A Case Based Approach to Hormone Therapy

Hope S. Rugo, MDProfessor of Medicine

Director, Breast Oncology and Clinical Trials Education

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, CA

Clinical UpdatesOptimizing Endocrine Therapy for Early Breast Cancer

Case 1

• A healthy 48 year old woman discovers a mass in the central right breast while showering. A mammogram 6 months before showed dense breasts without focal mass.– Exam: 2 cm central breast mass, no palpable axillary nodes

– Ultrasound: 1.8 cm ill-defined hypoechoic mass

• Ultrasound guided core biopsy reveals a grade II invasive ductal carcinoma with lymphovascular invasion

Case I (cont.)

• Lumpectomy and sentinel lymph node biopsy reveals a 2.1 cm grade II invasive ductal cancer that is ER+, PR+ and HER2 1+ (negative) by IHC, one sentinel lymph node is positive for 0.8 cm of invasive cancer

– Completion axillary lymph node dissection reveals 1 additional positive node for a total of 2/15 positive nodes

• She is well with no medical problems and is seeing you to discuss adjuvant therapy

– She is premenopausal, although she notes skipped menses every few months for the last year

Question

• The patient receives adjuvant chemotherapy and has completed radiation. Her last menstrual period was the month before starting chemotherapy.

• You recommend:1. An aromatase inhibitor (AI) for 5 years

2. Tamoxifen for 2-3 years followed by an AI for a total duration of 5 years

3. Tamoxifen for 5 years followed by discussion of extended adjuvant hormone therapy with an AI

4. Ovarian suppression or ablation with tamoxifen

5. Ovarian suppression or ablation with an AI

Important Points to Consider

• How to choose the best hormone therapy for your patient?

– When is a woman in menopause?

– When are AIs safe to give to perimenopausal women?

– Should ovarian suppression be used routinely?

What Hormone Therapy?

• Premenopausal at treatment start

– Amenorrheic after chemotherapy does not mean menopause

– Safest approach upfront is tamoxifen

• Options include

– Tamoxifen for 5 years followed by an AI

– Tamoxifen for 2-3 years to guarantee menopause, then AI to complete 5 years of therapy

– Tamoxifen with ovarian suppression if ovaries recover

Estradiol, FSH and Amenorrhea Following Chemotherapy for Breast Cancer

• Braverman et al, 2002– 16 women with amenorrhea

• 10 with E2 > 40pg, 8 were amenorrheic > 6 months

• 5 with E2 > 40pg but FSH > 40

– Ovarian function may persist for months, and possibly years after chemotherapy induced amenorrhea

• Amenorrhea is not menopause

• AIs stimulate ovarian function!– Beware of AIs in young women with chemotherapy induced

amenorrhea

AIs Stimulate Gonadotropin Production in Women Whose Ovaries are Still Active; Resulting in Ovarian

Stimulation and Follicle Growth

De Ziegler et al, J Steroid Biochem and Biol, 2005

Chemotherapy-induced AmenorrheaRoyal Marsden Experience - Case Series

45 women with CIA* on AIs

(16 upfront, 20 switching, 9 extended)

• Median age: 47 (range 39-52)

• 33 biochemically confirmed ovarian suppression before therapy

• 12 (27%) recovered ovarian function

– menses [10],

– pregnancy without menses [1],

– biochemical assay without menses [1]

• Median duration of amenorrhea before recovering ovarian function 12 months (range 4-59)

Smith I et al, JCO 2006

* Chemotherapy-Induced Amenorrhea

Criteria for Determining Menopause (NCCN v.2.2008)

• Prior bilateral oophorectomy

• Age > 60 y

• Age < 60 y and amenorrheic for 12 or more months in the absence of CT, Tam, toremifene or ovarian suppression and FSH and estradiol in the post-menopausal range

• If taking tamoxifen or toremifene, and age < 60 y, then FSH and plasma estradiol level in post-menopausal ranges

• It is not possible to assign menopausal status in women receiving LHRH agonist or antagonist

• In women pre-menopausal (by hormonal status and/or with menses) at the beginning of adjuvant therapy CT-induced amenorrhea is not a reliable indicator of menopausal status

IES - Intergroup Exemestane Study Cumulative HR Overall Survival

ExemestaneTamoxifen

Annual Hazard Rate, % (95% CI)

ITT 1 2 3 4 5

Exemestane 0.8 (0.5, 1.2) 1.8 (1.3, 2.5) 2.2 (1.6, 2.9) 3.6 (2.8, 4.5) 2.3 (1.6, 3.4)

Tamoxifen 1.0 (0.7, 1.5) 2.4 (1.8, 3.1) 2.5 (2.0, 3.3) 3.2 (2.5, 4.1) 2.9 (2.1, 4.1)

ITT ER+/Unknown

End

oftreatm

ent

0.02

0.00

0.04

0.06

0.08

0.10

0.12

0.14

Cum

ula

tive

Rat

e

0 1 2 3 4 5

Time since randomization (years)

0.00

End

oftreatm

ent

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0 1 2 3 4 5

Time since randomization (years)

Cum

ula

tive

Rat

e

Jassem, J. et al Anticancer Drugs. 2008 Feb;19 Suppl 1:S3-7.

IES - Intergroup Exemestane StudyConsistency of OS Across Subgroups

0.84 (0.61, 1.18)0.75 (0.60, 0.95)

0.85 (0.67, 1.07)

0.84 (0.69, 1.02)0.83 (0.52, 1.32)

0.83 (0.65, 1.05)0.84 (0.63, 1.13)

1.01 (0.70, 1.47)

0.70 (0.52, 0.95)

0.90 (0.67, 1.22)

0.83 (0.69, 0.99)

0.81 (0.60, 1.09)

Favors TamoxifenFavors Exemestane

OS (Adjusted)*

Age >70 yrs (1153)

Age 60-69 yrs (1969)

Age <60 yrs (1480)

Prior tam >2.5 yrs (1838)

Prior tam ≤2.5 yrs (2764)

ER unknown (560)

ER positive (4042)

Previous CT (1499)

No previous CT (3103)

Nodes positive (2038)

Nodes negative (2384)

Hazard ratio (95% CI)

0.5 0.6 0.8 1.0 1.2 1.5

CT=chemotherapy

*Adjusted for Nodal Status, Chemotherapy Use & HRT Use

ER+/Unknown

p=0.04

HR (95% CI)

Coombes RC et al. Lancet 2007; 369: 559-70.

IESn=4,274 0.76

ARNOn=979 0.62

ABCSGn=2579 0.61

ITAn=448

0.42

Results of Switch Trials

exemestane anastrozole tamoxifen

1.0AIs

betterTAM

better

HR DFS

Boccardo, F et al Ann Oncol. 2006 Jun;17 Suppl 7:vii10-4, Jakesz, R. et al Lancet. 2005 Aug 6-12;366(9484):455-62.

ABCSG12 ANA Does Not Improve DFS vs TAM in 1800

Premenopausal Women with Early Stage Disease

100

90

80

70

60

50

40

30

20

10

00 12 24 36 48 60 72 84

Time since randomization, months

Dis

ease

-fre

e su

rviv

al, %

No. of Hazard ratio (95% CI)events vs TAM P value

ANA 72 1.096 (0.78 to 1.53) .593

TAM 65

No. at risk

900 834 718 552 411 243 129 50

903 844 725 540 411 255 139 51

TAM

ANA

Median follow-up = 48 months.Gnant et al, NEJM 2009

Overall: 4-year DFS = 92.4%; 4-year OS = 97.7%30% with node positive disease

MA.17: Summary of Efficacy

Goss et al. J Natl Cancer Inst. 2005;97:1262.

DFS Distant DFS OS

Node+

patients

HR 0.61*

(95% CI, 0.45-0.84)

HR 0.53*

(95% CI, 0.36-0.78)

HR 0.61*

(95% CI, 0.38-0.98)

All patients HR 0.58; P<0.001 HR 0.60; P<0.002 HR 0.82+; P=0.3

Node–

patients

HR 0.45*

(95% CI, 0.27-0.75)

HR 0.63

(95% CI, 0.31-1.27)

HR 1.52

(95% CI, 0.76-3.06)

Extended adjuvant letrozole significantly decreased overall risk of recurrence by 42% (4.2% absolute reduction) and risk of developing distant metastases by 40% compared with placebo.

*Statistically significant benefit of letrozole. +Absolute increase of 0.4% for letrozole.HR = hazard ratio; CI = confidence interval.

Tamoxifen

Tamoxifen

ExemestaneTestPost-meno-

pause

2-3 years 2-3 years

Yes

No

Peri-menopausal WomenAssessment and Therapy

Switch to AI in peri-menopausal patients is an option but only if

close monitoring of ovarian function is performed

Adjuvant Endocrine Therapy Trials In Hormone-responsive Pre-menopausal

Breast Cancer Patients

StudyStudy

Design Patient Population Questions

SOFT(IBCSG 24-02)

TAM 5yvs

TAM 5 y + OFSvs

EXE 5 y + OFS

2,700 pre-menopausal women with endocrine responsive

disease treated with no adjuvant chemo or remain pre-

menopausal after chemo

Does OS add to TAM (or EXE) in pre-menopausal women not treated with chemotherapy?

Does OFS add to chemo in pre-menopausal women?

TEXT(IBCSG 25-02)

OFS = TAM 5 yvs

OFS + EXE 5 y

2,025 pre-menopausal women with endocrine responsive disease and candidates for

OFS, and who may or may not receive chemo

Is an AI superior to TAM in pre-menopausal women treated with

OFS?

ABC SG 12OFS + TAM

vsOFS + ANA

1,750 pre-menopausal women with endocrine responsive

disease

Is an AI superior to TAM in pre-menopausal women treated with

OFS?

OFS=Ovarian Function Suppression

ZOL Significantly Improves DFS Compared With Endocrine Therapy Alone

100

90

80

70

60

50

40

30

20

10

00 12 24 36 48 60 72 84

Time since randomization, months

Dis

ease

-fre

e su

rviv

al, %

No. of Hazard ratio (95% CI)events vs No ZOL P value

ZOL 54 0.64 (0.46, 0.91) .012

No ZOL 83

Median follow-up = 48 months.Gnant et al, NEJM 2009

No. at risk No ZOL 904 832 713 537 407 241 145 47 ZOL 899 846 730 555 414 257 123 54

What Would I Do?• Hormonal therapy

– This patient is likely to recover some degree of ovarian function• I would use tamoxifen upfront followed by an AI when clearly

menopausal, similar to the sequencing used in the IES trial

– Duration of therapy• Based on MA.17, I would consider extending the duration of AI

therapy to 5 years if given following a course of tamoxifen

• This patient would also be eligible for ongoing trials evaluating duration of AI therapy

– Consider bisphosphonate trials……

Case 2 Case 2 • A 62 year old healthy postmenopausal woman A 62 year old healthy postmenopausal woman

is diagnosed with:is diagnosed with:– 1.5 cm infiltrating ductal carcinoma1.5 cm infiltrating ductal carcinoma– Grade II, KI-67 20%Grade II, KI-67 20%– ER-positive (50%)/PR-negative (5%)ER-positive (50%)/PR-negative (5%)– HER-2 negative by FISHHER-2 negative by FISH

• She undergoes lumpectomy and sentinel lymph She undergoes lumpectomy and sentinel lymph node biopsynode biopsy– Margins of resection are negativeMargins of resection are negative– One sentinel node is positive for carcinomaOne sentinel node is positive for carcinoma– Completion axillary dissection reveals a total of 4 Completion axillary dissection reveals a total of 4

out of 20 nodes positiveout of 20 nodes positive

QuestionQuestion

She is treated with an anthracycline and taxane chemotherapy She is treated with an anthracycline and taxane chemotherapy regimen and radiationregimen and radiation

You then recommend: You then recommend:

– 5 years of tamoxifen5 years of tamoxifen

– 5 years of an aromatase inhibitor5 years of an aromatase inhibitor

– 2 years of tamoxifen followed by 3 years of an aromatase inhibitor2 years of tamoxifen followed by 3 years of an aromatase inhibitor– 2 years of an aromatase inhibitor followed by 3 years of tamoxifen2 years of an aromatase inhibitor followed by 3 years of tamoxifen– 5 years of tamoxifen followed by 5 years of an aromatase inhibitor5 years of tamoxifen followed by 5 years of an aromatase inhibitor– Use of CYP2D6 testing to help in the decision of what hormonal Use of CYP2D6 testing to help in the decision of what hormonal

therapy to usetherapy to use

Breast Cancer Adjuvant TherapyBreast Cancer Adjuvant TherapyReplacing 5 Years of Tamoxifen Replacing 5 Years of Tamoxifen

as the Gold Standardas the Gold Standard

AIs asInitial Therapy

AIs After2-3 Yrs of TAM

AIs After5 Years of TAM

TAM X 5 Yrs

AI X 5 Yrs TAM X 2-3 AI X 2-3

TAM X 5 YrsTAM X 5 Yrs

PLAC X 5 Yrs

AI X 5 Yrs

Three Strategies

Relative Reductions in Relative Reductions in DFS EventDFS Event As Reported in Eight AI Adjuvant TrialsAs Reported in Eight AI Adjuvant Trials

Per

cent

Per

cent

00

1010

2020

3030

4040

5050

6060

7070

24%

IESIES56 m56 m

ITAITA52 m52 m

After 2-3 yrs After 2-3 yrs of TAMof TAM

58%

18%

ABCSG/ABCSG/ARNOARNO72 m72 m

Boccardo et al. ASCO 2005Coombes RC et al. ASCO 2006Jakesz et al. SABCS 2008

AnastrozoleAnastrozoleLetrozoleLetrozoleExemestaneExemestane

MA.17MA.1730 m30 m

After 5 yrs After 5 yrs of TAMof TAM

42%

ABCSG-6ABCSG-660 m60 m

36%

Goss et al. JNCI 2005Jakesz et al. ASCO 2005Mamounas et al. JCO 2008

32%

B-33B-3330 m30 m

Up-FrontUp-Front

ATACATAC100 m100 m

15% 12%

BIGBIG76 m76 m

ATAC trialists’ group. Lancet Oncol 2008Mouridsen H, et al. SABCS 2008Jones S, et al: SABCS 2008

11%

TEAMTEAM2.75 y2.75 y

BIG 1-98 TrialBIG 1-98 Trial

Mouridsen. SABCS. 2008 (abstr 13); BIG 1-98 Collaborative Group. N Engl J Med. 2005;353:2747; Coates. J Clin Oncol. 2007;25:486.

SURGERY

YearsYears

Tamoxifen

Letrozole

Letrozole

Tamoxifen

Tam Let

Let Tam

N=911N=911

N=917N=917

N=1548N=1548

N=1546N=1546

N=1548N=1548

N=1540N=1540

N=1828N=1828Enrolled Enrolled 1998-20001998-2000

N=6182N=6182Enrolled Enrolled 1999-20031999-2003

N=8010N=8010

00 22 55

Previous analyses show 5 yrs of upfront letrozole significantly prolongs DFS and time to distant recurrence vs upfront tamoxifen

619 patients crossed over from tamoxifen only to letrozole arm

R

DFS=disease-free survival.

BIG 1-98: Sequential Therapy TTRBIG 1-98: Sequential Therapy TTR

TTR=time to recurrence.

OverallOverallTamTam Let vs LetLet vs Let

By Nodal Status*By Nodal Status*

Let Let TamTam vs Let vs Let

*42% of population is node+; 58% is node–.

OverallOverall By Nodal Status*By Nodal Status*

2200

1155

1100

55

00

2200

1515

1100

55

00

Bre

as

t C

an

ce

r R

ec

urr

en

ce

(%

)B

rea

st

Ca

nc

er

Re

cu

rre

nc

e (

%)

Bre

as

t C

an

ce

r R

ec

urr

en

ce

(%

)B

rea

st

Ca

nc

er

Re

cu

rre

nc

e (

%)

2200

1155

1100

55

00

2200

1515

1100

55

00

00 11 22 33 44 55 66Years From RandomizationYears From Randomization Years From RandomizationYears From Randomization

Bre

as

t C

an

ce

r R

ec

urr

en

ce

(%

)B

rea

st

Ca

nc

er

Re

cu

rre

nc

e (

%)

Bre

as

t C

an

ce

r R

ec

urr

en

ce

(%

)B

rea

st

Ca

nc

er

Re

cu

rre

nc

e (

%)

Years From RandomizationYears From Randomization Years From RandomizationYears From Randomization

00 11 22 33 44 55 66

00 11 22 33 44 55 6600 11 22 33 44 55 66

4.14.1

9.19.1

2.52.5

7.37.3

7.97.9

0.90.9

14.714.7

4.74.7

1.31.3

3.53.5

4.94.9

12.12.44

Node+Node+

NodeNode––

Tam LetTam LetLetrozoleLetrozole

Tam LetTam LetLetrozoleLetrozole

Let TamLet TamLetrozoleLetrozole

Let TamLet TamLetrozoleLetrozole

2.52.5

2.52.5

7.37.3

7.37.3

4.74.7

3.93.91.51.5

0.90.9

3.53.5

3.93.9

12.512.5

12.412.4Node+Node+

NodeNode––

Mouridsen. SABCS. Mouridsen. SABCS. 2008 (abstr 13). (abstr 13).

Recurrences Breast Cancer Deaths

More Than Half of Breast Cancer More Than Half of Breast Cancer Recurrences and Deaths Occur Post-TamoxifenRecurrences and Deaths Occur Post-Tamoxifen

Adapted with permission. Early Breast Cancer Trialists’ Collaborative Group Meeting, 2000.

YearsYears

85.285.2

76.176.1

68.268.2

73.773.7

62.762.7

54.954.9

68%68%

55%55%

00

2020

4040

6060

8080

100100

00 55 1010 1515

TamoxifenTamoxifenControlControl

15%15% 17%17%

00

2020

4040

6060

8080

100100

00 55 1010 1515

73%73%64%64%

80.980.9

73.073.087.887.8

73.273.2

64.064.0

YearsYears

TamoxifenTamoxifenControlControl

9%9% 18%18%

91.491.4

% o

f pa

tient

s%

of

patie

nts

% o

f pa

tient

s%

of

patie

nts

NSABP B-42NSABP B-42Trial Evaluating Adjuvant AI DurationTrial Evaluating Adjuvant AI Duration

AI X 5 yrs

AI X 3-2 yrs

TAM X 2-3 yrs

Letrozole X 5 yrs

Placebo X 5 yrs

Postmenopausal, Disease-free, Stage I, II, or III invasive BC Postmenopausal, Disease-free, Stage I, II, or III invasive BC at diagnosis ER-positive and/or PgR-positiveat diagnosis ER-positive and/or PgR-positive

Planned Accrual: 3,840

Other Duration Trials:NCIC MA.17RSole – intermittent dosing

Decreased Tamoxifen MetabolismDecreased Tamoxifen Metabolism

Non-compliance X

Enzymatic Repression Inhibitory Influences

Adapted from: Stearns, V et al. J Natl Cancer Inst. 2003 Dec 3;95(23):1758-64.

CYP2D6 Genotype and EndoxifenCYP2D6 Genotype and Endoxifen

0

20

40

60

80

100

120

140

160

180

Wt/Wt Wt/*4 *4/*4

Jin Y et al: J Natl Cancer Inst 97:30, 2005

CYP2D6*4CYP2D6*4 (most common genetic variant associated with the CYP2D6 poor metabolizer state)(most common genetic variant associated with the CYP2D6 poor metabolizer state)

P<0.001, rP<0.001, r22=0.24=0.24

Plasma Endoxifen

(nM)

RFS According to CYP2D6 (*4)RFS According to CYP2D6 (*4) Metabolizer Status in Women Receiving TAM as Adjuvant TherapyMetabolizer Status in Women Receiving TAM as Adjuvant Therapy

0

20

40

60

80

100

0 2 4 6 8 10 12

%%

Years after randomizationYears after randomization

2-year RFS2-year RFSEM 98%EM 98%IM 92%IM 92%PM 68%PM 68%

EM (n=115)EM (n=115)

IM (n=40)IM (n=40)

PM (n=16)PM (n=16)

Log rank Log rank

PP=0.009=0.009

Goetz M et al. Breast Cancer Res Treat 101:113-121, 2007Goetz M et al. Breast Cancer Res Treat 101:113-121, 2007

E: Extensive I: IntermediateP: Poor M: Metabolizer

Multivariate HRMultivariate HR(PM+IM/EM)=1.74(PM+IM/EM)=1.74PP=0.017=0.017

n=171n=171

Incidence of Moderate or Severe Incidence of Moderate or Severe Hot Flashes and CYP2D6 StatusHot Flashes and CYP2D6 Status

Genotype % of Patients With Moderate or Severe Hot Flashes

CYP2D6 *4/*4CYP2D6 *4/*4

CYP2D6 *4/WT or Wt/WTCYP2D6 *4/WT or Wt/WT

0%0%

20%20%

Goetz et al J Clin Oncol. 2005;23(36):9312-8.

Breast Cancer and Relevant Inhibitors of CYP2D6

Strong Inhibitors

Generic / Brand Names

Fluoxetine Prozac®

Paroxetine Paxil®

Qunidine Cardioquin®

Bupropion Wellbutrin®

Adapted from: http://medicine.iupui.edu/clinpharm/ddis

Non or weak Inhibitors

Generic / Brand Names

Venlavaxine Effexor®

Citalopram Celexa®

Escitalopram Lexapro®

Sertraline Zoloft® (moderate?)

Moderate Inhibitors

Generic / Brand Names

Diphenhydramine Benadryl®

Thioridazine Mellaril®

Duloxetine Cymbalta®

Cimetidine Tagamet®

Amiodarone Cordarone®

What Would I Do in This Case?What Would I Do in This Case?• She has a high risk cancer and is clearly postmenopausalShe has a high risk cancer and is clearly postmenopausal

• I would start with an aromatase inhibitorI would start with an aromatase inhibitor

• If she has significant side effects, consider changing to If she has significant side effects, consider changing to tamoxifen after two or three yearstamoxifen after two or three years

• The optimal duration of hormonal therapy has not yet been The optimal duration of hormonal therapy has not yet been defined, however:defined, however:– Several trials are evaluating the impact of longer duration AI Several trials are evaluating the impact of longer duration AI

therapytherapy

– When this patient is five years out from start of hormone therapy, When this patient is five years out from start of hormone therapy, additional data should be availableadditional data should be available

– For patients on therapy now, consider tolerance of hormone For patients on therapy now, consider tolerance of hormone therapy, co-morbidiity and risk of relapse in your recommendation therapy, co-morbidiity and risk of relapse in your recommendation regarding treatment durationregarding treatment duration

Conclusion

• The future for hormone receptor positive breast cancer is very exciting and will help us to understand the pathways responsible for resistance to hormone therapy – and then use appropriate targeted agents to prevent recurrence and improve the treatment of advanced disease.