Recenti avanzamenti nel carcinoma della mammella

(1)

PierFranco Conte

Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche Università di Padova

IOV – Istituto Oncologico Veneto I.R.C.C.S.

Recenti avanzamenti nel carcinoma della mammella

Pierfranco Conte Università di Padova

Dipartimento di Chirurgia, Oncologia e Gastroenterologia IOV – Istituto Oncologico Veneto I.R.C.C.S.

(2)

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

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

Adj ChemoRx Adj HT

Screening

Adj trastuzumab

For the first time in the history of

medicine, MORTALITY due to a lethal,

chronic and common disease is declining Availability of effective therapies is the

main reason for the reduction in mortality

(3)

Subgroup Treatment Comparator Risk reduction for recurrence

Estimated HR

HR+

TAM for 5y¹ No therapy 39% 0.61

AI (upfront or sequence)¹ 5y TAM 30% 0.43

Extended adjuvant ET^2,3,4 5y TAM 15-43% 0.37-0.58 Chemo + TAM 5y (age < 50y)⁵ TAM 5y 36% 0.40

Chemo + TAM 5y (age 50-69)⁵ TAM 5y 15% 0.59

HER2+ Trastuzumab + Chemo⁶ Chemo 40% 0.21

All

Polychemotherapy ⁷ No chemo 24% 0.76

Anthra regimens ⁷ CMF 20% 0.60

Anthra+Taxane regimens ⁷ Anthra 12% 0.53

Bisphosphonates (postmenopause)⁸ ET +/- chemo 14% 0.48-0.51

Adjuvant Systemic Therapy for EBC Summary of the Evidence

1EBCTCG, Lancet 2015; ²Goss P, NEJM 2003; ³Gray RG, ASCO 2008; ⁴Davies C, Lancet 2013;

⁵EBCTCG Lancet 2005;⁶Cochrane Library 2012; ⁷ EBCTCG Lancet 2012; ⁸ EBCTCG Lancet 2015

(4)

ER+/HER2-ve

Breast Cancer

From ONE Breast Cancer to Breast Cancer Subtypes ONE Size does not fit ALL anymore…….

TN HER2+

Comparison Absolute RR in

Recurrence %

NNT

Tamoxifen vs. Nil ^ 11.8 8

Aromatase Inhibitors vs TAM* 3- 5.3 19 - 33

Polychemo vs. Nil ( < 50)^ 12.3 8

Polychemo vs. Nil ( 50+)^ 4.2 23

Taxanes vs. Anthra^§  5 20

ChemoRx + Trastuzumab vs ChemoRx 6.3 - 18 6 - 15

(5)

- Personalized cancer medicine:

reduced treatment burden for patients at lower risk

neoadjuvant trials to identify patients with different outcomes

- Progress over time:

good news for HR+ early breast cancer

good news for HR+ advanced breast cancer good news for HER2+ advanced breast cancer TN BC: still an unmet clinical need

BC: the bright and the dark sides of a successful story

(6)

5 10 0

50 40 30 20 10

Nil

Tam

Tam+CT

years

Re curre nce %

Who can be spared adjuvant chemotherapy?

Which patients are still at risk after adjuvant HT and chemotherapy?

Who deserves extended adj HT

or HT plus OFS

The quest for precision cancer medicine:

the case of HR+ EBC

Can chemotherapy

benefit be predicted?

(7)

Reis-Filho J, Lancet 2011

Mammaprint Endopredict

GGI BCI

OncotypeDX PAM50 - ROR

Precision Medicine: GEPs

(8)

Trial Assigning IndividuaLized Options for Treatment (Rx), or TAILORx

Study arms for primary analysis To be reported at a later date (2017)

Oncotype DX^® assay

Primary study group Recurrence Score^® result

11–25

~44% of population

Secondary study group Recurrence Score^® result

>25

~27% of population Secondary study group

Recurrence Score^® result

<11

~29% of population

RANDOMISE ARM D: chemotherapy plus endocrine therapy

ARM A: endocrine therapy alone

ARM C: chemotherapy plus endocrine therapy

ARM B: endocrine therapy alone N=1626

(15.9%)

N=6897 (67.3%)

N=1730 (16.9%) Enrolled 10,071 pts

(2006-2010) 900 sites, 6 countries

Recurrence Score = 25

• 16.1% distant recurrence rate at 10 years

• 95% CI 13%, 20%

Recurrence Score = 11

• 7.3% distant recurrence rate at 10 years

• 95% CI 5%, 10%

Sparano JA et al. N Engl J Med 2015

Designed to determine whether HT is not inferior to CT+HT in women whose tumors fall in the Primary Study Group category (RS 11-25). The primary study endpoint is disease-free survival. Other co-primary endpoints include distant recurrence-free interval, recurrence-free interval, and overall survival.

(9)

5yrs rate 93.8%

(95% CI, 92.4 to 94.9)

5yrs rate 99.3%

(95% CI, 98.7 to 99.6)

5yrs rate 98.7%

(95% CI, 97.9 to 99.2)

5 yrs rate 98.0%

(95% CI, 97.1 to 98.6)

Sparano, NEJM 2015

TailorX: prognosis of RS low patients

(10)

0.16 0.92 1.39 1.81 2.16 2.61 2.98 3.35 0

20 40 60 80 100

Overall

5- ye ar B C F I ( % )

Median CPRS in Subpopulations

STEPP of 5-year BCFI according to

Composite Risk Score: Overall HER2-negative

45-49 yr N0 T≤2cm Grade 1 Ki67<14%

ER ≥50%

PgR ≥50% <35 yr

N 4+

T>2cm Grade 3 Ki67 >26%

ER <50%

PgR <20%

40-44 yr N 1-3 T≤2cm Grade 2 Ki67 14-19%

ER ≥50%

PgR ≥50%

40-44 yr N0

T>2cm Grade 3 Ki67 >26%

ER ≥50%

PgR ≥50%

M. Regan et al, BCRT 2015

(11)

0.16 0.51 1.00 1.50 0

20 40 60 80 100

E+OFS T+OFS T

5 -ye a r B C F I (% )

Median Composite Risk Score in Subpopulations (SOFT No Chemo)

STEPP of 5-year BCFI according to Composite Risk Score:

SOFT No Chemo

Median Composite Risk Score in Subpopulations

Exemestane + OFS Tamoxifen + OFS Tamoxifen

0.16 0.51 1.00 1.50

0 20 40 60 80 100

E+OFS T+OFS T

5 -ye a r B C F I (% )

Median Composite Risk Score in Subpopulations (SOFT No Chemo)

M. Regan et al, BCRT 2015

(12)

- Personalized cancer medicine:

reduced treatment burden for patients at lower risk

OncoTypeDx identifies very low risk HR+ patients not requiring chemotherapy A composite risk score (age,T,N,G,ER,PgR,Ki67) identifies pts not requiring OFS

neoadjuvant trials to identify patients with different outcomes

- Progress over time:

good news for HR+ early breast cancer

good news for HR+ advanced breast cancer good news for HER2+ advanced breast cancer TN BC: still an unmet clinical need

BC: the bright and the dark sides of a successful story

(13)

1703 1591 1434 1127 742 383 140

100

80

60

40

20

0 Patients(%)

Months from randomisation

Observation

No.

at risk 1698 1533 1301 930 606 322 114

1 year trastuzumab

218 316

Events HR 95% CI p value

0.63 0.53, 0.75 <0.0001 3-year

DFS 80.6 74.0

12 36

0 6 18 24 30

19.4% Necessary but not effective

74% Not necessary 6.6% Necessary

& effective

NNT=15

The quest for precision cancer medicine:

the case of HER2+ EBC

(14)

HERA: Precision Cancer Medicine or Over-treatment ?

100

80

60

40

20

0

Patients(%)

Observation

1 year trastuzumab

218 316

Events HR 95% CI p value

0.63 0.53, 0.75 <0.0001 3-year

DFS 80.6 74.0

12 36

0 6 18 24 30

Same efficacy with reduced toxicity&costs

Spare unnecessary treatments Reduce treatment burden

(15)

APT¹

12wks wPac+ 1y T

DocCtx x 4 + 1y T²

Patient # 406 493

Age median

(range)

55

(24-85)

55

(24-75)

T < 2cm % 91 67

Node Neg % 100 79

HR + % 67 65

DFS % 98.7

(3y DFS)

97.8

(2y DFS)

Cardiac events all G

n (%) 15 (3.7%) 29 (6 %)

Cardiac events G ¾

n (%) 2 (0.5%) 2 (0.4%)

Less Chemo for «low risk» HER2+ EBC – Phase II trials

1Tolaney S et al, NEJM 2015; ²Jones SE et al, Lancet Oncol 2013

(16)

Trials exploring different durations of trastuzumab administration

Trial Sponsor Duration

months

CT regimen

Start Accrual Status

HERA BIG 12 vs 24 Center’s

choice

12/2001 3,387 completed 06/2005

PHARE INCA 6 vs 12 Center’s

choice

5/2006 3,400 completed 05/2011 Hellenic

Oncology

Heraklion University

6 vs 12 ddFEC/D 10/2007 478 completed 12/2011 Short-HER Modena&Padova

Universities

2 vs.12 A+T vs T+FEC

12/2007 1,250 completed 09/2013

SOLD Finnish

BCG

2 vs 12 T+FEC 1/2008 2,168 completed 11/2014 Persephone Warwick

University

6 vs. 12 Center’s choice

10/2007 4,000 ongoing

total # > 15,000

(17)

Disease Free Survival

0.00 0.25 0.50 0.75 1.00

DFS Probability

1690 1586 1353 939 526 23

T-6m

1690 1613 1390 980 544 18

T-12m Trastuzumab

0 12 24 36 48 60

Months

T-12m T-6m

HR (95% CI): 1.28 (1.05 - 1.56)

3y Δ 2.9 %

395 events/1040 required

Pivot X et al, Lancet Oncol 2013

(18)

Kramar A et al, Ann Oncol 2014 Pts # 1,104

3y MFS % T 12 = 98.3 T 6 = 98.3

Pts # 1,211 3y MFS % T 12 = 95.8 T 6 = 94.2

Pts # 702 3y MFS % T 12 = 90.4 T 6 = 85.7

Pts # 322 3y MFS % T 12 = 78.4 T 6 = 74.8

Phare: Subgroup analysis

(19)

1EH Romond et al, JCO 2012; ²X Pivot et al, Lancet Oncol 2013 ³De Azambuja E et al, JCO 2014

NSABP-B31

¹

Phare

²

HERA

³

Age (median) 49 55 49

concomitant T 100% 57.8% 0

Duration of T 0 1 yr 6 m 1 yr 0 1 yr 2 yr Cardiac events % 1.3 4.0 1.9 5.7 1.0 5.2 9.4

P value p<0.001 p<0.0001 Not reported

Duration of Trastuzumab and

cardiac dysfunctions

(20)

- Personalized cancer medicine:

reduced treatment burden for patients at lower risk

Good outcome for low risk HER2+ pts with reduced chemo burden or trastuzumab duration

neoadjuvant trials to identify patients with different outcomes

- Progress over time:

good news for HR+ early breast cancer

good news for HR+ advanced breast cancer good news for HER2+ advanced breast cancer TN BC: still an unmet clinical need

BC: the bright and the dark sides of a successful story

(21)

Cortazar P et al, The Lancet 2014

Meta-analysis Results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC):

pCR correlates with long-term outcome

(22)

TRIAL Treatment tpCR % P value

NeoALLTO¹

# 455

wPac + T 27.6

wPac + L 20

wPac +TL 46.8 0.0007

NeoSphere² # 417

Doc+ T 21.5

Doc+ TP 39.3 0.019

HP 11.2

Doc + P 17.7

CherLob³

# 121

wPac/FEC+ T 25.7

wPac/FEC+ L 27.8

wPac/FEC+ TL 43.1 0.018

NSABP-B41⁴

# 518

AC/wPac + T 49.4

AC/wPac + L 47.4

AC/wPac + TL 60.2 0.056

CALGB 40601⁵

# 299

wPac + T 43

wPac + L 29

wPac +TL 52 NS

Dual HER2 inhibition for HER2+ EBC

1Baselga J et al, Lancet 2012;

2Gianni L et al, Lancet Oncol 2012;

3Guarneri V et al, JCO 2012;

4Robidoux A, JCO 2012;

5Carey L, ASCO 2013

T = Trastuzumab;

L = Lapatinib;

P = Pertuzumab

(23)

FDA approves Perjeta for neoadjuvant breast cancer treatment First drug approved for use in preoperative breast cancer

The U.S. Food and Drug Administration today granted accelerated

approval to Perjeta (pertuzumab) as part of a complete treatment

regimen for patients with early stage breast cancer before surgery

(neoadjuvant setting). Perjeta is the first FDA-approved drug for

the neoadjuvant treatment of breast cancer .

(24)

Loser in NeoALLTO = Loser in ALLTO

Following an interim analysis in September 2011 the lapatinib arm was discontinued and patients

were offered trastuzumab.

TRIAL Treatment tpCR % P value

NeoALLTO¹

# 455

wPac + T 27.6

wPac + L 20

wPac +TL 46.8 0.0007

Piccart M, ASCO 2014; Perez E ESMO 2014

(25)

Neo-adjuvant trials to drop the loser

Neo-adjuvant trials to identify biomarkers of resistance Neo-adjuvant trials to reduce treatment burden

Neo-adjuvant trials to select high-risk patients for post neoadj trials

NeoAdjuvant Trials:

a smart tool should be used for smart purposes….

(26)

PER ELISA: HR+/HER2+ operable breast cancer

S U R G E R Y

LVEF measurement Trastuzumab 8 mg/kg Paclitaxel 80 mg/mq

loading dose -> 6 mg/kg Pertuzumab 840 mg

loading dose -> 420 mg Letrozole 2.5 mg

CDD X 2 wks Diagnostic biopsy/ki67

Ki67 for molecular response

Molecular responders

Non-Molecular responders

Letrozole 2.5 mg CDD

Sample size 65 pts Biomarker analysis

(27)

Adjuvant post-neoadjuvant trials in patients with < than pCR

•

HR+

PENELOPE: ER + CDK4/6 or placebo after PCT

•

HER2+

KATHERINE: TDM1 vs Trastuzumab after PCT+T

•

TNBC

BRE09-146: Cisplatin vs Cisplatin + Rucaparib

•

BRCAm

OLYMPIA: Olaparib vs Placebo

(28)

- Personalized cancer medicine:

reduced treatment burden for patients at lower risk

neoadjuvant trials to identify patients with different outcomes

pCR identifies patients with a good prognosis

PST allows to modulate treatment according to the observed clinical or biological outcome Patients with residual disease after PST are good candidates for post-neoadjuvant trials

- Progress over time:

good news for HR+ early breast cancer

good news for HR+ advanced breast cancer good news for HER2+ advanced breast cancer TN BC: still an unmet clinical need

BC: the bright and the dark sides of a successful story

(29)

TEXT and SOFT joint analysis: results

Pagani O, NEJM 2014

Primary endpoint: DFS

Secondary endpoints: BCFI, DRFI, OS Tamoxifen + OFS x 5y

Exemestane + OFS x 5y

Tamoxifen + OFS x 5y Exemestane + OFS x 5y

TEXT trial (n=2672)

SOFT trial (n=3066) Tamoxifen x 5y

Joint Analysis (n=4690)

Tamoxifen + OFS x 5y Exemestane + OFS x 5y

R

(30)

1.35 1.93 2.47 3.08 0

20 40 60 80 100

E+OFS T+OFS T

5 -ye a r B C F I (% )

Median CPRS in Subpopulations (SOFT Prior Chemo)

STEPP of 5-year BCFI according to

Composite Risk Score: SOFT Prior Chemo

Median Composite Risk Score in Subpopulations

Exemestane + OFS Tamoxifen + OFS Tamoxifen

0.16 0.51 1.00 1.50

0 20 40 60 80 100

E+OFS T+OFS T

5 -ye a r B C F I (% )

Median Composite Risk Score in Subpopulations (SOFT No Chemo)

M. Regan et al, BCRT 2015

(31)

5-ys TAM in POSTMENOPAUSE

HR+ EBC: extended Endocrine Therapy

Trial Experimental arm # DFS Δ HR

ATLAS ⁴ 10y TAM 6,846 ▲3.7% 0.75

aTTom⁵ 10y TAM 6,953 ▲4% 0.85

YEARS 0-4 YEARS 5-9 YEARS 10+

Recurrence (% per year)

ER+ PR+ 3.41 2.47 2.10

ER-, PR- 5.26 1.86 1.09

Trial Experimental arm # DFS Δ HR

MA17 ¹ 5y Let 5,157 ▲6.0% 0.57

B33² 5y Exe 1,598 ▲2.0% 0.44

ABCSG6a³ 3y Ana 856 ▲4.7% 0.62

1Goss et al. NEJM 2003; ²Mamounas et al, JCO 2008; ³Jakesz et al JNCI 2007; ⁴ Davies et al, Lancet 2013; ⁵Gray et al, ASCO 2013

(32)

- Personalized cancer medicine:

reduced treatment burden for patients at lower risk

neoadjuvant trials to identify patients with different outcomes

- Progress over time:

good news for HR+ early breast cancer

OFS (premenopause) and 10y ET for high risk patients

good news for HR+ advanced breast cancer good news for HER2+ advanced breast cancer TN BC: still an unmet clinical need

BC: the bright and the dark sides of a successful story

(33)

Everolimus + Exemestane

(n=485), %

Placebo + Exemestane

(n=239), %

Palbociclib + Fulvestrant

(n=347), %

Placebo + Fulvestrant

(n=174), % Sensitivity to prior

hormonal therapy 84 84 79 78

Prior AI 100 100 69 68

Prior tamoxifen 47 49 61 60

Prior fulvestrant 17 16 0 0

Prior chemotherapy for

metastatic BC 26 24 31 36

Number of prior therapies for MBC

1 30 30 38 40

>2 54 53 38 34

Median PFS mo. 7.4

(

HR 0.44)

3.2 9.2

(

HR 0.42)

3.8 CBR % 50.5

(p<0.0001)

25.5 34

(p<0.0004)

19 BOLERO-2 and PALOMA-3: cross trials comparison

(34)

1

^st

line hormonal therapy 1

^st

line chemotherapy Determine sites and extent of disease & symptoms; ER status; HER2 status;

disease free & treatment-free intervals; performance status

No Response

No life-threatening disease Hormone-responsive

Hormone-unresponsive, or Life-threatening disease

Response

No Response 2nd-line hormonal therapy

2nd-line chemotherapy Progression

Progression

3rd-line hormonal therapy Response

No Response

3rd-line chemotherapy

Supportive care

Algorithm for Management of Post-menopausal ER+/HER2– MBC

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V3.2012

Median PFS 3-4 mo Median PFS 12-15 mo

Median PFS 11 mo

(35)

- Personalized cancer medicine:

reduced treatment burden for patients at lower risk

Good outcome for low risk HER2+ pts with reduced chemo burden or trastuzumab duration neoadjuvant trials to identify patients with different outcomes

- Progress over time:

good news for HR+ early breast cancer

good news for HR+ advanced breast cancer

STIs can overcome/delay secondary endocrine resistance good news for HER2+ advanced breast cancer TN BC: still an unmet clinical need

BC: the bright and the dark sides of a successful story

(36)

Cameron, Oncologist 2010 Verma, NEJM 2012

     

10 20 30 40 50 60

CT CT + H D + H 1

^st

line

2

^nd

line Cape Cape-Lap

Cape-Lap T-DM1

OS

25.1 m

D + H + P

Slamon, NEJM 2001 Swain ESMO 2014

Blackwell, JCO 2010

Krop, Lancet Oncol 2014

Treatment of HER2+ ABC: progress over time

25.1 m

40.8 m 20.3 m

2014 2001

56.5 m

2010 16.2 m

18.8 m

2012 30.9 m

3

^rd

line Lap Lap + H

9.5 m

14 m 2010

2014

TPC 14.9 m

T-DM1 ++ NR

(37)

- Personalized cancer medicine:

reduced treatment burden for patients at lower risk

neoadjuvant trials to identify patients with different outcomes

- Progress over time:

good news for HR+ early breast cancer

good news for HR+ advanced breast cancer

STIs can overcome/delay secondary endocrine resistance

good news for HER2+ advanced breast cancer

dual antiHER2 antibodies and ADC significantly prolong survival

TN BC: still an unmet clinical need

BC: the bright and the dark sides of a successful story

(38)

Palliative treatments of ABC molecular subtypes

Trastuzumab + Pertuzumab + taxanes

HER2+ HER2+

AI SERD

HER2–

T- DM1

HER2–

HR – HR +

MBC

Trastuzumab+Ana Lapatinib + Let

Lapatinib + capecitabine Chemotherapy

Chemotherapy

Metastatic Bone Disease: Bisphosphonates, Denosumab

BRCA mutated

Platinum salts Olaparib

AI + mTORi

Lapatinib + Trastuzumab

mOS for HR+ ABC

43-60 months

mOS for HER+ ABC

41-56 months

mOS for TN ABC

15-18 months

(39)

Basal-like 1: Cell cycle, DNA repair and proliferation genes

Basal-like 2: Growth factor

signaling (EGFR, MET, Wnt, IGF1R)

IM: Immune cell processes (medullary breast cancer)

M: Cell motility and differentiation, EMT processes

MSL: Similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers)

LAR: Androgen receptor and

downstream genes, luminal features

TNBC: Some Research Strategies

PARPi, ± DNA damaging agents homologous recombination

deficiency assay (BRCA-1 ness) EGFR (cetuximab, lapatinib)

Self-renewal pathways (stem cell) Wnt

Notch (PF03084014) Immune check point

PD1/PDL1, CTLA4

Vaccines: MUC1, NYO-ESO1

Agents targeting androgen receptor (enzalutamide, bicalutamide, etc)

Plus

PI3Ki, RAS/MEK/Erk,

MET, PTEN etc, etc

(40)

• gBRCA 1/2m

Platinum PARPi

• Androgen Receptor

• Bicalutamide (n=43, ORR: 0%, CBR-24 weeks: 19%, A. Gucalp et al, CCR 19:5505-12, 2013)

• Enzalutamide (n=75, ORR: 10%, CBR-24weeks: 29%; Traina et al ASCO 2015)

TNBC - Single Gene Targets

TBCRC009 Platinum mTNBC

(41)

(42)

Pembrolizumab

(Merck)

Humanized IgG4 anti- PD-1 antibody

http://www.nature.com/nrclinonc/journal/v11/n1/images/nrclinonc.2013.208-f2.jpg

MPDL3280

(Genentech)

engineered human IgG1 anti-PD-L1

antibody Nivolumab

(BMS)

Human IgG4 anti-PD-1 antibody

MEDI4736

(AZ)

Human IgG1 anti-PD-L1 antibody

Tremelimumab

(AZ)

Human IgG2

Anti-CTLA-4 antibody

Immune checkpoint inhibitors that are being tested in ongoing

phase II/III trials including MBC patients only.

(43)

Characteristics n = 32 N. Prior therapies

for MBC

0 5 (15.6%)

1 6 (18.8%)

2 6 (18.8%)

3 5 (15.6%)

4 3 (9.4%)

>=5 7 (21.9%)

Pembrolizumab in TNBC: Keynote-12 trial

Nanda, SABCS 2015 Objective response rate: 18.5%

Stable disases: 25.9 %

Confirmed complete response Confirmed partial response Stable disease

Progressive disease

(44)

Tailored Management of Breast Cancer

• Prognosis of Breast Cancer Patients has improved as the result of earlier diagnosis, molecular classification and more efficacious adjuvant treatments