Download the rationale and potential of breast cancer chemoprevention in high

THE RATIONALE AND POTENTIAL
OF BREAST CANCER CHEMOPREVENTION
IN HIGH RISK WOMEN
G. Giardina, L. Bascialla, G. Bini, I. Marcon
Oncologia Senologica e Farmacoprevenzione
ONCOLOGIA MEDICA - Varese
VARESE - 20 gennaio 2012
EPIDEMIOLOGY of Breast Cancer (BC)
* The most common cancer in women (45,000 cases/yr)
* The second most common cause of death (12,000/yr)
* 5%-10% of women who develop BC have a highly
penetrance genetic predisposition
* BRCA1/2 mutations occur in about one in 250
women
* Worldwide incidence and mortality rate in 2008
1,200,000 -- 400,000
* 5 years survival : 85%
I numeri del Cancro in Italia-AIOM 2011
INCIDENCE RATE seems levelled
MORTALITY RATE has declined since 1990
* early detection
* adjuvant therapies
* reduction in HRT use
* prevention strategies
5 years survival rate (Varese) : 84.3
(Modena 86.9 ; Romagna 85.1 ; Biella 85.9)
SEIZING THE OPPORTUNITY
Clinicians have long recognised that individuals with
a family history of Breast Cancer are themselves at
increased risk for developing the disease.
The description of kindreds in which there appears
to be an autosomal dominant pattern of predisposition
(BRCA1,BRCA2) is more recent.
The most striking feature of these families is the often
marked degree to which the risk is increased and the
young ages at which the cancer occur.
M.Robson, MSK Cancer Center,2009
Some cancer predisposition syndrome are probably
under-recognised, such as Cowden syndrome, which
can be highly variable in its presentation.
Knowledge of the specific range of cancer risk is
crucial to proper women management.
R.Dent, Sem. Oncol.,2008
The majority of breast cancer are sporadic,
endocrine-responsive (70%) and risk factors
are primarily related to
OESTROGEN EXPOSURE
BRCA 1 and BRCA2 mutations carriers
Women with inherit mutations in the BRCA 1 and BRCA2
genes have :
* 5-20 fold increased risk
** 45%-65% life-time probabilities for Breast Cancer
and
*** 11%-40% life-time probabilities for Ovarian
cancer
A.Curian, JCO, 2011
Pathology of Hereditary BC
* BC with BRCA1 germ-line mutations can often be
distinguished from non-BRAC1 related BC :
TRIPLE NEGATIVE PHENOTYPE
* BC associated with BRCA2 germ-line mutations
appear to be less specific morphologically
W.D. Foulkes, Sem. Oncol. 2007
VARIANT of UNCERTAIN SIGNIFICANCE (VUS)
VUS are sequence variations in a gene where the
effect of the sequence change on the function of
the protein is not known.
Between 10% and 15% of individuals undergoing
genetic testing for BRCA1/2 mutations will be found
to have VUS.
S.Domchek,JCO,2008
VUS is a clinically and emotionally difficult
situation and advising individuals with VUS
on surveillance, prophylactic surgery and
chemoprevention is challenging for providers,
confusing to families and distressing for
everyone.
S.Domchek,JCO,2008
LIFE TIME RISK for BC
GENERAL POPULATION
12%
STRONG FAMILY HISTORY
BRCA mutations
85%
R.Dent, Sem.Oncol. 2008
Preclinical and epidemiological data indicate that
breast cancer can be prevented or, at least
significantly delayed.
The rationale is based on the hypothesis that the use
of natural, synthetic or biological chemical agents
can reverse, suppress or prevent either the initial
phase of cancerogenesis or the progression of
neoplastic cells to cancer.
KEY CONCEPT UNDERLYING CHEMOPREVENTION
Cancerogenesis is :
*MULTISTEP (accumulation of genetic and epigenetic
alterations)
*MULTIPATH (self-sufficiency in growth signals,
insensitivity to antigrowth signals,
apoptosis evasion, limitless replicative
potential, tissue invasion and sustained
angiogenesis)
* MULTIFOCAL (multi-clonal : field cancerization
clonal : expansion leading to intraepithelial spread)
KIND OF CHEMOPREVENTION
* PRIMARY
: to prevent the onset of disease
in healthy individuals at risk
* SECONDARY : to treat a population with premalignant
condition in order to arrest the
developement of cancer
* TERTIARY
: to protect subjects cured of an initial
cancer against second primary tumour
INTRAEPITHELIAL NEOPLASIA (IEN)
Is a premalignant lesion occurring in most epithelial
tissues as moderate to severe dysplasia
Phenotype changes (genetic mutations, loss of cellular
control functions)
early dysplasia
severe dysplasia
superficial cancer
invasive cancer
TIME TO PROGRESSION
May happen within months to a few years when
the process is relatively aggressive, i.e. :
* DNA repair-deficient genotype
* Viral transformant (HPV)
BUT …………
These changes generally appear to occur over
A LONG PERIOD OF TIME
In BREAST CANCER :
atypical hyperplasia
ductal intraepithelial neoplasia (DIN or DCIS)
lobular intraepithelial neoplasia (LIN or LCIS)
invasive cancer
REQUIRES 10-20 yrs or more
SO ………
Subjects with IEN, particularly severe IEN, are at
significantly higher risk than unaffected population
and exceeds other measurable risk factors with the
exception of germ-line mutations that occur in
genetyc syndromes.
Selective oestrogen receptor modulators (SERMs)
* established role in the treatment and
chemoprevention of hormone-related BC
* antagonise oestrogens in some tissues and
mimic their action in others
PHASE III Trials of TAM vs Placebo
NSABP- P1
1992
13,388
RR = 0.51
Royal Marsden
1986
2,494
RR = 1.06
Italian Trial
1992
5,408
RR = NS
IBIS-I
1992
7,152
RR = 0.67
NSABP-P1 Key Messages
13,388 women with a GAIL model risk > 66% in 5 yrs
** TAM reduces the risk of invasive BC
49%
49%
and non-invasive BC
50%
50%
and ER+ve BC
69%
69%
** In Lobular carcinoma in situ (LCIS or LIN)
56%
56%
** In Athypical Hyperplasia
86%
86%
** The effect was seen in all age groups
** TAM produced a reduction in osteoporotic fractures
20%
20%
However ………
In women aged 50 or older
endometrial cancer risk
+ 4 -fold
pulmonary embolism
+ 3 -fold
and a signicant excess of cataract
NO EFFECT
ON IN
ER-ve
TUMOURS
!!!!!!!
NO EFFECT
ER-ve
TUMOURS
IBIS. I Trial Key Messages
** 33% reduction of BC
** Increase of thrombo-embolic events (VTE)
(within 3 months of major surgery, immobilisation,
or fractures)
** No-significant increase of endometrial cancer
** No differences in bone fractures and cataract
ROYAL MARSDEN and ITALIAN Trial
** At a median follow-up of 70 and 81 months
no-difference in risk reduction
BUT ………
significant reduction in women
taking HRT
PHASE III Trials of RALOXIFEN
MORE
Ral vs Plac
7,705 osteop. women
RR = 0.24
(no increase of endometrial cancer, VTE = TAM)
CORE
MORE+4yrs 4,011 osteop. women
RR = 0.41
(no increase of endometrial cancer, VTE = TAM)
RUTH
Ral vs Plac 10,101 CHD women
RR = 0.56
STAR
Ral vs Tam 19,747 high risk
RR = 1.02
(no diffrence between arms : 50% reduction.
endometrial cancer 38% lower in Raloxifen arm
no protective effect of Ral on non-invasive cancer)
MORE, CORE, RUTH, STAR Trial Key Messages
** Raloxifen is a SERM with a marked effect on :
- incidence reduction of invasive BC
- no effect on non-invasive BC
- no increase of endometrial cancer
- VTE risk similar to Tamoxifen
PEARL Trial
Lasoxifene vs Placebo in 8556 postmenopausal
osteoporotic women
Compared with placebo, 05 mg of Lasoxifene
statistically significantly reduced the risk of
total breast cancer by 79% and ER+ve breast
cancer by 83%; markedly for women with high
baseline estradiol levels.
A.Z.Lacroix,JNCI, 2010
Other agents
** AROMATASE Inhibithors or Inactivators
(data from ATAC, BIG-1, IES, ARNO Trials)
- lower risk of controlateral BC
- lack of increase in VTE and endometrial cancer
- increase in risk of osteoporosis and fractures
Ongoing Trials : IBIS-II (prevention/DCIS)
NCIC-MAP.3
** NON STEROIDAL ANTI-INFLAMMATORY DRUGS
Epidemiological studies have produced mixed results
and a direct relationship cannot be demonstrated yet
Evidence for an interaction of genetic polymorphism
of COX-2 (allele 8473) with NSAIDs to reduce risk
of HR+ve BC has been found in a population-based
case-control study.
Future
research
**** Research are needed to identify molecular
biomarkers that accurately predict an agent’s
cancer incidence-reducing effect
***** Actually, Tamoxifen at lower doses, seems to be
a simple and economic approach reducing the
risk of HR+ve BC. The rationale is :
- binding to HR follows saturation kinetics
- 20 mg/day is as effective as 30-40 mg/day
- endometrial effect is dose-dependent
- animal data show complete inibition at a dose
equivalent to 1 mg/day in humans
- preoperative trials show similar antiproliferative
effects of 1 mg and 5 mg/day compared to 20mg
* Most BRCA1 related BC are of Basal Phenotype and
are ER-negative, while BRCA2 related BC are much
more like sporadic tumors and are frequently
ER-positive.
* Hence, one might anticipate that hormonal chemoprevention strategies such as Tamoxifen may have
more benefit for BRCA2 carriers compared to
BRCA1 mutation carriers.
E.Rodriquez, Sem.Oncol, 2007
*There are a significant amount of data that hormonal
manipulation strategies such as bilateral oophorectomy
and Tamoxifen do affect BC risk in BRCA1 carriers.
* Future studies will need to stratify for mutation type
and include a longer follow-up period, because riskreducing strategies may have different effects in these
two related but different cancer susceptibilty syndrome.
E.Rodriquez, Sem.Oncol, 2007
STRATEGIES…… nowadays
* MRI based screening starting at age 25 yrs
* Bilateral salpingo-oophorectomy by age 40 yrs
(risk reduction: BC = 50%, Ov. Ca = 80%)
* Bilateral Mastectomy
(risk reduction: BC > 90%)
and CHEMOPREVENTION
.. is the future
????
C.Touboul,The Oncologist,2011
FENRETINIDE: background
Retinoids regulate cell growth, differentiation
and apoptosis.
Fenretinide is a synthetic amide derivative
of retinoic acid which:
* accumulates in the human breast
* can selectively induce apoptosis in vitro
* has antiangiogenic and antitumor effects
* has shown a good toxicity profile in clinical studies
RETINOIDS (vitamin-A analogues)
data from PHASE III Trial (U.Veronesi et al.)
(ER-ve pts.; median follow-up of 15 yrs)
50% reduction in women aged 40 yrs or younger
(persistent for 10 yrs after retinoid cessation)
U.Veronesi, Ann.Oncol.,2006
INCIDENCE OF SECOND BREAST CANCER
PREMOPAUSE
** HR = 0.62 95% C.I. 0.46-0.83
POSTMENOPAUSE
** HR = 1.23
95% C.I. 0.63-2.40
U.Veronesi, Ann.Oncol.,2006
TAKE HOME MESSAGES
* Breast Cancer prevention is feasible
** Toxicity concerns strongly affect the acceptability
of actually available agents
*** Salpingo-oophorectomy/prophylactic mastectomy
are effective in BRCA1/2 carriers but the impact
on quality of life, body image, sexuality and longterm well-being must be considered prior to surgery.
G.Wickman, Breast, 2010
**** Prevention strategies in selected high risk women
are needed to make chemoprevention safe and
widely used.
IL NOSTRO CONTRIBUTO
STUDIO TAM-01 (A. DeCensi)
- Tamoxifene a basse dosi x 3 anni
- Pazienti con DCIS G 1/2
STUDIO “Fenretinide” – IEO (U.Veronesi,B.Bonanni)
- Pazienti di età 25/44 anni
- Mutazione BRCA1/2 o BRCA-Pro > 20%
IBIS- II (Int. Breast Cancer Prevention Study; J. Cuzick)
- PREVENTION : Anastrozolo vs Placebo
- DCIS : Tamoxifene vs Anastrozolo)
Solo insieme possiamo dare il massimo !!!!!
grazie per l’attenzione
CASO CLINICO
F.R.S. , 42 anni
mutazione BRCA1
mentre stava pensando di partecipare allo studio IE0
con Fenretinide, esegue controllo MxEco:
QSE Dx, nodulo 1.0 cm, FNAC = C 5
cT1b cN0 M0
QUALI OPZIONI HIRURGICHE
discutere con la paziente ??????
(TENENDO CONTO CHE LA PROGNOSI NON SEMBRA ESSERE
NEGATIVAMENTE INFLUENZATA DA BRCA1 POSITIVITA’ )
P.Goodwin,JCO, 2011
A) MASTECTOMIA bilaterale + salpingoovariectomia
riduzione rischio BC > 90%
riduzione rischio Ovaio 80%
B) MASTECTOMIA monolaterale o QUADRANTECTOMIA + salpingoovariectomia
rischio di ricaduta locale eguale (Mastec/Quad +RT)
riduzione 50% rischio BC mammella controlaterale
con salpingoovariectomia