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SENTINEL LYMPH NODE BIOPSY: ROLE OF
TUMOR BURDEN ASSESSMENT IN
THERAPEUTIC DECISIONS
V CURSO DE ACTUALIZACIÓN EN PATOLOGÍA
MAMARIA
Dra Laia Bernet
H. Lluís Alcanyís-Xàtiva
STATUS OF AXILLARY NODES
The status of axillary nodes is vital in predicting the
outcome of patients with early stage breast cancer.
It has been shown in the past that metastases to the
axillary lymph nodes reduce the 5-year survival by up to
40% and the likelihood of treatment failure increases.
SENTINEL LYMPH NODE BIOPSY
Highly accurate predictor of overall axillary status
Pathologically negative sentinel nodes have been shown
to predict negative axillary status with a 98% degree of
accuracy
Standard method in breast cancer patients cN0
SENTINEL LYMPH NODE BIOPSY
Current practice guidelines recommend complete ALND
only in positive SLN breast cancer patients
50-70% of patients with SLN+ have not additional positive
nodes
SENTINEL NODE METASTASES: AXILLARY TREATMENT
STATE OF ART UNTIL Z0011 TRIAL
Stratified therapy by TNM criteria
Macrometastases: Axillary surgery
Micrometastases: Axillary surgery
ITC: Not axillary surgery
Z0011 TRIAL
ACOSOG- Z0011
Z0011 was expected to be “practice changing the gold
standard of therapy” (= ALND can be omitted in case of
positive SLN biopsy)
Seems to demonstrate no differences in terms of
axillary recurrence and survival
Failed to reach its targeted accrual (856 patients)
97% of patients received systemic therapy and
axillary radiotherapy (89%)
ACOSOG- Z0011
Results cannot be applied to subset of patients like:
Young patients (<50y)
Lobular carcinoma
Hormone receptor negative tumors
HER2 positive tumors
ACOSOG- Z0011
2012: CAGS/ACS Based Review in Surgery Commitee
“...should the results of Z0011 change practice? Owing to
its methodological limitations, if we had to depend on
Z0011 alone the standard of care following positive SN is
still ALND”
The same conclusions have been reached by German,
Austrian and Swiss Consensus Panel in 2013
IBCSG23-01 TRIAL
SLNB+ micrometastases were randomized to ALND vs no
further treatment
No differences between two arms both, in terms of
disease-free and overall survival
Patients accrual stopped prematurely (933 out of
1960). Study underpwered
ITC included in the micrometastases group
IBCSG23-01 TRIAL
Patient’s characteristics are at very good prognosis:
[ER+ and PR+] = 75%
Sentinel tumor size ≤ 1mm =69%
Primary Systemic Therapy
Additional positive non sentinel metastases = 13%
PREDICTION OF ALND STATUS FOR...
To design Axillary Surgical tratment?
To design Primary Sistemic Therapy?
To design Radiotherapic Treatment?
CUT OFF LEVEL
Which is the cut off level as acceptable risk when
deciding to omit ALND in patients with positive SLN?
No tools have been able to identify patients without
any risk of NSN metastasis
FN rate between 5-8% is often a target because this is
the FN rate of ALND
STRATIFIED THERAPY BY TNM CRITERIA
• Macrometastases: Axillary surgery
• Micrometastases: Axillary surgery
• ITC: Not axillary surgery
TO AVOID AN UNNECESSARY ALND
SN micrometastases
20% ALND+
SN macrometastases
50% ALND+
How to identify patients at low risk of NSN positivity?
MICROMETASTASIS CUT OFF SIZE
Defining cut off point of 1mm for
micrometastases in SLN would result in a better
discrimination of low risk patients for non SLN
metastasis.
MICROMETASTASIS CUT OFF SIZE
[ALND +] (Rahunsen)
< 1mm: 27%
> 1mm: 50%
[ALND +] (Viale)
< 1mm: 13-17%
1-2mm: 33-38%
WHAT WE LEARNED OF SNB EVOLUTION...
The cut-off values between ITC, micro and
macrometastases were not adequated to decide
the axillary surgery extension
NOMOGRAMSBerrang TS. Breast Cancer Res Treat 2012
AUC is a measure of how well a model discriminates across risk
levels
AUC 0.7 to 0.8 values are considered good
AUC ≥ 0.80 values are considered excellent
None of the models provides excellent discrimination between
additional positive and negative nodes
When models are applied to micrometastases, AUC figures falls
down from 0.57 to 0.68 in all of them
All models under-predict in low risk group and overestimate high-risk
group
LIMITATIONS OF NOMOGRAMS AND
SCORING SYSTEMS
Lack of the common set of measurements
Variation of clinical practice and patients
characteristics among institutes may influence the
accuracy of predictive models applied to different
patients-population
Limited clinical practicality
Patients’s percentatge with low scores is < 10% (low
enough to benefit from models)
NOMOGRAMS RESULTS
LOW RISK TUMOR
Higher percentageof residual disease
HIGH RISK TUMOR
Higher percentageof metastasis free
ALND
OSNA METHOD
Rapid intraoperative
evaluation of SLN status
Direct quantification of
the CK19- mRNA copies
Analysis time: 30 min
SENTINEL NODE -TOTAL TUMOR LOAD
Sum of the number of copies of each of the studied SN
The value of ”TOTAL TUMOR LOAD” may be more
predictive than prognostic groups defined by the TNM-
7th ed
TOTAL TUMORAL LOAD PREDICTIVE VALUE
• To assess the reliability of the whole sentinel lymph node
(SLN) analysis by the OSNA assay as a predictor of
non-SLN metastases.
• 742 patients with breast cancer were enroled in the
study.
• The association of non-SLN or X4 LN metastases with
clinicopathological variables was investigated using
multivariate logistic analysis.
TOTAL TUMORAL LOAD PREDICTIVE VALUE
• The CK19 mRNA copy number ≥ 5.0 x103 in the SLN was
the most significant predictor of non-SLN metastases (P=0.003)
• The CK19 mRNA copy number ≥1.0 ×105 in the SLN was
the only independent predictor of ≥4 metastatic nodes
non SLN (P=0.014)
• Multivariate model for prediction of non-SLN affectation
based on log TTL, tumour size, number of affected SLN,
presence of lymphovascular infiltration and Her2 status.
• TTL is an independent predictor of metastatic non-SLNs
• TTL = 15000
TOTAL TUMORAL LOAD PREDICTIVE VALUE
TTL PREDICTIVE VALUE
TTL PREDICTIVE VALUE
Deambrogio C. A new clinical cut-off of cytokeratin 19
mRNA copy number in sentinel lymph node better identifies
patients eligible for axillary lymph node dissection in breast
cancer. J Clin Pathol. 2014 Jun 6
RESULTS: The cut-off of 7700 successfully identifies patients
with positive ALN (p=0.001)
CONCLUSIONS: “We suggest that the level of CK19 mRNA
copy number could be the only parameter to consider in the intraoperative management of the axilla”.
PROGNOSTIC VALUE OF METASTATIC LYMPH
NODES NUMBER AND TTL
Very important information for the surgeon
4.500
copies
5.200
copies
TTL: NO ALND
ST GALLEN: ALND
2 positives SN
250.000
copies
1 positive SN
TTL: ALND
ST GALLEN: NO ALND
Patient 1
= 9.700 copies
Patient 2
= 250.000 copies
MX
Z0011
CRITERIA
PROGNOSTIC VALUE OF METASTATIC LYMPH
NODES NUMBER AND TTL
Very important information for the surgeon
4.500
copias
5.200
copias
1.500
copias
TTL: NO ALND
Z0011: ALND
3 positives SN
250.000
copies
1 positive SN
TTL: ALND
Z0011: NO ALND
Patient 1
= 11.200 copies
Patient 2
= 250.000 copies
2013 SESPM/SEAP GUIDELINE
TTL CUT-OFF
TTL AND MOLECULAR SIGNATURE
Bernet L. A multiparametric predictive model of the axillary
status in breast cancer patients: Tumor load & Molecular
Signature in a multicenter study.
The TTL has a positive predictive value of additional
metastatic axillary lymph nodes
Molecular signature modify the cut-off predictive value of
TTL
The inclusion od TTL and molecular signature in the predictive models improve their predictive value
OBSERVATIONS: PROBABILITY OF AXILLARY
RESIDUAL DISEASE
In patients with "low risk” tumor, the probability of residual
axillary disease is, according to published studies, 27%.
Risk of axillary residual disease for patients with low TTL
(molecular criteria) is 14.7% if we use the cut off level of
10,000 -15,000 copies CK19 mRNA
Every Breast Cancer Commitee will decide the best cut off
level for their patients in base of their aggreed Sensitivity
and Specificity
PREDICTION OF ALND STATUS FOR...
To design surgical tratment?
To design Primary Sistemic Therapy?
To design Radiotherapic Treatment?
LIKELIHOOD OF ADDITIONAL METASTASES
At the present time, intraoperative decision wether to
perform or not ALND is mainly based on the positivity of
the SN
Accurate estimate of a likelihood of additional may be of
paramount importance in the decision making about
further treatment (QT or RT)
IMPACT OF THE PATHOLOGICAL LYMPH
NODE STATUS ON PST
Risk of extensive lymph node disease is limited in patients
treated with breast conserving therapy
Incomplete information on the pathological lymph node
status did not significantly influence adjuvant systemic
treatment recommendations
Van Roozendaal, Breast Cancer Res Treat 2014
PROGNOSTIC VALUE OF METASTATIC
LYMPH NODES NUMBER
Castellano et al 2013
PI: Tumor size, Androgen receptor status, number of
metastatic nodes
Montemuro et al 2012 and Reimer et al 2008
Pannel of oncologists changed indication of adjuvant
chemotherapy in 31% of Luminal A and 16% of Luminal
B patients only after knowing that patients were
affected with > 3 involved nodes
PROGNOSTIC VALUE OF METASTATIC
LYMPH NODES NUMBER
Pathological nodal information changes treatment for
34,8% of cases
Involvement of more than three lymph nodes was
reaffirmed in the ST Gallen 2013 conference as a
parameter for decision for adjuvant chemotherapy
“...most felt that nodal positivity per se was not an indication
for chemotherapy buy fery few would forego chemotherapy
for patients with 4 or more positive nodes”...
PREDICTION OF ALND STATUS FOR...
To design surgical tratment?
To design Primary Sistemic Therapy?
To design Radiotherapic Treatment?
La aplicación del ACOSOG Z0011 genera una nueva necesidad
41
“With the recent publication of Z0011, the optimal design of radiation fields for patients with positive SLNs
who do not undergo ALND is uncertain. This will be increasingly important given that many patients with
positive SLNs will forego ALND”
“TF radiation that was used to treat the breast coincidently delivered radiation treatment to the lower
axilla and eradicated the disease. If a large component of the axilla were in the TF region, this is likely to
have contributed significantly. We believe that this observation is important and consequently that the
results of Z0011 should not be extrapolated to patients who are treated with mastectomy without
radiation, partial breast irradiation, irradiation of the breast in the prone position, intraoperative
irradiation, or other techniques in which the axilla may not be included in the radiation fields”
“The lymph nodes in the level III/SCV region are believed to be at risk when four or more positive nodes
and one to three positive nodes in selected high-risk patients are detected at ALND. Without ALND, this
information is no longer available to the radiation oncologist. However, there are several predictive
models to determine which patients with positive SLNs have four or more positive nodes”
ALND IN PATIENTS WITH POSITIVE SENTINEL LYMPH
NODE BIOPSY
23,7% patients with > 4 positive lymph nodes
could be understadified and not be propposed
to post-operative RT
Hussain, T; Kneeshaw, PJ. Annals of The Royal College of
Surgeons of England 2014; 3:199
ASCO/ESMO
ASCO and ESMO recommend postmastectomy radiotherapy
(PMRT) in the presence of four or more metastatic ALNs (pN2
disease)
ESMO recommends the inclusion of supraclavicular lymph
nodes within the target radiotherapy field in the presence of
pN2 disease, after mastectomy as well as breast-conserving
surgery.
Therefore, the knowledge of both the total axillary tumor
burden and the extent of residual axillary disease are important
in case of one or more metastatic SN.
SESPM GUIDELINES 2013
SN macrometastases are indication of axillary
Radiotherapy (levels I, II and III) when ALND is not
performed
SN micrometastases are not indication of axillary
Radiotherapy except in high risk patients, where it could
be considered
EUROPEAN OSNA USER CLUB
NOMOGRAM
European OSNA database (2460 patients)
Multivariate logistic regression analysis
CK19- mRNA number copies
T size
Lymphovascular invasion
FN rate is 7.5%
Useful to identify patients with NSNs ≥ 4
IN XÀTIVA’S HOSPITAL...
34 patients > 5000 < 15.000 copies (2009-2013)
Applying TTL concept, we could be avoided:
26,5% of ALND
25% Lymphedema
75% parestesia
THANK YOU FOR YOUR ATTENTION
V CURSO DE ACTUALIZACIÓN EN PATOLOGÍA
MAMARIA
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