“treatment of bone metastases from breast...

“Treatment of Bone Metastases from

Breast Cancer”

Luís Costa, MD, PhDHospital de Santa Maria - CHLNInstituto de Medicina MolecularUniversity of Lisbon

Disclosure

Luis Costa received research funding from Amgen, Novartis, and

Roche; and speakers fee from Amgen, Novartis, and Roche

Reprinted from Shiozawa Y, et al. Leukemia. 2008;22(5):941-950.

Bone and Breast or Breast and Bone

Homing

Quiescence

Mobilization

Stem cell “sanctuary”

What attracts tumour cells to bone?

“When a plant goes to seed, its seeds are carried in all directions…

But they can only live and grow if they fall on congenial soil"

Stephen Paget, 1889

‘Seed and soil’ hypothesis

Paget S. Lancet 1889;1:571–3

615 breast tumours for which genome-wide gene expression data was available…43% relapsed and the median metastasis-free survival time was 22.1 months

…a gene expression signature that denotes c-Src activity (designated as Src responsive signature, SRS) was tightly associated with overall bone metastasis and late-onset of bone metastasis

“Latent bone metastasis in breast cancer tied to Src-dependent survival signals”

1.0

0.8

0.6

0.4

0.2

0.0

0 20 40 60 80 100 120 140 160 180Bone metastasis-free survival (months)

Bone relapse eventsTotal47140

0.001

> 5 yrs (%)2 (4.3)

21 (15.0)0.003

n244371

ER–

ER+

p

Bone relapse by ER statusB

Pro

babi

lity

1.0

0.8

0.6

0.4

0.2

0.0

0 20 40 60 80 100 120 140 160 180Metastasis-free survival (months)

Overall relapse eventsTotal1011840.08

> 5 yrs (%)2 (4.3)

27 (14.6)0.003

n244371

ER–

ER+

p

Overall relapse by ER statusA

Pro

babi

lity

1.0

0.8

0.6

0.4

0.2

0.0

0 20 40 60 80 100 120 140 160 180Bone metastasis-free survival (months)

Bone relapse eventsTotal

32155

7x10–9

> 5 yrs (%)0 (0)

23 (14.8)0.0002

n231384

SRS–

SRS+

p

Bone relapse by SRS statusC

Pro

babi

lity

Zhang XH-F, et al. Cancer Cell 2009;16:67-78

Molecular Mechanisms of Bone Metastases Formation

Therapeutic Targets

The Vicious Cycle of Bone MetastasesMedical Treatment Strategy

Cancer cells

42-year-old woman with alytic / mixed lesion in T5 as presentation of breast cancer

The Vicious Cycle of Bone Metastases

BPs

DemabBPs; bisphosphonatesDemab; Denosumab

Cancer treatment-induced bone loss

Treatment of bone metastases

What is the role of Bone-targeted therapy in Breast Cancer to treat Bone Metastases?

Early cancer Advanced cancer

Prevention/delayof bone metastases

Prevalence of SREs in patients with bone metastases frombreast cancer

Pathologic Fracture

43%

Radiation to Bone

52%

Surgery to Bone

3%

Spinal Cord Compression

11%

Lipton A, et al. Cancer. 2000;88:1082-1090; Rosen LS, et al. Cancer. 2004;100:2613-2621.

Mean cost across countries by index skeletal-related event (N = 744)

€11 509 €11 101

€7043

€5242

0

2000

4000

6000

8000

10000

12000

14000

Local currencies were converted to euros (24.096CZK/9.200SEK = 1€)Gunther et al. Support Care Cancer 2012;20:1–283. Presented at MASCC 2012.

Mea

n co

st (€

)

n = 62 71 356 255

Spinal cordcompression

Surgeryto bone

Pathologicalfracture

Radiationto bone

Individual patient profiles in advanced breast cancer

Data from Hortobagyi GN, et al. J Clin Oncol. 1998;16:2038-2044.

Time since randomization, years

Prof

iles

for i

ndiv

idua

l pat

ient

s

0.0 0.5 1.0 1.5 2.0

Duration of survival

SRE

Reproduced with permission from Major PP, et al. Am J Clin Oncol. 2002;25 (Suppl 1):S10-S18

Prior SRE increases the risk for subsequent SRE

1. Kaminski M, et al. Poster presented at ASCO 2004 [Abstract 857] 2. Saad F, et al. Clin Genitourin Cancer 2007;5:390−63. Hirsh V, et al. Clin Lung Cancer 2004;6:170−4

Pat

ient

s w

ith o

n-st

udy

SR

Es

(%)

58

32

5147

52

40

0

10

20

30

40

50

60

70

Prior SRE No Prior SRE

Breast cancer1

Prostate cancer2

Lung cancer and other solid tumours3

Molecular mechanisms of action of nitrogen-containing bisphosphonates (N-BPs)

Mevalonate

Geranyldiphosphate

Farnesyl diphosphate (FPP)

Geranylgeranyl diphosphate (GGPP)

FPP synthase

Ras S

Rho S

Kavanagh et al. Proc Natl Acad Sci 2006;103:7829-34.Rondeau et al., Chem Med Chem 2006;1:267-73.Kavanagh et al., JBC 2006; 281:22004-12.

GGPP synthase

NBPs inhibits FPP synthase, thus blocking the prenylation of small signaling proteins required for cell function and survivalX

Targeting Osteoclasts with Bisphosphonates

A

Sato M, et al. J Clin Invest.1991;88:2095-105.

B

Coxon F, et al. Bone 2008

Bisphosphonates ↓ the Risk of SREs in Metastatic Breast Cancer

CLO = clodronate; IBN = ibandronate; IV = intravenous; PAM = pamidronate; SRE = skeletal-related event; ZOL = zoledronic acid.

Data from Pavlakis N, et al. Cochrane Database Syst Rev. 2005;(3):CD003474.

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

ZOL

N = 227

PAM

N = 751

IBN (IV)

N = 312

IBN (oral)

N = 564

CLO (1999)N = 100

CLO (1993)N = 185

CLO (2001)N = 137

% R

educ

tion

in R

elat

ive

Risk

of

SRE

s vs

Pla

cebo

P = .001P = .03 (pooled)

P = .08

P = .04P < .001

ZICE StudyOral ibandronic acid versus intravenous zoledronic acid in treatment ofbone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial.Barrett-Lee P, et al. Lancet Oncol. 2014

The log relative risk (LRR) for ibandronic acid versus zoledronic acid was 0.138 (95% CI -0.033 to 0.309) which exceeds the margin of non-inferiority.

Peptide-bound collagen type I cross-links N-telopeptide (NTX) and C-telopeptide (ICTP)

Zoledronic Acid Normalized NTX Levels Within 3 Months in the Majority of Patients

Breast cancer NSCLC and OSTsPrimary tumor

HRPC

80

90

70

60

50

40

30

20

10

0

Normalized 3-month NTX (EN group)Elevated 3-month NTX (EE group)

Patie

nts,

%

NTX = N-telopeptide of type I collagen; HRPC = Hormone-refractory prostate cancer; NSCLC = Non-small cell lung cancer; OST = Other solid tumors.

Lipton A, et al. Presented at: ECCO 2007. Abstract 304.

• Fully human monoclonal antibody

• Precisely binds to RANK Ligand

• Inhibits osteoclast

– Formation

– Function

– Survival

RANK Ligand inhibitor − denosumab1

Osteoblasts

Denosumab

RANK Ligand

1. XGEVA® SPC. Amgen Ltd. Updated March 2013.

Denosumab normalised uNTx more frequently than ongoing IV bisphosphonate

0

10

20

30

40

50

60

70

80

90

100

All randomisedpatients

uNTx 50-100 nM/mM creatinine

uNTx >100 nM/mM creatinine

IV BP Q4WDenosumab Q12WDenosumab Q4W

29%

41%

17%

64%b 65% 63%b

78%a

88%b

68%b

Pat

ient

s w

ith u

NTx

<50

nM

B

CE

/mM

cre

atin

ine

at W

eek

13, %

Corrected by creatinine. aP<0.001 vs IV BP, bP≤0.005 vs IV BP

Fizazi, et al. J Clin Oncol 2009;27:1564-71.Denosumab (120 mg Q4W) is not approved for use in patients with advanced cancer to delay SREs. Denosumab is investigational in that setting.

Study Design: International, Randomized, Double-Blind, Active-Controlled Study

24

IV zoledronic acid 4 mg and SC placebo every 4 weeks

SC denosumab 120 mg and IV placebo every 4 weeksPatients aged ≥18 years with:

• Histologically or cytologically confirmed breast adenocarcinoma

• Evidence of 1 or more bone metastases

• Adequate organ function• ECOG PS 0, 1, or 2

R

Time to first on-study SRE (noninferiority test)

Time to first on-study SRE (superiority test) Time to first and subsequent on-study SRE (superiority test, multiple

event analysis)

Overall survival, disease progression, skeletal morbidity rate Percent change from baseline to week 13 in uNTx and BSAP levels

Primary

Secondary

Exploratory

Endpoints

Recommended: Daily supplementation with calcium ( ≥500 mg) and vitamin D (≥400 U)

Stopeck AT, et al. J Clin Oncol. 2010;28:5132-9

Primary End Point: Time to First On-Study SRE

Stopeck AT, et al. J Clin Oncol. 2010;28:5132-9.

SC denosumabIV zoledronic acid

2699189306437514602697839102629941912964274985846768291020

No. at riskMonths

0

1.00

Pro

porti

on w

ithou

t SR

E

0 3 6 9 12 15 18 21 24 27

0.25

0.50

0.75

Zoledronic acid (n = 1020)Denosumab (n = 1026)

HR = 0.82 (95% CI, 0.71–0.95)P = 0.01 (superiority)*

P < 0.001 (noninferiority)

*Adjusted for multiplicity

18% risk reduction(5.8% absolute risk reduction)

26.4 months

1. Stopeck AT, et al. J Clin Oncol 2010;28:5132–9;

Denosumab reduced the risk of developing multiple SREs

Time to first and subsequent SRE

Cum

ulat

ive

mea

n nu

mbe

r of S

REs

per

pat

ient

Breast cancer1

23% risk reduction

2.0

1.8

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.00 3 6 9 12 15 18 21 24 27

RR = 0.77 (95% CI, 0.66–0.89) P = 0.001 (superiority)

Total SREs:

Zoledronic acid

Denosumab

608

474

data from primary analyses.

Study month

Summary of Efficacy Outcomes: Denosumab vs ZOL in Patients With Bone Metastases From Breast Cancer

1. Stopeck A, et al. Presented at: 15th ECCO-34th ESMO Congress, 2009. Abstract 2LBA; 2. Stopeck A, et al. Presented at: 32nd Annual SABCS, 2009. Abstract 22.

In favor of denosumab In favor of Zol

Time to 1st and subsequent SREs2

Overall survival1

Time to 1st SRE1

Time to cancer progression1

Time to 1st SRE or HCM2

Time to 1st radiation to bone2

P value

0.01

0.001

0.007

0.01

0.50

0.90

0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4 1.5

Relative risk of SRE

2-year Extended Analysis: Study Design

*IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine (per Zometa® label); †Among patients previously receiving denosumab or zoledronic acid, 89% in each treatment group chose to receive open-label denosumab

Stopeck AT, Lipton A, Martín M, et al. SABCS2011: abstract P3-16-07 and poster presentation.

Adults with advanced

breast cancer and confirmed

bone metastases

Denosumab 120 mg SC

+Placebo IV

Q4Wn=1026

Placebo SC+

Zoledronic acid 4 mg IV*

Q4Wn=1020

Primary

Analysis

Superiority of Denosumab

overZoledronic

AcidPositive

risk: benefit profile

Patient choice for open label

denosumab (n=752)

Denosumab120 mg SC Q4W for 2

years(n=652)

Yes (89%)†

2-year survival Follow-up(Q12W)

Phase 320050136

Denosumab/Denosumab

(n=318)n (%)

Zoledronic/ Acid/Denosumab

(n=334)n (%)

All adverse events 283 (89) 303 (91)

Serious adverse events (SAEs) 126 (40) 133 (40)

Most common AEs

Nausea 72 (23) 77 (23)

Fatigue 70 (22) 74 (22)

Back pain 66 (21) 56 (17)

Arthralgia 57 (18) 61 (18)

Decreased appetite 55 (17) 57 (17)

Osteonecrosis of the jaw 20 (6) 18 (5)

Hypocalcemia 12 (4) 9 (3)

Hypocalcemia of Grade 3 or 4 4 (1) 3 (1)

2-year Extended Analysis: Adverse Events During Open-Label Treatment Phase


*Positively adjudicated by an independent panel of experts; †Derived from a standard MedDRA (version 14.0) query that included blood calcium decrease, calcium deficiency, calcium ionized decrease, and hypocalcemia; ‡There were no fatal events of hypocalcemia.

2-year Extended Analysis:Overall Survival For the Entire Study*


*Includes blinded treatment phase and open-label treatment phase or survival follow-up

Risk Set:Zoledronic Acid/Denosumab 952 832 708 585 452 344 250 158 58Denosumab/Denosumab 985 850 706 585 459 342 255 159 44

Study Month0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Pro

porti

on o

f Pat

ient

s S

urvi

ved

1.0

0.8

0.6

0.4

0.2

0Zoledronic Acid/DenosumabDenosumab/Denosumab

Denosumab1 Bisphosphonates2-5

Administration Subcutaneous Intravenous

Osteonecrosis of the Jaw

Hypocalcaemia (+)

Renal Toxicity/renal elimination –

Dose Adjustments (for renal function) –

Flu-like symptoms –

Bone, joint, muscle pains –

Comparison of bisphosphonate and denosumab toxicities

1.XGEVA ® Summary of Product Characteristics August 2012 2. Zometa Summary of Product Characteristics February 2012. 3. Aredia Summaryof Product Characteristics January 2012. 4. Bonefos Summary of Product Characteristics August 2012. 5. Bondronat Summary of Product Characteristics January 2013

Treatment goal: prolong symptom-free AND overall survival

Symptom-free survival

Overall survival

?Bone-targetedtherapy

Anti-tumourtherapy

+

SREs

Bone metastases lead to increased activation of pain receptorsPe

riost

eum

NOCICEPTOR ACTIVATION Chymase

Interleukin-1Interleukin-6TNF-α and

other factors

Inreased release of bradykinin by bone

Mast cells

Macrophages

Tumour cells

Activated osteoclasts

Secretion of acidsReduction of pH in bone matrix

BONE PAIN

Reduced mechanical stability of bone

Prostaglandin E2

Bone matrix

TNF-α, tumour necrosis factor-α.

Cleeland CS, et al. Ann Oncol 2010;21:(Suppl 15) [Abstract 1248P].†Patients on studies progressing from no or mild pain

to moderate or severe pain (> 4 points).

Denosumab delayed progression from no or mild to moderate or severe pain vs zoledronic acidM

edia

n tim

e fro

m n

o or

mild

pai

n to

m

oder

ate

or s

ever

e pa

in (d

ays)

†

+ 55 days

HR, 0.83 (95% CI, 0.76−0.92)P = 0.0002

Integrated analysis

Points of Discussion and Future Work

Role of Biochemical Markers of Bone Turnover

Assessment of Response in Bone Metastases

Duration of Treatment with Bone Targeted Agents

New Targets in Bone Metastases

JCO, 2004

Bone is the only site of metastatic disease that has separate criteria for evaluation of response to treatment, based on bone repair anddestruction rather than on changes in tumor volume…

ZOOM: Change in On-Study NTX LevelsDuring 2 Different ZOL Treatment Schedules

Abbreviations: BC, breast cancer; NTX, N-telopeptide of type I collagen; q, every; SRE, skeletal-related events; ZOL, zoledronic acid.

Amadori D, et al. ASCO 2012, Abstract 9005.

No difference in risk of SREs between treatment groups

37

-40

-20

0

20

40

60

80

3 mo 6 mo 9 mo 12 mo

ZOL q 12 wk ZOL q 4 wk

Chan

ge in

NTX

vs

Base

line,

%(M

edia

n W

ith

Inte

rqua

rtile

Ran

ge)

*P < .05 by Wilcoxon test comparing arms

* **

Arm 1:ZOL (4 mg q 12 wk)

Arm 2:ZOL (4 mg q 4 wk)

Treatment duration 48 wk

R1:1

N = 420 (Planned)Key eligibility criteria• BC stage IV

• Prior ZOL (4 mg q 4 wk) × 9-12

infusions

OS in mBC Patients Whose NTX Levels Normalized Within 3 Months of Initiating ZOL

38

Abbreviations: mBC, metastatic breast cancer; OS, overall survival; NTX, N-telopeptide of type I collagen; EE, patients whose NTX levels remained elevated(≥ 64 nmol/mmol creatinine) at 3 months; EN, patients whose NTX levels normalized (< 64 nmol/mmol creatinine) at 3 months from elevated baseline levels.

Reprinted from Lipton A, et al. Cancer. 2008;113(1):193-201.

100

80

60

40

20

0

3 6 9 12 15 18 21 24

Prop

orti

on D

ecea

sed,

% P

atie

nts

Time on Study, mo (Starting at Month 3)

P = .002

Elevated Normalized NTX at 3 mo

Elevated Elevated NTX at 3 mo

Evolution of NTX in Breast Cancer Patients With Bone Metastases ± Extraskeletal Metastases

Breast Cancer Patients Treated With ZOL (n = 71)

BM + ESM BM-only

Abbreviations : BM, bone metastases; ESM, extraskeletal metastases; mo, month; NTX, N-telopeptide of type I collagen.

Presented at ASCO 2013, abstract # 9634

0

50

100

150

200

250

0 2 4 6 8 10 12 14ZOL Treatment Period, mo

Alive, NTX < 50, extra mets

Alive, NTX > 50, extra metsDead, NTX < 50, extra mets

Dead, NTX > 50, extra mets

0

50

100

150

200

250

300

0 2 4 6 8 10 12 14ZOL Treatment Period, mo

Alive, NTX < 50, bone mets

Alive, NTX > 50, bone metsDead, NTX < 50, bone mets

Dead, NTX > 50, bone mets

Uri

nary

NTX

Uri

nary

NTX

Monica Fornier, JCO 2010

Osteoclast Inhibition in Cancer

41

Cell, Volume 154, Issue 5, 1060-1073, 29 August 2013

Joan Massagué

Influence of tumor microenvironment

http://www.cell.com/issue?pii=S0092-8674(13)X0018-2�

At 4 weeks

Change from baseline* [95% CI] P

Saracatinib (n=46) −71.1% [−75.9, −65.4] P <0.001

ZA (n=65) −68.4% [−73.0, −63.2] P <0.001

Saracatinib vs zoledronic acid P = 0.432

Mean baseline scaled ratio (%) ± SE

*Derived from the geometric least square estimate of the baseline scale ratio; ZA, zoledronic acid

−90

−80

−70

−60

−50

−40

−30

−20

−10

0

Time (weeks)

4210

uNTXSaracatinib 175 mg qdZoledronic acid 4 mg on day 1

Serum ICTPSaracatinib 175 mg qd Zoledronic acid 4 mg on day 1

−50

−40

−30

−20

−10

0

10

20

Time (weeks)4210

At 4 weeks

Change from baseline* [95% CI] P

Saracatinib (n=47) −40.2% [−46.3, −33.4] P <0.001

ZA (n=66) 7.4% [−2.0, 17.7] P = 0.126

Saracatinib vs zoledronic acid P <0.001

The company decided not go forward with a phase 3 clinical trial

Phase II multicentre study to assess saracatinib effects on bone markers in cancer patients with bone metastasis

Combined treatment with ZA + AZD0530 has an increased effectin inhibition of osteoclastogenesis in vitro (RAW 264.7 cells)

ZA 25µM + AZD0530 1µMAZD0530 1µM

Control ZA 25µM

TRAP staining, x200

Pre-clinical study combining Src inhibitor with Zoledronic acid


BPs

Demab

mTOR inhibitors

mTOR Inhibition Bone Resorption, Osteoclast Maturation, and Osteoclast Apoptosis (Mouse Models)

Formation and enzymatic activity of mature osteoclasts

Osteoclast apoptosis

Abbreviations: CTX, C-telopeptide of type I collagen; h, hour; mTOR, mammalian target of rapamycin; TRAP, tartrate-resistant acid phosphatase.

Adapted/Reprinted from Glantschnig H, et al. Cell Death Differ. 2003;10(10):1165-1177.

Rapamycin concentration, nM

Rele

ase

of C

TX (r

elat

ive

unit

s)

0

20

40

60

80

100

120

0 1.0 3.0 10 30 100

0-72 h

mTOR inhibition bone resorption

TRA

P A

ctiv

ity

(rel

ativ

e un

its)

EVE Bone Turnover Marker Levels at 6 and 12 Weeks (Overall Population)

Δ26.4% Δ55.9% Δ35.9% Δ20.3% Δ66.2%Δ40.5%

Data from full analysis set.Proportions of patients with bone metastases or bisphosphonate use reflect the status at study entry among patients with baseline bone marker assessments.

Abbreviations: BSAP, bone-specific alkaline phosphatase; CTX, C-terminal cross-linking telopeptide of type I collagen; P1NP, amino-terminal propeptide of type I collagen.

Gnant M, et al. JNCI. 2013 February 19 Epub, doi: 10.1093/jnci/djt026. 46

Everolimus + Exemestane (n = 485)Placebo + Exemestane (n = 239)

P = .04 (Gray’s test, 2-sided)

Patients at riskEverolimus + ExemestanePlacebo + Exemestane

485 436 366 304 257 221 185 158 124 91 66 50 35 24 22 13 10 8 2 1 0239 190 132 96 67 50 39 30 21 15 10 8 5 3 1 1 1 0 0 0 0

At 54 weeks:CR = 0.1241 (95% CI, 0.0941-0.1583) for everolimus + exemestaneCR = 0.2122 (95% CI, 0.1596-0.2698) for placebo + exemestane

EVE Disease Progression in Bone: Overall Population (N = 724)

Cumulative incidence of disease progression was determined using the competing risk method; exploratory P = .036 by Gray’s test.

Abbreviations: CI, confidence interval; CR, competing risk estimate.

Gnant M, et al. JNCI. 2013 February 19 Epub, doi: 10.1093/jnci/djt026. 47


BPs

Demab

?

49

Plos One 2013

Current treatment options for Bone Metastasesfrom Breast Cancer

Radiotherapy ↓ Bone pain↓ Neurologic complications from

spinal cord compression

Radioisotopes ↓ Bone pain; Survival (?).. 223RaCl2 (alpharadin)

Surgery ↑ Healing of pathologic fracture↓ Neurologic complications from

spinal cord compression

Cementoplasty ↑ Stability

Analgesia ↓ Bone pain

palli

ativ

epr

even

tive

Bone targeted agents ↓ Bone pain↓ Incidence of SREs

Translation of New Treatments Into Improved Patient Outcomes in Breast Cancer

Endocrine therapy:

Tam, AIs, fulvestrantmTOR inhibitors

Anti–HER2: Trastuzumab, Lapatin

ibPertuzumab

TDM-1

Chemotherapy: taxane, fluorpirimidines, vi

norelbine, gemcitabine,anthracycline, platin,cyclophosphamide,

Eribulin

ER+

65–75%

HER2+

15–20%

Triple-neg.TNBC15%

'BRCAness' of tumors

PARP Inhibitors

Anti-angiogenictherapy:

bevacizumab (?)

osteoclasts Bone-targetedtherapy:

bisphosphonates,denosumab

“You willunite, or you will fall.”

surgeons

radiotherapist

Medical oncologist

Protecting andAdvocating for Frodo

diagnostic specialities

Specialist Nurse

Gollum is also a survivor, but ..he haswalked alone with the burden of the ring.

JCO, 2005

Summary and Perspective

• Bisphosphonates were the first form of therapy targeting the host to protect the patient from the occurrence of bone complications.

• Denosumab is a more effective option to delay and prevent bone complications in BC patients with BM.

• Bone marker data suggest that EVE suppresses bone turnover and reverses the increase in bone resorption associated with EXE.

• Results from ongoing clinical trials evaluating the potential applications of bone markers are awaited to identify the true value of bone markers in clinical practice.

• Findings of tumour–bone interactions have uncovered numerous therapeutic opportunities. Hopefully this will continue to yield new and exciting therapeutic targets to treat bone metastases.

Abbreviations: BC, breast cancer; BM, bone metastases; EVE, everolimus; EXE, exemestane;

“Treatment of Bone Metastases from Breast Cancer”

Lisbon Academic Medical Center

Integrate forefront scientific research

with medical teaching, medical training and patient care

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