Inteligentaj decidoj... Intelligente Entscheide bei der adjuvanten Therapie des Mammakarzinoms. Intelligent Questions?

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1 Intelligente Entscheide bei der adjuvanten Therapie des Mammakarzinoms Stefan Aebi Universitätsspital Bern, Inselspital Klinik für Medizinische Onkologie und Brust /Tumorzentrum der Frauenklinik Inteligentaj decidoj... inter + legere between + read Intelligent Questions? Adjuvant chemotherapy for every patient with node positive breast cancer? Always use a taxane? and anthracycline? Aromatase inhibitor after chemotherapyinduced amenorrhea? Start adjuvant hormonal therapy with an aromatase inhibitor? Routine use of adjuvant bisphosphonates? Participation in a clinical trial? Decision aids Tumor biology Prediction of efficacy Patient Preferences Co Morbid Conditions (Pharmacogenetics) Recommendation Communication Pharmacology Toxicity Risk Tumor biology Adjuvant Chemotherapy for Every Patient with N+ Breast Cancer Mrs N.N., age 60 T1cN1a(2/19)Mx, ER+, G1, HER 2 Adjuvant! Online Reliable estimate of prognosis BCOU Observation Year Event free Survival Reliable overestimation of the efficacy of chemotherapy for the majority of patients (i.e. ER+ breast cancer) Extrapolation to conditions that have not been studied % Adjuvant! Estimate adapted form Olivotto IA et al. JCO

2 Studies Intergroup 0100 Intergroup 0100: Postmenopause N+, ER+, T vs. CAF T T vs. CAF T N1a, ER+ Oncotype Dx Recurrence Score < 18 Studies Intergroup 0100 BCIRG001 Intergroup 0100: Postmenopause N+, ER+, T vs. CAF T T vs. CAF T N1a, ER+ Oncotype Dx Recurrence Score < 18 Albain K et al. Proc ASCO 2002 SABCS 2004 SABCS 2007 #10 Albain K et al. Proc ASCO 2002 SABCS 2004 SABCS 2007 #10 BCIRG001: Pre and Postmenopause N+, FAC vs. DAC, ( Tam for ER+) No interaction with ER N1 vs. 2 HER 2 ER and PR positive HER 2 negative Low Ki67 (<13%) Luminal A Stefan Aebi, Universitätsspital Martin BernNEJM Hugh JCO Mrs N.N., age 60 T1cN1a(2/19)Mx, ER+, G1, HER 2 and in Premenopause? Studies IBCSG 11 and ABCSG 12 Tamoxifen + OFS ±Chemotherapy(pN1, ER+) ABCSG 12 N0 and N1a, 80% G1/G2, ER+ Thürlimann Breast Cancer Res Treat Gnant NEJM Summary Aromatase Inhibitors Following Chemotherapy induced Amenorrhea? Chemotherapy for each patient with N+ breast cancer? Small (if any) advantage if ER and PR positive HER 2 negative Low proliferation rate

3 Upfront Aromatase Inhibitors vs. Tamoxifen BIG 1 98 Letrozole vs. Letrozole Tamoxifen Median Follow up DFS Distant Metastasis Free Survival OS ATAC BIG 1 98 Censored BIG 1 98 ITT TEAM Months Hazard Ratio ATAC. Lancet Oncol ff Mouridsen SABCS 2008 Jones SABCS 2008 Mouridsen SABCS 2008 Chemotherapy Amenorrhea Probability of Permanent Amenorrhea CMF/CEF +Tamoxifen CMF/CEF Age at Diagnosis 14 years Tamoxifen Natural History Amenorrhea after Chemotherapy Proportion of Patients with Menses Age Chemotherapy Regimen No Chemotherapy (any age) No Chemotherapy Age < 35 Age 35 to < 40 AC ACT ACD Age 40+ CMF Months after Chemotherapy adapted from Goodwin P et al. JCO ff adapted from Petrek J et al. JCO Aromatase Inhibitors Stimulate Ovarian Estrogen Synthesis Target Concentration for Estradiol with Aromatase Inhibitors? Royal Marsden Hospital women, chemotherapy induced amenorrhea, estradiol < 60 pmol/l 16 frontline aromatase inhibitor 20 aromatase inhibitor following 2 to 3 years of tamoxifen 9 aromatase inhibitor after 5 years of tamoxifen 12 patients convert to premenopausal status (27%) 10 with mestruations 1 pregnancy 1 biochemically premenopausal, with continuing amenorrhea Smith JCO Suppression of Serum Estradiol (@ 6 months) Tamoxifen Letrozole + + Triptorelin Triptorelin Rossi JCO Menstruation Disappearance of symptoms of menopause Contact oncologist or gynecologist Serum estradiol > 10 pmol/l Switch to tamoxifen (or suppress ovarian function)

4 No Target Concentration of Estradiol with Tamoxifen! Summary 17β Estradiol (pg/ml) E2 with Tam Risk of Death x Age Tamoxifen ±GnRH Agonist Tam±GnRH (Chemo+Tam)±GnRH RFS OS Chemotherapy for each patient with N+ breast cancer? Aromatase inhibitors after chemotherapy induced amenorrhea Small (if any) advantage if ER and PR positive HER 2 negative Low proliferation rate Perhaps, but Alternative = tamoxifen, switch to aromatase inhibitor at a later time Beware: Stimulation of the ovaries. E2 < 10 pmol/l Day of Cycle Cohen Gynecol Oncol EBCTCG. Lancet Cuzick J. Lancet ff Adjuvant Therapy with Bisphosphonates? ABCSG 12 ZO FAST Z Gnant NEJM ; adapted from Eidtmann SABCS 2008 It s so new we don t know what it does, but nobody else has it so we re selling the hell out of it. ZO FAST ABCSG 12 Adjuvant Bisphosphonates What else do we need? 1060 patients Adjuvant letrozole [ Menopause, ER+] Randomization: immediate zoledronate vs. delayed (osteopenia, T< 2) Primary end point: DFS Median age: 58 Median FU : 36 months DFS events: patients Adjuvant GnRH Agonist [ 100% prämenopausal] Randomization: Tamoxifen vs. anastrozole Primäry end point: DFS Median age: 45 Median FU: 48 months DFS events: 137 Bundred Cancer ; Eidtmann SABCS 2008 Gnant NEJM Events, follow up DFS OS? DFS = surrogate end point ATAC Monochemotherapy after menopause Pre menopause ER negative breast cancer Treatment without GnRH analogs Adjuvant Chemotherapy Post menopause ER negative breast cancer

5 Bisphosphonate Trials German Finnish British ZO-FAST ABCSG12 LOE II >II II II (I-)II Patient and High Intermediate, High Intermediate Low treatment heterogeneity imbalances Bone mets n.s. n.s. n.s. n.s. (D)DFS (D) n.s.? OS n.s. Subgroup analyses Multivariate time-toevent models n.s. n.s. n.s. No Yes Yes No Yes No Yes, but clo*er interaction not analyzed No No No reporting by endocrine treatment group Summary Chemotherapy for each patient with N+ breast cancer? Aromatase Hemmer bei Chemotherapie induzierter Amenorrhoe Routine indication for zoledronic acid (or other bisphosphonates)? Small (if any) advantage if ER and PR positive HER 2 negative Low proliferation rate Perhaps, but Alternative = tamoxifen, switch to aromatase inhibitor at a later time Beware: Stimulation of the ovaries. E2 < 10 pmol/l Not yet, but promising Very promising If inclusion criteria are met, search for a reason to use zoledronic acid 25 Intelligent Decisions? ENDE Who Needs Anthracyclines? Who Needs 10 years = 4.1% NNT = 25 Oxford Overview 2000 NEAT + McNEAT, CMF vs a CMF MA.5 Pre menopause N+ CEF 1,8 vs. CMF EBCCTG Lancet Poole NEJM B n + b N B = n + N Levine JCO Average benefit = large benefit in a few patients + no benefit in the majority divided by the total number of patients

6 Anthracyclines? MA.5 Anthracyclines? MA.5 HER 2 Top2α [amplified or deleted] HER 2 Top2α [amplified or deleted] Patients whose tumors do not have TOP2A alterations or do not amplify HER2 appear to receive virtually no benefit from CEF as compared with CMF. Pritchard NEJM O'Malley JNCI Pritchard NEJM O'Malley JNCI Anthracyclines? Top2α