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 Version : Jackisch / Harbeck / Huober / Lisboa / Maass / von Minckwitz / Schaller / Scharl / Schneeweiss / Solomeyer / Untch Version 2010: Gerber / Göhring

3 Adjuvant Endocrine Therapy in Premenopausal Patients Assessment of menopausal status: AGO Menstruation history + FSH, E2 ++

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 Adjuvant Endocrine Therapy in Premenopausal Patients GnRHanalogues (GnRHa) = Ovarectomy = Radiotherapy Oxford LoE: 4

7 (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 (if relevant 1a B +/ contraindications against TAM Oxford / AGO LoE / GR * Study participation recommended

8 Aromatase Inhibitors in Premenopausal Patients with Endocrine Responsive Tumors Oxford / AGO LoE / GR GnRHa + Anastrozole 1b B * if relevant contraindications against TAM 1b B AI alone 1c A AI after GnRHa (induced amenorrhea) 5 D Upfront AI in patients with chemotherapyinduced amenorrhea (CIA, TIA) 4 C * Study participation recommended

9 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

10 Ovarian Protection and Fertility Preservation in Premenopausal Patients Receiving Adjuvant Chemotherapy (CT) CT + GnRHa (GnRHa application > 2 weeks prior to chemotherapy) Oxford / AGO LoE / GR HR+ 3b C HR 1b B BRCA 1 and / or 2 mutation 5 D Impairment of CT effect cannot be excluded! Fertility preservation counselling 5 D +

11 Ongoing RCTs SOFT (Suppression of Ovarian Function) trial + Chemo Randomisation premenopausal Tam 5 y OFS* + Tam 5y OFS* + Tam 5y OFS = Ovarian Function Supression = Triptorelin 5y or BSO or radiomenolysis TEXT (Tamoxifen Exemestan) trial OP premenopausal Randomisation (+ Chemo) Triptorelin x 5y + Tam 5y (+ Chemo) Triptorelin x 5y + Exemestan 5y

12 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 = 0.82 (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

13 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 = 0.94 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; 113:13744

14 Cochrane Metaanalyses of 14 randomized trials that involved over patients assessing the effect of GnRHa + Tamoxifen + Chemotherapy concluded (A) GnRHa monotherapy: results suggest that adjuvant GnRHa monotherapy is similar to older chemotherapy protocols (eg. CMF) in terms of recurrencefree and overall survival in ER+ patients. There are insufficient data to compare GnRHa monotherapy to tamoxifen alone, but available results suggest that these treatments are comparable in terms of recurrencefree survival. (B) GnRHa + antioestrogen therapy: there are insufficient data to compare the combination of an GnRHa plus tamoxifen to tamoxifen alone. Results suggest that the GnRHa plus tamoxifen combination may be superior to an GnRHa alone or to chemotherapy alone, but the chemotherapy protocols tested are outdated. The data comparing GnRHa plus aromatase inhibitors to GnRHa plus tamoxifen are currently inconclusive. (C) GnRHa + chemotherapy: there are insufficient data to compare the GnRHa + chemotherapy combination to an GnRHa alone, although results from a single study suggest comparable efficacy in ER+ patients. There is a trend towards improved recurrencefree and overall survival in patients who received an GnRHa plus chemotherapy combination in comparison to chemotherapy alone. (D) GnRHa + chemotherapy + tamoxifen: there is a trend towards improved recurrencefree and overall survival in patients who received an GnRHa plus tamoxifen plus chemotherapy in comparison to chemotherapy alone.

15 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 23, 58 % 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% 13, 55 % 86 % FEC, ACT 94% (<40y) 42% (>40y) Urruticoechea % FEC, FECT, AC, ECT 86% Pregnancies/ Births 3% / 2% 21% / 8% 20% / 16%

16 GnRHa: RCTs Badawy (2009) IsmailKhan (2008) ZOR0 (2009) Chemo+ GnRHa Chemo Chemo+ GnRHa Chemo Chemo+ GnRHa Chemo N Pts.charact. pt N+ Horm. rec. pos. Age (med., years) Med. F/U [mths] % % % 0% % 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