Download Carcinoma della mammella Her2 positivo Ruolo della radioterapia

Università degli Studi “G. D’Annunzio”
Facoltà di Medicina e Chirurgia
Scuola di Specializzazione in Radioterapia
Prof. Giampiero Ausili Cefaro
CHIETI
Carcinoma
della mammella
Her2 positivo
Ruolo della
radioterapia
Prof. Giampiero Ausili Cefaro
Dott.Marianna Trignani
EARLY BREAST CANCER
Opzione standard
Chirurgia conservativa + Radioterapia
BCS + RT vs Mastectomia
BCS + RT Mastectomia
Recidive locali
5% - 13%
2% - 14%
Sopravvivenza
59% - 79%
59% - 82%
Milano I, NSABP, EORTC, IGR, NCI, DBCG
Pooled-Analysis
9422 paz
Rischio relativo (RR) di Rec. Locale= 3
Rischio relativo (RR) di morte= 1,086
BCS + RT vs sola BCS
BCS + RT vs sola BCS
No beneficio RT
Beneficio RT
No beneficio RT
Beneficio RT
Vincent V-H, J Natl Cancer Inst 2004
Principali parametri che
influenzano la recidiva locale
Dimensioni del T
Margini
Grading
EIC
Età
1901 pz
Komoike Y, Cancer 2006
Over the past ten years, the genomic analysis has
revolutionized research in oncology.
Mammary tumors
5 "molecular subtypes" characterized
by different aspects of gene expression
Sorlie T Proc Natl Acad Sci USA 98(19):10869-74
Molecular
subtypes
Make a clinic
decision
Tayloring locoregional
and sistemic treatment
Estrogen receptor (ER), progesterone receptor (PR), and c-ERBB2
(HER2/neu) are therapeutically and prognostically important
markers in the management of breast carcinoma.
About 60% to 70% of breast carcinomas express ER protein, and
these tumors are associated with better prognosis.
Thike AA, Chng MJ, Chong SF, et al. Pathology. 2001;33:21-25.
ER status is important in predicting the response to adjuvant
tamoxifen (hormonal) therapy. PR is a surrogate marker of
functional ER because PR is an estrogen-regulated gene.
More than half of ER+ tumors express PR. Hence, simultaneous
analysis of ER and PR gives more information regarding likely
hormonal response.
ER, PR and HER2 are indipendent prognostic and predictive
biomarkers Esteva FJ Breast Cancer Res 2004;6:109-118
Payne SJ Hystopathology 2008; 52:82-90
c-ERBB2
is
amplified
and/or
overexpressed in approximately 25%
of breast cancers and is associated
with aggressive disease as shown
by an association with shorter
disease-free survival (DFS) and
overall survival (OS).
Balcerczak E J Exp Clin Cancer Res.
2003;22:247-253.
Carcinomas that overexpress c-ERBB2 respond to treatment with humanized
anti–c-ERBB2 monoclonal antibody (trastuzumab) and are associated with
resistance to hormonal therapy.
Administration of trastuzumab with chemotherapeutic agents has been
shown to produce longer DFS and OS, with 25% to 50% of c-ERBB2+
patients with metastatic breast cancer responding favorably to trastuzumab.
Simon R J Natl Cancer Inst. 2001;93:1141-1146
Bedard PL Clin Breast Cancer 2008;8(Suppl 4):157-165
TAILORING OF MEDICAL THERAPY
Hormone therapy remains the mainstay
for hormone receptor–positive breast
cancer. The decision for hormone
treatment has traditionally relied on
assessment of ER and PR status of
primary tumors, with the response
generally related directly to ER and PR
content.
The efficacy of trastuzumab is
highly dependent on the cERBB2 status of the tumor and
in the metastatic breast cancers
that overexpress c-ERBB2 has
been proven.
TAILORING OF LOCOREGIONAL TREATMENT
?
Studies specifically relating receptor
status of primary tumors with local
Few
published
reports
recurrences are also few.
regarding the comparison of
Few studies have examined these c-ERBB2 status between the
biomarkers as predictors of primary and metastatic or
locally recurrent sites.
locoregional recurrence (LRR)
Am J Clin Pathol 2010;133:416-429
Am J Clin Pathol 2010;133:416-429
To identify patients who had an increased risk of LRR and therefore might
benefit from adjuvant systemic treatment or more aggressive local treatment
uniform evaluation of ER, PR, and HER2 expression.
Whole breast 50 Gy in 25 fractions using medial
and lateral tangent fields, followed by a tumor bed
boost of 10 Gy in 5 fractions.
Tumors ER or PR positive were categorized as
HR positive. Tumors that were both ER and PR
negative were categorized as HR negative
resulting in four tumor subtypes: HR+HER2,
HR+HER2+, HRHER2+, and HRHER2.
The 8-year LRR rate was greater in
patients with ER-negative disease,
PR-negative disease, and HER2positive (17.5% vs. 3.9%, p = .009).
HER2-positive breast cancer
and
ER/PR-negative disease independently
predicted for LRR.
Additionally, close/positive margins (with
close defined as <2 mm) and lobular
histologic features continued to predict
for LRR.
The mechanism explaining how HER2 positivity predicts for
LRR is unknown.
HER2 positivity predicted for LRR in the BCT subgroup.
HER2-positive tumors might have been resistant to postlumpectomy radiotherapy.
These data suggest that ER/PR-negative and HER2-positive
patients might benefit from chemotherapy, anti-HER2 therapy,
or more aggressive locoregional therapy, even in very earlystage disease.
Was
the potential
betweenwas
biological
subtype
increased
RT to investigated
the breast (42.5–50
Gy association
in 16–25 fractions)
offered
to all and
patients
after
risk
of LRR resection;
comparedregional
with conventional
prognostic
factors.
segmental
LN irradiation
being offered
if 4 LN-positive.
Patients
baseline
characteristics
stratified
by biological
(4 subgroups
Post-mastectomy
chest
wall and regional
LN irradiation
(45–50subtype
Gy in 20–25
fractions)
HR±/HER2±).
if they had LN positive or T3.
On
multivariate analysis HR-/HER2+ and LN (>1) were found indipendent
prognostic factors with increased risk of LRR after BCT.
For the subgroups radical mastectomy on multivariate analysis triple negative and
LN (>1) were found prognostic factors.
CHIETI UNIVERSITY
RADIOTHERAPY
PERICOLO RICADUTA
OUR EXPERIENCE
OUR EXPERIENCE
OUR EXPERIENCE
OUR EXPERIENCE: SUBTYPES
MILESTONE
• HER2-positivity predicts for recurrence, with
an increased risk of LRR.
• These issues seem to be confirmed in patients
HER2+ surgically treated or conservatively
than with mastectomy.
• Given the risk of relapse, HER2-positive
patients might benefit from chemotherapy,
anti-HER2 therapy, or more aggressive
locoregional therapy, even in very early-stage
disease.
Which is the more aggressive loco
regional treatment that should be
considered?
WHICH IS THE MORE AGGRESSIVE
LOCOREGIONAL
TREATMENT
THAT
SHOULD BE CONSIDERED?
- BOOST: increase the dose to the tumor
bed;
- WHOLE BREAST: increase the dose to the
whole breast;
- NODAL IRRADIATION: irradiation of the
clavicularregion even if less than 4 lymph
nodes involved.
- RT associated to adjuvant trastuzumab.
Conclusion
Future prospective studies, including clinical trials, are needed to fully
determine the utility of these biomarkers in guiding treatment decisions in
this patient population.
Several forthcoming clinical trials have begun to address medical and loco
regional therapy basing on molecular characteristics.
These prospective clinical trials, and other
future trials, might provide
insight as to whether combining radiotherapy with HER2-directed therapies.