Trial Information

Prospective Evaluation of the Reliability of the Combined Use of Two Models to Predict Non-sentinel Lymph Node Status in Breast Cancer Patients With Metastatic Sentinel Lymph Nodes: the MSKCC Nomogram and the Tenon Score.

EXPERIMENTAL PLAN AND COURSE OF STUDY This is a prospective non-randomized
non-interventional multicenter study including the respect of a quality charter and
involving a prospective registration of clinical and histological data to test the
hypothesis of a proportion of false negative rate (=rate of metastatic SN) of 5% +/- 5%
within the population at low risk by the combined use of the MSKCC nomogram and Tenon score.
No modification therapy will be conducted because the scores will not be provided to
operators.

6.1 Conduct of the study 6.1.1 Before and during surgery Every surgeon agreeing to
participate in the study - and thus to respect the quality charter - will make the inclusion
of his eligible patients with an e-CRF which will generate automatically a number of
anonymity. A form of inclusion specifying the number of anonymity of the patient, the
initials of the name and the first name as well as the date of birth of the patient will be
send back by e-mail by the study coordinator and clinical study technician (CST) of the
URC-Est. The surgeon will have at his disposal 60 boards of labels of anonymity elaborated
by the CST of the URC-Est corresponding to 30 patients (2 boards of labels by patient). The
resupplying of labels will be managed by the CST.

A label will contain i) the number of anonymity, ii) the address and phone number of the
surgeon, iii) the address and phone number of the pathology laboratory, iv) the address and
phone number of the study coordinator including fax number where pathological results should
be send.

During the first intervention, the surgeon will send the histological specimen (i.e.
lumpectomy or mastectomy, SN, and possibly non-SN in case the ALND is completed during the
first surgical procedure with a board of labels of anonymity.

In case of additional surgical procedure to complete ALND, the histological specimen (i.e.
non-SN) will be sent to the pathology laboratory with the second board of label of anonymity
corresponding to this patient.

The laboratory of pathology will have to label with anonymity labels all histological
reports that should be sent to the study coordinator. To eventually calculate combined
prediction (MSKCC nomogram and Tenon score) and ensure respect of the quality charter,
specific data must appear in the pathology report:

- Clinical information: age of the patient, the location of the primitive tumor (upper
outer quadrant, SUPERO-medial, INFERO-lateral, INFERO-internal retroareolar or other),
palpable tumor or not, the results of histological or cytological diagnosis performed
preoperatively.

- Regarding the number of lumpectomy: size of invasive cancer (largest diameter),
histologic type, associated intra ductal carcinoma (type and percentage), existence of
vascular or lymphatic emboli, estrogen receptor status, progesterone receptor status,
HER-2-neu status, SCAFF and Bloom-Richardson grade or equivalent, if realized, the
level of expression of antigen Ki 67; regarding sentinel lymph nodes: number of SN
harvested ; for each metastatic SN: type of metastasis: macrometastasis,
micrometastasis, isolated cells, method of intraoperative diagnosis of metastasis (if
performed): frozen section, cytology, RT-PCR. Final pathologic exam: routine H&E,
serial sectioning H&E, IHC. Regarding non-sentinel lymph nodes: number of non-SN

- number of metastatic non-SN, postoperative TNM. 6.1.2 Collection of histological
results from the pathology laboratories The study data will be informed through
pathology reports. Ten weeks after receiving the e-CRF, the CST of the URC-EST under
the responsibility of the study coordinator will contact the pathology laboratory. The
latter will label with anonymity labels all histology reports corresponding to the
first and possibly, if an additional ALND has further been done, and will fax reports
to the study coordinator(fax number on the label).

6.2 Procedure to calculate the risk of non-SN involvement A calculation of the
probability of metastatic non-SN using the MSKCC nomogram and the the Tenon score will be
performed for all patients. Calculations will be implemented under the responsibility of
coordinating doctor.

The result of these calculations will not be communicated to surgeons. 6.2.1 Calculating
the score of Tenon

- Variable 1: Existence of macrometastasis in a non-SN: if macrometastases, 2 points are
assigned, 0 otherwise.

- Variable 2: histological size of invasive tumor: 3 points if the tumor is greater than
20 mm, 1.5 points if the size is in 10 and 20 mm and 0 points if less than 10 mm.

- Variable 3: Ratio between the number of metastatic SN (whatever the type of metastasis
(macrometastasis, micrometastasis or isolated tumor cells)) and the number of SN
harvested: 2 points if the ratio is 1; 1 point if between 0.5 and 1, and 0 points if
less than 0.5.

The scores for the 3 variables are then added together to calculate the score of Tenon.

6.2.2 Calculation of risk by the MSKCC nomogram This calculation involves 8 variables: 1)
histological type associated with SBR grade (infiltrating ductal carcinoma grade 1, grade 2,
grade 3 and invasive lobular carcinoma (ILC)), 2) the existence of a LYMPHO-vascular
invasion (LVI) (yes, no), 3) the multifocal nature of the tumor (yes, no), 4) status of
estrogen receptor (present, absent), 4) the number of non-metastatic SN (0 to 14), 5) the
number of metastatic SN (from 1 to 7), 6) the size of the tumor (from 0 to 9 cm), 7) method
of detecting metastases in the SN. For the latter, there are 2 different situations: when
using the technique CRYOCONGELATION, 4 items were proposed (CRYOCONGELATION analysis,
analysis by H&E : routine H&E and serial sectioning H&E, and IHC), and in the absence of use
of technology by cryocongelation only 3 items were proposed (analysis by H&E : routine H&E
and serial sectioning H&E, and IHC).

1. The calculation must be done using the calculator developed by the authors and easily
accessible on the website http://www.mskcc.org/MSKCC/htlm/5794.cfm.

- First Row "Performed Frozen Section. The item must be checked if the pathologist
has performed frozen section intra-operatively. Otherwise, the item must not be
checked.

- Second line "Pathological size (cm)" must refer the histological size of the
largest tumor diameter in centimeters.

- Third line "Tumor type and grade": you must select the corresponding item from the
4 items offered: ductal I (for infiltrating ductal carcinoma (TCC) grade 1),
ductal II (for TCC grade 2), ductal III (for TCC grade 3) and lobular (for
infiltrating lobular carcinoma).

- Fourth line "Number of Positive Sentinel Lymph Nodes" must report the number of
metastatic SN, whatever the type of flooding (by macrometastasis a micrometastasis
or isolated cells).

- Fifth line "SN Method of Detection": you must select the item. Two scenarios:

1. In the first line item "Frozen Section Performed" was checked: 4 item are
then offered: Frozen (if the metastasis was diagnosed at the frozen section).
However, this scenario can not produce it because in this case, the patient
has received ALND in the same operation as the procedure of SN; Routine (if
the metastasis was diagnosed by analyzing routine H&E), Serial (if the
metastasis was diagnosed after serial sectioning in H&E), IHC (if the
metastasis was diagnosed by IHC)

2. the first line item "Frozen Section Performed" was not checked: 3 item are
then proposed: Routine (if the metastasis was diagnosed by analyzing routine
H&E), Serial (if the metastasis was diagnosed after serial sectioning in
H&E), IHC (if the metastasis was diagnosed by IHC).

- Sixth row "Number of Negative Sentinel Lymph Nodes': the number of non-metastatic
SN.

- Seventh row "Lymphovascular Invasion." The item must be checked in case of
lymphatic or vascular emboli.

- Eighth row "Multifocality. The item must be checked in case of multifocality.

- Ninth Line "Estrogen Receptor Positive". The item must be checked if the tumor
estrogen receptors.

2. The use of the nomogram (defined as the graphical representation of the model) is not
recommended because the calculation is less precise than the web interface.

6.2.3 Risk calculation combining the MSKCC nomogram and the Tenon score

- Group at low risk of metastatic non-SN: probability with the MSKCC nomogram of ≤ 10%
and a score of Tenon ≤ 3.5.

- Group at risk of metastatic non-SN: probability with the MSKCC nomogram of > 10% and/or
Tenon score > 3.5.

6.3 Monitoring of patients included in the study The study evaluates the combined use
of two predictors at baseline. It does not require monitoring. However, all patients will be
monitored regularly for any breast cancer and adjuvant treatment of breast cancer will
remain unchanged by this study.

6.4 Total time of research The recruitment and the opening of study centers is planned
over a period of 6 months. Inclusion of patients is planned over a period of 18 months. The
total duration of the study is 24 months.