ASCO Advanced Course

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Godwin Kelley
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1 Breast Cancer in The Elderly Prof Dr. Atef Yousef Head of Clinical Oncology Department Ain Shams University ( ASCOD)

2 Breast cancer Problem of Breast Cancer -In the World & USA -In Middle East & Egypt Problem of Breast Cancer in the elderly

3 Problem of Breast Cancer In the World & USA Incidence Estimated new cases and deaths from breast cancer in New cases- Deaths In the world >1000, ,000 In USA 182,460 40,480-1 st cause of cancer in women (1 in 4 cancers diagnosed in US women) -2 nd cause of cancer death in women, (after lung cancer) - Life time risk 1:8 (12.3%) who live to be 85 years of age American Cancer Society (ACS).. Breast Cancer Facts & Figures (Statistics based on data, ).)

4 Breast cancer incidence rates worldwide according to GLOBOCAN 2002 Rates are age-standardized (worldstandard) rates (per 100,000).. The Breast Journal, Volume 12 Suppl. 1, S70 S80, 2006

5 Female Breast cancer indicators in Cyprus,Israel,Egypt,Jordan,and US SEER Egypt US SEER* *SEER 13 Registries, Public Use Data Set, from data submitted November 2004 Rates /100,000 females and are standard to age standard to WorldStandard Million

7 Problem of Breast Cancer in the elderly Incidence : in US : extremely common among elderly 65 ys : US¹ : 50% of new cases in women ( > 70y : 47%) Egypt & Jordan² : 15% life expectancy at 70y =15.5y in fit women & 8.5y with comorbidity ( with Enouph time for Exposure to potentially preventable risk of relape &Death) They are less likely to receive standard care & treatment for their disease (accounting for higher rate of rec & mortality in elderly)? ³ Lack of data in clinical trials, ( few elderly are accrued in clinical trial)⁴ -higher prevalence of comorbidity, -lowered life expectancy -increased adverse effects of treatment 1-Breast Cancer Facts & Figures Crivellari DJ Clin Oncol 25: , www cancer 4 Bouchardy C J Clin Oncol, 25, 14, , 2007,

8 Tamoxifen for Prevention of Breast Cancer NSABP P-1 Eligibility: ibilit IBC risk ikof 1.7% over 5years Randomization: 13,388 women : tamoxifen or placebo for 5y Opened : April 1992and closed September 1997 After 7 y of FU : Benefits: Tam caused 50% reduction in invasive and in situ breast ca 30% reduction in osteoporotic fractures Benefit was for ER+ IBC Risk (increased with Age) endometrial cancer. risk ratio = 2.53 stroke, DVT, PE and cataracts. JNCI Journal of the National Cancer Institute 97(22): ,

9 Tamoxifen Chemoprevention in older women ¹ remains a complex decision, The ideal patient being the older woman with a high risk of breast cancer who has no major comorbidities and a high predicted five year survival. The use of the Gail model² for estimating individual patient risk may aid in decision making by the patient and physician Precausions: Annual Pap tests and pelvic examinations, as well as Periodic eye examinations because of a modest increase in cataract risk ¹ 1 Holmes CE CA Cancer J Clin; 53:227, / /

10 Treatment end points in elderly for Early disease : & Advanced disease: Improving survival palliation protection of QL is crucial il So The absolute benefit of treatment is critical Crivellari D J Clin Oncol 25: , 2007

11 Biology of Breast Cancer in Elderly I-A more favorable biologic phenotype 1 Lower expression of (HER2), 2 a higher content of ER (PgRs) (87%of pts >65y) 3 a higher frequency of diploidy 4 a lower frequency of p53 accumulation, and, 5 a better outcome most important Endocrinal treatment..lesser role of chemotherapy II Tumor stage at diagnosis is more advanced than in patients< 65 III 20 30% have aggressive diseaseer PR Endocrinal treatment: Inadequte Need for Chemotherapy Gennari R Cancer 101: , 2004 Diab SG, J Natl Cancer Inst, 2000 Molino A, Crit Rev Oncol Hematol 59: , 2006

12 ASSESSMENT OF OLDER PATIENTS 1 Ravdin et al have developed a computer program ( online.com) that: accurately estimates The benefits of endocrine therapy, chemotherapy,or both according to standard clinical and biologic variables and age. Life span on the basis of age, The effects of comorbidity and its effect on DFS& OVS 2 The Comprehensive Geriatric Assessment (CGA)¹ is a tool initially 1 identify frail patients for supportive care alone 2 interventions based on CGA can improve function and reduce hospitalizations in elders 3 Rarely obtained by medical oncologists 4 Controversy : interventions based on CGA can improve survival? CGA is cost effective? 1 Repetto L, J Clin Oncol, ,2002

13 MAMMOGRAPHY SCREENING IN OLDER WOMEN Annual mammography in women y reduces breast-cancer related mortality by approximately 26% ( due to increased sensitivity with age) ¹ Recommendation² All elderly women in reasonably good health Except:- -estimated life expectancy of <3-5y -multiple l or severe comorbidities likely l to limit it life expectancy, 1-K. Kerlikowske A meta-analysis. JAMA; 273: , American Cancer Society Guidelines for Breast Cancer Screening: Update 2003 CA Cancer J Clin 53:141,2003;

14 MANAGEMENT OF EARLY STAGE BREAST CANCER 1-Surgery Operative morbidity and mortality (Mastectomy & CBS) similar in healthy Older and younger women Primary treatment with tamoxifen only -Response:- CR and PR: 60% to 70% with persistence up to 5y in 90% of patients - Overall Survival :- Similar to surgery - Local recurrence rates:- 25% to 30% -~60% treated with TAM only will evetually need Surgery A Cochrane review concluded that Pi Primary endocrine therapy should only be offered to women with (ER + tumours) who are unfit for or who refuse surgery CA Cancer J Clin; 53:227,2003 The Cochrane Collaboration, Cochrane reviews,2008 :- -

15 16 Rec Rate/y (%) 8 Annual Hazard Risk of Rec. JCO, Vol 14, , 1996 In 1996, Saphner et al reviewed data from - 7 clinical trials of early breast ca - by the Eastern Cooperative Oncology Group (ECOG) pts, they found that annual hazard risk of rec :as following 1- the greatest Rec. R. occurred -at years 1-2 y after surgery. ( highest in tumors > 3 cm and > 4 positive nodes) -From 2-5 y, the RR began to decline slowly. - From 5 10y, the RR in the entire group was ~ 1/3 of that at the highest peak, but remained constant at over 4%. 2-analysis by ER status, showed that: -In years 0-3, Rec.R. was sign. greater in ER- patients. -in year 4 The curves crossed, and , RR was sign. greater in ER+ patients.& remained constant RR of ER- patients decreased 0 0 2y 5y 10y 3y 4y 10y 0

16 Treatment t benefit (For : Rec/Mortality) Absolute benefit & proportional benefit Example:- Control ttt Control ttt group A group B Death Rate (DR ) 50% 40% 25% 20% 1- Proportional benefit = 25% 25% HR = Absolute benefit = 10% 5% Early Breast Cancer Trialists Group (EBCTG ) Lancet,365,1687,2005

17 2-Radiotherapy Effect on 5y Local Rec. By Age 5-year local recurrence risk (%) in trials of: Characteristics (a) BCS ± RT (b) Mast+AC ± RT (where known*) node-negative node-positive Radiotherapy vs control Absolute reduction (SE) Radiotherapy vs control Absolute reduction (SE) Age (years) < vs (2) 6 vs (1) vs23 16 (2) 6 vs (2) vs (1) 5 vs (2) vs (2) - - Tumour grade Well differentiated 4 vs (2) 4 vs (3) Moderately differentiated 9 vs (2) 4 vs (2) Poorly differentiated 12 vs (3) 6 vs (4) -Similar proportional reduction among different groups ~ 2/3 Absolute reduction depends on the magnitude of risk of recurrence. Tumour size (T category) 1-20 mm (T1) 5 vs (1) 5 vs (2) mm (T2) 14 vs (3) 6 vs (2) >50 mm (T3) or T vs (4) ER status ER-poor 12 vs (3) 8 vs (2) ER-positive 6 vs (2) 6 vs (2) Number of involved nodes vs (2) 4 or more vs (2) EBCTCG Lancet; 366: , 2005 All women 7 vs (1) 6 vs (1)

18 Radiotherapy effect on Breast cancer Mortality risks by category of absolute reduction in 5-year local recurrence risk (cont.) Category of absolute reduction in 5-year local recurrence risk 5-year risk Breast cancer mortality (%) 5-year absolute 15-year risk 15-year absolute recurrence risk reduction reduction Active vs control Active vs control (a) <10% (mean 1%) 18.8 vs (SE 0.6) 41.3 vs (SE 0.9) (b) 10-20% (mean 17%) 21.8 vs (SE 0.6) 44.0 vs (SE 0.8) (c) >20% (mean 26%) 24.9 vs (SE 1.3) 47.4 vs (SE 1.6) Subtotal (b+c) >10% (mean 19%) 22.4 vs (SE ) 44.6 vs (SE08) ) For every 4 local recurrences avoided,about 1 breast cancer death, would be avoided over the next 15 y EBCTCG CCGLancet; 366: ,2005

19 Radiotherapy Benefit on Survival After BCS & M in elderly -Recent trials (Cont.) 1 Omission Of RT after BCS reduced survival¹ 2 Minimal comorbidity were the most likely to benefit improved Local Control² 4 Ongoing trials :PRIME (Postoperative Radiotherapy in Minimum Risk Elderly)³ (IORT) Single fraction to the tumor bed, immediately after the lesion removal especially in the elderly, with very low risk of recur. outside the index quadrant. 1 Truong PT, Am J Surg 191: , Smith BD, J Natl Cancer Inst 98: , Bernier J, Breast 15: , 2006

20 Radiotherapy Recommendatioms (Cont.) Clinical practice guidelines for Locoregional post mastectomy radiotherapy¹ 1-After Mastectomy i Primary Tum: size =/>5cm. invasion of: skin /pectoral msl /chest wall ii +Ax LN : ( >3+nodes) iii Currently unclear indications are: Age, histologic grade, lymphovascular invasion, ER status, No. of axillary nodes removed, 1 3+LN axillary extracapsular extension and (1 3 + node) NCCN² EBCTCG benefit of 16%³ 5cm surgical margin status, (although may affect locoregional control), 2-After Conservative Breast Surgery:-Standard of care for all patients 1 Meta analysis of randomized trials from 1966 till June 2003,Truong et al CMAJ. 170(8): ,, EBCTCG Lancet; 366: ,2005

21 3-Adjuvant Systemic Therapy in the Elderly I- Hormonal TAMOXIFEN Golde Standard? EBCTCG, after 15y FU 5y TAM IN ER+ Women : 50% reduction in recurrence.& Contralat.breast 31% reduction in mortality, Irrespective to age/n/ use of CT /Menop.Standard BUT, Not Golden? - Endometrial ca and / thromboembolic risks / cerebrovascular events - Recurrence (50% mostly after 5y) -TAM resistence Lancet.;365(9453):60-2,2005 Lancet 365: Fornander T Lancet 1 (8630): , 1989,

22 Adjuvant AI Trials ; DFS / OS/ Less TAM Tox.? (Cont.) Initial Head to head After 2-3y of Tam Sequential ATAC ms ARNO/ABCSG/3,224 pts(ita 828 pts / 78ms) ) Tam Anastrazole Fracture higher DFS 4 8% Tam Tam Anastrazole DFS/OVS A meta-analysis :- Jonat W; Lancet Oncol 7, Forbes JF, Lancet toncol; 9(1): 45 53, ITA : Beccardo, Cancer.,109(6):1060-7, 2007 After 5y of Tam Extended BIG pts 51ms BIG 1-98 MA-175,187 pts 30ms Tam Tam Letrezole Tam TEAM IES 4742pts 55.7 ms NSABP B-33 DFS 4.6% OVS N+: 0.4% Letrezole Letrezole DFS 2.9% Letrezole Tam Unblinded after 2.4y Coates AS, J Clin Oncol 25 (5): ,2007 Goss PE, JNatl Cancer Inst 97 (17): , 2005 Tam Exemestane Tam Tam Exemestane DFS 3.3% Coombes RC, Lancet 369 (9561): , 2007 Tam 2y Exemestane Jahanzeb M, Clin Ther. 29(8):1535, 2007

23 Adjuvant Aromatase Inhibitors (Cont.) Adverse effectseffects : increase in: bone fractures & arthritis, arthralgia, myalgia, Cardiovascular events & hypercholesterolemia In the elderly: l 1 No data are available evaluating outcome and tolerance in elderly patients¹. 2 The optimal strategy in postmenopausal,(optimal timing & Duration) including elderly remains controversial² 3 Careful evaluation of concomitant comorbidities & different spectrum of toxicity of TAM vs AI and the cost/benefit ratio for AIth therapy in elderly³ l ³ 1 Crivellari,J Clin Oncol 25: Winer et al,asco Technology Assessment Group recommenations, JCO 23,619, Osborne CK, J Steroid Biochem Mol Biol 95: , 2005

24 3-Adjuvant Systemic Therapy in the Elderly l II- Chemotherapy 1 The EBCTCG overview 2000¹ : Improved both DES & OVS for women aged 50 to 69 years old Lesser benefit (proportional and absolute ) with increasing age 50 69y, Lacking data for women aged 70 2 Recent studies with standard regimens: Similar DFS to younger with N+, but : worse OVS in older( 65y ) from other causes of death, & higher rate of treatment related mortality), :CALGB² improved OVS in ER N+( 66y) MSKCC³, (>65y)Giordano et al⁴ 3 Data in these studies were derived from a small minority of elderly and,highly selected patients,, probably not representative of the overall elderly population⁵ 4 Optimalregimens and doses and schedules have notyet been defined, in elderly.⁵ 1 ECBRCG,Lancet.365: , Muss HB JAMA , Elkin EB, J Clin Oncol,,24,2757, Giordano SH, J Clin Oncol, 24:8s, 2006 (suppl; abstr521) 5 Crivellari CrivellariD J ClinOncol 25: ,

25 TABLE 4 Early Breast Cancer Trialists ili Collaborative Group (EBCTCG):Lancet CG) 365: ,

26 What is the role of anthracyclines in the adjuvant treatment 1 ECBRCG¹ Anthracyclins Vs CMF the absolute difference at 5 y = 3% at 10 y = 4% in Rec /Breast & overall morta 2 Higher rates of CHF with anthra containing tii regimens reported tdin healthy women 66 to 70y² A Report from SEER data : toxicity increased through 10 years of FU³. 3 A Systemiv Review of radomized trials of HER2⁴ 1 The Superior efficacy benefits for anthracyclines (when present) appears to derive from their effects on (topo II α amplification and/or overexpression in 1/3 of HER2 +pts ( 25% of all pts) and NOT HER2 about 8%of all breast cancers He questioned its use in the adjuvant treatment in all breast cancer pts considering its more toxicity as reported in BCIRG 006 trial (CHF & leukemia ) 1 ECBRCG,Lancet.365: , Giordano SH, J Clin Oncol, 24:8s, 2006 ASCO meeting (suppl; abstr 521) 3 Doyle JJ J Clin Oncol 23: , Slamon DJ, SABCS meeting 2007, [abstract 13 ]

27 Ongoing ( or pending ) Randomized Trials of Chemotherapy for Early Breast Cancer in Older Women Crivellari D J Clin Oncol 25: ,

28 Adjuvant systemic therapy in older women recommendations (Cont.) Risk Category St Gallen meeting 2007, Goldhirsch A, Annals of Oncology 18(7): ,2007 HER2 HER2+ ER+ ER- ER+ ER- Minimal N + Tum: size 2cm G= I No vas. Invas. HER2 - ER/PR+ E sequntial Intermediate N N at least one Tum: size >2cm G = 2 &3 Vascular invasion HER2 + ER/PR- + ER/PR+ and HER2 - E C C>E C C>E +Tr +Tr E C>E High N 1-3 N+ >4 + ER/PR- OR HER2+ C C>E C +Tr +Tr C>E C C>E C +Tr +Tr

30 I-Hormonal Therapy in Metastatic setting 1 - As 1 st line endocrine (-No prior endocrinal ) :-Aromatase Inhibitors (AI) ¹ - As 2 nd line (Progressed d on Adj Tam / off such therapy for more than 1 year ) :- AI / Fulvestrant² / Megace³/ Estrogen⁴ - Metronomic Oral Cycloph + letrozole Vs letrozole⁵ RR = (88%) & (72%) 2-The proper sequence of these therapies is currently not known. 3-Continue HT for as long as possible in older patients, until refractory mets. & Delay the use of chemotherapy Bisphosphonates Recommended For all patients with lytic bone metastases irrespective of age ⁶ 1 Gibson LJ,Cochrane Database Syst Rev (1): CD003370, Peethambaram P, Breast Cancer Res Treat. Mar;54(2):117-22, Annals of Oncology 18(1):64-69, Bottini A, J Clin Oncol 24: , :Buzdar A,J Clin Onco19,14 : , Pavlakis N The Cochrane Database of Systematic Reviews 2002

31 II-Chemotherapy in Metastatic setting 1 Goal of treatment is palliative¹ improving QL: Conroling cancer & Improving cancer related symtops 2 Combination VS sequential single agent? ² Sequential Single =reduce toxicity/improving QL. combination =higher RR and TTP and also higher toxicity, but not improved survival 3 Age is the main risk ikfactor for doxorubicin related i ltdchf ³ with older patients (65 years) showing a greater incidence of CHF after a cumulative doxorubicin dose of 400 mg/m2. 1 Crivellari,J Clin Oncol 25: Miles D, Oncologist 7:13 19, Swain SM Cancer 97:2869,

Choosing between different hormonal therapies. Rudy Van den Broecke UZ Ghent

Choosing between different hormonal therapies Rudy Van den Broecke UZ Ghent What is the golden standard in premenopausal hormonal sensitive early breast cancer? Ovarian Suppression alone 5 years Tamoxifen