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'

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'

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

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.

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'

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

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

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'

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.

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'

''

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''

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

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''

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'

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'

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'

MRI'Studies'–'Bilateral''Dynamic'

•  MRI'assessment'of'disease'

•  Tumor'Size'Measurement'on'MRI'

– MIPs'7'maximum'intensity'projec2ons'– Subtrac2on'images'

•  27dimensional'sizes'

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)

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

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

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''

MASS'LESION'

NON'–'MASS'LIKE'ENHANCEMENT'

60y'7'pre7,'during,'and'post7NAC'MIP'''M'�M'''

Pre7treatment7'MIP'7'6.1'cm

Post'NAC7treatment7MIP73.2cm

'48'y'–'pre,'during','post'NAC7MIP'''pathologically'proven'as'pCR

Pre7treatment7'MIP'7'2.9'cm

Post'NAC7treatment7MIP7complete'response'

35y'IDC'–'Mass'lesion'NAC''changed'surgery'from'mastectomy'to'lumpectomy

Pre7treatment

AQer'2'cycles'NAC

End'treatment

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'

•  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'

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

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''

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''

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

Non7Mass'lesion7'scafered'dis.''

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'''

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

Microcalcifica2ons'9'Mammography

•  In'cases'where'the'cancer'is'associated'with'microcalcifica2ons'

•  MG'may'be'important'because'calcifica2ons'are'not'reliably'iden2fied'on'MRI

PLOS'ONE2014

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'

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'

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

Clip'Mark'

40!

CLIP'MARK'

'AQer'tumor'resec2on'''Neoadjuvant'chemotherapy'/'prior'to'surgical'resec2on'''AQer'biopsy'''Planning'irradia2on'therapy'

41!TUMARK

CLIP'MARK''

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

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)'

•  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'

40y'LT'IDC'DCIS'PRE7TREATMENT

THANK'YOU'