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These slides were released by the speaker for internal use by Novartis
Optimal treatment strategies based on current data Hope S Rugo (UCSF Comprehensive Cancer Center, San Francisco, CA, USA)
AIs as the adjuvant therapy of choice in postmenopausal HR+ early BC Recent guidelines based on current data recommend that adjuvant endocrine therapy for postmenopausal women with HR+ disease should include an AI ASCO Guidelines 2005 –‘Optimal adjuvant hormonal therapy for a postmenopausal woman with HR+ BC should include an AI either as initial therapy or after treatment with tamoxifen’ Winer et al. J Clin Oncol 2005;23:619–29; Goldhirsch et al. Ann Oncol 2005;19:3817–27; Rieber & Theriault J Natl Compr Canc Netw 2005;3:309–14
The ASCO guidelines – what's new? In postmenopausal women with HR+ disease treatment options include –5 years of AI treatment –sequential therapy consisting of tamoxifen (for 2–3 or 5 years) followed by an AI for 2–3 years Patients intolerant of AIs should receive tamoxifen AIs are contraindicated in premenopausal and perimenopausal women Winer et al. J Clin Oncol 2005;23:1–11
The St Gallen guidelines – what's new? Basis for risk selection in adjuvant systemic Tx: hormone responsiveness clinicopathological/molecular information –First consideration for adjuvant Tx selection = hormone responsiveness, not risk New classes of drugs in the adjuvant setting –AIs, taxanes ATAC & BIG 1-98 support AIs as upfront therapy in postmenopausal patients with HR+ BC Goldhirsch et al. Ann Oncol 2005;16:1569–83 Senn & Thürlimann The Breast 2005;14:427–8
St Gallen treatment guidelines for adjuvant therapy of early breast cancer The 2005 St Gallen guidelines redefine risk categories ER status no longer sole determinant of risk and treatment response Piccart M. Plenary lecture SABCS 2005 St Gallen 2005: endocrine responsiveness from a biological continuum to ‘practical’ subgroups Endocrine responsiveness AbsentUncertainCertain ER and PgR absentER and PgR low and/or any of the following PgR absent UPA/PAI-1 high HER-2 over- expressed ↑ proliferation markers Both receptors moderate to high No
Advantages of tamoxifen Proven efficacy Mature and plentiful safety data Confers some protection against bone loss and cardiovascular disease
Advantages of tamoxifen Proven efficacy Mature and plentiful safety data Confers some protection against bone loss and cardiovascular disease BUT no longer the most effective treatment Upfront AI improves DFS compared with tamoxifen Sequential tamoxifen followed by an AI improves DFS compared with tamoxifen alone Survival data with adjuvant AIs at least equivalent to tamoxifen
ATAC and Milan Institute database New insights into natural history of EBC Biphasic recurrence curve with early peak at 1–2 years in ATAC trial –Similar for relapses after surgery and no adjuvant therapy (Milan database) –Hypothetical interpretation Hypothesis: surgery may stimulate development of metastatic disease –An AI before or immediately after surgery might better counter that effect Update of Baum J Clin Oncol 2005;23(16S):31s(abstract 612) Recurrences Follow-up (years) A B C A: Induced angiogenesis (10 months) B: Induced cell division at surgery (18–40 months) C: Steady stochastic transitions (natural history, 60–200 months) 20
Change in hazard ratio with time AI upfront or after initial tamoxifen?
Smoothed hazard ratio for recurrence Start early or switch? Follow-up time (years) Anastrozole Tamoxifen 0 AI: Prevention of early distant relapses should translate into mortality reduction Acquired tamoxifen resistance developing at ~2–3 years? Annual HR for HR+ Howell et al. Lancet 2005;365:1225–6 Buzdar & Cuzick Clin Cancer Res 2006;12(3 Suppl):1037s
Trials using AIs upfront TAMOXIFEN ANASTROZOLE LETROZOLE EXEMESTANE ATAC* BIG 1-98* 5 years 5 years † 5 years 2 years 3 years 5 years Randomization TEAM ‡ *Registration trials; † Combination arm discontinued at first analysis; ‡ amended TEAM protocol 5 years 2–3 years
Switching and sequential therapy trials TAMOXIFEN ANASTROZOLE LETROZOLE EXEMESTANE BIG 1-98* ABCSG-8 IES 5 years 3 years 2 years 2–3 years 2 years 3 years 5 years Randomization ITA 2–3 years 3 years 2 years ARNO TEAM ‡ 5 years 2–3 years * Registration trials; † Combination arm discontinued at first analysis; ‡ TEAM protocol altered to affect switch to Exem after 2–3 years Tam; **ABCSG: randomization immediately after surgery, ARNO: randomization up to 2 years after surgery
Annual recurrence rate (%) Time (years) N+ N– ATAC BIG 1-98 Randomization Start AI upfront Highest relapse rate years 2–3 TEAM Based on data from Saphner et al. J Clin Oncol 1996;14:2738–46 Letrozole is not licensed in all European countries for use in the early adjuvant setting
BIG 1-98: all endpoints Comparison with ATAC Favors TAM Hazard ratio (LET:TAM) DFS OS Distant DFS Time to recurrence DFS (w/o 2nd malignancy) Time to distant metastasis 0.72 Favors LET Howell et al. Lancet 2005;365:60–2; Baum et al. Lancet 2002;359:2131–9; Arimidex ® PI 2005; Thürlimann et al. N Engl J Med 2005;353:2747–57 ATAC HR+ 68 mo33 mo Letrozole is not licensed in all European countries for use in the early adjuvant setting
BIG 1-98 & ATAC* in comparison Efficacy summary Risk of distant metastases –significant by 27% with letrozole in BIG 1-98 –no significant reduction with anastrozole in ATAC* Non-significant reduction in risk of death in both studies to date – by 14% with letrozole – by 3% with anastrozole Subgroup analyses –BIG 1-98: letrozole showed a significant DFS advantage in patients who received chemotherapy patients with node+ disease –ATAC: anastrozole showed a significant DFS advantage in Patients with node– disease Patients who did not receive chemotherapy *HR+ population Howell et al. Lancet 2005;365:60–62 Thürlimann et al. N Engl J Med 2005;353:2747–57 Letrozole is not licensed in all European countries for use in the early adjuvant setting
Distant recurrences are associated with high risk of death All breast cancer recurrences associated with increased risk of mortality Substantially higher risk of death in patients with distant recurrences than with locoregional recurrences and new contralateral breast cancers Distant metastases are more prevalent in high-risk N+ disease than in N– disease Lamerato et al. J Clin Oncol 2005;23(16S):62s(abstract 738) Lawrence et al. Breast Cancer Res Treat 2005;94(Suppl 1):S211(abstract 5019)
Annual recurrence rate (%) Time (years) N+ N– Randomization/ analysis Start AI after 2–3 years of tamoxifen Randomization/analysis upfront or at switch IES, ABCSG/ARNO, ITA BIG 1-98 TEAM Based on data from Saphner et al. J Clin Oncol 1996;14:2738–46 Letrozole is not licensed in all European countries for use in the early adjuvant setting
1. ATAC Trialists’ Group Lancet 2005;365:60–2; 2. Thürlimann et al. N Engl J Med 2005;353:2747–57; 3. Coombes et al. N Engl J Med 2004;350:1081–92; 4. Jakesz et al. Lancet 2005;366:455–62; 5. Jakesz et al. Breast Cancer Res Treat.2005;94:(abstract 13) DFS and OS benefits with AIs (sequential and substitution trials) ATAC 1 BIG IES 3 ARNO/ ABSCG-8 4 ABCSG-8 5 No. patients Follow-up (mo) * Absolute DFS benefit (%) 2.5 at 5 y2.6 at 5 y4.7 at 3 y at 3 y1.5 at 5 y Hazard ratio p value OS benefit (%) **7 p value *Sequence **Analysis from switch Suggests greater absolute reduction in risk of recurrence vs tamoxifen with switch than achieved with upfront AI – but in a lower-risk population Letrozole is not licensed in all European countries for use in the early adjuvant setting
Optimal timing of AI use in adjuvant treatment of ER+ early breast cancer Risk of recurrence lowest with 5 years’ upfront AI therapy Years Years lost to recurrence (%) years Tam 5 years Tam + 5 years AI 2.5 years Tam years AI 5 years AI Model of the impact of the sequence of hormonal therapy on recurrence of ER+ breast cancer (based on published data) Cuzick et al. Br J Cancer 2006;94:460–4
Is there a difference in AEs between upfront and sequential AI use?
Adverse events in adjuvant AI trials UpfrontSequentialExtended adjuvant AI vs tamoxifen Let vs placebo Hot flushes or == Arthralgia Thromboembolic NR Osteoporosis/ fracture or = Gynecol. symptoms Hypercholesterolemia = CV events = Quality of life= (anastrozole)=(exemestane)= ATAC Trialists’ Group Cancer;98: ; Thürlimann et al. N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al. Lancet 2005;366:455–62; Jakesz et al. Breast Cancer Res Treat 2005;94:(abstract 13) NR: not reported; Slide adapted from: Review, Mouridsen, 2005 Letrozole is not licensed in all European countries for use in the early adjuvant setting
AE profiles are not significantly different with upfront and sequential AI In all trials comparing an AI (sequential and upfront) with tamoxifen Non-significant increase in CV events Tamoxifen has cardioprotective effects 1,2 Increase in hypercholesterolemia Lipid-lowering effect of tamoxifen (12–15%) 3 No evidence that 2–3 years of tamoxifen protects against subsequent bone loss Pretreatment with tamoxifen may delay onset of fracture risk 1. EBCTCG Lancet 2005;365:1687–717; 2. Braithwaite et al. J Gen Intern Med 2003;18:937–47; 3. Herrington & Klein Womens Health Issue 2001:11:95–102
Are AIs cost-effective?
Cost-effectiveness in adjuvant treatment Cost of agent Cost of monitoring/managing/treating side effects Cost of treating relapsed disease
Lee et al. J Clin Oncol 2002;20:2713–25; Orr et al. Surgery 1999:126:568–76; Hillner et al. J Clin Oncol 2000:18:72–9; Elkin et al. J Clin Oncol 2004;22:854–63; Zbrozek et al. Am J Hosp Pharm 1994:51:1555 63 Cost-effectiveness ratios in oncology Postmastectomy radiation therapy in EBC Axillary node dissection in ER+ EBC Pamidronate in MBC & bone lesions receiving CTx FISH testing for HER2 in MBC Ondansetron in cisplatin-induced emesis, 40 kg patient Ondansetron in cisplatin-induced emesis, 70 kg patient Letrozole early adjuvant treatment vs tamoxifen in postmenopausal women with HR+ EBC $ x 1000 / QALY
Are all AIs the same?
Are all AIs the same? Inhibition of aromatase activity in vitro Increasing potency Miller et al. Endocr Relat Cancer 1999;6:187 IC 50* (nmol/L) Relative Potency Letrozole Anastrozole10450 Exemestane15300 Aminoglutethimide45001 Letrozole is the most potent third-generation AI in vitro *In breast cancer homogenates
AnastrozoleLetrozole Anastrozole Inhibition of whole-body aromatization in 12 postmenopausal patients with BC Anastrozole vs letrozole, p = Crossover Crossover 2 % Inhibition Increasing inhibition Geisler et al. J Clin Oncol 2002;20:751–7 Letrozole
In adjuvant trials: upfront AI ATAC: 68 months’ median follow-up – 17% reduction in recurrence risk (HR+ population) BIG 1-98: 26 months’ median follow-up – 19% reduction in recurrence risk significant risk reduction in subgroups (N+ disease, patients who had received adjuvant CT) In specific patient populations (e.g. higher-risk) benefit may depend on the AI used ATAC Trialists’ Group. Lancet 2005;365:60–2; Thurlimann et al. N Engl J Med 2005;353:2747–57 Letrozole is not licensed in all European countries for use in the early adjuvant setting
Direct comparative trials MA.27 –Upfront for 5 years –Anastrozole vs exemestane –> 6800 postmenopausal HR+ early BC –Nearing completion of accrual FACE –Upfront for 5 years –Anastrozole vs letrozole –~4000 N+ postmenopausal HR+ early BC –Open to accrual, 19 patients to date
FACE trial: letrozole vs anastrozole Primary endpoint –DFS Secondary endpoints –Safety –Overall survival –Time to distant metastasis –Time to contralateral disease Early breast cancer ER+ and/or PgR+ N+ Postmenopausal (FSH/LH/E 2 levels) De novo adjuvant therapy Anastrozole 1 mg/day RANDOMIZERANDOMIZE Letrozole 2.5 mg/day
Does PgR status or HER2/neu status affect response to an AI?
Benefit with AIs vs tamoxifen according to ER/PgR status *Local pathological assessment † Central pathological assessment ER+/PgR+ER+/PgR– StudyAIHR (95% CI) ATAC 1 Anastrozole 0.84 (0.69–1.02) p = (0.31–0.61)* p = BIG ,3 Letrozole 0.84 (0.69–1.03)* 0.67 (0.51–0.88) † 0.83 ( )* 0.88 (0.55–1.41) † 1. Dowsett et al. J Clin Oncol. 2005;23:7512; 2. Update of Thürlimann et al. N Engl J Med 2005;353:2747–57; 3. Update of Viale et al. Breast Cancer Res Treat. 2005;94(Suppl 1):S13(abstract 44); Letrozole is not licensed in all European countries for use in the early adjuvant setting
BIG 1-98 DFS by central pathological assessment Favors LFavors T Hazard ratio (L:T) ER+/PgR+ (n = 3330) ER+/PgR– (n = 832) All patients (n = 4399) 0.71 Viale et al. Breast Cancer Res Treat 2005;94(Suppl 1):S13(abstract 44)
BIG 1-98 DFS by central pathological assessment Favors LFavors T Hazard ratio (L:T) ER+/HER2+ (n = 234) ER+/HER2– (n = 3971) All patients (n = 4399) 0.71 Viale et al. Breast Cancer Res Treat 2005;94(Suppl 1):S13(abstract 44)
PgR and HER2/neu status BIG 1-98 is only trial to perform central assessment of ER and PgR status Letrozole achieved benefit in all patients with ER+ tumors irrespective of PgR status, based on local and central assessment –In contrast, local assessment in ATAC showed a benefit in only the ER+/PgR– subgroup Treatment decisions should not be based on PgR status
What do we do now and what are we looking for in the future? Which patients should receive an AI upfront? –Most postmenopausal women with early-stage, HR+ breast cancer Is there a population that can safely be treated with tamoxifen followed by an AI? –Women who are pre- or peri-menopausal –Women intolerant of an AI –Strongly ER/PR+ with low-grade, low-risk disease? The future –Genomic analysis will help us to determine sensitivity and resistance to hormone therapy May help to differentiate risk groups and appropriate endocrine approach between different classes of drugs Will identify patients who can be safely treated with hormonal therapy