hormone therapy in breast cancer patients with comorbidities · • bmd screening in breast cancer...

Hormone therapy in Breast Hormone therapy in Breast Cancer patientsCancer patients

with comorbiditieswith comorbidities

Diana CrivellariDiana CrivellariCentro di Riferimento OncologicoCentro di Riferimento Oncologico

AvianoAviano-- ITALYITALY

Madrid November 9th, 2007

Main issuesMain issues

•• Comorbidities in elderly womenComorbidities in elderly women

•• Hormonal drugs in adjuvant settingHormonal drugs in adjuvant setting

•• Hormonal drugs in metastatic Hormonal drugs in metastatic settingsetting

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 statusEvaluation of mental statusPolypharmacySocial support networkNutrition

Estrogen reduction

LDL Cholesterol

HDL Cholesterol

Increased Cardiovascular risk

Total n°of pts European Journal of Cancer 2005

2313 4185 1668 800

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

Breast carcinoma in elderly Breast carcinoma in elderly women: EIO experiencewomen: EIO experienceApril 1997 to February April 1997 to February 20022002

Total 2999 Total 2999 postmenopausal postmenopausal patientspatients

Young Post (50Young Post (50--64 yrs)64 yrs) 2052 pts (68.4%)2052 pts (68.4%)

Older Post (65Older Post (65--74 yrs)74 yrs) 801 pts (26.7%)801 pts (26.7%)

Elderly post (> 75 yrs)Elderly post (> 75 yrs) 146 pts (4.9%)146 pts (4.9%)

Gennari R et al Cancer 2004

Breast carcinoma in elderly Breast carcinoma in elderly women: EIO experiencewomen: EIO experience

ComorbidityComorbidity YPM YPM (50(50--64 yrs)64 yrs)

OPMOPM(65(65--74 yrs)74 yrs)

EPMEPM(> 75 yrs)(> 75 yrs)

% with % with HypertensionHypertension

12.712.7 21.521.5 22.622.6

% with % with Cardiovasc. Cardiovasc.

4.14.1 12.912.9 20.520.5

%with %with DiabetesDiabetes

0.90.9 1.41.4 0.70.7

Two or more Two or more comorbid dis.comorbid dis.

10.510.5 13.413.4 21.921.9

Gennari R et al Cancer 2004

Type of Type of treatmenttreatment

YPMYPM5050--64 yrs64 yrs

OPMOPM6565--74 yrs74 yrs

EPMEPM> 75 yrs> 75 yrs

PP--valuevalue

Surgery Surgery 20512051 801801 146146BCS (%)BCS (%) 73.973.9 76.976.9 72.672.6MastectomyMastectomy 22.322.3 20.220.2 23.323.3OtherOther 3.83.8 2.92.9 4.14.1 0.470.47Radiother.Radiother. 15061506 613613 104104

Receiving RTReceiving RT 86.686.6 84.584.5 54.754.7 <0.01<0.01Systemic Systemic therapytherapy

20322032 795795 141141

No treatmentNo treatment 4.74.7 5.45.4 19.119.1CT onlyCT only 22.822.8 12.612.6 6.46.4HT onlyHT only

CT + HTCT + HT

37.337.3

35.235.2

58.458.4

23.623.6

71.671.6

2.82.8 <0.01<0.01

Gennari et al Cancer 2004

Different options in adjuvant hormonal treatment

• Tamoxifen

• Aromatase inhibitors up-front

• Switching (tam AI or inverse)

• Extended adjuvant

Tamoxifen therapy outcome

373755113434545470+70+

35354545333354546060--6969

24243434202045455050--5959

2424292933004747<50<50

OS %OS %DFS %DFS %OS %OS %DFS %DFS %AgeAge

15 yrs (2005)15 yrs (2005)10 yrs (1998)10 yrs (1998)

EBCTCG, Lancet 1998 and 2005

J Gen Intern Med 2003

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)

Lipid lowering effect of Lipid lowering effect of SERMs?SERMs?•• YesYes–– Tamoxifen studiesTamoxifen studies

•• 10 trials, 6 vs placebo; 657 patients10 trials, 6 vs placebo; 657 patients

•• Decrease in cholesterol seen in all studiesDecrease in cholesterol seen in all studies

•• Median decrease: 12.5% (range 3Median decrease: 12.5% (range 3––17)17)•• Decrease due to LDL cholesterolDecrease due to LDL cholesterol

•• But no protection against coronary But no protection against coronary events despite favorable changes in events despite favorable changes in lipid levelslipid levels

Herrington & Klein Womens Health Issues 2001;11:95−102Barrett-Connor E et al New Engl J Med 2006;355:125-137

Aromatase inhibitors trialsStudy Modality N. of pts %

A/TamMedian age

yrsHR [ RFS]

ATAC Up Front 3215/3116 64 0.74

BIG1–98 Up Front 4003/4007 61 0.72

IES SwitchExemestane

2362/2372 64 0.70

ITA SwitchAnastrozole

208/218 63 0.42

ABCSG/ARNO SwitchAnastrozole

1618/1606 63 0.60

MA17 ExtendedLetrozole

2575/2582 62 0.57

ABCSG6a ExtendedAnastrozole

387/409 63 0.64

RFS [relapse Free Survival]

Howell A. Modified Lancet 2005

Adverse events in AI trialsAdverse events in AI trials

•• AI and tamoxifen associated with hot flushesAI and tamoxifen associated with hot flushes•• Compared with tamoxifen, AIs associated withCompared with tamoxifen, AIs associated with–– Higher incidence of arthralgia Higher incidence of arthralgia –– Lower incidence of gynecological symptoms Lower incidence of gynecological symptoms including lower rates of invasive endometrial including lower rates of invasive endometrial cancercancer–– Lower incidence of thromboembolic events Lower incidence of thromboembolic events (including grade 3(including grade 3––5 events, letrozole vs 5 events, letrozole vs tamoxifen)tamoxifen)

ATAC TOLERABILITY DATA

Adverse events (AEs) on A (%) T (%) p-valuetreatment or within n=3092 n=309414 days of discontinuationDrug-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 0.0005to 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 0.6Mansel R et al, ESMO 2006

BIG 1BIG 1--98 TRIAL DESIGN98 TRIAL DESIGN•• Postmenopausal women with receptorPostmenopausal women with receptor--positive early breast positive early breast

cancercancer•• International, randomized, doubleInternational, randomized, double--blind Phase III trialblind Phase III trial

8028 pts Randomized between March 1998 and May 2003

7963 received therapy

Includes initial treatment Arms C & D

TamoxifenLetrozole

LetrozoleLetrozole Tamoxifen

RANDOMIZE

0 2 5YEARS

ABCD

Tamoxifen

Coates et al. ASCO 2007

Data CollectionData Collection——AEsAEs


OBJECTIVEOBJECTIVE

To compare tamoxifen and letrozole To compare tamoxifen and letrozole with regard to the incidence and with regard to the incidence and timing of cardiovascular AEs, timing of cardiovascular AEs, including baseline cardiac risk including baseline cardiac risk factors, prior cholesterol, and factors, prior cholesterol, and serial cholesterol measurements.serial cholesterol measurements.


Cardiovascular AEsCardiovascular AEs


CONCLUSIONSCONCLUSIONS•• Taken together, cardiovascular AEs were relatively rare.Taken together, cardiovascular AEs were relatively rare.•• Cholesterol values decreased over time on both treatments, Cholesterol values decreased over time on both treatments,

but the decrease was greater and earlier on tamoxifen.but the decrease was greater and earlier on tamoxifen.•• Prior hypercholesterolemia was associated with an increase in Prior hypercholesterolemia was associated with an increase in

grade 3grade 3--5 cardiac AEs.5 cardiac AEs.•• Overall incidence of cardiac AEs was similar on both Overall incidence of cardiac AEs was similar on both

treatments. An unplanned subset analysis suggested a possible treatments. An unplanned subset analysis suggested a possible excess of Gr 3excess of Gr 3--5 cardiac AEs on letrozole. These events 5 cardiac AEs on letrozole. These events were reported at low frequency on both arms. were reported at low frequency on both arms.

•• Any increased incidence of cardiac AEs on letrozole seems to Any increased incidence of cardiac AEs on letrozole seems to be outweighed by the superior control of locobe outweighed by the superior control of loco--regional and regional and distant recurrence afforded by letrozole compared with distant recurrence afforded by letrozole compared with tamoxifen.tamoxifen.

•• Different methods and rigor of AE collection make crossDifferent methods and rigor of AE collection make cross--study comparisons with other AI trials inappropriate.study comparisons with other AI trials inappropriate.


BIG 1BIG 1--98 TRIAL DESIGN98 TRIAL DESIGN•• Postmenopausal women with receptorPostmenopausal women with receptor--positive early breast positive early breast

cancercancer•• International, randomized, doubleInternational, randomized, double--blind Phase III trialblind Phase III trial

TamoxifenLetrozole

LetrozoleLetrozole Tamoxifen

RANDOMIZE

0 2 5YEARS

ABCD

Tamoxifen

8010 pts randomized between March 1998 and May 2003

4922 pts allocated to five years of letrozole or tamoxifen

BIG 1BIG 1--98 TRIAL98 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 METHODSOBJECTIVE and METHODSTo explore potential differences in To explore potential differences in efficacy, treatment completion, and efficacy, treatment completion, and adverse events in older women receiving adverse events in older women receiving adjuvant tamoxifen or letrozole for five adjuvant tamoxifen or letrozole for five years in the BIG 1years in the BIG 1--98 trial.98 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.

Baseline characteristics of patients in BIG 1 study

Age groupAge groupAge <=64Age <=64 Age 65Age 65--7474 Age Age ≥≥7575

TREATMENTTREATMENT TREATMENTTREATMENT TREATMENTTREATMENT

LetrozoleLetrozole TamoxifenTamoxifen LetrozoleLetrozole TamoxifenTamoxifen LetrozoleLetrozole TamoxifenTamoxifen

Mean age, yrs Mean age, yrs (SD)(SD)

56.9 56.9 (4.8)(4.8)

56.9 56.9 (4.8)(4.8)

69.0 69.0 (2.8)(2.8)

68.8 68.8 (2.8)(2.8)

78.0 78.0 (2.7)(2.7)

77.0 77.0 (2.5)(2.5)

Body mass Body mass index, kg/m2 index, kg/m2 (SD)(SD)

26.60 26.60 (5.1)(5.1)

26.71 26.71 (5.2)(5.2)

27.22 27.22 (4.8)(4.8)

27.27 27.27 (5.1)(5.1)

26.70 26.70 (4.3)(4.3)

27.08 27.08 (4.3)(4.3)

Cholesterol,Cholesterol,mg/dLmg/dL

(SD)(SD)

235.3 235.3 (44.2)(44.2)

235.3 235.3 (42.8)(42.8)

231.5 231.5 (41.8)(41.8)

231.4 231.4 (41.8)(41.8)

226.8 226.8 (38.3)(38.3)

227.4 227.4 (43.9)(43.9)

Total NTotal N°° of ptsof pts 15451545 15661566 757757 733733 146146 148148

1590 294





1590 294

Percentage with Percentage with history of receiving history of receiving medication for medication for hypercholesterolemiahypercholesterolemia

6.96.9 5.85.8 12.712.7 10.410.4 13.013.0 8.88.8

HypertensionHypertension 24.124.1 23.623.6 41.141.1 42.742.7 61.061.0 51.451.4Diabetes (requiring Diabetes (requiring treatment other treatment other than diet)than diet)

3.53.5 3.73.7 7.37.3 8.68.6 10.310.3 10.810.8

Cerebrovascular Cerebrovascular accident accident (CVA)/Transient (CVA)/Transient ischemic attack(TIA)ischemic attack(TIA)

1.41.4 1.11.1 2.42.4 2.02.0 4.84.8 4.14.1





Percentage with Percentage with disease history of disease history of thromboembolic thromboembolic eventsevents

2.32.3 2.02.0 5.05.0 5.05.0 4.84.8 2.72.7

Any cardiac eventsAny cardiac events 6.56.5 5.95.9 12.512.5 14.314.3 23.323.3 19.619.6OsteoporosisOsteoporosis 2.52.5 3.13.1 5.25.2 5.55.5 10.310.3 7.47.4

Percentage with Percentage with history of receiving history of receiving bisphosphonatesbisphosphonates

0.10.1 0.30.3 0.50.5 0.10.1 0.70.7 00

Bone fracturesBone fractures 7.87.8 8.78.7 11.211.2 10.110.1 16.416.4 15.515.5

757 733 146 148N°of pts

RESULTSRESULTS

•• Median followMedian follow--up 40.4 months.up 40.4 months.•• Patients 75 years of age and older Patients 75 years of age and older were less likely to complete trial were less likely to complete trial treatment, but at rates that were treatment, but at rates that were similar in the two treatment groups: similar in the two treatment groups: 39.7% (58/146) did not complete 39.7% (58/146) did not complete letrozole and 37.2% (55/148) did not letrozole and 37.2% (55/148) did not complete tamoxifen (p = 0.72).complete tamoxifen (p = 0.72).

Types of AEsTypes 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)Adverse Events (AEs)Bone FracturesBone FracturesSTEPP analysis shows that the incidence of bone fractures, obserSTEPP analysis shows that the incidence of bone fractures, observed ved more often in the letrozole group, did not differ by agemore often in the letrozole group, did not differ by age. .

Frequency Distribution of Osteoporosis at Spine,Hip, Femoral Neck by age:

Total 1346 Total 1346 menopausal womenmenopausal women Spine (%)Spine (%) Hip (%)Hip (%) Femoral Femoral

Neck (%)Neck (%)50 yrs or younger50 yrs or younger 5.65.6 5.25.2 5.95.9

51 51 –– 55 yrs55 yrs 9.39.3 6.46.4 9.09.0

56 56 –– 60 yrs60 yrs 10.610.6 6.86.8 1010

61 61 –– 65 yrs65 yrs 15.915.9 14.514.5 14.214.2

66 66 –– 70 yrs70 yrs 23.723.7 19.719.7 20.420.4

71 71 –– 75 yrs75 yrs 17.117.1 22.122.1 16.616.6

76 yrs and older76 yrs and older 17.817.8 25.325.3 23.923.9

Weinstein L Obstet Gynecol Vol 93,1999

ASCO bone health guidelinesASCO bone health guidelines

•• BMD screening in breast cancerBMD screening in breast cancer–– All women aged > 65 yearsAll women aged > 65 years–– All women aged 60All women aged 60––64 years with risk 64 years with risk factorsfactors–– Postmenopausal women of any age Postmenopausal women of any age receiving AIsreceiving AIs–– Premenopausal women with therapyPremenopausal women with therapy--associated premature menopauseassociated premature menopause

•• Repeat BMD annually after initial Repeat BMD annually after initial examexam

Hillner et al. J Clin Oncol 2003;21:4042–57

8

ASCO 2003 Guidelines for Osteoporosis ASCO 2003 Guidelines for Osteoporosis Screening for Breast Cancer PatientsScreening 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.

Black D M et al

Lyles KW et al New Engl J Med 2007

35% risk reduction

Lyles KW et al New Engl J Med 2007

28% risk reduction

TAM vs AIs:

TAM AIs

Controlateral tumors

Osteoporosis

Arthralgias

Serum lipids

Contralateral tumors

DVT

Endometrial cancer

Hot Flashes

Neurocognitive function?

Physicians should begin to individualize treatment in elderly patients based on comorbidities and risk factors

Recurrence hazard rates are dependent Recurrence hazard rates are dependent on knownon known prognostic factorsprognostic factors

0

5

10

15

20

25

0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5Year

Haz

ard

of r

ecur

renc

e by

yea

rly

inte

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TotalNode 0Node 1-3Node (4+)Tumour size (<1cm)Tumour size (1.1-3cm)Tumour size (>3cm)ER+ER-PremenPostmen

•• Prominent early peak of recurrences (~ 3 yrs) in absence Prominent early peak of recurrences (~ 3 yrs) in absence of adjuvant therapyof adjuvant therapy

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

WHAT’S GOING ONADJUVANTADJUVANT 11°° LINELINE 22°° LINE LINE

TAMOXIFENTAMOXIFEN LETROZOLELETROZOLEEXEMESTANEEXEMESTANEANASTROZOLEANASTROZOLE

EXEMESTANE or EXEMESTANE or FULVESTRANTFULVESTRANTLETROZOLE or LETROZOLE or FULVESTRANTFULVESTRANTEXEMESTANE or EXEMESTANE or FULVESTRANTFULVESTRANT

ANASTROZOLE orANASTROZOLE orLETROZOLE UP FRONTLETROZOLE UP FRONT

TAMOXIFEN TAMOXIFEN or EXEMESTANE or EXEMESTANE or FULVESTRANTor FULVESTRANT

FULVESTRANT FULVESTRANT or EXEMESTANE or EXEMESTANE or TAMOXIFENor TAMOXIFEN

SWITCH TAM +SWITCH TAM +EXEMESTANE or EXEMESTANE or ANASTROZOLEANASTROZOLE

LETROZOLE LETROZOLE or FULVESTRANTor FULVESTRANT

FULVESTRANT FULVESTRANT or EXEMESTANEor EXEMESTANEor ANASTROZOLEor ANASTROZOLE

EXTENDEDEXTENDEDTAMOXIFEN + TAMOXIFEN + LETROZOLELETROZOLE

FULVESTRANT FULVESTRANT or EXEMESTANEor EXEMESTANE ANASTROZOLEANASTROZOLE

or FULVESTRANT or FULVESTRANT

Randomized phase III studiesRandomized phase III studiesof antiof anti--Aromatase Agents vs TamoxifenAromatase Agents vs Tamoxifen

as Initial Therapy of Metastatic Breast Canceras 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 trialsand 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 = 0.8795% 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 Fulvestrant: Prospective Combined Analysis Analysis -- Best Objective ResponseBest Objective Response

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)

Number of patients (%)Anastrozole

(n=423)Fulvestrant(n=428)

*Odds ratio (95.14% CI):1.21 (0.84–1.74); p=0.31

Robertson JFR et al. Cancer 2003; 98: 229–238.

Mean Mean ±± SD changes in plasma lipidSD changes in plasma lipidparameters during fulvestrant treatment parameters during fulvestrant treatment (n=31)(n=31)

ASCO 2007, Abstract 1085

ActivityActivity

•• Clinical Benefit 43% Clinical Benefit 43% –– 12 patients SD 12 patients SD ≥≥ 24 weeks24 weeksmedian TTP 6.5 median TTP 6.5 ±± 3.9 mesi3.9 mesi

Lipid lowering effect of fulvestrant in hormone-sensitive metastatic breast cancer patients A. Camerini, D. Amoroso et al.

ASCO 2007 Abs 1085ASCO 2007 Abstract 1085

ConclusionsConclusions•• More than 40% of HERMore than 40% of HER--2 +, heavily pretreated and 2 +, heavily pretreated and

with numerous metastatic sites, received a clinical with numerous metastatic sites, received a clinical benefitbenefit

•• Fulvestrant was active also in visceral sitesFulvestrant was active also in visceral sites

•• Therapy was well toleratedTherapy was well tolerated

FULVESTRANT IN THE TREATMENT OF HER2-POSITIVE ADVANCED BREAST CANCER (ABC)JFR Robertson, G Steger, P Neven, S Barni

Courtesy of Dr Barni, ECCO 2007, Poster 2127

CONCLUSIONS

••Patients at risk for thromboembolic disease should Patients at risk for thromboembolic disease should avoid tamoxifenavoid 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

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hormone therapy in breast cancer patients with comorbidities · • bmd screening in breast cancer...

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