Breast MRI in neoadjuvant chemotherapy : A Predictive

response marker ?

Sophie Taïeb, Luc Ceugnart – Centre Oscar Lambret – Lille

Fabienne Thibault - Institut Curie - Paris

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

MRI provides :

Ø Morphological informations

Ø Functional informations ü  Microvascularisation ü  Cellularity ü  Metabolism

Lumpectomy

Mastectomy

Concentric response

Split up response

For the surgeon Local-regional assessment

Courtesy Pr K.Kinkel - Genève

32-year-old, IDC, HR –, 3cm p 8mm

28-year-old, IDC, HR –, 2cm p 2cm

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 ?

DCE imaging

Assessment of NAC efficacy Extent of residual disease : standard practice

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

ü  MRI / Clin exam (4 studies)

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

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

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

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 ?

PRE-Chimio

•  37-year-old •  IDC •  Mass •  High grade •  Triple – •  AC + Taxanes

pRC

IRM CR

•  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

Diffusion imaging

Assessment of NAC efficacy Extent of residual disease : Standard practice

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

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]  

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

pRC

Courtesy Dr C.Balleyguier - IGR

Artifact !!!

DCE functional and DWI

Assessment of NAC efficacy 1.  Early prediction of response 2.  Pre-treatment prediction of residual disease after NAC

1. Arterial enhancement

2. Capillary enhancement

3. Intersticium enhancement

4. Veinous enhancement

Intensité

 de  sig

nal  

Temps C.de Bazelaire – St Louis - Paris

Artere Q

artere 1

Capillaire Q

cap 2

Kep

Ve

Interstitium Q

inter 3 Ktrans

Blood flow

k(0,2)

flux F

veine artère

Volume V de tissus

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]

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

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 ….

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.

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

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

Need further studies !!!

Ø Standardising ü DCE-MRI parameters ü MRI thresholds ü pCR definition

Ø  Reporting changes in NAC based on MRI results

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

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

57 evaluable pts :

Ø Decrease SUV < 15% after 1st cycle = failure of NAC

New developments

1H-MR Spectroscopy (MRS)

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

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

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

DWI and MRS Clinical cases 3T

•  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  

Right  Breast  ?  

SubtracGon  3   NaGve  3  

DWI  b  1000  

ADC  Map  

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  

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  

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  

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  

•  3  mn  post  contrast  •  Right  breast:  Fibroadenoma  at  biopsy  

MIP image Subtraction image

•  Time  Intensity  curve  :  persistent,  atypical  enhct  

•  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

•  Time  Intensity  curve  :  no  change  aMre  Trt  

Before  Tt   AMer  Trt  

•  MRS  before  and  aMer  Trt  :  ↑  in  the  choline  peak,  suggest  no  response  aMer  3  FEC  100  

   Before  Tt   AMer  Trt  

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 ??