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Early Breast Cancer Updates

Why

Effect of adjuvant therapy : adjuvant hormonal with Tam. (ER +ve)

• 40% decrease in risk of recurrence by 5 years.

• 34% decrease in br. cancer mortality by 5 years.

adjuvant polychemotherapy .• < 50 years old: 10% decrease in br.

cancer mortality by 15 years.• 50-69 years old: 3% decrease in risk of

br. cancer mortality by 15 years

Meta-analyses of adjuvant therapies for women with early breast cancer: the Early Breast Cancer Trialists’ Collaborative Group overview Annals of Oncology

17 (Supplement 10): x59–x62, 2006.

Outline

•Molecular Classification.•Adjuvant Chemotherapy.•Adjuvant Hormonal.•Adjuvant Targeted Therapy.•Neoadjuvant therapy.

Molecular Classification:•Early EBC was 2 groups only

• Now we reached to more recent approach utilizing both TNM staging Plus ER/PR status and Her2 status. Dividing EBC into 4 main groups

Node –ve

Node +ve

Luminal

AER ++

Luminal

BER +

Her 2 +veTriple –ve Basal like virulent

Disease outcome in subgroups

What are the lessons we achieved from molecular classification •Lumina A: more benefit in hormonal and

less in chemo.•Luminal B: grey zone: chemo, hormonal

and/or Her 2 blockade (Luminal B2)•Her 2 +ve: benefit from single and more

recently dual Her 2 blockade + chemo•Triple negative: the hidden mystery,

rapid response to chemo, but still survive poor.

Prognostic and Predictive markers: are we there yet?• In the last decade, advances in gene expression

profiling dramatically changed our understanding of genomic and transcriptomic landscape of breast cancer, with improved our ability to prognosticate behavior and response to treatment.

• Traditional prognostic factors: Tumor size, Nodal status, Histological grade ER/PR status , Her 2 status and age. Multiparametric tools have been developed to improve the predictive value of those factors

TNM staging Nottingham Prognostic index Adjuvant online ( http://www.adjuvantonline.com)

http://www.adjuvantonline.com/

• Prognostic multigene classifiers in routine clinical practice: among the them, the top 3 assays in current clinical decision making are

Oncotype Dx, the 21 gene assay.Mammaprint the 70 gene signature of Van’t veer.PAM50 clinically updated version of intrinsic subtypes.

→Why Oncotype Dx in EBC:• Use paraffin embaded fixed materials• Prognostic • Predictive value for the value of chemo in those of HR+ve.

Her 2-ve, -ve Node• Validated in randomized trail : NSABP B14, B20

The Oncotype DX

•16 BREAST CANCER RELATED GENES

Estrogen

ERPR

Bcl2SCUBE2

Proliferation

Ki-67STK15

SurvivinCyclin B1

MYBL2

HER2

GRB7HER2

Invasion

Stromelysin 3Cathepsin L2

Others

CD68

GSTM1

BAG1

• 5 REFERENCE GENES

Beta-actin GAPDH RPLPO GUS TFRC

Paik S, et al. N Engl J Med. 2004;351:2817-2826.

• The Oncotype DX Recurrence Score is correlated with distant recurrence rate at 10 years, hormone therapy benefit, and chemotherapy benefit.

▫Low risk is up to 17▫Intermediate risk 18-30▫High risk > 30

• Validation: a study was performed to clinically validate the prespecified 21-gene RT-PCR assay and Recurrence Score algorithm as a predictor of the prospectively defined primary endpoint of distant recurrence-free survival in node-negative, estrogen receptor–positive patients treated with tamoxifen from the large multicenter study NSABP -B14.

Distant recurrence over time

10-Year rate of recurrence = 6.8%*

95% CI: 4.0%, 9.6%

0 2 4 6 8 10 12 14 16

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Pro

port

ion

wit

hou

t d

ista

nt

recu

rren

ce

RS < 18, n = 338

RS 18-30, n = 149

RS ≥ 31, n = 181

All Patients, n = 668

P < 0.001

10-Year rate of recurrence = 14.3%

95% CI: 8.3%, 20.3%10-Year rate of recurrence = 30.5%*

95% CI: 23.6%, 37.4%

Oncotype DX Clinical Validation: NSABP B-14, Distant Recurrence

Paik S, et al. N Engl J Med. 2004;351:2817-2826.

Oncotype DX Clinical Validation: NSABP B-20•Objective: Prospectively determine the

relationship between Recurrence Score result and chemotherapy benefit in node-negative, ER+ patients

Randomized

Tam + MF

Tam + CMF

Tam

Paik S, et al. J Clin Oncol. 2006;24:3726-3734.

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

4.4% absolute benefit from tamoxifen +

chemotherapy

N Events

All patients

Tamoxifen + chemotherapyTamoxifen

424227

3331 P = 0.02

RS 18-30


8945

94 P = 0.39

RS < 18Tamoxifen + chemotherapyTamoxifen

218135

84 P = 0.61

N Events

RS 18-30


8945

94 P = 0.39

PATIENTS WITH HIGH RS28% absolute benefit from

tamoxifen + chemotherapy

RS ≥ 31


11747

1318 P < 0.001

2 4 6 8 10 12

Years

Pro

port

ion

wit

hou

t d

ista

nt

recu

rren

ce

Paik S, et al. J Clin Oncol. 2006;24:3726-3734.

Adjuvant Chemotherapy

The Oxford OverviewEarly Breast Cancer Trialists’ Collaborative Group

(EBCTCG)

• The most comprehensive analysis of the adjuvant settings

• 1984, 1990, 1995, 2000, 2005/6, 2010• 2010: cover more than 100,000 patients

among 123 randomised trails, published 2012, postulating 3 questions to be answered in meta-analysis▫ Benefit of polychemotherapy Vs non.▫ Benefit of anthracycline (A) vs CMF.▫ Benefit of Taxane + (A) vs (A) alone.

Polychemotherapy versusNo chemotherapy

10y results in 23500 women

• RRs were 0·69 (SE 0·04) for distant recurrence• RRs were 0·73 (SE 0·03, χ²1=70·3) for any recurrence.• RRs 0·79 (SE 0·04, χ²1=33·7) for breast cancer mortality.

• the proportional effects of anthracycline based regimens on breast cancer outcomes did not depend much on age, nodal status, ER status, or, if ER-positive, on endocrine therapy, age, nodal status, tumor differentiation, or ER level

Anthracycline regimens vs

standard CMF


•Almost equal 4 AC, vs CMF.

• shows results from the trials with anthracycline dose per cycle at least 60 mg/m2 doxorubicin or 90 mg/m2 epirubicin and with cumulative anthracycline dosage more than 240 mg/m2 doxorubicin or 360 mg/m2 epirubicin.

• RRs were 0·89 for recurrence.• RRs were 0·80 for breast cancer mortality

ANTHRACYC

LINE

MORE

Taxane + Anthracycline regimens vsAnthracycline regimens


•Recurrence RRs were 0.85.•Mortality RRs were 0.87.

T+AVssameA

5 y results

5 years results • Recurrence RRs were 0.83.•Mortality RRs were 0.86.

T+AVsmoreA

Adjuvant Hormonal

Estrogen and Breast Cancer

Estrogen

Cell Growth and Division

Estrogen Receptor

SERMS, SERDSAromatase inhibitors, ovarian suppression

Endocrine Therapy in Breast Cancer

• Selective Estrogen Receptor Modulators▫tamoxifen ▫toremifene ▫raloxifene

• Aromatase inhibitors (postmenopausal)▫anastrozole▫letrozole ▫exemestane

• Medical or surgical oophorectomy (premenopausal)

• Selective Estrogen Receptor Downregulators▫fulvestrant

• Others: Progestins, Estrogens, Androgens

Selective Estrogen Receptor ModulatorsEBCTCG 2000 (Oxford Overview)

Tamoxifen vs. Nil: Disease-free Survival

ER Negative ER Positive

5 years of adjuvant tamoxifen became standard in ER+ patients

tamoxifen

nil

ER status matters!!

5 yrs

15 yrs

Aromatase InhibitorsAdrenal Hormones

Cortisol Androstenedione Aldosterone

Estradiol

TestosteroneEstrone

Aromatase inhibitors block post-menopausal estrogen production

AnastrozoleLetrozoleExemestane

Adjuvant Aromatase Inhibitors

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

Survival benefit for AI arm

ATAC and BIG1-98 studiesReduction in recurrences

Upfront Use of Aromatase Inhibitors vs. Tamoxifen

ATAC Trial: Anastrozole vs. Tamoxifen Howell A et al, Lancet 365:60-62, 2005

BIG 1-98 Trial: Letrozole vs. Tamoxifen Thurlimann B et al, NEJM 353: 2747-57, 2005

68 months follow-up:17% relative reduction in events for A vs T (3% absolute difference)

26 months follow-up:19% relative reduction in events for L vs. T(3% absolute difference)

Extended Adjuvant Hormonal Therapy Trials

MA17 Trial: Letrozole vs. Placebo After Completing 5 Years of Tamoxifen Goss P et al, J Natl Cancer Inst 97: 1262-71, 2005

30 months of follow-up:42% decrease in breast cancer eventsNode positive patients show statistically significant improvement in survival

Letrozole + Zoledronic Acid 4 mg

q6m

Letrozole + Delayed* Zoledronic Acid 4 mg

q6m

Stage I-IIIa breast cancer Postmenopausal or

amenorrheic due to cancer treatment

ER+ and/or PgR+ T-score ≥ -2 SD N = 1065

Treatment duration 5 yrs

De Boer R, et al. SABCS 2011. Abstract S1-3.

ZO-FAST: 5-Yr Final AnalysisTreatment duration 5 yrs

ZO-FAST: Conclusions

•Immediate initiation of ZOL at start of letrozole significantly prolonged DFS vs delayed initiation of ZOL in postmenopausal women with endocrine-responsive EBC▫Continued to improve BMD after 5 yrs of

follow-up▫34% improvement in DFS

Adjuvant Targeted Therapy

37

HER-2 as a Target for Therapy

cell division

HER-2

nucleus

cancer cell

Trastuzumab (Herceptin) Anti-HER-2 Antibody

HER-2 Oncogene: amplified and overexpressed in 20-25%

of breast cancer

Lapatinib (Tykerb) Dual HER-1/HER-2 Tyrosine Kinase Inhibitor

Adjuvant trastuzumab trials: >13,000 patients

NCCTG N9831 (USA)

HERA (ex-USA) BCIRG 006 (global)

NSABP B-31 (USA)

Piccart-Gebhart et al 2005;Romond et al 2005;

Slamon et al 2006

IHC orFISH

(n=5090)2 years Herceptin

Observation

Standard chemotherapy

1 year Herceptin

IHC orFISH

(n=2030)

Herceptin 1 year

IHC orFISH

(n=3505)

Herceptin 1 year

FISH(n=3222)

Herceptin 1 year

IHC or FISH

(n=5090)

Docetaxel Docetaxel + carboplatin

Doxorubicin + cyclophosphamide Paclitaxel

FISH (n=3222)

IHC or FISH

(n=3505)

IHC or FISH

(n=2030)

Herceptin 1 yr

Herceptin 1 yr

Herceptin 1 yr

Herceptin 1 yr

Herceptin 2 yr

Observation

aBased on small subgroups of patients with HER2-positive breast cancer; brelapse-free survival; V, vinorelbine CEF, cyclophosphamide, epirubicin, 5-fluorouracil

DFS benefit across 5 out of 6 trials

4

2

3

4

Joensuu et al 2006; Slamon et al 2006 Perez et al 2007; Smith et al 2007

Spielmann et al 2007

3

3

Median follow-up, years

0 1 2FavoursHerceptin

Favours noHerceptin

HR

DFS benefit

B-31 / N9831 ACPH

HERA CTxH 1 year

FinHera VH / DHCEFb

PACS-04a CTxH 1 year

BCIRG 006 ACDH

BCIRG 006 DCarboH

0 1 2Favours

HerceptinFavours noHerceptin

HR

Adjuvant Trastuzumab trials: proven OS benefit

B-31 / N9831 ACPH

BCIRG 006 ACDH

HERA H 1 year

BCIRG 006 DCarboH

FinHer VH / DHa

4

3

2

Median follow-up,years

3

Joensuu et al 2006; Perez et al 2007;Slamon et al 2006; Smith et al 2006

3

Cumulative incidence of cardiac events: N9831/NSABP B31 updated analysis

• Longer follow-up showed no additional concerns regarding the cardiac safety profile Cardiac events occurred early No evidence of increased toxicity or late toxicity

• In NSABP B 31 the following factors were shown to be predictive for CHF: Age (p=0.03) Hypertensive medications (p=0.02) Baseline LVEF (p=0.0003)

• The incidence of cardiac events reach a plateau at around 1 year

• Cardiac effects of trastuzumab were largely reversible

Perez et al Abs 512 ASCO 2007Perez et al Abs 512 ASCO 2007

Slamon et al 2006 Rastogi et al 2007 Suter et al 2007 Perez et al 2008

Incidence of trastuzumab-related cardiac events in EBC trials

3.0

NR

NR

18.0

8.6

Asymptomatic LVEF decline,

%aH 1 year

ACPH

ACPH

ACDH

DCarboH

Arm

HERA

NSABP B-31

NCCTG N9831

BCIRG 006

1,678

947

570

1,068

1,056

nSevere CHF, %

0.6

3.8cum (5 yr)

3.3cum (3 yr)

1.9

0.4

Cardiac death, n

0

0

0

0

0

Surgery & ChemoComplete

Randomize

Trastuzumab 1

Lapatinib 2

Lapatinib + Trastuzumab 4

Lapatinib 3Trastuzumab

Taxane

Taxane

Taxane

Taxane

Wash out

52 Weeks

All Patients: Radiotherapy, if indicated

Hormone receptor-positive patients:Endocrine therapy for at least 5

yrs

34 Weeks6 Weeks12 WeeksConsent &Send Blocks for Central Path Review

Neoadjuvant Therapy

Goals of Neoadjuvant Theapy in Early Breast Cancer• Make tumours more operable, increase the rate of breast conserving

surgeries

• Improve prognosis of certain disease subtypes (i.e. HER2+)

• Have a better idea of prognosis based on response to neoadjuvant treatment

• Allow patients to start treatment earlier

• Reduce the extent of surgery required in breast and axilla

• Improve DFS and OS using pathological response rate for selection of subsequent treatment in individual patients

Definition of pCR

Different definition of pCR are in use: - Absence of invasive cancer in the breast - Absence of invasive cancer in the breast and in the

axillary lymph nodes. - Absence of invasive and in situ cancer cells in the

breast and in the axillary nodes There is high degree of concordance between the

different definition With very definition pCR identifies cases with

favorable disease

Marchiò C. & Sapino A. JNCI Monogr 2011;43:86–90

There was no significant difference in overall survival (OS) between the treatment arms (data not shown). Pathologic complete response, which was doubled by addition of preoperative T, was a significant predictor of OS regardless of treatment (HR 0.33; P .0001).

Bear HD, et al. J ClinOncol. 2006;24(13):2019-2027.

Disease free-survival

Overall Survival

pCR to Neoadjuvant Chemotherapy is correlated with improved DFS & OS (NSABP B-27)

Intrinsic sub-types have different prognosis and different response to Neoadjuvant therapy.

Impact of treatment characteristics on the pCR

Untch M. et al J Nat Cancer Inst

Monogr 2011.

Pre and Post-operative Chemotherapy plus Trastuzumab Improve DSF

Women with operable or

locally advanced

breast cancer

(N = 2072)

TAC-NX*(4 cycles NX)

(n = 301)

TAC x 6(4 additional cycles TAC)

(n = 321)


(n = 704)


(n = 686)

TAC*(2 cycles)

Assessresponse†

Minimalresponse‡

(n = 622)

CR or PR(n = 1390)

*TAC regimen: docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 all on Day 1 q21d. NX regimen: vinorelbine 25 mg/m2 on Days 1 and 8, capecitabine 1000 mg/m2 on Days 1-14 q21d.†Response assessed by ultrasound/palpation.‡< 50% tumor reduction.

Von Minckwitz G, et al. SABCS 2011. Abstract S3-2.

GeparTrio Trial: Study Design

Not working? Try another type of chemotherapy

Working? Give more of the same

chemotherapy

GeparTrio Trial: DFS and OS• Median follow-up: 62 mos

• DFS benefit in early responding and nonresponding patients who received response-guided vs conventional chemotherapy


Endpoint HR for Response-Guided vsConventional Chemotherapy (95% CI)

P Value

DFS 0.71 (0.60-0.85) < .001

OS 0.79 (0.63-0.99) .048

Patient Subgroup

Treatment Comparison

HR for DFS (95% CI)

P Value

Responders TAC x 8 vs TAC x 6 0.78 (0.62-0.97) .026

Nonresponders TAC-NX vs TAC x 6 0.59 (0.49-0.82) .001

GeparTrio Trial: DFS by Patient Subgroup

Response-guided treatments better

Conventional treatments better

0.2 0.4 0.6 0.8 1.0 1.2 1.4

SubgroupOverallAge (yrs)

<40≥ 40

cT-stagecT1-3cT4

cT-size< 40 mm≥ 40 mm

cN statusNegativePositive

Histological typeDuctal or

otherLobular

Grade1 or 23

Hormone receptor status

NegativePositive

HER2 statusNegativePositive

Breast cancer phenotype

Luminal ALuminal B

(HER2-)Luminal B

(HER2+)HER2+

(nonluminal)Triple

negative

N patients2012

3531659

1737267

7751212

894NR

1571270

1176725

7171295

1145486

572211281178362

Test for Interaction

0.67

0.66

0.22

0.19

0.71

0.25

0.008

0.54

0.12-0.01

HR (95% CI)

0.74 (0.60-0.85)

0.66 (0.42-1.03)0.73 (0.60-0.88)

0.70 (0.56-0.85)0.79 (0.54-1.17)

0.62 (0.44-0.85)0.79 (0.63-0.98)

0.84 (0.61-1.14)0.66 (0.53-0.82)

0.73 (0.60-0.88)0.61 (0.37-1.03)

0.79 (0.61-1.01)0.65 (0.49-0.85)

0.94 (0.73-1.22)0.56 (0.44-0.73)

0.63 (0.49-0.81)0.72 (0.51-1.04)

0.55 (0.37-0.82)0.40 (0.20-0.79)0.56 (0.33-0.96)1.01 (0.61-1.67)0.87 (0.61-1.25)


GeparTrio Trial: pCR by Breast Cancer Subtype


pC

R (

%)

40

35

30

25

20

15

10

5

0Luminal A (n = 572)

Luminal B (HER2-)

(n = 211)

Luminal B (HER2+)(n = 281)

HER2+ (Nonluminal)

(n = 178)

Triple Negative (n =

362)

GeparTrio Trial: Conclusions

•Adapting neoadjuvant chemotherapy based on early response significantly improved DFS and OS vs conventional chemotherapy

•Response-guided chemotherapy most effective in patients with luminal A or luminal B tumors▫Low pCR rates in these tumors▫pCR not prognostic

•No DFS benefit with response-guided chemotherapy in patients with HER2-positive or triple-negative tumors


Baselga J et al. Lancet 2012

• pCR rate was significantly higher in the group given lapatinib and trastuzumab (78 of 152 patients [51·3%; 95% CI 43·1—59·5]) than in the group given trastuzumab alone (44 of 149 patients [29·5%; 22·4—37·5]; difference 21·1%, 9·1—34·2, p=0·0001).•no significant difference in pCR between the lapatinib (38 of 154 patients [24·7%, 18·1—32·3]) and the trastuzumab (difference −4·8%, −17·6 to 8·2, p=0·34) groups.

Baselga J et al. Lancet 2012