Evaluation of Virtual Touch Tissue Imaging Quantification (VTIQ - 2D-SWE) in the Assessment of BI-RADS® 3 and 4 Lesions

Elastography is a method of imaging tissue stiffness. It is based on shear wave velocity
information that can be mapped to create an image of the stiffness in the region of interest.

Sonoelastography is used to differentiate benign from malignant lesions since malignant
lesions alter tissue elasticity.

Adding Shear Wave elastographic features to BI-RADS® feature analysis- especially in lesions
scored BI-RADS® 3 and 4a- improved specificity of breast US mass assessment without loss of
sensitivity.

The BI-RADS® categories are defined by the risk for a malignant lesion varying from benign
BI-RADS® 2 lesions, up to a 2% malignancy rate in BI-RADS® 3 and 2- 95% in BI-RADS® 4 (4a
2-10%; 4b 10-50%; 4c 50-95%). Based on these probabilities, biopsies are recommended for
BI-RADS® 4 and 5 lesions and short-term follow-up examinations for BI-RADS® 3. Consequently,
up to 2% of the in Ultrasound visible breast cancers are not directly detected as such and
put into the BI-RADS® 3 category. In contrast, in the BI-RADS® 4a category more than 90% of
the biopsies are unnecessary.

The main aim of the confirmatory study is to use Virtual Touch Tissue Imaging Quantification
in order to reduce unnecessary benign biopsies without a reduction of the number of detected
cancers.

This multi-center study is planned to involve 12 sites in 7 countries. Recruitment started at
the first sites in February 2016. Recruitment takes place in the course of the patient's
routine visit at a certified breast unit. All study participants will receive VTIQ in
addition to standard ultrasound.

Enrollment goal is a total of 1000 cases, split into groups of a minimum of n= 300 BI-RADS®
3, n= 400 BI-RADS® 4a, n= 100 BI-RADS® 4b, n= 100 BI-RADS® 4c. All patients will be
documented in a screening list. Monitoring will be performed by the Coordination Center for
Clinical Trials (KKS Heidelberg). Completeness, validity and plausibility of data will be
checked in time of data entry (edit-checks) and using validating programs, which will
generate queries. The investigator or the designated representatives are obliged to clarify
or explain the queries. If no further corrections are to be made in the database it will be
closed and used for statistical analysis. All data management procedures will be carried out
on validated systems and according to the current Standard Operating Procedures (SOPs) of the
Institute of Medical Biometry and Informatics.

The standard BI-RADS® Ultrasound (US) category (BI-RADS® 3-4c) and VTIQ values will be
correlated with the histological result. Additionally, local (BI-RADS® given at each site)
and central expert BI-RADS® assessment will be compared (BI-RADS® assessment and assessment
of the variables leading to the BI-RADS® value separately) to assess the inter-rater
reliability. In addition, the BI-RADS® assessments will be compared with the histological
results.

The variable "measurement lesion (in m/s)" is derived from three VTIQ measurements as
follows:

I. For confirmatory analysis of primary objectives an algorithm was established,

1. using the first measurement for analysis if the value is smaller than 2.5 m/s or if the
value is larger than 4.5 m/s. If the first measurement is smaller than 2.5 m/s, the
lesion can be considered benign and no further diagnostics is needed. If the lesion is
larger than 4.5 m/s the lesion should be considered suspicious and further diagnostics
is required.

2. requiring two additional measurements (in total three measurements) if the first
measurement is in the range of ≥ 2.5 m/s to ≤ 4.5 m/s. In this case the average of all
three measurements is used for analysis.

II. For descriptive analysis other options for derivation of this variable from the three
VTIQ measurements will be calculated for discussion:

1. First measurement only

2. Average of all three measurements

3. Median of all three measurements

4. Maximum of all three measurements

In conjunction with the maximum VTIQ shear wave velocity the quality display will be used to
aid in the classification of lesions as malignant or benign as follows:

1. If the shear wave velocity ≥ the cut-off value (3.5 m/s), the lesion is considered
potentially malignant, regardless of the outcome of the quality factor

2. If a lesion or lesion rim has a completely high quality factor (all green) and a shear
wave velocity < the cut-off value (3.5 m/s), the lesion is considered benign.

3. If a lesion or lesion rim has mixed high and low quality factors (there are areas with
low quality within the mass) and the only area of high quality (green) has a shear wave
velocity < the cut-off value (3.5 m/s), then the lesion is indeterminate and malignancy
cannot be excluded.

Inclusion Criteria:

- Female

- Age ≥18 years

- Patients with a lesion ≥ 0.5 cm in largest diameter size, initially scored BI-RADS® 3,
4a, 4b or 4c in B-mode ultrasound

- Informed consent about histological examination (core cut biopsy (CCB),
vacuum-assisted biopsy (VAB), fine needle aspiration (FNA) or surgery) has already
been given in the course of clinical routine

- Signed informed consent of study participation

Exclusion Criteria:

- Pregnant or lactating women

- Women with breast implants on the same side as the lesion

- Women that underwent local radiation or chemotherapy within the last 12 months

- Women with history of breast cancer or breast surgery in the same quadrant

- Lesions in or close to scar tissue (< 1cm)

- Skin lesions or lesions that have been biopsied previously

- Lesion larger than 4 cm in the longest dimension

- No lesion should be included when more than 50% of the lesion is further down than 4
cm beneath the skin level.