Hormone therapy in Breast Cancer patients with comorbidities Diana Crivellari Centro di Riferimento Oncologico Aviano- ITALY Madrid November 9th, 2007
Main issues Comorbidities in elderly women Hormonal drugs in adjuvant setting Hormonal drugs in metastatic setting
COMORBIDITIES CAN ENHANCE THE RISK OF TREATMENT-RELATED COMPLICATIONS CAN HAVE A MAJOR INFLUENCE ON SURVIVAL
MINIMAL GERIATRIC ASSESSEMENT Comorbidities (Charlson scale, CIRS-G) Functional status (ADL, IADL) ECOG performance status Evaluation of mental status Polypharmacy Social support network Nutrition
Estrogen reduction LDL Cholesterol HDL Cholesterol Increased Cardiovascular risk
Total n 2313 4185 1668 800 of pts European Journal of Cancer 2005
European Journal of Cancer 2005
Relative 5-year survival rates: 87% without comorbidity 77% with previous cancer 78% with diabetes mellitus 59% with 2+ coexistent diseases European Journal of Cancer 2005
Gennari R et al Cancer 2004 Breast carcinoma in elderly women: EIO experience April 1997 to February 2002 Total 2999 postmenopausal patients Young Post (50-64 yrs) 2052 pts (68.4%) Older Post (65-74 yrs) 801 pts (26.7%) Elderly post (> 75 yrs) 146 pts (4.9%)
Gennari R et al Cancer 2004 Breast carcinoma in elderly women: EIO experience Comorbidity % with Hypertension % with Cardiovasc. %with Diabetes Two or more comorbid dis. YPM (50-64 yrs) OPM (65-74 yrs) EPM (> 75 yrs) 12.7 21.5 22.6 4.1 12.9 20.5 0.9 1.4 0.7 10.5 13.4 21.9
Type of treatment YPM 50-64 yrs OPM 65-74 yrs Surgery 2051 801 146 EPM > 75 yrs BCS (%) 73.9 76.9 72.6 Mastectomy 22.3 20.2 23.3 P-value Other 3.8 2.9 4.1 0.47 Radiother. 1506 613 104 Receiving RT 86.6 84.5 54.7 <0.01 Systemic therapy 2032 795 141 No treatment 4.7 5.4 19.1 CT only 22.8 12.6 6.4 HT only 37.3 58.4 71.6 CT + HT 35.2 23.6 2.8 <0.01 Gennari et al Cancer 2004
Main issues Comorbidities in elderly women Hormonal drugs in adjuvant setting Hormonal drugs in metastatic setting
Different options in adjuvant hormonal treatment Tamoxifen Aromatase inhibitors up-front Switching (tam AI or inverse) Extended adjuvant
Tamoxifen therapy outcome 10 yrs (1998) 15 yrs (2005) Age DFS % OS % DFS % OS % <50 47 30 29 24 50-59 59 45 20 34 24 60-69 69 54 33 45 35 70+ 54 34 51 37 EBCTCG, Lancet 1998 and 2005
J Gen Intern Med 2003
Relative risk ratio for fatal MIs (tamoxifen vs control): 0.62 (95% CI: 0.41 0.93) Risk ratio (excluding Scottish trial): 0.81 (95% CI: 0.48 1.37) J Gen Intern Med 2003
Lipid lowering effect of SERMs? Yes Tamoxifen studies 10 trials, 6 vs placebo; 657 patients Decrease in cholesterol seen in all studies Median decrease: 12.5% (range 3 17) 3 Decrease due to LDL cholesterol But no protection against coronary events despite favorable changes in lipid levels Herrington & Klein Womens Health Issues 2001;11:95 102 Barrett-Connor E et al New Engl J Med 2006;355:125-137
Aromatase inhibitors trials Study Modality N. of pts % A/Tam Median age yrs HR [ RFS] ATAC Up Front 3215/3116 64 0.74 BIG1 98 Up Front 4003/4007 61 0.72 IES ITA ABCSG/ARNO MA17 ABCSG6a Switch Exemestane Switch Anastrozole Switch Anastrozole Extended Letrozole Extended Anastrozole RFS [relapse Free Survival] 2362/2372 64 0.70 208/218 63 0.42 1618/1606 63 0.60 2575/2582 62 0.57 387/409 63 0.64 Howell A. Modified Lancet 2005
Adverse events in AI trials AI and tamoxifen associated with hot flushes Compared with tamoxifen, AIs associated with Higher incidence of arthralgia Lower incidence of gynecological symptoms including lower rates of invasive endometrial cancer Lower incidence of thromboembolic events (including grade 3 53 5 events, letrozole vs tamoxifen)
ATAC TOLERABILITY DATA Adverse events (AEs) on A (%) T (%) p-value treatment or within n=3092 n=3094 14 days of discontinuation Drug-related Aes 60.9 68.4 <0.0001 Aes leading to withdrawal 11.1 14.3 0.0002 Drug-related Aes leading 6.5 8.9 0.0005 to withdrawal All serious Aes ( SAEs ) 33.3 36.0 0.03 Drug-related SAEs 4.7 9.0 0.0001 SAEs leading to death 3.3 3.6 0.6 Mansel R et al, ESMO 2006
BIG 1-981 TRIAL DESIGN Postmenopausal women with receptor-positive positive early breast cancer International, randomized, double-blind blind Phase III trial R A N D O M I Z E A B C D Tamoxifen Letrozole Tamoxifen Letrozole Letrozole Tamoxifen 0 2 5 YEARS 8028 pts Randomized between March 1998 and May 2003 7963 received therapy Includes initial treatment Arms C & D Coates et al. ASCO 2007
Data Collection AEs Coates et al. ASCO 2007
OBJECTIVE To compare tamoxifen and letrozole with regard to the incidence and timing of cardiovascular AEs, including baseline cardiac risk factors, prior cholesterol, and serial cholesterol measurements. Coates et al. ASCO 2007
Cardiovascular AEs Coates et al. ASCO 2007
CONCLUSIONS Taken together, cardiovascular AEs were relatively rare. Cholesterol values decreased over time on both treatments, but the decrease was greater and earlier on tamoxifen. Prior hypercholesterolemia was associated with an increase in grade 3-53 5 cardiac AEs. Overall incidence of cardiac AEs was similar on both treatments. An unplanned subset analysis suggested a possible excess of Gr 3-53 5 cardiac AEs on letrozole. These events were reported at low frequency on both arms. Any increased incidence of cardiac AEs on letrozole seems to be outweighed by the superior control of loco-regional and distant recurrence afforded by letrozole compared with tamoxifen. Different methods and rigor of AE collection make cross- study comparisons with other AI trials inappropriate. Coates et al. ASCO 2007
BIG 1-981 TRIAL DESIGN Postmenopausal women with receptor-positive positive early breast cancer International, randomized, double-blind blind Phase III trial R A N D O M I Z E A B C D Tamoxifen Letrozole Tamoxifen Letrozole Letrozole Tamoxifen 0 2 5 YEARS 8010 pts randomized between March 1998 and May 2003 4922 pts allocated to five years of letrozole or tamoxifen
BIG 1-981 TRIAL 4922 pts allocated to five years of letrozole or tamoxifen 1590 patients are older (65-74 yrs) 294 patients are elderly (over 75 yrs) Although these numbers seem small compared to the larger group of younger patients, they do represent an impressive data set for elderly women with breast cancer Crivellari D et al. ASCO 2007
OBJECTIVE and METHODS To explore potential differences in efficacy, treatment completion, and adverse events in older women receiving adjuvant tamoxifen or letrozole for five years in the BIG 1-981 trial. Subpopulation Treatment Effect Pattern Plots (STEPP) were used to examine the patterns of differences in disease-free survival and incidences of AEs according to age.
1590 294 Baseline characteristics of patients in BIG 1 study Age group Age <=64 Age 65-74 Age 75 TREATMENT TREATMENT TREATMENT Letrozole Tamoxifen Letrozole Tamoxifen Letrozole Tamoxifen Mean age, yrs (SD) 56.9 (4.8) 56.9 (4.8) 69.0 (2.8) 68.8 (2.8) 78.0 (2.7) 77.0 (2.5) Body mass index, kg/m2 (SD) 26.60 (5.1) 26.71 (5.2) 27.22 (4.8) 27.27 (5.1) 26.70 (4.3) 27.08 (4.3) Cholesterol, mg/dl (SD) 235.3 (44.2) 235.3 (42.8) 231.5 (41.8) 231.4 (41.8) 226.8 (38.3) 227.4 (43.9) Total N N of pts 1545 1566 757 733 146 148
1590 294 Baseline characteristics of patients in BIG 1 study Age group Age <=64 Age 65-74 Age 75 TREATMENT TREATMENT TREATMENT Letrozole Tamoxifen Letrozole Tamoxifen Letrozole Tamoxifen Percentage with history of receiving medication for hypercholesterolemia 6.9 5.8 12.7 10.4 13.0 8.8 Hypertension 24.1 23.6 41.1 42.7 61.0 51.4 Diabetes (requiring treatment other than diet) Cerebrovascular accident (CVA)/Transient ischemic attack(tia) 3.5 3.7 7.3 8.6 10.3 10.8 1.4 1.1 2.4 2.0 4.8 4.1
Baseline characteristics of patients in BIG 1 study Age group Age <=64 Age 65-74 Age 75 TREATMENT TREATMENT TREATMENT Letrozole Tamoxifen Letrozole Tamoxifen Letrozole Tamoxifen Percentage with disease history of thromboembolic events 2.3 2.0 5.0 5.0 4.8 2.7 Any cardiac events 6.5 5.9 12.5 14.3 23.3 19.6 Osteoporosis 2.5 3.1 5.2 5.5 10.3 7.4 Percentage with history of receiving bisphosphonates 0.1 0.3 0.5 0.1 0.7 0 Bone fractures 7.8 8.7 11.2 10.1 16.4 15.5 N of pts 757 733 146 148
RESULTS Median follow-up 40.4 months. Patients 75 years of age and older were less likely to complete trial treatment, but at rates that were similar in the two treatment groups: 39.7% (58/146) did not complete letrozole and 37.2% (55/148) did not complete tamoxifen (p = 0.72).
Types of AEs D Crivellari et al JCO in press
Subpopulation Treatment Effect Pattern Plots (STEPP) of 4-year DFS percents for L vs T according to age. D Crivellari et al JCO in press
Adverse Events (AEs) Bone Fractures STEPP analysis shows that the incidence of bone fractures, observed more often in the letrozole group, did not differ by age.
Frequency Distribution of Osteoporosis at Spine,Hip, Femoral Neck by age: Total 1346 menopausal women Spine (%) Hip (%) Femoral Neck (%) 50 yrs or younger 5.6 5.2 5.9 51 55 yrs 9.3 6.4 9.0 56 60 yrs 10.6 6.8 10 61 65 yrs 15.9 14.5 14.2 66 70 yrs 23.7 19.7 20.4 71 75 yrs 17.1 22.1 16.6 76 yrs and older 17.8 25.3 23.9 Weinstein L Obstet Gynecol Vol 93,1999
ASCO bone health guidelines BMD screening in breast cancer All women aged > 65 years All women aged 60 64 64 years with risk factors Postmenopausal women of any age receiving AIs Premenopausal women with therapy- associated premature menopause Repeat BMD annually after initial exam Hillner et al. J Clin Oncol 2003;21:4042 57
ASCO 2003 Guidelines for Osteoporosis Screening for Breast Cancer Patients ASCO 2003 Recommendations High risk: BMD screening recommended T-score <-2.5: begin calcium and vitamin D, and begin therapy with alendronate, risedronate, zoledronic acid, or raloxifene; repeat BMD annually T-score between -1 and -2.5: begin calcium and vitamin D; repeat BMD annually T-score >-1: reassure; begin calcium and vitamin D; repeat BMD annually Low risk: BMD screening not recommended Begin calcium and vitamin D Monitor annually for risk status by history ASCO, American Society of Clinical Oncology. Hillner, et al. J Clin Oncol. 2003;21:4042-4057; Chlebowski, et al. Amer J Oncol Rev. 2006;5(suppl 1):1-40. 8
Black D M et al
35% risk reduction Lyles KW et al New Engl J Med 2007
28% risk reduction Lyles KW et al New Engl J Med 2007
TAM vs AIs: Controlateral tumors Osteoporosis Arthralgias Neurocognitive function? Serum lipids Contralateral tumors DVT Endometrial cancer Hot Flashes TAM AIs Physicians should begin to individualize treatment in elderly patients based on comorbidities and risk factors
Recurrence hazard rates are dependent on known prognostic factors Prominent early peak of recurrences (~ 3 yrs) in absence of adjuvant therapy Hazard of recurrence by yearly interval 25 20 15 10 5 0 0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 Year Early Breast Cancer Trialists Collaborative Group. Lancet. 1998;351:1451. Update of Houghton. J Clin Oncol. 2005;23(16S):24s. Abstract 582. Saphner et al., J Clin Oncol. 14: 2738-2746, 1996 Total Node 0 Node 1-3 Node (4+) Tumour size (<1cm) Tumour size (1.1-3cm) Tumour size (>3cm) ER+ ER- Premen Postmen
Main issues Comorbidities in elderly women Hormonal drugs in adjuvant setting Hormonal drugs in metastatic setting
ADJUVANT WHAT S GOING ON 1 LINE 2 LINE TAMOXIFEN ANASTROZOLE or LETROZOLE UP FRONT SWITCH TAM + EXEMESTANE or ANASTROZOLE EXTENDED TAMOXIFEN + LETROZOLE LETROZOLE EXEMESTANE ANASTROZOLE TAMOXIFEN or EXEMESTANE or FULVESTRANT LETROZOLE or FULVESTRANT FULVESTRANT or EXEMESTANE EXEMESTANE or FULVESTRANT LETROZOLE or FULVESTRANT EXEMESTANE or FULVESTRANT FULVESTRANT or EXEMESTANE or TAMOXIFEN FULVESTRANT or EXEMESTANE or ANASTROZOLE ANASTROZOLE or FULVESTRANT
Randomized phase III studies of anti-aromatase Agents vs Tamoxifen as Initial Therapy of Metastatic Breast Cancer
Survival With Aromatase Inhibitors and Inactivators Versus Standard Hormonal Therapy in Advanced Breast Cancer: Meta-analysis The meta-analysis included a total of 23 eligible trials and 8504 patients, of whom 4559 had been randomly assigned to receive aromatase inhibitors or inactivators and 3945 had been assigned to receive standard hormonal treatments. Mauri - J Natl Cancer Inst 2006; 98:1285-91
Survival With Aromatase Inhibitors and Inactivators Versus Standard Hormonal Therapy in Advanced Breast Cancer: Meta-analysis HR = 0.87 95% confidence interval [CI] = 0.82 to 0.93; P <.001 Mauri - J Natl Cancer Inst 2006; 98:1285-91
Fulvestrant ER-Down Regulator
Fulvestrant vs Anastrozole: results of Trial 020 Howell et al JCO, 2002
Fulvestrant: Prospective Combined Analysis - Best Objective Response Number of patients (%) Fulvestrant (n=428) Anastrozole (n=423) Complete response (CR) Partial response (PR) Objective response (CR+PR) 20 (4.7) 11 (2.6) 62 (14.5) 59 (13.9) 82 (19.2) 70 (16.5)* Stable disease ³24 weeks Clinical benefit (CR+PR+SD ³24 weeks) 104 (24.3) 103 (24.3) 186 (43.5) 173 (40.9) *Odds ratio (95.14% CI): 1.21 (0.84 1.74); p=0.31 Robertson JFR et al. Cancer 2003; 98: 229 238.
Mean ± SD changes in plasma lipid parameters during fulvestrant treatment (n=31) ASCO 2007, Abstract 1085
Lipid lowering effect of fulvestrant in hormonesensitive metastatic breast cancer patients A. Camerini, D. Amoroso et al. Activity Clinical Benefit 43% 12 patients SD 24 weeks median TTP 6.5 ± 3.9 mesi ASCO 2007 Abs 1085
FULVESTRANT IN THE TREATMENT OF HER2- POSITIVE ADVANCED BREAST CANCER (ABC) JFR Robertson, G Steger, P Neven, S Barni Conclusions More than 40% of HER-2 2 +, heavily pretreated and with numerous metastatic sites, received a clinical benefit Fulvestrant was active also in visceral sites Therapy was well tolerated Courtesy of Dr Barni, ECCO 2007, Poster 2127
CONCLUSIONS Patients at risk for thromboembolic disease should avoid tamoxifen Even if there is an excess fracture risk with letrozole, it is encouraging to see this was not worse in the elderly group We hoped to be able to better identify among older patients who should or should not take an AI in adjuvant setting Fulvestrant (administered monthly im) is a new interesting treatment option for metastatic elderly patients with comorbidities
Thanks for your attention