo.) after adjuvant chemotherapy (Exploratory retrospective analysis suggests higher benefit in younger age) OFS (ovarian function suppression) 5 yrs. + TAM 5 yrs. 1b B +/- Voting: 100% acceptance OFS 5 yrs. + AI 5 yrs. 1b B +/- Voting: 100% acceptance 1. Pagani O, Gelber S, Colleoni M et a. Impact of SERM adherence on treatment effect: International Breast Cancer Study Group Trials and Breast Cancer Res Treat Nov;142(2): doi: /s x. Epub 2013 Nov Ganz PA, Land SR, Geyer CE Jr, Cecchini RS, Costantino JP, Pajon ER, Fehrenbacher L, Atkins JN, Polikoff JA, Vogel VG, Erban JK, Livingston RB, Perez EA, Mamounas EP, Wolmark N, Swain SM. Menstrual history and quality-of-life outcomes in women with node-positive breast cancer treated with adjuvant therapy on the NSABP B- 30 trial. J Clin Oncol Mar 20;29(9): Goel S et al: LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women. Cochrane Database Syst Rev Oct 7;(4):CD Francis PA, Regan MM, Fleming GF, Láng I, Ciruelos E, Bellet M, Bonnefoi HR, Climent MA, Prada GA, Burstein HJ, Martino S, Davidson NE, Geyer CE Jr, Walley BA, Coleman R, Kerbrat P, Buchholz S, Ingle JN, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Colleoni M, Viale G, Coates AS, Goldhirsch A, Gelber RD; the SOFT Investigators and the International Breast Cancer Study Group. Adjuvant Ovarian Suppression in Premenopausal Breast Cancer. N Engl J Med Dec 11. [Epub ahead of print] 5. Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Perez EA, Ciruelos E, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Pinotti G, Puglisi F, Crivellari D, Ruhstaller T, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Bernhard J, Luo W, Ribi K, Viale G,

32 Coates AS, Gelber RD, Goldhirsch A, Francis PA; TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med Jul 10;371(2): doi: /NEJMoa Epub 2014 Jun Gnant M et al: Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med Feb 12;360(7): Munholz RR, et al: Gonadotropin-Releaseing hormone agonists for ovarian function preservation in premenopausal women undergoing chemotherapy for early stage breast cancer- A systematic Review and Meta Analysis. JAMA Oncol 2016;2:65-73

33 Premenopausal Patients Adjuvant Endocrine Therapy (9/21) Further information and refeernces: AI alone 1c A - - Voting: 100% acceptance 1. Smith IE et al: Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: caution and suggested guidelines. J Clin Oncol Jun 1;24(16): Ortmann O, et al: Adjuvant endocrine therapy for perimenopausal women with early breast cancer. Breast Feb;18(1): Dieudonné AS, Vandenberghe J, Geerts I, Billen J, Paridaens R, Wildiers H, Neven P. Undetectable antimüllerian hormone levels and recovery of chemotherapy-induced ovarian failure in women with breast cancer on an oral aromatase inhibitor. Menopause Jul;18(7): AI after GnRHa (induced amenorrhea) 5 D - - Voting: 100% acceptance 1. Smith IE et al: Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: caution and suggested guidelines. J Clin Oncol Jun 1;24(16): Dieudonné AS, Vandenberghe J, Geerts I, Billen J, Paridaens R, Wildiers H, Neven P. Undetectable antimüllerian hormone levels and recovery of chemotherapy-induced ovarian failure in women with breast cancer on an oral aromatase inhibitor. Menopause Jul;18(7): Goss PE et al: Outcomes of women who where premenopausal at diagnosis of early stage breast cancer. Cancer Res 69(Suppl.1);2009:487s(#13) Upfront AI in patients with chemotherapyinduced amenorrhea (CIA, TIA) 4 C - - Voting: 100% acceptance

34 1. Smith IE et al: Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: caution and suggested guidelines. J Clin Oncol Jun 1;24(16): EAT in perimenopausal pts. with validated postmenopausal status after 5 yrs. of Tam 2b B + Voting: 100% acceptance 1. Smith IE et al: Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: caution and suggested guidelines. J Clin Oncol Jun 1;24(16): Goss PE et al: Outcomes of women who where premenopausal at diagnosis of early stage breast cancer. Cancer Res 69(Suppl.1);2009:487s(#13)

35 Postmenopausal patients adjuvant endocrine therapy (10/21) Further information and references: AI for 5 yrs. 1a A + Voting: 100% acceptance Preference in lobular inv. Cancers 2b B + Voting: 100% acceptance 1. Baum M et al.. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet Jun 22;359: Erratum in: Lancet 2002;360: Cuzick J et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol Dec;11(12): Epub 2010 Nov BIG 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005;353: Coates AS 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, pub ahead January Cella D et al. Five years quality of life follow up of adjuvant endocrine therapy for postmenopausal women in the ATAC trial. Proc ASCO 2005, Abstract Duffy S. Gynecological adverse events including hysterectomy with anastrozole tamoxifen: Data from the ATAC ('Arimidex', Tamoxifen, Alone or in Combination) trial. J Clin Oncol 2005;23(Suppl.):58S, Abs 723. Sequential therapy for 5-10 yrs. ++ Tam followed by AI (2-5 yrs.)* 1a A AI (2-5 yrs.)* followed by Tam 1b C Voting: 100% acceptance

36 1. Goss PE et al. a randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer N Engl J Med 2003; 349: Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 2005;97: Jakesz R, Samonigg H, Greil R, et al. Extended adjuvant treatment with anastrozole: results from the Austrian Breast an Colorectal Cancer Study Group Trial 6a (ABSCG 6a). J Clin Oncol 2005;23(Suppl.):10S, Abs Mamounas E et al.benefit from exemestane as extended adjuvant therapy after 5 years of tamoxifen intent to treat analysis of the NSABP-B33. Breast Cancer Res and Treat 2006; 100 (suppl1):abstract Whelan TJ, Goss PE, Ingle JN, et al. Assessment of quality of life in MA.17: A randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 2005;23: Wasan KM, Goss PE, Pritchard PH, et al. The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L). Ann Oncol 2005;16: Tamoxifen 20 mg/d for 5-10 yrs. 1a A ++ Voting: 100% acceptance 1. Davies C, Hongchao P, Godwin J et al. Long-term eff ects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet, published online Early Breast Cancer Trialists' Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of randomised trials. Lancet 2005;365: Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment an the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report J Clin Oncol 2005;23: Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Davies C, Godwin J, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet, 378:771-84, 2011

37 5. Metzger O, Giobbie-Hurder A, Mallon E et al. Relative effectiveness of letrozole compared with tamoxifen for patients with lobular carcinoma in the BIG 1-98 trial. SABCS 2012, S Davies C, Hongchao P, Godwin J et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381:

38 Ovarian Protection and Fertility Preservation in Premenopausal Patients Receiving Adjuvant Chemotherapy (CT) (11/21) Further information and references: Ovarian Function Protection CT + GnRHa (Wechselwirkung mit CT unklar) 1b B +/- (GnRHa application > 2 weeks prior to chemotherapy) Voting: 100% acceptance 1. Gerber B: Controversies in preservation of ovary function and fertility in patients with breast cancer. Breast Cancer Res Treat Mar;108(1): Tham YL: The rates of chemotherapy-induced amenorrhea in patients treated with adjuvant doxorubicin and cyclophosphamide followed by a taxane. Am J Clin Oncol. 2007; 30: Recchia F, Saggio G, Amiconi G et al. (2006) Gonadotropin-releasing hormone analogues added to adjuvant chemotherapy protect ovarian function and improve clinical outcomes in young women with early breast carcinoma. Cancer 106: Fox K, Scialla J, Moore H: Preventing chemotherapy-related amenorrhea using leuprolide during adjuvant chemotherapy for early-stage breast cancer. Proc Am Soc Clin Oncol 22, Del Mastro L, Catzeddu T, Boni L et al. (2006) Prevention of chemotherapy-induced menopause by temporary ovarian suppression with goserelin in young, early breast cancer patients. Ann Oncol 17: Gerber B, von Minckwitz G, Stehle H, Reimer T, Felberbaum R, Maass N, Fischer D, Sommer HL, Conrad B, Ortmann O, Fehm T, Rezai M, Mehta K, Loibl S; German Breast Group Investigators.Effect of luteinizing hormonereleasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: the GBG 37 ZORO study. J Clin Oncol Jun 10;29(17): Epub 2011 May 2 7. Del Mastro L, Ceppi M, Poggio F, Bighin C, Peccatori F, Demeestere I, Levaggi A, Giraudi S, Lambertini M, D'Alonzo A, Canavese G, Pronzato P, Bruzzi P. Gonadotropin-releasing hormone analogues for the prevention of

39 chemotherapy-induced premature ovarian failure in cancer women: systematic review and meta-analysis of randomized trials. Cancer Treat Rev Jun;40(5): doi: /j.ctrv Epub 2013 Dec 8. Fertility preservation counselling* 4 C + Voting: 100% acceptance Fertility preservation with assisted reproduction therapy 4 C + Voting: 100% acceptance 1. Lawrenz B, Jauckus J, Kupka MS et al. Fertility preservation in >1,000 patients: patient's characteristics, spectrum, efficacy and risks of applied preservation techniques. Arch Gynecol Obstet Dec 1. [Epub ahead of print]. 2. Shalom-Paz E, Almog B, Shehata F et al. Fertility preservation for breast-cancer patients using IVM followed by oocyte or embryo vitrification. Reprod Biomed Online Oct;21(4): Epub 2010 May Besse D, Bellavia M, de Ziegler D, Wunder D.Fertility and cancer: psychological support in young women who contemplate emergency assisted reproductive technologies (ART) prior to chemo- and/or radiation-therapy. Swiss Med Wkly Jul 16;140:w doi: /smw Del Mastro L, Boni L, Michelotti A et al. Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial. JAMA Jul 20;306(3): Munster PN, Moore AP, Ismail-Khan R, Cox CE, Lacevic M, Gross-King M, Xu P, Carter WB, Minton SE. Randomized Trial Using Gonadotropin-Releasing Hormone Agonist Triptorelin for the Preservation of Ovarian Function During (Neo)Adjuvant Chemotherapy for Breast Cancer. J Clin Oncol Jan 9. [Epub ahead of print] 6. Loibl S, Gerber B. Gonadotropin-releasing hormone analogue for premenopausal women with breast cancer. JAMA Oct 26;306(16):1760; author reply Munholz RR, et al: Gonadotropin-Releaseing hormone agonists for ovarian function preservation in premenopausal women undergoing chemotherapy for early stage breast cancer- A systematic Review and Meta Analysis. JAMA Oncol 2016;2:65-73

40 Testing ovarian reserve (12/21) No further information References: 1. Su HI, Sammel MD, Green J, Velders L, Stankiewicz C, Matro J, Freeman EW, Gracia CR, DeMichele A. Antimullerian hormone and inhibin B are hormone measures of ovarian function in late reproductive-aged breast cancer survivors. Cancer Feb 1;116(3): Partridge AH, Ruddy KJ, Gelber S, Schapira L, Abusief M, Meyer M, Ginsburg E. Ovarian reserve in women who remain premenopausal after chemotherapy for early stage breast cancer. Fertil Steril Jul;94(2): Anders C, Marcom PK, Peterson B, Gu L, Unruhe S, Welch R, Lyons P, Behera M, Copland S, Kimmick G, Shaw H, Snyder S, Antenos M, Woodruff T, Blackwell K. A pilot study of predictive markers of chemotherapy-related amenorrhea among premenopausal women with early stage breast cancer. Cancer Invest Apr-May;26(3): Anderson RA, Cameron DA. Pretreatment serum anti-müllerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer. J Clin Endocrinol Metab May; 96(5): ACOG Committee Opinion No. 618: Ovarian Reserve Testing. Obstetrics & Gynecology 2015 ;125 : Su HI, Chung K, Sammel MD, Gracia CR, DeMichele A. Antral follicle count provides additive information to hormone measures for determining ovarian function in breast cancer survivors. Fertil Steril Apr;95(5):

41 Contraceptive Options for Women after Diagnosis of Breast Cancer (13/21) No further information References: 1. Backman T, Use of the levonorgestrel-releasing intrauterine system and breast cancer. Obstet Gynecol Oct;106(4): Strom BL, Absence of an effect of injectable and implantable progestin-only contraceptives on subsequent risk of breast cancer. Contraception May;69(5): Moormann PG, Havrilesky LJ, Giersch JM et al. Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and meta-analysis. J Clin Oncol Nov 20;31(33): doi: /JCO Epub 2013 Oct 21.

42 Emergency Contraception after Diagnosis of Breast Cancer(14/21) No further information No references

43 Ovarian Function Preservation - Comparison of Randomized Trials (15/21) No further information No references

44 Metaanalysis of GnRH for Prevention of Premature Ovarian Failure (16/21) No further information No references

45 TEXT/SOFT Joint Analysis (17/21) No further information No references

46 Aromataseinhibitors in Adjuvant Therapy (18/21) No further information No references

47 Aromataseinhibitors in Adjuvant Therapy Overview over Published Trials (19/21) No further information No references

48 Assessment of Ovarian Reserve (20/21) No further information No references

49 10 Yrs versus 5 yrs Breast Cancer Mortality in ER+ (21/21) No further information No references