Evoluzione del trattamento del tumore mammario: dalla ricerca alla clinica Nonantola, 18 Novembre, 2011 PierFranco Conte Dipartimento di Oncologia, Ematologia

Evoluzione del trattamento del tumore mammario: dalla ricerca alla clinica

Nonantola, 18 Novembre, 2011

PierFranco ConteDipartimento di Oncologia, Ematologia e Malattie dell’ Apparato Respiratorio

Università di Modena e Reggio Emilia

AZIENDA OSPEDALIERO-UNIVERSITARIA DI MODENA

– Where we are now

– How we got here

– Standard of Care for EBC

– Remaining questions

– The Challenges ahead

The Conquest of Breast Cancer: a few more steps ahead….

http://globocan.iarc.fr/factsheets/cancers/breast.asp

TRENDS IN MORTALITY FROM BREAST CANCER IN SELECTED COUNTRIES: AGE-STANDARDISED RATE (W) PER 100,000


– How we got here





P Autier et al; BMJ 2011

• Breast cancer mortality in three pairs of countries (North Ireland vs Rep. of Ireland, the Netherlands vs Belgium and Sweden vs Norway) from 1989 to 2006

• Countries in each pair had similar healthcare services, but differing implementation of mammography screening, with a gap of about 10-15 years

• No correlation between the introduction of screeening and reduction in breast cancer mortality

• The steepest fall in mortality observed was among the women under 50 who had not been invited for screening • Screening did not play a direct role in the reductions of breast cancer mortality

• Improvements in adjuvant treatment may be a more plausible explanation.

Breast cancer mortality in neighbouring European countries with differentlevels of screening but similar access to treatment: trend analysis of WHO mortality database

Cancer Mortality in women - Italy

Adj HT Screening

Annu

al c

ance

r mor

talit

y /

100,

000

wom

en, a

ges

35–6

9*

70

60

50

40

30

20

10

0

70

60

50

40

30

20

10

0

1950 1960 1970 1980 1990 2000 2010

*Mean of annual rates in the component 6-year age groups

Source: WHO mortality andUN population estimates

ITALY1951–2001

Breast

Stomach

Uterus

Lung

AdjChemoRx

EBCTCG META-ANALYSIS Adjuvant chemotherapy versus no treatment

5-y absolute DFS gain with polychemotherapy: - 14.6% in N+ pt under 50 y- 9.9% in N- pt under 50 y- 5.9% in N+ pt aged 50-69 y- 5.3% in N- pt aged 50-69 y

Lancet 365: 1687, 2005

50-69 N- 50-69 N+

< 50 N- < 50 N+

EBCTCG META-ANALYSIS ER + EBC: Tamoxifen for 5y

EBCCTG, Lancet 2011

At 15 yrs, Tamoxifen increases DFS by 13.2% and OS by 9.2%


– How we got here





1990 on: increasing use of anthracyclines

2000 on: increasing use of taxanes increasing use of aromatase inhibitors

2005 on: increasing use of trastuzumab

Adjuvant Treatment of EBC:Refinement of Standard of Care

Anthra-based ChemoRx vs no ChemoRx10 y Breast Cancer Mortality

Patients # N+ 10y gain RR p

all 8575 82% 6.5 0.79 <0.00001

< 55 y 2808 70% 5.6 0.81 0.004

55-69 y 5373 88% 6.5 0.79 <0.00001

ER-poor 2076 73% 7.1 0.80 0.003

ER + 5433 86% 6.4 0.77 <0.00001

ER+& <55 y 1582 77% 5.6 0.83 0.05

ER+ & 55-69 y 3578 90% 6.0 0.78 0.0002

EBCTCG 2011 in press

Anthra + Taxane vs non Taxane ChemoRx

(33,084 pts; 82% N+)

RR5 y

gainp

recurrence 0.86 2.9 <0.00001

BC mortality 0.88 1.4 0.0001

EBCTCG Meta-analysis

EBCTCG 2011 in press

Adjuvant Chemotherapy for EBC

• Regimens of proven efficacy:– 1st generation: CMF, AC– 2nd generation: FAC, FEC, DC, AC/P– 3rd generation: FEC/D, AC/wP, ddAC/P,TAC

• Evidence and Recommendations:– Anthracycline/taxane based regimens provide meaningful DFS

and OS benefit – Sequential anthracycline/taxane are NOT inferior and more

tolerable than combined regimens – The most effective schedules are 3-weekly docetaxel and weekly

paclitaxel – TC x 4 is superior to AC x 4 (this is NOT one of the most active

regimen and should be considered only when anthracyclines are contraindicated)





Meta- Analysis of adjuvant trials of AIs vs Tamoxifen

M Dowsett et al, JCO 2010

UP-FRONT : • two trials (ATAC, BIG 01-98)• 9,856 patients• 8 y gain = 3.9 % in DFS, 0.5 % in OS

M Dowsett et al, JCO 2010

SWITCH : • four trials (ARNO, IES, ITA, ABCSG VIII) • 9,015 patients• 6 y gain = 3.6 % in DFS, 1.7 % in OS

Meta- Analysis of adjuvant trials of AIs vs Tamoxifen

Predictors of Early Distant Metastasis

• Patients treated with tamoxifen at greatest risk for distant metastasis, within the first 2.5 years – Age 75 years– Tumors 2 cm– Grade 2 1 node involved– Lymphovascular invasion– Not screen detected

Mansell J et al. Breast Cancer Res Treat 2008; Dec 27 [Epub ahead of print].

Adjuvant Endocrine Therapy for HR+ EBC

• Treatments of proven efficacy:– Pre-menopause: Tamoxifen for 5y; LHRH agonists for 2-5y; Tam+LHRH– Post-menopause: AI for 5y; either sequence of Tam/AI for 5y – Extended adjuvant AI after 5y tamoxifen

• Evidence and Recommendations:– AIs provide a better DFS (OS gain ?) than Tamoxifen– Either sequence of Tam/Letrozole is not inferior to upfront Letrozole– Upfront AIs may be superior to sequential therapy in high risk pts– Extended adjuvant AIs may provide a DFS and OS gain in high risk pts





0 1 2

HERA 1 year (0.54)

Combined analysis 2 years (0.48)

Median follow-up (HR)

FavoursHerceptin

Favours noHerceptin

HR

BCIRG 006 DCarboH2 years (0.67)

2 years (0.61)BCIRG 006 ACDH

HERA 2 years (0.64)

N9831 AC-T-H 1.5 years (0.87)

PACS 04

FinHER VH / DH3 years (0.42)

4 years (0.86)

HER2+ Early Breast Cancer

Piccart-Gebhart NEJM 2005; Romond NEJM 2005; Slamon SABCS 2006; Smith, Lancet 2007; Perez ASCO 2005; Joensuu NEJM 2006; Spielmann SABCS 2007

N9831- Sequential vs Concurrent Trastuzumab

E Perez et al, JCO 2011

Slamon D et al. N Engl J Med 2011;365:1273-1283

BCIRG 006 - outcomes

Slamon D et al. N Engl J Med 2011;365:1273-1283

ArmDFS Survival

Events # HR Events # HR

AC-T 257 1 141 1

AC-TH 1860.64

p< 0.00194

0.63 p< 0.001

TCH 2140.75 p= 0.04

1130.77 p=0.04

Adjuvant Trastuzumab for HER2+ EBC

• Treatments of proven efficacy:– Any chemotherapy followed by trastuzumab for 1y– AC-TH followed by trastuzumab up to 1y– TCH followed by trastuzumab up to 1y

• Evidence and Recommendations:– Trastuzumab for 1y reduces the risk of relapse by 25-50%– Trastuzumab administered concomitantly to chemotherapy and up to 1y is superior to sequential administration alone– TCH is less cardiotoxic than AC-TH (is it also equally effective?)


– How we got here





– Genomic assays to predict outcome and chemo-sensitivity of HR+ tumors

– Trastuzumab for small, N-ve HER2+ tumors

Adjuvant treatments of EBC Remaining questions

Genomic assays to predict clinical outcome

C Sotiriou & L Pusztai

Benefit of Tamoxifen or Chemotherapy by RS

0 2 4 6 8 10 12 14 16

Years

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

DR

FS

P lacebo Tam oxifen

Low Risk (RS<18)

0 2 4 6 8 10 12 14 16

Years

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

DR

FS

P lacebo Tam olxifen

Int Risk (RS 18-30)

0 2 4 6 8 10 12 14 16

Years

0.0

0.2

0.4

0.6

0.8

1.0

DR

FS

P lacebo Tamoxifen

High Risk (RS≥31)

NSABP B-14 NSABP B-20

• OncotypeDx testing requests:

- more than 10,000 doctors

- 55 countries

- 175,000 patients

Genomic Health Web Site (november 2011)

Meta-analysis: overall impact of RS on treatment decisions

Treatment plan prior to Oncotype DX®

Treatment plan after RS

Treatment plan after RS

4% change 33% change

Overall, the RS led to a 37% change in treatment decisions•33% from CT+HT HT•4% from HT CT+HT

CT + HT

HT

Hornberger J, et al. SABCS 2010. Poster P2-09-06.

IHC4 score vs GHI-RS

Predicted TTDR for a >65ys patient with node-neg, 1-2cm poorly differentiated tumor receiving anastrozole.

Kaplan Meyer curves for either the 25° or 75° percentile of each score .

13.9%13.4%

9.2%

7.6%

Predicted 9-year distant recurrence probabilities for 25° and 75° percentiles of the IHC4 and GHI-RS scores for different G, Nodal status for a woman >65yrs with a 1-2cm tumor receiving anastrozole. Cuzick J et al, JCO 2011

– Genomic assays to predict outcome and chemo-sensitivity of HR+ tumors

– Trastuzumab for small, N-ve HER2+ tumors

Adjuvant treatments of EBC Remaining questions

High Risk of Recurrence for Patients with HER2+, Node-negative Tumors 1 cm or Smaller

Gonzalez-Angulo et al. J Clin Oncol 2009

93.7%

77.1%

95.8%

86.4%

p<0.0001 p<0.0001

• N=965, 10% HER2+ tumors• More T1a than T1b were HER2+ (32.3 vs 43.9%)• No patient got chemo or trastuzumab• All tissues were reviewed and re-measured• Median follow up: 6.2 yrs

RFS DRFS

Supplement to: Slamon et al., NEJM 2011; 365:1273-83

BCIRG 006 – Subset analysis

Characteristic Adjuvant trastuzumab trials (B31/N9831/HERA/FinHer/BCIRG006/PACS04)

Modena Cancer Registry

Age (median) 49 59

> 60 y % ~ 16 43.9

T1 % 44.5 71.9

N0 % 21 57.9

T1N0 % ~ 2 48.7

HER2+ EBC patients Adjuvant trastuzumab trials vs Modena Cancer Registry

Piccart N Engl J Med 2005; Romond N Engl J Med 2005; Joensuu N Engl J Med 2006; Slamon D, SABCS 2006;

Spielmann M et al, SABCS 2007; Federico M, RTM 1998-2007

Adjuvant Trastuzumab for T1 N0 HER2+ EBC

• Prognosis of small, N0, HER2+ tumors is poorer

• Trastuzumab has shown efficacy in these patients • Small, node negative tumors as well as elderly patients, are

underepresented in clinical trials

• Cardiac safety and cardiac recovery in elderly patients treated with trastuzumab are basically unknown

• In these patients, competitive deaths are prevalent, and the decision to treat should be based on a careful evaluation of the risk/benefit ratio

• Trials designed for frail and low risk patients are warranted


– How we got here





All Breast Cancers

ER+65-75%

HER2+15-20%

Triple negative

15%

Breast Cancer Diseases – 2011

All Breast Cancers

ER+65-75%

HER2+15-20%

Triple negative

15%

HER3+

IGFR1+

p95+ 4%

P53mut

30-40 %

FGFR1Ampl 8%

PTENloss

30-50%

PI3Kmut

10%

BRCAMut

8%

Breast Cancer Diseases – 201…

Clinical Genomics: The Next Frontier

Stratton, Campbell and Futreal Nature 2009 PhRMA Report 2011, Medicines in development for cancer

ER+65-75%

mTOR inhibitorsPI3K inhibitors

New agents for the breast cancer molecular subtypes

LapatinibNeratinibPertuzumabTDM-1AntiHER2 combinationsTrastuzumab + mTORi

Triple negative15%

HER2+15- 20 %

New cytotoxics (eribulin, ixabepilone, vinflunine)Platinum saltsBevacizumabPARP inhibitorsAntiEGFR (Cetuximab, erlotinib)Anti androgens

Neo-Adjuvant: A Faster Approach

Adjuvant Neo-adjuvant

Number of Patients thousands hundreds

Efficacy Endpoint DFS pCR

Primary analysis years after end of recruitment

months after end of recruitment

Biological Window No Yes

Functional Imaging No Yes

Sample Collection baseline multiple time points

Cost +++++ ++

43

HER2+ EBCRCTs of PCT + dual antiHER2 blockade

Trial pts # Regimen pCR % (breast & N)

Neo-ALLTO1 455 wPac+T/L/TL 20 /27.6/46.9*

NeoSphere2 417 DT/DTP/TP/DP 21.5/39.3*/11.2/17.7

CherLob3 121 wP-FECT/L/TL 25.7/27.8/43.1*

* p value < 0.05T = trastuzumabL = LapatinibP = Pertuzumab

1Baselga J et al, SABCS 2010; 2Gianni L et al, SABCS 2010; 3Guarneri V et al, ASCO 2011

ALTTO study design: use of lapatinib in adjuvant setting for ErbB2-positive breast cancer1

Surgery

Completion of all (neo) adjuvant anthracycline-based chemotherapy (≥4 cycles)

Design 1

No taxane

Design 2

Concomitant paclitaxel

(12 wks)

Trastuzumab LapatinibWash out

Lapatinib

Trastuzumab

Lapatinib + trastuzumab

Ra

ndo

mis

atio

n

12 wks 6 wks 34 wks

52 wksN = 8000 (2000 patients per treatment arm)

1. www.clinicaltrial.gov NCT00490139

The Conquest of Breast Cancer: from Evidence Based to Personalized Medicine

• Breast Cancer mortality is declining because of earlier diagnosis and effective adjuvant treatments

• Randomized clinical trials have allowed to define the appropriate therapy for the average patient population

• The backbone of adjuvant treatments is based on the molecular characterization of the disease:

• HR+ Endocrine therapy• HER2+ AntiHER2 therapy• Triple negative Chemotherapy

• Clinical genomics will allow to move forward personalized cancer medicine:

• More refined prognosticators to spare unecessary therapy• More reliable predictors of sensitivity to administer individualized therapy• More reliable predictors of resistance to develop innovative therapies

Documents

Evoluzione del trattamento del tumore mammario: dalla ricerca alla clinica Nonantola, 18 Novembre, 2011 PierFranco Conte Dipartimento di Oncologia, Ematologia