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