Adjuvant Endocrine Therapy in Premenopausal Patients

Transcription

1 Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer Adjuvant Endocrine Therapy in Premenopausal Patients

2 Adjuvant Endocrine Therapy in Premenopausal Patients Version 2002: Scharl Versions : Fersis / Gerber / Göhring / Harbeck / Huober / Jackisch / Lisboa / Maass / von Minckwitz / Schaller / Scharl / Schneeweiss / Solomeyer / Untch Version 2012: Maass / Loibl

3 Adjuvant Endocrine Therapy in Premenopausal Patients Assessment of menopausal status Oxford / AGO LoE / GR Menstruation history + FSH, E Assessment of ovarian reserve AntiMüllerian Factor 3b B +/ Antral follicle count 3b B +/

4 Standard Treatment for Premenopausal Patients with Endocrine Responsive Disease Standard therapy in endocrine responsive tumors: Oxford / AGO LoE / GR Endocrine therapy 1a A ++ Chemoendocrine therapy 1a A ++ (dependent on individual risk and level of ER/PgR expression)

5 Assessment of Steroid Hormone Receptor Status Oxford LoE: 1 GR: A AGO: ++ Endocrine responsiveness: Immunohistochemistry (ER and / or PgR) 0% pos. cells: endocrine nonresponsive 1 pos. cells: endocrine responsive Status unknown: endocrine responsive

6 (Chemo)Endocrine Therapy in Premenopausal Patients with Endocrine Responsive Tumors High or intermediate risk Chemo TAM 1a A ++ Chemo TAM + GnRHa 1a B +/ < 40 yrs. 2a C + Low or intermediate risk TAM alone 1a A ++ TAM + GnRHa 1a B + GnRHa alone (only if relevant 1a B + contraindications against TAM) Oxford / AGO LoE / GR

7 Aromatase Inhibitors in Premenopausal Patients with Endocrine Responsive Tumors Oxford / AGO LoE / GR GnRHa + AI 1b B If severe contraindications against TAM 5 D +/ 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 +

8 Duration of Treatment Oxford / AGO LoE / GR Tamoxifen 5 yrs. 1a A ++ Tamoxifen 5 10 yrs. 2b a C +/ GnRHanalogues 2 5 yrs. 1b A ++ Induction of amenorrhea 2b D +/ after CT by GnRHanalogues The prognosis of the disease after GnRHa (> 2 years) treatment is independent of ovarian function (restored / non restored) LoE 2b

9 Ovarian Protection and Fertility Preservation in Premenopausal Patients Receiving Adjuvant Chemotherapy (CT) CT + GnRHa 1b B (GnRHa application > 2 weeks prior to chemotherapy) Oxford / AGO LoE / GR HR 1b B HR+ 1b B Impairment of CT effect cannot be excluded! Fertility preservation counselling* 4 C + Fertility preservation with assisted reproduction therapy 4 C +

10 Contraceptive Options for Women after Diagnosis of Breast Cancer Oxford / AGO LoE / GR Barrier methods 5 D + Sterilization (tubal ligation / vasectomy) 5 D + Nonhormonal intrauterine devices (IUDs) 5 D + Levonorgestrelreleasing IUDs 5 D Removal in newly diagnosed patients 4 D +/ Timing methods 5 D Injectable progestinonly contraceptives 5 D Progestinonly oral contraceptives 5 D Combined oral contraceptives 5 D No trial included women after diagnosis of breast cancer, nonestrogen containing devices do not increase the risk to develop primary breast cancer

11 Ovarian Function Preservation comparison of randomized trials ZORO PROMISE Munster et al. US Patient number 60 (60 HR) 281 (50 HR) 49 (13 HR) of 124 Age median 38 years 39 years 39 years Treatment goserelin triptorelin triptorelin Start of treatment >2 weeks 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 rate of early menopause at month 12 after chemotherapy to detect at least 20% absolute reduction in early menopause menstruation rate within 2 years after cht to detect 20% difference in amenorrhea rate from 10% to 30% Multivariable analysis Resumption of menses at month 12 in HR cohort Median time to restoration of menstruation (months) age as only independent predictive factor 83% with LHRH vs. 80% w/o 6.1 with LHRHa vs. 6.8 w/o; p=0.30 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 n.d. 74% with LHRH vs. 68% w/o 5.8 with LHRH vs. 5.0 w/o; p=0.58 Cyclophosphamide dose 4600 vs. 4700mg 4080 vs mg n.r.

12 Premenopause: Adjuvant Effect of Tamoxifen Chemo + Tam vs. Chemo alone EBCTCG, Lancet 2005 May;365(9472):

13 Use of LuteinisingHormoneReleasing Hormone Agonists as Adjuvant Treatment in Premenopausal Patients with HormoneReceptorPositive Breast Cancer: A MetaAnalysis of Individual Patient Data from Randomised Adjuvant Trials Chemo ± LHRH n RRR* 95% CI Age 40 years (39.5 to 6.2), p = 0.01 Age > 40 years (20.1 to 12.7), p = 0.55 Chemo + TAM ± LHRH Age 40 years (67.5 to 46.0), p = 0.33 Age > 40 years (33.3 to 66.3), p = (Chemo ± TAM) ± LHRH (combination of previous comparisons: chemo ± LHRH and chemo + TAM ± LHRH!) Age 40 years (39.4 to 7.7), p = 0.01 Age > 40 years (18.1 to 12.9), p = 0.63 * relative risk reduction Cuzick J et al., Lancet 2007; 369:171123

14 Chemo + Castration + TAM vs. Castration + TAM 174 patients premenopausal median age 45 nodepositive, endocrineresponsive Randomisation 4xAC OFS + TAM OFS + TAM 10y fup DFS hazard ratio = 1.02 ( ); P = 0.94 OS hazard ratio = 0.97 ( ); P = Trial was closed prematurely due to low accrual rate. No evidence that AC chemotherapy provides additional disease control for premenopausal patients with lowerrisk nodepositive endocrineresponsive breast cancer who receive adequate adjuvant endocrine therapy. Thürliman B et al. 10year update of IBCSG 1193 Breast Cancer Res Treat. 2009; 113:137 44

15 GnRHa: RCTs Badawy (2009) IsmailKhan (2008) ZOR0 (2009) Chemo+ GnRHa Chemo Chemo+ GnRHa Chemo Chemo+ GnRHa N Pts.charact. pt N+ Horm. rec. pos. Age (med., years) Med. F/U [mths] % % % 0% Chemo % 0% GnRHa appl. during Chemo during Chemo during Chemo Chemotherapy 6x FA500C d1q68w 6x FAC, ACT, TAC 6x FEC, ACT, TAC Regular menstr. <1 year end of F/U 90% 33% 83% 88% 79% 84% 83% 93% 80% 97% Pregn. / Births 0 8% 3% / 3% 3% / 0

16 GnRHa: Observation Studies Recchia 2006 Fox 2003 Del Mastro 2006 N Pts.charact. pt N+ Horm. rec. pos. Age (med., years) Med. F/U [mths] GnRHa application % 52% during Chemo up to 1 year Chemotherapy FAC, CMF, E 120 CMF, Taxane, highdose Chemo Regular menstr. <1 year after Chemo 100% (<40 y.) 56% (>40 y.) % during Chemo AC, ACT, FAC, AT CMF 96% % 86% FEC, ACT 94% (<40y) 42% (>40y) Urruticoechea % FEC, FECT, AC, ECT 86% Pregnancies/ Births 3% / 2% 21% / 8% 20% / 16%