1. Biospy'in'NAC'
Recommanda2ons'and'
impact'treatment'
Miri'Sklair9Levy,'M.D.'
Department of Diagnostic Imaging
Sheba Medical Center
Department'of''Diagnos2c'Imaging'
Sheba'Medical'Center'
Sackler'School'of'Medicine'9''Tel'Aviv'University'

2. Biospy'in'NA.'Recommanda2ons'and'
impact'treatment
• Introduc2on'
– Nat'7'indica2ons,'purpose'
• Response'to'NAC'
– Evalua2on'of'response'
• Clinical'exam'
• Imaging'
» Mammography'
» US'
» MRI'
• Biopsy'in'NAC''
– Recommenda2on''
– Impact'on'treatment'
– Surgery'recommenda2on''
• Conclusion'

3. Introduc2on'
• Neoadjuvant'therapy''
– Preopera2ve'therapy'7'systemic'treatment'
of'breast'cancer'prior'to'defini2ve'surgical'
therapy'
• The'ra2onale'
• Pa2ent'selec2on'
• Pretreatment'evalua2on'
• Treatment'op2ons'for'neoadjuvant'therapy'
• Tumor&response&evalua.on,'surgical'
treatment'
• 'adjuvant'treatment,'and'prognosis

4. Introduc2on'
• Neoadjuvant'systemic'therapy'(NAC)'–'indica2ons;''
• Downstage'the'tumor'prior'to'surgery'
– Locally'advanced'breast'cancer'for'whom'immediate'surgery'is'not'
feasible'
– Operable'cancer'to'facilitate'breast'conserva2on'surgery'
• ShiQ'7'aim'of'NAC'is'the'achievement'of'pathologic'complete'
response'(pCR)'prior'to'surgery'
• Ann'Oncol'2007'
• J'Clin'Oncol'2006'
– Improvements'in'long7term'disease7free'and'overall'survival'
• Br'J'Cancer'2002'
• Breast'Cancer'Res'Treat'2010'
• Advantage'of'NAC'is'the'opportunity'to'assess'response'early'
during'treatment'as'a'predictor'of'final'pathologic'response'
• Poten2al'for'modifica2on'of'therapy'to'increase'rates'of'pCR,'tumour'
volume'reduc2on,'and'treatment'tolerability.

5. Introduc2on'
• Accurate'evalua2on'of'tumor'extent'7'staging''
– Before''NAC'
– During'NAC'
– AQer'NAC''
• IMPORTANT'to''
– Evaluate'response'
– Surgical'planning'to'achieve'tumor'free'margin'

6. PRETREATMENT'EVALUATION'
• Histopathologic'confirma2on''
– Evalua2on'of'receptor'status'ER,'PR,'HER2'
• Ini2al'staging'prior'to'neoadjuvant'systemic'
therapy'
• Lymph'nodes'status'at'baseline'before'
ini2a2on'of'neoadjuvant'therapy'
– Neoadjuvant'therapy'is'expected'to'impact'
pathologic'findings'at'surgery

7. Lymph'Node'evalua2on'
• Nodal'assessment'7'clinical'exam'of'the'axilla'
• Clinically'suspicious'axillary'exam''
– Palpable'axillary'adenopathy'
• US7guided'–'FNA'/'core'needle'biopsy'
– FNA/CNB'is'nega2ve'
• Sen2nel'lymph'node'biopsy'(SLNB)'
– FNA/CNB''is'posi2ve'
• No'further'evalua2on'is'required.''
• Final'decisions'regarding'locoregional'treatment'
take'place'following'neoadjuvant'therapy'and'
will'depend'on'the'treatment'response

8. Response'Assessment'during'and'aLer'NAC
• Tumor'size'is'assessed'with'7'Response'
Evalua2on'Criteria'in'Solid'Tumors'(RECIST)'
criteria'
• The'correla2on'between'tumor'
measurements'by'physical'examina2on,'
mammography,'US'or'MRI'and'tumor'size'on'
final'pathologic'analysis'is'variable'

9. Response'Assessment'aLer'Treatment
• 2010'meta7analysis'of'25'studies''
• Total'of'1212'pa2ents'receiving'NAC'
• Conclusion:'
– MRI'7'high'specificity791%'
• sensi2vity'7'63%'to'predict'pathologic'complete'
response'(pCR)'7'
• AJR'Am'J'Roentgenol.'2010;195(1):260.

10. Response'Assessment'aLer'Treatment
• 189'pa2ents'
• Accuracy'7'defined'as'the'ability'to'predict'
greatest'tumor'dimension'within'1'cm'
– Clinical'exam'766%'
– US'–'75%'
– Mammography'–'70%'
• Compared'to'findings'at'final'pathologic'analysis'
• Ann'Surg.'2006;243(2):257'
''

11. Response'assessment'aLer'treatment
• Variable'paferns'of'tumor'response'to'
neoadjuvant'treatment''
– Symmetric'shrinkage'around'a'central'core'(that'may'
contain'residual'cancer'or'fibro2c'2ssue)''
– Complete'resolu2on'of'a'discrete'mass'despite'
persistence'of'microscopic'foci'of'residual'invasive'
cancer.
• The'lack'of'concordance'between'
clinical',imaging'and'pathologic'assessment'of'
response''

12. Breast'surgery'
• The'indica2ons'for'breast'surgery'aQer'
neoadjuvant'therapy'are'similar'to'those'used'
for'women'with'newly'diagnosed'breast'
cancer'who'did'not'undergo'neoadjuvant'
therapy

13. TREATMENT'EVALUATION'
DO'WE'NEED'BIOPSY'
• There'is'no'role'for'repeat'biopsy'of'the'index'
tumor'during'neoadjuvant'treatment'
– 'unless'performed'as'part'of'a'clinical'trial.'
• Special'case'–'MICROCALCIFICATIONS''

14. Assessment'of'Treatment'Response'
• Physical''examina2on'
• Mammography''''''''''''''''''''''''Assessment'of'response'not'reliable''
• US'
– Marinovich'et'al.'The'Breast'2012
• MRI'7'the'most'reliable'technique'for'evalua2ng'residual'disease'
aQer'NACT'

15. Evalua2on'of'Response'
• Imaging&
• MRI''
– Pre7treatment'baseline'MRI'
– During'the'course'of'therapy7'2'f/u'studies'(Ann.'Surg'2009)'
– End'of'treatment'7'final'MRI'
• The'accuracy'of'MRI'has'been'shown'to'be'much'higher'
compared'to'mammography'and'ultrasound'
• The'American'Journal'of'Surgery'2010'
• MRI'the'imaging'modality'for'evalua2ng'pre7'and'post7NAC'
extent'of'disease'used'for'selec2ng'pa2ents'suitable'for'
breast'conserva2on'surgery'
– Ann'Surg'2009'
– BioMed'Research'Interna2onal'2013'

16. Evalua2on'of'Response'9''MRI''
• The'accurate'assessment'of'residual'disease'at'MR'imaging'
is'required'for'presurgical'planning'
• Posi2ve'margins'following'surgery'are'associated'with'an'
increased'long7term'risk'of'recurrence'
– Low'rates'of'locoregional'or'ipsilateral'recurrence'in'
appropriately'selected'pa2ents'for'BCS'
– pa2ents'with'T3'or'T4'disease'
– 'pCR'aQer'NAC7''96.5%'107year'disease7free'survival''
» Pein2nger'et'al.'Cancer 2006'
– Mul27focal'or'mul27centric'cancer'at'the'2me'of'diagnosis'7'
similar'57year'locoregional'control,'disease7free'survival,'and'
overall'survival'as'those'with'unicentric'disease'
» Oh'et'al'J'Clin'Oncol'2006'

17. MRI'Studies'–'Bilateral''Dynamic'
• MRI'assessment'of'disease'
• Tumor'Size'Measurement'on'MRI'
– MIPs'7'maximum'intensity'projec2ons'
– Subtrac2on'images'
• 27dimensional'sizes'

18. Recommenda2on'of'Surgical'Procedures'Based'on'
MRI'Findings'
• Pre7NAC'7'MRI'
– Recommenda2on'of'mastectomy'or'lumpectomy'
• Tumor'size7large'tumor'the'primary'determining'factor'for'MX
• extent,'mul2focality'
• Loca2on'
• Tumor'to'breast'volume'ra2o'
• Pathological'tumor'type'
• Post'–NAC'–'MRI'
• According'to'the'pre7'and'post7NAC'
• Recommenda2ons''7'3'groups:'
– 'M M'(mastectomy'pre7NAC'and'post7NAC),'
– 'M L'(mastectomy'pre7NAC'7'to'lumpectomy'post7NAC)'
– 'L L'(lumpectomy'pre7NAC'and'post7NAC)

19. Accuracy'of'MRI'in'Determining'Residual'Disease'aLer'
Comple2ng'NAC'
• MRI''for'evalua2ng'the'extent'of'residual'disease'aQer'NAC''
– Superior'accuracy'when'compared'with'other'modali2es'
• MRI'can'over7'or''Underes2mate'residual'tumor'extent'
• MRI'Accurate''
– Mass'type'lesions',well'defined,'concentric'shrinkage'aQer'
therapy''
• Chen'et'al,!Cancer!2008

20. MRI'Accurate764y,'LT.'IDC'–'well7defined'mass''
'concentric'shrinkage''

21. MRI''ACCURACY'OF'DIFFERENT'SUBTYPES'OF'CANCER''
• MRI'7'high'accuracy'in'HER72'(+)''7'to'predict'pCR'
• MRI'7'higher'false'nega2ve'rate'in'HER72'nega2ve'
cancers'
• Chen'et'al.'Cancer'2008'
• MRI''IMAGING'FEATURES'–'predic2ng'residual'
disease''
– MRI'7mass'lesions'–'accurate'in'predic2ng'residual'dis.'
– MRI'7'non7mass'enhancements'7'high'false'nega2ve'
rate'
• MRI'cannot'detect'residual'disease'that'presents'as'
scafered'cells/clusters'within'a'large'fibro2c'region','ILC''

22. MASS'LESION'
NON'–'MASS'LIKE'ENHANCEMENT'

23. 60y'7'pre7,'during,'and'post7NAC'MIP''
'M' M'''
Pre7treatment7'MIP'7'6.1'cm
Post'NAC7treatment7MIP73.2cm

24. '48'y'–'pre,'during','post'NAC7MIP''
'pathologically'proven'as'pCR
Pre7treatment7'MIP'7'2.9'cm
Post'NAC7treatment7MIP7complete'response'

25. 35y'IDC'–'Mass'lesion'
NAC''changed'surgery'from'mastectomy'to'lumpectomy
Pre7treatment
AQer'2'cycles'NAC
End'treatment

26. Breast'MRI'Methods'for'NAC'Response'
Evalua2on
• MRI7Dynamic'contrast7enhanced'7'the'current'
standard'for'breast'MR'imaging'
• MRI7measured'tumor'size'aQer'NAC''
– Well'correlated'with'pathologically'determined'tumor'size'
aQer'comple2ng'therapy'
– Early'change'of'tumor'size'has'been'shown'to'be'a'good'
response'indicator'
• BioMed'Research'Interna2onal'2013'
'
• However,'changes'in'lesion'size'on'MRI'are'usually'not'
detected'un2l'several'weeks'following'chemotherapy'

27. • MRI'–'PRETREATMENT';'POSTREATMENT'
• Pretreatment'MR'parameters'could'differen2ate'
between'responders'and'nonresponders'
• Nonresponders'7chemoresistance'
– NME'7'a'diffuse'lesion'without'mass'effect'
– High'intratumoral'signal'intensity'on'T2W'
• Responders''
– Mass'lesions'with'wash'out'
Pretreatment'MRI'for'Predic2ng'NAC'Response'&'
Prognosis'

28. Breast'MRI'Methods'for'NAC'Response'Evalua2on9'
Predictors'Using'Different'MR'Imaging'Methods
• MRI'response'–'based'on'size'change'on'DCE7MRI'
• Search'for'addi2onal'indicators'to'evaluate'response''
– DCE7MRI'7'%'enhancements'measured'at'different'2mes'during'the'DCE'imaging'period,'
ini2al'area'under'the'curve,'and'pharmacokine2c'parameters'(such'as'!trans'and'"ep)'''ep)'''
• DWI9Diffusion9weighted'imaging;'ADC'9'apparent'diffusion'coefficient'
– Meta7analysis'of'6'studies'–'Wu'et'al,!Breast!Cancer!Res.!Treat!2012'
– DWI'7'predic2ng'pathological'response'
• sensi2vity7'93%,'specificity'782%'
– Worse'resolu2on'than'DCE
• 'MRS'9'MR'spectroscopy'
• detects'elevated'choline'concentra2on''
• Many'studies'inves2gated'the'role'of'MRS'''for'therapy'response'predic2on''
• Inconsistent'results'7'technical'difficulty'in'quan2fica2on'
– Therefore,'the'value'of'MRS'was'not'well'established

29. Evalua2on'of'Response'–'Mammography'–'
Microcalcifica2ons'
• MRI'7'non7mass'enhancements'7'high'false'nega2ve'
rate'
• MRI'cannot'detect'residual'disease'that'presents'as'
scafered'cells/clusters'within'a'large'fibro2c'region'
• Mammography'
• Evaluate''mammographic'findings'–'presence'
of'microcalcifica2ons?'
– Microcalcifica2ons''distribu2on''
– Extensive'diseases'
– Mastectomy'–'appropriate'surgery''

30. Accuracy'of'MRI'in'Determining'Residual'
Disease'aLer'Comple2ng'NAC
• MRI'is'not'accurate'for'non9mass9like'
enhancement'lesions''
• More'likely'to'break'up'into'pieces'and'
present'residual'disease'as'scafered'cells'or'
cell'clusters'
– Invasive'lobular'cancers''
– Extensive'ductal'carcinoma'in'situ''

31. 41y'–'RT.'IDC'–'Non7Mass'like'Enhancement'
Extent'cannot'be'measured'precisely''
Pathology'–con2nuous'clusters'6.5cm'
Non7Mass'lesion7'scafered'dis.''

32. 31y;'non7mass7like'enhancement'7'IDC';'DCIS''
Extent'cannot'be'measured'precisely'';''good'response'
Pathology'post'NAC'–'scafered'cancer'10cm'region'
MRI'7'scafered'dis.'Within'original'tumor'bed'';''despite'response'–'mastectomy''
'

33. MRI'ACCURACY
Accurate
Morphology
Mass'
lesion
Molecular'
subtype
HER2(+)'
TN
Non9Accurate
Morphology'
Non9Mass'like'
enhancement'
Molecular'
subtype
ER(+)'
HER2(9)
• Loo'et'al,!JCO!2011!
• Nakahara'et'al,'Breast!Cancer!2011!
• J'Clin'Oncol.'2012

34. Microcalcifica2ons'9'Mammography
• In'cases'where'the'cancer'is'associated'with'
microcalcifica2ons'
• MG'may'be'important'because'calcifica2ons'
are'not'reliably'iden2fied'on'MRI

35. PLOS'ONE2014

36. Paferns'of'change'in'calcifica2on'before'and'
aQer'NACT
• Evaluate'whether'the'appearance'of'
malignant'calcifica2ons'has'value'for'
predic2on'and'surgical'decision'making'in'
neoadjuvant'seongs'

37. Paferns'of'change'in'calcifica2on'before'
and'aQer'NACT
• Microalcifica2ons'did'not'change'significantly'aQer'NACT'
– Do'not'disappear''
– Can'change''
• The'tumor'shrinkage'modes'can'be'used'to'explain'changes'
in'the'calcifica2on'range'or'density'aQer'NAC'
– Concentric'shrinkage'
– M'ay'induce'a'decrease'in'the'range'and'an'increase'in'the'density'
– Shrinkage'with'residual'mul27nodular'lesions'
• Persistent'calcifica2ons'did'not'indicate'residual'tumors'
• Pa2ents'with'calcifica2ons'occurring'outside'of'the'mass'
aQer'NACT'could's2ll'be'treated'by'BCT'
• Consider'biopsy'at'the'end'of'treatment'

38. Tumor'evalua2on
• Prior'to'the'start'of'neoadjuvant'chemotherapy'
• Clip&marks&should'be'placed'in'the'tumor'
– Diagnos2c'biopsy''
– Other'2me'prior'to'ini2a2on'of'neoadjuvant'therapy'
• The'aim'of'neoadjuvant'therapy'is'to'shrink'the'
primary'tumor,'the'clip'will'aid'in'
• planning'locoregional'treatment'(surgery'and'radia2on'
therapy)''
• Pathologic'assessment'of'the'surgical'specimen

39. Clip'Mark'

40. 40!
CLIP'MARK'
'AQer'tumor'resec2on'
''
Neoadjuvant'chemotherapy'/'prior'to'surgical'
resec2on'
''
AQer'biopsy'
''
Planning'irradia2on'therapy'

41. 41!
TUMARK
CLIP'MARK''

42. Tumor'evalua2on9'Clip'Mark'
• Placement'of'a'clip'in'the'tumor'bed'
– Bracke2ng'large'tumor'with'mul2ple'clips''
• Tumor'size'7'prior'to'treatment'
– Mammography''
– US'
– MRI''
• Mul2focal,'mul2centric','contralateral'disease

43. In'Summary'
• An'accurate'evalua2on'of'tumor'extent'before'
and'aQer'NAC'is'crucial'for'surgical'planning'to'
achieve'tumor'free'margin'
• MRI'is'a'valuable'imaging'modality'for'evalua2ng'
– Pretreatment'disease'
– Response'during'NAC'
– Residual'disease'aQer'comple2ng'NAC'
• Accurate''
• Mass'lesions''
• HER2','TN'
• Less'accurate'–'NME','ER;PR+,'HER2(7)'

44. • Surgical'decision'may'be'the'difficult'in:'
– Pa2ents'with'large,'diffuse,'or'mul2focal'disease'
– Substan2al'response'to'NAC'
• What'is'the'surgical'approach''7'pa2ents'with'
extensive'pre7treatment'disease'
– Mastectomy,'despite'the'excellent'response'to'NAC'
– Lumpectomy''
• Importance&of&the&evalua.on&of&response&,&
residual&disease&a:er&NAC&&
Recommenda2on'of'Surgical'Procedures'Based'on'
MRI'Findings'

45. 40y'LT'IDC'DCIS'PRE7TREATMENT

46. THANK'YOU'