Download BREAST CANCER

Corso Integrato di Clinica Medica
ONCOLOGIA MEDICA
AA 2008 - 2009
IL CARCINOMA
DELLA MAMMELLA. IV.
Prof. Alberto Riccardi
BREAST CANCER. IV.
TREATMENT
PRIMARY BREAST CANCER
PRIMARY BREAST CANCER. I.
breast conserving surgery
* breast - conserving
treatments (= removal of
primary tumor by some form of
lumpectomy ± breast
irradiation) → survival as good
(or slightly ↑) as after extensive
surgical procedures, e.g.,
mastectomy or modified radical
mastectomy ± further
irradiation;
- post - lumpectomy breast
irradiation greatly ↓ risk of
recurrence in breast
PRIMARY BREAST CANCER. II. MASTECTOMY
* mastectomy = surgical procedure with most or all
breast tissue removed
PRIMARY BREAST CANCER. III. MASTECTOMIES
* simple, or total mastectomy = removal of all breast tissue
(with none of underlying muscle nor lymph nodes removed);
* modified radical mastectomy = removal of all breast tissue,
as well as lymph nodes on same side of body as breast;
* radical mastectomy (“Halsted mastectomy”) = removal of
all breast tissue, underlying muscle and lymph nodes on
same side of body (now rarely done);
* skin - sparing mastectomy = breast tissue removed, but
breast skin maintained [for immediate breast reconstruction
(plastic surgery) no skin grafts needed, to cover breast
implant]
PRIMARY BREAST CANCER. IV.
SIMPLE OR TOTAL MASTECTOMY
removal of all breast tissue
(with none of underlying
muscle nor lymph nodes
removed)
PRIMARY BREAST CANCER. IV.
SIMPLE OR TOTAL MASTECTOMY
removal of all breast tissue
(with none of underlying
muscle nor lymph nodes
removed)
PRIMARY BREAST CANCER. V.
MODIFIED RADICAL MASTECTOMY
removal of all breast tissue, as well as lymph nodes
on same side of body as breast
PRIMARY BREAST CANCER. VI.
RADICAL MASTECTOMY (“HALSTED MASTECTOMY”)
removal of all breast tissue, underlying muscle and lymph
nodes on same side of body
PRIMARY BREAST CANCER. VII. COMPLICATIONS OF
AXILLARY NODE REMOVAL
* with axillary lymph nodes
removal (as part of breast cancer
surgery), complications include:
- postoperative fluid collections
(seromas);
- altered skin sensation;
- lymphedema of arm (swelling
of arm), caused by blockade of
lymph vessels (running
throughout body carrying fluid,
cells, and other material: blocked
with lymph nodes removed)
PRIMARY BREAST CANCER. VIII. SENTINEL NODE BIOPSY
* technique to determine if cancer spreads to regional nodes;
- with cancer detected, next step = find loco - regional nodes (closest
to tumor site) and retrieve it for analysis;
* concept of "sentinel node” (= 1st first node draining area of cancer)
allows staging of cancer, and leaves unaffected nodes behind to
continue important job of draining fluids;
- procedure: injection of dye or radioactive tracer to identify node
closest to cancer site;
- sentinel node biopsy used to stage cancers, including breast and
skin (melanoma)
PRIMARY BREAST CANCER. IX.
SKIN - SPARING MASTECTOMY
* breast tissue removed, but breast skin maintained [for
immediate breast reconstruction (plastic surgery) no skin
grafts needed, to cover breast implant]
PRIMARY BREAST CANCER. X.
BREAST CONSERVING SURGERY
PRIMARY BREAST CANCER. XI.
BREAST CONSERVING SURGERY
PRIMARY BREAST CANCER. XII.
BREAST CONSERVING SURGERY + RADIATION THERAPY
FRONT VIEW
A = breast being treated;
B = part of beam not
touching woman:
C = linear accelerator;
D = arm holder supports
woman's right arm
SIDE VIEW
PRIMARY BREAST CANCER. XIII.
BREAST CONSERVING SURGERY + RADIATION THERAPY
CROSS - SECTION
A = middle radiation
beam;
B = side radiation beam
C = place where radiation
is given to breast;
D = rib cage / chest wall;
E = heart;
F = lungs;
G = backbone;
H = sternum
PRIMARY BREAST CANCER. XIV.
BREAST CONSERVING SURGERY
+ INTRAOPERATIVE RADIATION THERAPY
PRIMARY BREAST CANCER. XV.
BREAST CONSERVING SURGERY + MAMMOSITE BALLOON
CATHETHER (MBC)
* lumpectomy = cancer and some adjacent normal breast tissue
removed → cavity created for uninflated MBC, inserted in
lumpectomy cavity (either at time of lumpectomy or in post lumpectomy procedure);
* after MBC inflated with saline / contrast to position tissue,
radiation source advanced into catheter and radiation therapy
delivered over 5 days (2 treatments / day);
* after each treatment, seed removed (no radiation remains in
breast between treatments);
* after final treatment, MBC easily removed
PRIMARY BREAST CANCER. XVI.
* left) breast conservation associated with ↑ recurrence in
breast, but 20 - yr survival as good as more radical surgery
*
right) lower curves = observed survival, taking into account
deaths from any cause; upper curves = expected survival
rate from mortality rates in age - matched cohorts of Italian
women
Veronesi U et al NEJM 2002
PRIMARY BREAST CANCER. XVIbis.
* breast conservation + radiotherapy associated with ↓
recurrence in breast, but 20 - yr survival = that of mastectomy
o breast conserving surgery alone
Fisher B et al NEJM 2002
PRIMARY BREAST CANCER. XVII.
* ?postoperative radiation (RT - group) to regional
(unremoved) nodes following simple (S - group) mastectomy
also associated with ↑ survival (since radiation therapy
reduces rate of local or regional recurrence, be strongly
considered following mastectomy for women with high - risk
primary tumors, e.g., T2, +margins, +nodes)
disease free survival
p < .003
overall survival
p = ns
Spruit PH et al Radiation Oncology 2007
PRIMARY BREAST CANCER. XVIII.
* at present, ~ 2 / 3 of women in USA managed by lumpectomy
PRIMARY BREAST CANCER. XIX. LOCAL RECURRENCE
* breast - conserving surgery not suitable for all pts, e.g.,
for:
- tumors > 5 cm (or smaller tumors with small breast);
- tumors involving nipple - areola complex;
- tumors with extensive intraductal disease involving
multiple quadrants;
- women with history of collagen - vascular disease, and
- women who either do not have motivation for breast
conservation or convenient access to radiation therapy;
* these groups account for < 33% of pts who are treated with
mastectomy
→ thus, many women still undergo mastectomy who could
safely avoid if appropriately counseled
PRIMARY BREAST CANCER. XX. LOCAL RECURRENCE
* extensive intraductal component = predictor of recurrence
in breast, toghether with other several clinical variables,
including
- axillary lymph node involvement and involvement of breast
vascular or lymphatic channels by tumor cells (but not contra
- indications to breast - conserving surgery)
intraductal component
vascular (A) or lymphatic (B) invasion
PRIMARY BREAST CANCER. XXI. LOCAL RECURRENCE
lymphatic invasion
vascular invasion
PRIMARY BREAST CANCER. XXII. LOCAL RECURRENCE
lymph node invasion
micrometastases
to lymph node
PRIMARY BREAST CANCER. XXIII. LOCAL RECURRENCE
* with these pts
excluded and
lumpectomy with
-tumor margins
achieved, breast
conservation →
recurrence rate in
breast < 10%
Bartelink H et al NEJM 2001
PRIMARY BREAST CANCER. XXIV. LOCAL RECURRENCE
- however, ?local recurrence in breast facilitates distant
metastasis (if recurrence in breast causes metastatic disease
→ women treated with lumpectomy, with ↑ rate of recurrence
in breast → poorer survival than women treated with
mastectomy, and they “possibly” do not);
- most pts should consult radiation oncologist before
making a final decision concerning local therapy;
- however, a multimodality clinic in which surgeon, radiation
oncologist, medical oncologist, and other caregivers
cooperate to evaluate pt and develop treatment usually
considered major advantage by pts
PRIMARY
BREAST
CANCER. XXVI.
LOCAL
RECURRENCE
RECURRENCE
MORTALITY
PRIMARY BREAST CANCER. XXVII. EFFECT OF 5 - YR RISK OF
LOCAL RECURRENCE ON BC MORTALITY AT 15 YRS
* survival of pts with recurrence in
breast worse than that of pts who do
not? → recurrence in breast =
negative prognostic variable for long term survival?;
- actually, ≠ magnitudes of ↓ in 5 - yr
risk of local recurrence between
control groups (blue) and little- or
great- active treatment group (green)
(left in panel) correspond to ≠ effects
on BC mortality at 15 yrs (right in
panel) (EBCTCG meta - analysis of
local therapy);
* treatments with little effect on risk
of local recurrence → no effect on
mortality (A), whereas treatments with
greater effect on recurrence →
corresponding reduction in mortality
(B and C)
Punglia RS et al NEJM 2007
ADJUVANT THERAPY
ADJUVANT THERAPY. I.
= use of systemic therapy in pts with disease treated with
(radical) local therapy, but still at risk of relapse;
* systemic therapy after local management of BC
substantially ↑ survival (> 33% of women destined to die of
metastatic BC remain disease - free with appropriate
systemic regimen)
ADJUVANT THERAPY. II. MONOCHEMOTHERAPY
ADJUVANT THERAPY. III. POLYCHEMOTHERAPY
ADJUVANT THERAPY. IV. POLYCHEMOTHERAPY
ENTRY AGE < 50 yrs
RECURRENCE
MORTALITY
ADJUVANT THERAPY. V. POLYCHEMOTHERAPY
ENTRY AGE 50 - 69 yrs
RECURRENCE
MORTALITY
ADJUVANT THERAPY. VI. HORMONAL THERAPY
~ 5 yrs of hormonal therapy (tamoxifen) vs not
in ER+ or ER unknown disease
RECURRENCE
MORTALITY
ADJUVANT THERAPY. VII. 5 - YR SURVIVAL RATE BY STAGE
Stage
5 - yr OS,
%
0
99
I
92
IIA
82
IIB
65
IIIA
47
IIIB
44
IV
14
National Cancer Institute - Surveillance, Epidemiology, and End Results (SEER)
ADJUVANT THERAPY. VIII.
PRIMARY PROGNOSTIC FACTORS
* most relevant prognostic variable = tumor stage = status
of axillary lymph nodes and size of tumor → reasonably
accurate information on likelihood of tumor relapse → for
most women, need for adjuvant therapy readily defined on
this basis alone
ADJUVANT THERAPY. IX.
SECONDARY PROGNOSTIC FACTORS
* rarely justification for adjuvant chemotherapy in most
women with tumors < 1 cm with axillary lymph nodes-;
* greatest controversy for women with intermediate
prognoses → search for “secondary prognostic factors”;
- without lymph node involvement, involvement of
microvessels (either capillaries or lymphatic channels) ~ =
lymph node involvement
ADJUVANT THERAPY. X.
SECONDARY PROGNOSTIC FACTORS
* estrogen and progesterone receptor status of prognostic
(beside therapeutic) significance = tumors lacking either or
both receptors more likely recur
R+
R-
R+
R-
ADJUVANT THERAPY. XI.
SECONDARY PROGNOSTIC FACTORS
G1
* tumors with poor nuclear grade → ↑
risk of recurrence vs tumors with good
nuclear grade;
- semiquantitative measures (e.g.,
Elston score) ↑ reproducibility of
measurement
G2
G3
ADJUVANT THERAPY. XII. ELSTON GRADE
* pathologist assigns cancer an Elston grade (G) on scale of 1 - 3 based
upon how aggressive it looks under microscope (Elston G1 best = "well differentiated”, while Elston G3 worst = "poorly - differentiated”);
* pathologist considers 3 factors in determining G, with each factor
given point score on scale of 1 - 3;
* point (p) score for each factor then added for final score, as follows:
- how much of tumor makes duct structures, like normal breast
epithelium does?: 75% (1 p); 10 - 75% (2 ps); < 10% (3 ps);
- mitotic activity: how many mitotic figures in 10 high power (400 X)
fields: < 5 (1 p); 5 - 10 (2 ps); > 10 (3 ps);
- nuclear pleomorphism: do tumor nuclei look uniform similar to normal
breast duct epithelial cells, or are larger, irregular, and darker
(hyperchromatic)?: uniform nuclei (1 p); moderate nuclear variation (2
ps); marked nuclear variation, hyperchromasia, irregular large nucleoli (3
ps);
* points added to yield Final Elston Grade:
- final score 3 - 5 = Elston grade 1
- final score 6 - 7 = Elston grade 2
- final score 8 - 9 = Elston grade 3
ADJUVANT THERAPY. XIII.
SECONDARY PROGNOSTIC FACTORS: MOLECULAR
CHANGES
* molecular changes also useful;
- tumors overexpressing erbB2 (HER - 2 / neu) or with
mutated p53 gene → worse prognosis;
* especial practical interest on erbB2 overexpression (as
measured by histochemistry or fluorescence in situ
hybridization)
[- tumors overexpressing erbB2 more likely to respond to
higher doses of doxorubicin - containing regimens and
predict response to HER - 2 / neu antibodies (trastuzumab,
Herceptin®) and Her - 2 / neu kinase inhibitors]
ADJUVANT THERAPY. XIV.
MOLECULAR CHANGES
* examples of p185c - erbB-2
immunostaining in cancer cell lines: (A)
BT - 474 (mammary cell line with ERB B2 amplification and 3+ membrane
overexpression); (B) SK - OV - 3 (ovary
cell line with ERB - B2 amplification and
3+ membrane overexpression); (C) ZR 75.1 (mammary cell line without ERBB2
amplification and 2+ membrane
overexpression); (D) HTm29 (colon cell
line without ERB - B2 amplification and
2+ cytoplasmic 1+ membrane
overexpression); (E) HepG2 (liver cell
line without ERB - B2 amplification and
2+ cytoplasmic overexpression); (F)
SU.86.86 (pancreatic cell line without
ERBB2 amplification and no
cytoplasmic / membrane expression)
(X400)
ADJUVANT
THERAPY. XV.
MOLECULAR
CHANGES
A - C) FISH of ERBB2 probe on paraffin - embedded tissue of 3 cases of
BC: A) tumor without amplification (mean no. of 2 signals / nucleus; B)
tumor with high amplification (numerous signals, arranged in clusters); C)
tumor with lowest amplification (dual color FISH): 5 - 6 signals of ERB - B2
probe (red) and two centromeres of chr 17 (green); D) strong expression
of protein (membrane labeling) by immunohistochemistry (CB11 anti - c erbB - 2 Ab)
ADJUVANT THERAPY. XVI.
SECONDARY PROGNOSTIC FACTORS
* several measures of tumor growth
rate correlate with early relapse;
EUPLOIDY
* direct S - phase analysis by flow
cytometry (= most accurate
measure) or indirect S - phase
analysis with antigens associated
with cell cycle (e.g., PCNA = Ki 67)
also valuable;
* tumors with high proportion (>
median) of cells in S phase →
ANEUPLOIDY
greater risk of relapse
(chemotherapy offers survival
benefit for these tumors);
* assessment of DNA content as
ploidy of modest value (aneuploid
tumors somewhat worse prognosis)
ADJUVANT THERAPY. XVII.
SECONDARY PROGNOSTIC VARIABLES
- detection of BC cells either in circulation or bone marrow
associated with ↑ relapse rate
QDA = quadratic
discriminant
analysis?
ADJUVANT THERAPY. XVIII.
SECONDARY PROGNOSTIC VARIABLES
* to grow, tumors generate a neovasculature ;
- presence of more microvessels in tumor (especially
particularly when localized in so - called "hot spots"
associated with worse prognosis [greater significance for
“blood vessel - targeting therapies”, e.g., bevacizumab
(Avastin@), anti vascular growth factor (VEGF) MoAb ]
CD31 immunostained blood vessels invasive BC:
low and high microvessel density ('hot spot‘)
ADJUVANT THERAPY. XIX.
SECONDARY PROGNOSTIC VARIABLES
* ↑ microvessel density associated with poor overall
survival: a) low, b) median and c) high microvessel density
(anti - CD34, 400x); d) Kaplan - Meier analysis → poor overall
survival with ↑ microvessel density (p = .047)
ADJUVANT THERAPY. XIX.
SECONDARY PROGNOSTIC VARIABLES
* other variables also been used to evaluate prognosis
include proteins associated with invasiveness (e.g., type IV
collagenase, cathepsin D, plasminogen activator,
plasminogen activator receptor) and metastasis - suppressor
gene nm23;
- none of these actually accepted as prognostic variable for
therapeutic decision (problem in interpreting these
prognostic variables = most of them not been examined in
studies using large cohort of pts)
nm23
ADJUVANT THERAPY. XX. GENE EXPRESSION PROFILE
* most exciting development = use of gene expression
arrays to analyze patterns of tumor gene expression;
- from several retrospective, independent studies → gene
sets reliably predict disease - free and overall survival far
more accurately than any single prognostic variable;
- their value being assessed in prospective randomized
trials;
- in addition, gene sets for predicting responses to
endocrine therapy and specific chemotherapeutic drugs also
reported