Breast cancer

– challenges
and
controversies
THE BURDEN OF CANCER

Bray et al, CA Cancer J Clin 2018;0:9–31

Globcan 2018
 THE BURDEN OF CANCER

2030: an estimated 13.1

million deaths/year

Soon, 1 OUT OF 2 PEOPLE

WILL GET CANCER IN
THEIR LIFETIME

Globocan 2012
 THE BURDEN OF CANCER in FEMALES - incidence

Bray et al, CA Cancer J Clin 2018;0:9–31

Globcan 2018
Incidence THE BURDEN OF BREAST CANCER

GLOBOCAN 2018 data*

5-year Prevalence

Mortality

* Bray F et al. Global cancer statistics 2018: GLOBOCAN

estimates of incidence and mortality worldwide for 36
cancers in 185 countries. CA Cancer J Clin, 2018.
 Adjuvant
Early stage systemic Advanced stage
therapy

Lymph node
 30%
negative
(50-60% of BC
diagnosed today)

Stage 1
Stage 4

Lymph node  50%

positive
INCURABLE !
70%
Stage 2

Chemotherapy +/-
Endocrine therapy +/-
Stage 3
Biological therapy
EBC OUTCOME EVOLUTION

Breast Cancer
Despite ↑ incidence - ↓ mortality

* Screening & early diagnosis

* Education & advocacy
but also
* Better treatment options
* Better treatment strategies
International Cooperation in the Treatment
of Breast Cancer is making huge progress!

The Breast BIG NETWORK

ABCSG GBG JBCRG
Cancer ABS at BASO GBOC MOSG
Intergroup (TBCI) Communication ACCOG
ANZ BCTG
GECO PERU
GEICAM
NBCG
NCIC-CTG
ACOSOG BOOG GOCCHI NCRI BCSG
CALGB BREAST GOIRC SAKK
ECOG CEEOG GONO SBCG
NCCTG DBCG HBSS SOLTI
NCIC-CTG EORTC BCG IBCSG TCOG
SWOG FBCG IBIS WSG
Collaboration FBSG ICCG WMBG
GBECAM ICORG YBCRG
on ad hoc basis ICR CTSU
RTOG ITMO

• Acceleration in the conduct

of difficult trials
Reduced • Cooperation in translational Reduced
duplication of research substudies
duplication of
efforts efforts
 CURRENT B.C. MANAGEMENT

The “Revolutions” that are shaping BC

management today

1. Changes in scientific paradigms/dogmas

2. Changes in social paradigms/dogmas
3. Widespread screening
4. Efficacious systemic treatments
5. The “omics” & translational medicine era
6. Patient-centered medicine (treatment
individualization & QoL)
 CURRENT B.C. MANAGEMENT

1st “Revolution”: 50’s to 70’s

CHANGES IN SCIENTIFIC PARADIGMS/DOGMAS

More is not always better

Breast Cancer: from local to systemic disease

CURRENT B.C. MANAGEMENT
More is not always better SURGERY
 CURRENT B.C. MANAGEMENT
More is not always better SURGERY

Lymphedema
Sentinel Lymph
Node Biopsy
CURRENT B.C. MANAGEMENT
ONCOPLASTIC SURGERY

Not every reconstruction

is oncoplastic surgery!!!
 CURRENT B.C. MANAGEMENT
More is not always better RADIOTHERAPY

Brachytherapy

Cobalt Linear accelerators

Tridimensional RT Intraoperative RT= 1 day
CURRENT B.C. MANAGEMENT
RADIOTHERAPY
 CURRENT B.C. MANAGEMENT

2nd “Revolution” – 60’s & 70’s

CHANGES IN SOCIAL PARADIGMS/DOGMAS

Breast Cancer “out of the closet”

Women’s role in society & in medicine
and SPEAK MORE
 3rd “Revolution”

Political will
Widespread Screening
Information Campaigns

HISTOIRE NATURELLE

Taille en mm
12
Non détectable Dépistage Palpable
10

0 ans
6 10
 CURRENT B.C. MANAGEMENT
SCREENING/EARLY DIAGNOSIS

Mammography

Ultrasound

BC < 1,5 cm N0 = Surival > 90%

 ASYMPTOMATIC WOMEN AT LOW RISCK FOR BREAST
CANCER (REFERRED OR SELF-REFERRED)

Clinical breast examination (CBE) as part of

• Before 40 the annual gynecologic surveillance

CBE + Biannual complete MG (CC and MLO)

• 40 – 49 + US

CBE + Biannual complete MG (CC and MLO)

• 50-69 + US

CBE + Biannual complete MG (CC and MLO)

• After 70 + US, or in selected cases every 3y

MG: mammography; CC: craniocaudal view;

MLO: mediolateral oblique view; US: ultrasonography
25
 ASYMPTOMATIC WOMEN AT INTERMEDIATE RISK FOR BREAST
CANCER
Family history: Women from families not tested or inconclusively
tested for BRCA mutation with <20% lifetime risk

• Before 35 Annual CBE + US

MRI in selected cases

• After 35 Annual CBE + MG + US

MRI in selected cases

MG: mammography; CC: craniocaudal view;

MLO: mediolateral oblique view; US: ultrasonography

27
 ASYMPTOMATIC WOMEN AT HIGH RISCK FOR BREAST CANCER

▪ 20-30% lifetime risk or greater 30-35: Annual MRI + US

Women from families not tested or
inconclusively tested for BRCA mutation
▪ Genetic predispositon
BRCA1, BRCA2 and TP53 mutation carriers
50% risck for BRCA1, BRCA2 or TP53 mutation
(runs in first degree relatives)
▪ Previous mantle radiotherapy before 30
(e.g. Hodgkin disease)
(if CI to Gd enhanced MRI: whole
breast US + CBE)
≥ 35: Annual MRI + MG + US
(except in TP53 mutation carriers)
Annual MRI starting 8y after
treatment (if≥35: annual MRI+
MG)

MG: mammography; MRI:magnetic resonance imaging

CI: contraindication; Gd: gadolinium. 28
 CURRENT B.C. MANAGEMENT
Breast Cancer: from local to systemic disease

EFFICATIOUS SYSTEMIC TREATMENTS

4th “Revolution” – from 70’s on

More recently …. more is not always better also for

systemic treatment
CURRENT B.C. MANAGEMENT
5th “Revolution” – 2000’s

THE “OMICS” &

TRANSLATIONAL MEDICINE ERA
 A tumor cell in the Seventies

Nucleus ?

Cytoplasm

Courtesy of T. Tursz
 A tumor cell in the 2000’s
HGF EGF

E-cad MET EGFR

GRB2 GTP GDNF
NF2 SOS
PTEN MEN1
PTCH
APC
SMO

ELG-C
ELG-B VHL
-cat ELG-A
? Target genes ?

CYC D1 ? Target genes ? mismatch

WT1 PMS2 MLH1

? Target genes ?

(MSH3)
S-Phase genes
Rad51
p53 P21 Gene BRDCA2
ATM ? Other targets ?
Mdm-2
Courtesy of T. Tursz
 SUCCESSIVE REVOLUTIONS IN MEDICINE

MICROSCOPE GENOSCOPE PROTEOSCOPE

1950 - 2000 2000 - 2010 2010 - ….

A complex 4 to 5 different ?
disease diseases
and functional imaging
Adapted from M Piccart
 CURRENT B.C. MANAGEMENT
The Present & The Future

Examples of benefits from the translational research era:

• Better understanding of the biology of BC
• Better definition of who needs chemotherapy for early BC
• Better treatments

Treatment individualization or tailoring

WHY? HOW?
 The Present & The Future

6th & Current Revolution:

PATIENT-CENTERED MEDICINE

Main goals of today’s BC management & Research

• Multidisciplinarity & Interdisciplinarity
• Treatment individualization/tailoring
• Quality of Life & survivorship issues
• New treatments
• New exams (imaging, genomics, proteomics, etc…)
The Present & The Future: PATIENT-CENTERED MEDICINE
QUALITY OF LIFE

SYMPTOMS’ CONTROL
LESS AGGRESSIVE TREATMENTS
KNOW WHEN TO STOP…
 The Present & The Future: PATIENT-CENTERED
MEDICINE

BREAST CLINICS

TUMOR BOARDS (for both early and advanced BC!)

USE INTERNATIONAL GUIDELINES

ALL ASSOCIATED WITH BETTER SURVIVAL!!

 CLINICAL ASSESSMENT

• Complete personal medical history and physical examination

• Menopausal status (if in doubt, serum estradiol and LH/FSH
levels)
• Family oncological history (breast/ovarian tumors and other
cancers)

41
Relative risk for breast cancer
Risk Factor RR
First degree relative with breast 2.4
cancer
Late first child birth(>35) 1.3
Two first degree relatives with 2.9
Breast cancer
Three first degree relatives with 3.9
Breast cancer
ADH 4
HRT for greater than 5 years 2.0
Oral Contraceptive Use 1.2
Obesity 2.0
BRCA1 carrier 6.0‐8.0
 ASSESSMENT OF PRIMARY TUMOR

• Physical examination
• Imagiological evaluation
• Pathological diagnosis

42
 ASSESSMENT OF PRIMARY TUMOR

Imaging evaluation
• Assessment of: tumor size, location, relation with nipple-areolar
complex, multifocality and multicentricity
• All patients must perform an internal imaging evaluation with:
• whole breast and axillary US and mammography
• Microbiopsy (14G, us, stereotaxic or MRI guided) of all suspicious
breast lesions, if not yet confirmed
• Microbiopsy (14G us guided ) of at least one suspicious axillary
node, if not yet confirmed

US: ultrasonography
MRI: magnetic resonance imaging
43
 ASSESSMENT OF PRIMARY TUMOR
Pathological diagnosis
• Histological type, grade, imunohistochemical (IHC) evaluation
of estrogen and progesterone receptors status, HER2 receptor
expression status and Ki67 proliferation marker measurement

45
 ASSESSMENT OF REGIONAL LYMPH NODES
• Physical examination
• Imagiological evaluation: Axillary ultrasound. Core needle biopsy
14G if suspicious lymph node
• Pathological diagnosis

46
 STAGING
Physical
• examination
All• ASSYMPTOMATIC patients with an invasive carcinoma except
T1 N0 AND positive hormone receptors and HER2 negative,
without indication for neoadjuvant systemic therapy (not to be
done also for DCIS), will also have:
Tumor
•
markers: Ca 15.3
Imagiological
•
staging:
• For patients undergoing neoadjuvant systemic therapy: Chest-abdominal-
pelvic CT and bone scan.
• For “lower risk” patients: abdominal ultrasound can be used instead of CT
• If scans are inconclusive or for LABC: FDG-PET/CT (limited use only)
Pathological
•
diagnosis: Biopsy of suspected lesions if possible
(core needle biopsy (preferred), surgical biopsy, or fine needle aspiration)
47
 THE « WEAPONS » OF MEDICAL ONCOLOGY

The “bomb” The “missiles”

Chemotherapy Endocrine Therapy Ant-HER-2 therapy

Tumor cell in division Tumor cell with hormonal Tumor cell with HER-2
receptors receptors
(about 2/3 of BC) (about 1/5 of BC)
 TREATMENT INDIVIDUALIZATION : WHY?
Chemotherapy benefit / risk balance
Lessons learned from 2 decades of clinical trials

BENEFIT
 Survival
(2 to 12%)
LONG-TERM RISKS
• Secondary cancers
• Cardiac toxicity
• Early menopause
•  Cognitive function

Clinical trials identify better treatments in terms of benefit versus risk but for the
population of BC and not for each individual patient!
 Outcomes of Adjuvant Chemotherapy in Breast Cancer

Copyright © American Society of Clinical Oncology

Walgren et al. JCO 2005;23:7342-7349
 2 MAIN QUESTIONS NEEDED TO BEANSWERED
WHO NEEDS TREATMENT? WHICH TREATMENT IS BEST?

TREATMENT CHOICES

AVOID UNDERAND OVER TREATMENT INDIVIDUALIZE TREATMENT

New/better PROGNOSTIC FACTORS New/better PREDICTIVE FACTORS

 VALIDATED PREDICTIVE MARKERS

Breast Cancer
Cut off 1%

HER2 ER/PGR

Negative predictive value Positive predictive value

HIGH 95% 30-50%

(<5% chance to respond to
anti-estrogens or trastuzumab)

Courtesy F. Penault-Llorca
CLINICOPATHOLOGICAL PROGNOSTIC FACTORS IN EBC

• Tumor size

• Lymph node status

• Grade

• ER, PR and HER-2 receptor expression

• Presence of lymphovascular invasion

 MOLECULAR CLASSIFICATION OF BREAST CANCER - SURROGATES
Subtype Molecular characteristics
Luminal A •luminal CK expression
•resembles normal
Epithelium cells
Luminal B •similar to luminal A
Basal-like
•without expression of ER,PR
And HER-2genes
•basal CK expression(CK5)
•expression of growth factors
(EGFR,c-kit,HGF,IGF)
•BRCA disfunction
•genetic instability
Her-2 •amplification of HER-2gene
enriched And overexpression of HER-2
receptor
Histological characteristics Biology/treatment
SURROGATES
•ER+ •indolent behavior
•low grade/low proliferation •sensitive to hormonal therapy
•ER+(lower expression than •more aggressive behavior
In luminal A) Than luminal A
•high grade/high •less sensitive to hormonal
proliferation Therapy than luminal A
•“Triple negative” •aggressive behavior
(ER-,PR-,HER2-) •sensitive to chemotherapy
•high grade/high
proliferation
•HER2+ •aggressive
•sensitive to anti-HER-2 therapy
•sensitive to chemotherapy
PROGNOSTIC VALUE OF BC MOLECULAR SUBTYPES

Courtesy of MJ Brito
 GENOMIC TESTS IN ALL OR ONLY SELECTED BREAST CANCER CASES?

TRIPLE NEGATIVE HER-2 POSITIVE

(ER-, PR-, HER-2 neg) LUMINAL
ER+ HER-2 neg
CT + anti-HER
CT indispensible indispensible

“Clear” indication from classical factors

All LOW risk: high levels All HIGH risk: low levels “No Clear” indication from
ER, PR, grade 1, node ER, PR, grade 3, node classical factors; some high
negative, low proliferation positive, high proliferation & some low risk
CRUCIAL IMPORTANCE OF HIGH QUALITY PATHOLOGY

HT alone CT → HT GENOMIC TEST

 NEOADJUVANT CT
• Neoadjuvant CT is safe & efficient
– Facilitates less invasive loco-regional treatment
– No difference in DFS and OS between neoadj & adjuvant CT
– Slight difference in locoregional recurrence rate

• Dose dense specially useful for high proliferativeand/or ER neg tumors

• Incorporation of taxanes
– Increase in RR; not consistent benefit in long term outcome
– Responders to A-based seem to derive greater benefit from switching to taxane-
based than from continuing A-based
– Weekly paclitaxel superior to 3-weekly
 ENDOCRINE THERAPY
1st example of TARGETED THERAPY

Aromatase
inhibitors

ER: estrogen
receptor
THE LIGAND
THE TARGET

Tamoxifen
Fulvestrant
EARLY BREAST CANCER: WHO NEEDS ADJUVANT ET?

(almost) All ER+ EARLY BREAST CANCER patients!

Until the early 90’s: decision was based on

menopausal status:
All post-menopausal: Yes
All pre-menopausal: No
• HR the only
predictive factors

• Levels of positivity
also important

EBCTCG,The Lancet 2011

 TAMOXIFEN
Bad news... Good news...

No increase in
Steatosis cardiovascular risk

Slight increase in
Endometrial cancer
Favorable effect
in bone density
Thrombo-embolic
risk
 AROMATASE INHIBITORS
Good news... Bad news...

Cardiovascular risk
Less steatosis Dislipidemia

No increase in
endometrial cancer Arthralgia/Myalgia

Osteoporosis
Less thrombo-embolic Bone fractures
risk
 Annual Risk of Recurrence by ER Status
0.3
ER+ (n = 2257)

Recurrence hazard rate

ER– (n = 1305)

0.2

0.1

0
0 1 2 3 4 5 6 7 8 9 10 11 12
Years
• Over half of breast cancer recurrences occur >5 years post-surgery!
• The annual risk of late recurrence is particularly high in ER+ tumors (5.2%
between years 5 and 8, 4.6% between years 8 and 12).

Hormone receptor positivity is a strong predictor for late recurrence !

Saphner T et al., J Clin Oncol 1996

 2nd EXAMPLE OF TARGETED THERAPY:
HER-2 RECEPTOR & TRASTUZUMAB

Activated receptor

HER-2 receptor Ligand

TRASTUZUMAB
binding Cell
membrane

Signal
transmition

Proliferation
STOP Survival Migration

Tumor Growth and

Metastases
 TAKE HOME MESSAGES regarding HER2+ EBC

• Trastuzumab is life-saving and has changed the natural history of

HER2+ EBC! (should be the focus of lobbying/pressure for access)
• Dual blockage with Pertuzumab adds only a small benefit in Node +
or ER negative disease.
• Lapatinib not useful. Neratinib too toxic and small benefit.
• T-DM1 role in post-neoadjuvant improves outcomes in patients who don’t
achieve a pCR

• Open questions:
•Role of 2 anti-HER-2 agents alone (with no CT)?
•Resistance
•Biomarkers to decide for dual-blockade
 DEFINITION OF Advanced Breast Cancer (ABC)

Includes 2 clinical situations:

1. Inoperable Locally Advanced Breast Cancer (LABC), that
has not yet spread to distant sites
2. Metastatic Breast Cancer, that has spread to distant sites
(most common are bone, liver, lung, brain, lymph nodes); also called
Stage IV breast cancer.
 Goals of the Treatment in ABC

• Balancing treatment efficacy and toxicity is the main objective

• Goals of treatment:
– Improve survival (very few agents achieve it!)
– Delay disease progression
– Prolong duration of response
– Palliate symptoms
– Improve or maintain quality of life
– Transform into a chronic disease
Quantity Quality
of of
Life Life
 5 year survival rates for mBC still around 25%
5-year Survival Rates by Stage at Diagnosis (Female Breast Cancer, US SEER),
1992-1999 Compared with 2005-20111,2

Have things really

changed?

1. American Cancer Society. Breast Cancer Facts & Figures 2003-2004. Atlanta, GA: American Cancer Society; 2003.
2. National Cancer Institute. SEER stat fact sheets: breast cancer. http://seer.cancer.gov/statfacts/html/breast.html.Accessed July 31, 2015.

Analysis suggests limited improvement in quality of life

for patients with mBC over the last decade

Quality of life in patients with mBC as assessed

Yes ... but not as much

by EQ-5D, 2004-2012, Generic (non-Cancer
Specific) Health Utility Score2 • An analysis of the trends in
quality of life for mBC* indicates

as needed!
0.8
0.7423 that there has not been
0.7201
0.6990 significant improvement over
0.6914
0.7 the past decade2

EQ-5D Score
0.6313
• In fact, there has been a slight
0.6
decrease in quality of life2

0.5
2004 2006 2008 2011 2012

*Analysis was based on a review of 132 articles, of which a quantitative analysis was conducted of 14 studies reporting QoL measure
values for mBC. Values are weighted based on sample size. This analysis indicates a numerical decrease over time. It does not intend to demonstrate
statistical significance

1. Here & Now, Novartis, 2013. 2. Global Status of Advances/Metastatic Breast Cancer, 2005-2015 Decade Report, March 2016.
In the early 2000’s…
2 SURVEYS ON LIVING WITH ABC STARTED TO CHANGE THE SCENE…

• Most women do not feel that healthcare professionals, researchers, the

media, women with EBC, and the governments pay enough attention to MBC.

•Throughout the survey there is a worrying picture of feelings of guilt,

abandonment, isolation, and loneliness during the hard journey through MBC..

• 44% of respondents reported being afraid to talk open about their disease
and 52% said their friends and family were uneasy talking about the disease.

Seminarsin Oncology Nursing (26) 3, 2010; CommunityOncology, Sep. 2010

 48–76% of the general public believe that
advanced/metastatic breast cancer is curable

The Challenges of Extreme Societal

Opinions about mBC

Death sentence mBCAttitudes Curable

Others overly positive,

Some believe people with
Thinking people can “beat”
mBC will die very soon
mBC

Driven by perception that all

Cancer is terrible/
Imminently fatal
Or by perception that once
Cancer spreads, end of life
Must be close
Typically driven by visibility of
Success stories in eBC FIGHT STIGMA!
Patients themselves may
Believe their mBC can be
cured
–in some cases,the medical
Team appears to have
Painted an overly positive
picture
 MAIN PRINCIPLES OF ABC RECOMMENDATIONS
✓Apply the main principles of modern oncology:
✓Multidisciplinary treatment
✓ Specialized breast cancer units
✓ Evidence-based medicine
(please STOP “eminence-based” medicine!!)
✓ Individualized (tailored) therapy

✓Remember the specificities of ABC setting

✓Patient’s preferences & active participation

✓Identify areas of UNMET NEEDS & RESEARCH PRIORITIES

Incidence HOW MANY ABC PATIENTS EXIST?

GLOBOCAN 2018 data*

5-year Prevalence

If 1 third would be MBC: about 2.2 million MBC patients

BUT it is just a very rough estimation
Mortality

* Bray F et al. Global cancer statistics 2018: GLOBOCAN

estimates of incidence and mortality worldwide for 36
cancers in 185 countries. CA Cancer J Clin, 2018.
 IMAGING, TUMOR MARKERS &
EVALUATION OF RESPONSE

Minimal staging workup for MBC includes a history and physical

examination, hematology and biochemistry tests, and imaging of
chest, abdomen and bone.
(LoE/GoR: II/A) (67%)

Notes:
✓ Biochemistry tests including liver function tests, renal function,
electrolytes, calcium, total proteins and albumin
✓ A PET-scan should NOT be part of the minimal staging workup but it is
very useful in specific situations (e.g. high suspicion of metastases that can
not be found in previous exams)
 IMAGING, TUMOR MARKERS &
EVALUATION OF RESPONSE

Brain imaging should NOT be routinely performed in asymptomatic

patients. This approach is applicable to all patients with MBC including
those patients with HER-2+ and/or TNBC MBC.
(LoE/GoR: II/D) (94%)

BUT
✓Careful evaluation of signs and symptoms is needed, particularly among
patients with HER-2+ or TN MBC, since clinical manifestations of brain
metastases may sometimes be quite subtle.

✓In the setting of suggestive signs or symptoms, a lower threshold to

image such patients should be considered given the higher pre-test
probability for CNS involvement.
 IMAGING, TUMOR MARKERS &
EVALUATION OF RESPONSE

The clinical value of tumor markers is not well established for diagnosis
or follow-up after adjuvant therapy, but their use (if elevated) as an aid
to evaluate response to treatment, particularly in patients with non-
measurable metastatic disease, is reasonable.A change in tumor
markers alone should not be used to initiate a change in
treatment.

(LoE/GoR: II/C) (89%)

GENERAL RECOMMENDATIONS
TREATMENT

THE 2 MAIN PROBLEMS IN ONCOLOGY TODAY

✓ PATIENT SELECTION

✓ TUMOR RESISTANCE
 TREATMENT TAILORING IN ABC

Treatment choice should take into account at least these factors:

HR & HER-2 status,
previous therapies and their toxicities, disease-free interval,
biological age, performance status, co-morbidities (including organ dysfunctions),
menopausal status (for ET),
need for a rapid disease/symptom control,
patient’s country
and patient preference.
DISEASE clinical CHARACTERISTICS
TUMOR CHARACTERISTICS

TAILOR FOR THE PATIENT TAILOR FOR THE DISEASE

bothbiologicallyand clinically

(LoE/GoR: Expert opinion/A) (100%) Target

INDIVIDUALIZED
TREATMENT
THE MAJOR PROBLEM OF TUMOR RESISTANCE TO THERAPY

Resistance Response
Response

Progression

Treatment Treatment

J. Ribeiro & F. Cardoso

 BIOPSY OF METASTATIC DISEASE

A biopsy (preferably providing histology) of a metastatic lesion should

be performed, if easily accessible, to confirm diagnosis particularly
when metastasis is diagnosed for the first time. (LoE/GoR: I/B) (98%)

Biological markers (especially HR and HER-2) should be reassessed at

least once in the metastatic setting, if clinically feasible.
(LoE/GoR: I/B) (98%)

Depending on the metastatic site (e.g. bone tissue), technical

considerations need to be discussed with the pathologist.
 HOW TO TREAT ER+/HER-2 neg (LUMINAL) ABC:

➢ Many available options today

➢ Major questions:
➢ Best sequence for each individual patient
➢ Best therapy after CDK4/6 inhibitors

HOW TO TACKLE HETEROGENEITY OF LUMINAL-LIKE ABC?

Are there ready-to-use (bio)markers to individualize sequence of
therapies?
 HOW TO TREAT ER+/HER-2 neg (LUMINAL) ABC:

MAIN QUESTIONS:
a) Do we need Chemotherapy (CT)?
b) If Endocrine Therapy (ET) which agent?
c) Is a targeted agent also necessary or is ET alone sufficient?
d) If CT: combination vs. sequential monotherapy?
e) If CT: which agent(s)?
 ER POSITIVE / HER-2 NEGATIVE MBC

Endocrine therapy (ET) is the preferred option for hormone receptor

positive disease, even in the presence of visceral disease, unless there is
visceral crisis or concern/proof of endocrine resistance.

(LoE/GoR: I/A) (93%)

ALL guidelines are in agreement for this recommendation

 ESMO Guidelines for the Use of First-Line
Endocrine Therapy in Postmenopausal HR+ ABC

ENDOCRINE TREATMENT STRATEGY

ET1 ET2 ET…

response response ET3 response

CT

MAIN RESEARCH QUESTION:

OPTIMAL SEQUENCE
Image adaptedfrom Senkus & Cardoso F, et al. Ann Oncol. 2013, ESMO GUIDELINES
Combining Targeted and Antiestrogen
Therapies in HR-Positive Breast Cancer
EGFR E Aromatase Inhibitor
HER2 Nonsteroidal AIs:
Anastrozole
Letrozole
Steroidal AI:
Exemestane
P P
TKI
E
RAS PI3K
PTEN
ER Downregulator
Raf
E Fulvestrant
mTOR Inhibitors MEK
Akt ER
Everolimus
Sirolimus MAPK
Temsirolimus mTOR
Selective ER
Modulators
CDK4/6 Inhibitors Tamoxifen
Palbociclib Toremifene
Abemaciclib
Ribociclib Cell E E ER target gene
Cycle ER ER transcription
HDAC Inhibitor
Entinostat Transcription
Silencing
Johnston SR. Clin Cancer Res. 2010;16:1979-1987. Slide credit: clinicaloptions.com
 ER POSITIVE / HER-2 NEGATIVE MBC

The optimal sequence of endocrine-based therapy is uncertain.

It depends on which agents were previously used (in the (neo)adjuvant
or advanced settings), the burden of the disease, patients’ preference,
costs and availability.

Available options include AI, tamoxifen, fulvestrant, AI/fulvestrant +

CDK4/6 inhibitor, AI/tamoxifen/fulvestrant + everolimus. In later lines,
also megestrol acetate and estradiol, as well as repetition of previously
used agents, may be used.
(LoE/GoR : I/A) (95%)

It is currently unknown how the different combinations of endocrine +

targeted agents compare with each other, and with single agent CT.
Trials are ongoing.
* for pre and peri with OFS/OFA, men (preferably with LHRH agonist) and post-menopausal women
• GOAL: to treat for as long as possible with a good QoL

• Then:
– TOXICITY PROFILE is crucial
– DOSE REDUCTIONS are acceptable and often
needed (and better than interruptions)
– ORAL vs IV (convenient, cost-effective, maintain work
responsibilities…)
– PATIENT PREFERENCES (oral treatment approaches and
time saving drug delivery strategies are usually preferred by
the patients)
 CHEMOTHERAPY (general)

Duration of each regimen and number of regimens should be tailored to

each individual patient. (LoE/GoR: Expert opinion/A) (96%)

Usually each regimen (except anthracyclines) should be given until

progression of disease or unacceptable toxicity. What is considered
unacceptable should be defined together with the patient.

(LoE/GoR: I/B) (72%)

✓ A meta-analysis of published trials (Gennari et al) concluded that

longer 1st line CT duration is associated with a marginally longer OS
and a substantially longer PFS.
 • Longer OS: 25.1 vs. 20.3 ms (p=0.046)
• Longer TTP: 7.4 vs. 4.6 ms (p0.001)
• Higher RR: 50 vs. 32% (p0.001)
• Longer duration: 9.1 vs. 6.1 ms (p0.001)

MCBS: 5
 Treatment of HER2+ ABC: Progress over time
First-line
CT 20.3 mos. 20011

CT + Trastuzumab 25.1 mos.

D + Trastuzumab 40.8 mos.

20152
D + Trastuzumab + Pertuzumab
Second line 56.5 mos.

Capecitabine 16.2 mos.

20103
Capecitabine + Lapatinib 18.8 mos.

Capecitabine + Lapatinib 25.1 mos.

20124
T-DM1 30.9 mos.

Third / Later line

Physicians choice 15.8 mos.
20155
T-DM1 22.7 mos.

10 20 30 40 50
Overall survival, months
1
Slamon et al. NEJM 2001; 2 Swain et al. NEJM 2015; 3 Geyer et al. NEJM 2011; 4 Verma et al. NEJM 2012
5 Geyer et al. SABCS 2015. mod. from Loibl SABCS 2015
 Heterogeneity of TRIPLE NEGATIVE BC:
TNBC Classification
Mesenchymal-like TNBC IM Immune-associated
(ML-TNBC)
Immune (IM) TNBC
signature Angiogenesis
M Claudin-
EMT signature:Low
cell motility
growth factor signaling
BL1
(TFG6, Notch,
Wnt/β-catenin, Hedgehog) Cell cycle
DNA damage
Growth
MSL signaling
(EGF,
BL2 BL
Normal Low
IGF) cytokeratine
BL Basal-like (BL)
proliferation
TNBC
PI3K
LA/LB mutations

HER2e
Luminal/apocrine (LA) AR
Pathway
TNBC
HER2-enriched (HER2e)
LAR TNBC
Lehmann's classification
PAM50/claudin-low classification
Le Du F. Oncotarget. 2015;6:12890-12908. This work is licensed under a
Creative Commons Attribution 3.0 Unreported License. Slide credit: clinicaloptions.com
 The principle of synthetic lethal tumour targeting

Normal tissue cells Few normal tissue effects

Homologous

HR repair

HR repair
recombination
DNA (HR) repair
repair PARP inhibitor
DNA
Base excision Base excision
repair
DNA repair DNA repair

BRCA1/BRCA2 deficient Specific tumor cell killing

Tumor cells
HR repair

PARP inhibitor

Base excision
DNA repair

Tutt and Ashworth Cold Spring Harb Symp Quant Biol 2005;70:139–148; McCabe N et al. Cancer Res 2006;66:8109–8115
 How does PARP inhibition compare with CT in ABC?

Potent PARP inhibitor

at MTD as continuous
exposure
gBRCA1 / BRCA2 Carriers

Advanced anthracycline
Primary
taxane resistant breast R endpoint
cancer
PFS
Physician Choice
within SOC options
Capecitabine
or
Vinorelbine
or
Eribulin
or
Gemcitabine
Niraparib – BRAVO Trial EORTC / BIG

Talazoparib– EMBRACA - NCT01945775

Olaparib - OLYMPIAD NCT02000622

National Institutes of Health, Available at: https://clinicaltrials.gov/ct2/results?term=NCT01945775 and

https://clinicaltrials.gov/ct2/results?term=NCT02000622 . Accessed: September 27, 2015.
Heredetary risk vs general population
Breast/ovarian cancer
Gene Summary: High Penetrance Genes
Syndrome Gene Cancers Lifetime risk of breast
cancer
Breast‐Ovarian BRCA1 Female breast, Ovarian 40‐80%

Breast‐Ovarian BRCA2 Female and male breast, ovarian, prostate and 20‐80%
pancreatic

Li‐Fraumeni Tp53 Breast, sarcoma, leukaemia, brain, 56‐90%

Adreno-cortical, lung

Cowden’s PTEN Breast,thyroid,endometrial 25‐50%

Peutz‐Jeghers STK11 Breast,ovarian,cervical,uterine,testicular, 32‐54%

colon, small bowel
Hereditary CDH1 Early onset diffuse gastric cancer, lobular
Diffuse gastric Breast cancer 60% (lobular)
cancer 11-12

0
 Gene Summary: Moderate
Penetrance Genes
Gene Cancers Lifetime risk of breast
cancer

20‐50 (depending on
ATM Breast and ovarian age)%
25‐37%
CHEK2 Breast, colorectal, ovarian, bladder

20‐40%
PALB2 Breast, pancreatic, ovarian,male breast

RAD51C Breast,ovarian variable

BRIP1 Breast, ovarian, variable

ABRAXAS Breast variable

 Risk Management Categories

4 risk levels as per UK NICE guidelines:

Population Risk: Lifetime risk 12%
Near population risk: Lifetime risk less than 17%
Moderate risk: Lifetime risk 17‐30% - Manage locally
High risk: Lifetime risk over 30% - Genetic testing
• Definite gene carriers Lifetime risk up to 80%
• Testing not available Lifetime risk 30‐40%
11-12
October
2017
Lisbon,PT
 Carrier/Patient Choices

 Intensified Surveillance
 Risk Reducing Surgery (RRS)
 Chemoprevention
Insurance plan reimbursement

25
Pregnancy and fertility issues in BC patients
birth
Assessing the risk of infertility CHEMOTHERAPY

CRITICAL FACTORS:

 Drugs administered (schedule

and dosage)
 Age at diagnosis (oocyte quantity
and quality)
 Age at pregnancy (treatment
duration)
 Is there anything we can do?

THINK PROACTIVELY !

 Inform the patient about the risk of infertility

 Refer her to the reproductive endocrinologist asap
 Consider egg/embryo freezing before chemotherapy
 Consider LHRHa during chemotherapy
Male breast cancer
• Klinefelter’s (XXY) Syndrome (Estimated 50-fold increase risk of BC &
higher breast cancer mortality)
• Family history
• Age & Race
• Radiation exposure (Study on Japanese atomic bomb survivors showed
dose response & overall rate 1.8 vs 0.5 per 100,000 PY)
• Obesity
• Hormonal factors (Testicular abnormalities OR = 2.2 (1.5-3.3); Cirrhosis:
3-fold to 4-fold increase in risk ; estradiol levels inconclusive data)
• Previous breast disease (Previous breast pathology OR = 2.7 (1.7-4.2);
Gynecomastia: Meta-analysis showed OR = 6.2 [3.4-11.4])
• Environmental exposures (Inconclusive evidence)
 Genetics
BRCA1
- Mutations reported in male patients; increase in risk (lifetime risk
probably around 2%, corresponding to a 11-fold increase in risk)
BRCA2
Prevalence: 4%-11% affected men have BRCA2 mutations; 40% of
Icelandic men with breast cancer have founder mutation (999del5)
Marker for “at-risk” families (60%-76% breast cancer
families with men have BRCA 2 mutations)
Men with mutations have 8% lifetime risk of breast cancer
corresponding to a 22-fold increase in risk

OFFER GENETIC COUNSELING AND TESTING TO ALL MALE

BREAST CANCER PATIENTS
If BRCA+, baseline mammogram and annual mammograms if gynecomastia or glandular
breast density on baseline study
Tai YC, et al. J Natl Cancer Inst. 2007;99(23):1811-1814. Thompson D, et al. Am J Hum Genet. 2001;68(2):410-419. Giordano SH. Oncologist.
2005;10(7):471-479.
SPECIFIC ISSUES AND CONCERNS
• Delay in diagnosis
• Shock
• Stigma
• Altered body image
• Lack of support
• Inappropriate information

Courtesy S. Giordano
Is BC during pregnancy different?
GEICAM/2012-03 study – genomic profile of gestational BC
• 70 patients diagnosed during pregnancy (43%) /post-partum (57%)
• 50 evaluable tumors
• Evaluation of 105 gene expression
• Intrinsic subtypes
• Proliferation & risk of recurrence scores
• Claudin-low & chemo-endocrine sensitivity predictor

De la Haba et al, Ann Oncol 2016

Presented at ESMO 2016
De la Haba et al, Ann Oncol 2016
Presented at ESMO 2016
 Diagnosis
Gestational changes alter tissue structure!! (hyper-proliferative changes)

 Breast ultrasound - 93% sensitivity

 Mammography – 68% sensitivity
 MRI? – no data from clinical trials
- Yes, IF it would alter clinical decision - Gadobenate dimeglumine (Multihance®)
(approved by EMA and FDA) and Gadoterate meglumine (Dotarem®) (approved by EMA)
- Contrast agents pass through the placental barrier and enter the fetal circulation
 Surgery

Fetal monitoring if fetus is viable

Adequate oxygenation

SAFE during pregnancy

 Mastectomy
 BCS+ sentinel Ly-node

SLN biopsy during pregnancy has a low axillary recurrence rate. This staging method can be considered
during pregnancy instead of standard ALND for early stage, clinically node negative breast cancer. (INCIP and
German Breast Group – ESMO 2014 abstract 266D_PR)

Immediate breast reconstruction with expander can be safely performed in pregnant breast cancer patients
(Lohsiriwat et al., The Breast 2013)
Radiotherapy
Safe during 1st and early 2nd trimester (Mazonakis et al., 2003)

with ↑ gestational age: ↑ proximity of the fetus to the primary irradiation field,

↑ conceptus dose (threshold dose 10 – 20 cGy)

Abortion, stillbirth, congenital malformations, mental retardation, low birth weight, second
cancers during childhood or adult life
 When a drug is
administered to the
mother, placental Chemotherapy
transfer of the drug
could be hazardous
to the fetus

Cardonick E et al. Lancet Oncol 2004;5(5):283-291

Gedeon (2006)
  Preferred standard regimen:

EC/ AC q3w -> wP/ Doce q3w

TAC q3w

 Dose dense regimens:

ddEC/AC q2w -> wP (In high-risk patients, with G-CSF)

EC/AC q3w -> P q2w

Anthracyclines transplacental transport is higher vs. taxanes; PK unghanged vs

non-pregnant women
Taxanes transplacental transport very low
Nab-paclitaxel No data, not indicated
Carboplatin May be considered for neoadjuvant therapy in TNBC +/- BRCA
mutation
Fluorouracil Not indicated

Loibl et al., JAMA Oncol 2015

Take home message
All cases must be discussed in a multidisciplinary setting !
Movie heroes vs. Real life heroes