1. Breast MRI in neoadjuvant
chemotherapy : A Predictive
response marker ?
Sophie Taïeb, Luc Ceugnart – Centre Oscar
Lambret – Lille
Fabienne Thibault - Institut Curie - Paris

2. MRI : Evaluation of response to
neoadjuvant chemotherapy
Ø Neoadjuvant Chemotherapy : When ?
ü Prior to surgical treatment to reducing the size of tumour to
avoid radical surgery (28-89%)
ü Inoperable breast tumors at initial diagnosis (Secondary
curative surgery in 50-80%)
ü Assessment in vivo efficacy of chemotherapy

3. MRI provides :
Ø Morphological informations
Ø Functional informations
ü Microvascularisation
ü Cellularity
ü Metabolism

4. Lumpectomy
Mastectomy
Concentric
response
Split up
response
For the surgeon
Local-regional assessment

5. Courtesy Pr K.Kinkel - Genève

6. 32-year-old, IDC,
HR –, 3cm
p 8mm
28-year-old, IDC,
HR –, 2cm
p 2cm

7. For the medical oncologist
Multiple-level information potentially useful
Ø In vivo assesst of NAC efficacy, adjuvant Trt guidance
Ø Predicting the final response after only 1 or 2 cycles
stop or switch therap. agent in non-responders ?
Ø Gaining prognostic information
ü Prediction of complete path. response (pCR) ?
ü Prediction of rec. free and overall survival ?

8. DCE imaging
Assessment of NAC efficacy
Extent of residual disease : standard practice

9. Ø 19 studies : 958 patients
Ø Mean differences in tumour size :
ü MRI / DM (6 studies)
Overestimation MRI 0.1 cm < DM 0.4cm
ü MRI / US (2 studies)
Overestimation ≈ for MRI & US : 0.1cm

10. ü MRI / Clin exam (4 studies)

11. Causes for FN cases
Ø Tumor fragmentation, scattered residual tumour cells
Ø Initial nonmasslike lesion
Ø Low-intensity enhancing residium (uncertainty about
positive enhanct threshold criteria)
Ø Taxane-containing NAC regimen
Ø HER 2 negative tumors treated with bevacizumab
Authors reporting under-estimation and FN cases
Rieber 1997, 2002
Balu-Maestro 2002
Wasser 2003
Denis 2004
Thibault 2004
Bhattacharyya 2008
Chen JH 2008
Straver 2010
Chen JH 2011
Chen JH 2014

12. Impact of Factors Affecting the Residual Tumor Size Diagnosed by MRI
Following Neoadjuvant Chemotherapy in Comparison to Pathology
98 pts
Ø 1.5T imager : 51 pts, 3T imager : 47 pts
Ø 74 mass type lesions, 24 non-mass-like enhancement
Ø 85 IDC, 10 ILC, 3 mixed IDC-ILC
Ø 37 high grade, 60 low or medium grade
Ø Her2 + n = 40
Ø Triple - n = 16
Ø Her2- ER+ n = 41
Ø 63 : AC + Taxane, 35 Taxane without AC
Chen JH et al, Journal of Surgical Oncology 2014

13. Impact of Factors Affecting the Residual Tumor Size Diagnosed by MRI
Following Neoadjuvant Chemotherapy in Comparison to Pathology
Ø MRI diagnosis of residual invasive C.
Se 70.4% Sp 88.6% Acc 78.6%
Ø MRI / p residual tumor size : 1 + 2 cm [0-14cm]
Chen JH et al, Journal of Surgical Oncology 2014

14. Impact of Factors Affecting the Residual Tumor Size Diagnosed by MRI
Following Neoadjuvant Chemotherapy in Comparison to Pathology
Ø MRI diagnosis of residual invasive C.
Se 70.4% Sp 88.6% Acc 78.6%
Ø MRI / p residual tumor size : 1 + 2 cm [0-14cm]
Chen JH et al, Journal of Surgical Oncology 2014
Contrast media ?

16. PRE-Chimio
• 37-year-old
• IDC
• Mass
• High grade
• Triple –
• AC + Taxanes
pRC
IRM CR

17. • 31-year-old
• IDC + DCIS
• Non mass
• High grade
• HR+ , Her2-
• NAC ?
• post NAC MRI : 3cm
• post NAC path : scattered cancer cells = 10cm
Chen JH et al, Journal of Surgical Oncology 2014

18. Diffusion imaging
Assessment of NAC efficacy
Extent of residual disease : Standard practice

19. DWI-MRI
Ø Rational
ü Measure of the movement of water molecules within
tissues
ü Quantified using Apparent Diffusion Coefficient (ADC)
ü In general, cancer tend to a restricted diffusion because
of high cellular densities and abundance of intra and inter
cellular membranes
Ø Assessing NAC efficacy
Studies have shown that successful treatment of many
tumor types can be detected using DWI as an early increase
in the ADC values

20. Extent of residual disease after NAC
Can diffusion-weighted MR imaging and contrast-enhanced MR
imaging precisely evaluate and predict pathological response
to neoadjuvant chemotherapy in patients with breast cancer ?
Ø 2000-2012 : 34 / 542 studies – 1932 pts
Ø 6 DWI-MRI studies, 30 DCE-MRI studies
Wu LM et al, Breast Cancer Research 2012
Se
Sp
LR+
LR-­‐
DOR
DWI-­‐MRI
93%
[82-­‐97]
82%
[70-­‐90]
5,09
[3,09-­‐8,38]
0,09
[0,04-­‐0,22]
55,59
[21,8-­‐141,8]
DCE-­‐MRI
68%
[57-­‐77]
91%
[87-­‐94]
7,48
[5,3-­‐10,57]
0,36
[0,27-­‐0,48]
20,98
[13,24-­‐33,24]

21. Ø Higher performance with DCE-MRI + DWI
Kuroki Y, Breast Cancer 2008
Se (%) Sp (%) Accuracy(%) PPV(%) NPV (%)
DCE MRI 50 88 44 64 81
DCE MRI + DWI ↑ 86 88 76 75 ↑ 94
Extent of residual disease after NAC

22. pRC

23. Courtesy Dr C.Balleyguier - IGR
Artifact !!!

24. DCE functional and DWI
Assessment of NAC efficacy
1. Early prediction of response
2. Pre-treatment prediction of residual disease after NAC

25. 1. Arterial enhancement
2. Capillary enhancement
3. Intersticium enhancement
4. Veinous enhancement
Intensité
de
signal
Temps
C.de Bazelaire – St Louis - Paris

26. Artere
Q
artere
1
Capillaire
Q
cap
2
Kep
Ve
Interstitium
Q
inter
3Ktrans
Blood
flow
k(0,2)
flux F
veineartère
Volume V de tissus

27. à 02/2011
Ø 13 studies : 9 prospective, 6 retrospective – 605 pts – 1.5T
Ø Early response therapy monitoring
DCE-MRI after 1-2 cycles of AC + Taxane compared to pre-NAC baseline
Ø Parameters :
ü Tumour diameter, volume
ü Ktrans, Kep, Ve, ECU (early contraste uptake),
Ø Response : pCR, near-pCR and residual tumour
Prediction of pCR : Tumour volume & ECU
Prediction of near-pCR : Tumour volume & Ktrans
Se : [83-100] ; Sp : [7-100] ; AUC : [28-100]

28. à 01/2012
Ø 15 studies : 9 prospective, 6 retrospective – 644 pts – 1.5T
Ø 4 : pre-treatment differences between responders and non-
responders
Ø 6 : early response therapy monitoring
Ø 5 : both
Ø DCE-MRI (14), DWI-MRI (3), MRS (1), BOLD (1) à 31 parameters

29. Ø 15 studies, 31 parameters
Ø Tumour diameter, volume
Ø Ktrans, Kep, Ve, ECU (early contraste uptake), SIR (signal intensity
ratio), signal intensity time curves, ADC, MTT (mean transit time),
relative blood volume and blood flow, tCho peak, T2* relaxivity ….

30. Ø No Pre-treatment differences between responders and non-
responders : Tumour diameter, volume, kinetic parameters.
§ Nor ADC (Woodhams R et al, Radiology 2010) – 398 pts
§ ADC useful (Li X et al. Med Oncol 2012) – 32 pts Before NAC Mean
ADC of responders lower than in non-resp. p<0,001
Ø Early response :
ü Tumor diameter AUC [0.73-0.9]
ü Kinetic parameters : Ktrans AUC [0.63-0.93]
ü ADC : Useful but ADC cut off depends : B[800-1000],
multiB, 1.5 or 3 T.

31. ü Objective: to identify biomarkers of early response to therapy associated
with better survival
ü Imaging component
ü MRI results correlated with molecular markers
Phase II prospective clinical trial design in the neoadjuvant setting for
women with LABC Academic investigators, National Cancer Institute, FDA,
Pharmaceutical and biotechnology industries,
ACRIN participation (American College of Radiology Imaging Network)
Hylton N et al. Radiology 2012

32. Ø 216 pts : Prediction pCR & Residual tumor ?
Ø Tumor volume after first cycle (209 pts) : AUC 0,70
Ø TV + Longest diameter +SER (signal enhanct ratio) + CE : AUC 0,73
Hylton N et al. Radiology 2012

33. Need further studies !!!
Ø Standardising
ü DCE-MRI parameters
ü MRI thresholds
ü pCR definition
Ø Reporting changes in NAC based on MRI results

34. Ø 2000-2011
Ø 15 studies / 234 – 745pts
Ø Baseline (15), 1 (8 studies), 2 (7 studies), before surgery (15)
Ø Histologic tumor response : > ou < 50%
Ø Se : 85.2% [32 – 100]; Sp : 82.6% [17 – 97]
Ø ≈ after 1 or 2 cycles CT

35. Ø 63 consecutive pts. 6/2005 – 12/2007.
Ø Non-metastatic, non-inflammatory.
Ø NAC : 3FEC100 – 3 Docetaxel
Ø PET : BL and before 2nd cycle
Sataloff classification for T
ü TA : pCR
ü TB : > 50 %
ü TC : < 50%
ü TD : 0

36. 57 evaluable pts :
Ø Decrease SUV < 15% after 1st cycle = failure of NAC

37. New developments
1H-MR Spectroscopy
(MRS)

38. 1H-MR Spectroscopy
ü Malignant breast tissues show
elevated choline-containing
compounds (total choline: tCho)
and water-to-fat ratios
Tozaki M et al, MR Med Science 2011

39. MRS : metabolic response to
chemotherapy
Ø Effect of therapy on tissue metabolism manifests as changes in these levels
Ø Sequential MRS studies have shown significantly reduced tCho levels during
the course of therapy in patients who were responders
Bolan PJ et al Breast Cancer Res. 2005

40. MRS, predicting response
Ø Few studies, 1.5T (Meisamy 2004, 4T)
Ø Small series
4 studies 10-16 pts,
2 studies 30 and 35 pts
Ø tCho peak
Not demonstrated in all of the pts (Jagannathan 2001, in 10/14 pts only)
Ø Response prediction
ü Change in [tCho] after Tp2, and Tp1 (Meisamy 2004, after 24H)
ü More sensitive than Tumour Size and Volume (Tozaki 2010, Sah 2010)
ü NS difference between pCR and non-pCR groups (Baek 2009)
Advantages of 3 Tesla / 7 Tesla fields : on going studies

41. DWI and MRS
Clinical cases 3T

42. • 27
y-­‐old
w.
Pregnancy,
8
weeks
of
amenorrhea
• Mass
in
the
upper
outer
leM
quadrant
:
IDC
Grade
3
ER-­‐
PR-­‐
DWI
T1 WI
ADC Map
DCE MRI
Case
1

43. Right
Breast
?
SubtracGon
3
NaGve
3
DWI
b
1000
ADC
Map

44. Diffusion
images
and
ADC
map
:
characterizaXon
FLORID
ADENOSIS
High
ADC:
1,26.10-­‐
3
But
reliability
?
Right
breast
Left breast
Low
ADC:
0,83.10-­‐3

45. Ø During
Trt
• muscle
ADC
:
2,03
x
10-­‐3mm2/s
• lesion
ADC
:
1,04
(raXo
51%)
Monitoring
response
ADC
and
MRS
tCho
peak
DWI
ADC
Map
MRS

46. Ø Mid
trt
•
muscle
ADC
:
1,63
x
10-­‐3mm2/s
•
Increase
in
lesion
ADC
:
1,42
(raXo
87%)
Decrease
in
tCho
peak
Responder
But,
some
invasive
residual
foci
at
lumpectomy
Pb
of
the
sensiXvity
of DWI
and
MRS
for
small
lesions
DWI
ADC
Map
MRS

47. Case
2
Ø 34
ans
Ø LeM
breast
inflammatory
cancer
:
RE-­‐
RP-­‐
Her-­‐
Ki67
:
95%
Ø MRI
1
pre
Trt
Ø MRI
2
aMer
3
cycles
of
FEC
100
–
Bevasizumab

48. • 3
mn
post
contrast
• Right
breast:
Fibroadenoma
at
biopsy
MIP image Subtraction image

49. • Time
Intensity
curve
:
persistent,
atypical
enhct

50. • DWI
at
b1000
• Cancer,
hyper
Intense
on
DWI,
but
ADC
not
reduced
:
T2
effect
due
to
edema
After 3
FEC 100-
Avastin
Before
Trt
DW images ADC Map
FA : not visible

51. • Time
Intensity
curve
:
no
change
aMre
Trt
Before
Tt
AMer
Trt

52. • MRS
before
and
aMer
Trt
:
↑
in
the
choline
peak,
suggest
no
response
aMer
3
FEC
100
Before
Tt
AMer
Trt

53. Breast MRI in neoadjuvant chemotherapy:
A Predictive response marker ?
Ø Local breast status assessment after primary medical Trt
Reliability of DCE MRI and DWI, but underestimation response in
3T, Taxane only, ILC, HER- HR+ tumours.
Ø Efficacy of systemic Trts
ü Imaging tools : functional, earlier information
ü Technical challenges, standardized methods needed
ü For practice and research objectives : integration of other
(molecular, biological) decisional parameters in the individual
Trt decision process
Ø Who really changes treatment basis on earlier MRI results ??