Evaluation of Tumor Response to Neoadjuvant Chemotherapy for Breast Cancer Focus on Breast MRI After NAC Jane Wang, MD, PhD Department of Radiology Taipei Veterans General Hospital

Summary MRI: more accurate than Mam, US MRI techniques Tumor pattern on MRI after neoadjuvant chemotherapy (NAC) Measurement of residual disease (RD) 1D, 2D, 3D and correlation with pathology Factors influence MRI accuracy for size measurement MRI evaluation of pCR (pathologic complete response)

Rationale NAC: downstage the tumor; increase the possibility of BCS Tumor-free margin- lower long term recurrence (2-7% in 5 yr; vs 22% with positive margin) Imaging: aid in surgical planning Pitfalls in evaluation, factors affecting MRI accuracy over, underestimation

Sahoo, et al Arch Pathol Lab Med 2009 Best

MRI techniques

Technical aspects Most studies use 1.5 T MR scanners DCE MRI Adjunct 1.5T and 3T: no difference Some studies: 1.5 T superior to 3T?? But insignificant (different readers) DCE MRI Adjunct Proton MRS DWI/ADC

The tumor pattern on MRI after NAC

Tumor pattern changes Thibault 2004 Kim 2007 Kim 2012 Pre-C/T: circumscribed nodules vs spiculated tumor; uni- vs multifocal Post-C/T: shrinkage vs fragmentation nodules—shrinkage; spiculated– fragment Kim 2007 Shrinkage vs nested/rim vs mixed Kim 2012 Pre-C/T: solitary, grouped, separated, replaced Post-C/T: I, II concentric shrinkage (II with satellite); III, multinodular; IV: diffuse contrast E I, III good responders; IV nonreponder Summary: shrinkage vs fragmentation/scattered foci (prone to underestimate)

1. 60 y/o. TNBC Pre-chemo mammo

Pre-chemotherapy

Scattered invasive tumor foci in a tumor bed spanning about 2.4*1.1cm Post-chemotherapy Scattered invasive tumor foci in a tumor bed spanning about 2.4*1.1cm

2. 35 y/o pre chemotherapy mammo/TNBC

Pre-chemotherapy MR

Minimal scattered invasive carcinoma cell <1% cellularity Post-chemotherapy Minimal scattered invasive carcinoma cell <1% cellularity

Threshold criteria of no RD enhancement NO enhancement at all (spe 54%)(exclude benign inflammation) Enhancement at tumor bed <= adjacent normal glandular tissue (spe 83%) Compare with pre-C/T MR

Measurement of RD and Response Evaluation by MRI

PERCIST 1.0: PET response criteria in solid tumors JNCI 2000; 92: 179-181 Bethesda Handbook of Clinical Oncology, Appendix IV. RECIST: Response evaluation criteria in solid tumors. NC: no change. PERCIST 1.0: PET response criteria in solid tumors descriptions of methods for controlling the quality of FDG PET comparability of PET from different time points quantitative expression of the PET parameter changes  assessment of overall response Hyun, et al2016 Radiology

WHO RECIST Continued

WHO RECIST Continued

MRI measurement of RD Sensitivity: 78- 90.5%; Spe: 67-100%; acc: 76-91.3%. Early DCE MRI phase; occasional late phase TIC: may change (to less washin, sometimes  persistent) 1D (RECIST; more compatible with patho measure): correlation with patho 2D (WHO; bi-product): response evaluation 3D: response evaluation

Correlation of MR and patho Size (r): MRI (0.59- 0.896)> CBE (0.55-0.6); US (0.484-0.552) MR mass (0.85); NME (0.69) Agreement of response: MRI (69.6-79.2%) > CBE (19%); US (35%); mammo (26%)

MRI kinetics volume transfer constant (Ktrans), exchange rate constant (Kep), early contrast uptake (ECU) –early prediction response AUC of Ktrans (0.93) > bi-dimensional size (0.68) (Ah-See 2008 Clin Ca Res) Sen= predict responders; Spe= predict “non-Res” ECU Sen 100%, Spe 71% for pCR prediction These usually for early stage MRI—prediction of final response (Marinovich 2012 Breast)

Why MRI over ? Over: MRI may include DCIS (but RD only measure invasive ca) Inflammation around the tumor can enhance Radiologists measure total extent but pathologists measure only the largest one Taxanes increase permeability/ contrast uptake Change of TIC pattern, measure at late phase

Why MRI under? Antivascular agent: decreased contrast uptake Fragmented, scattered tumor foci

factors affecting MRI accuracy to measure RD MRI pattern: Non-focal (NME): lower correlation than mass Molecular subtypes, C/T, targeting Tx, age… TNBC most accurate (r= 0.781) Usually mass type, shrinkage pattern ER-pos (or ER pos/ HER neg 0.502 to 0.504): least accurate (scattered foci) HER2 (+) acc > HER2 (-) Herceptin kills scattered foci so increase acc? (other showed contradictory result) Age: <45 y/o , higher discrepancy

Factors affecting MR acc Proliferation index Ki-67 More accurate for high Ki-67 more aggressive tumor, more accurate Taxane: reduce accuracy (scattered foci?) r=0.5 compared with FEC group (0.89) Avastin: NS effect on MR accu. sen for RD detection, 76% vs 70% for with vs without group Patho: ILC underestimate by MR- NME, multicentric, less solid than IDC 5FU Epi cyclo

Factors affecting the residual tumor size dx by MR Chen, et al Factors affecting the residual tumor size dx by MR Chen, et al. 2014 JSO N= 98. MRI dx of pCR ((-) at OP)- overall FN 16/98 (16.3%); acc 77/98 (78.6%) FN significantly lower in: Tumor type: IDC (P 0.007) MR scanner: 1.5T (P 0.005) NS in morphology (mass vs NME), grade (high/ low + intermed); HR, HER2; Regimen Multivariate: tumor type, morphology, molecular subtype-predictor for MR-patho size discrepancy pCR = 44; MR dx 39

Chen et al JSO 2014 MRI-patho Size discrepancy AC: doxorubicin cyclophosphamide

Author /published year Recruitment period n Molecular subtypes r Acc *Size discrepancy, cm, mean (SD) Moon, 2009 [30] 2006/Jan -2008/2 195 Overall TNBC Lum A Lum B HER2(+) Validation (n=63) Age>45, HER2(-) Age>45, HER2(+)/age<45, HER2(-) Age<45, HER2(+)   0.781 0.504 0.502 0.384 0.849 0.733 0.513 #Moon, 2013 [29] 2006/1 -2010/5 463 Overall: US MR Lum B/no †tra HER2(+)/no tra HER2(+)/with tra 0.552 0.644 0.531 0.583 0.740 0.754 0.608 0.746 0.688 1.39cm(1.44) Chen, 2011 [35] 2006/11 -2010/10 50 1. HER2(+) HER2(-) 2. HR(-)/HER2(-) HR(+)/HER2(-) 3. Ki-67>=40% Ki-67<=10% 0.5 (0.9) 2.5(3.5) (P=0.009) 1 (1.1) 3(4) (P=0.04) 0.8 (1.1) 3.9 (5.1) (P=0.06) Kuzucan, 2012 [24] 2002/5 -2010/2 54 All HER2 (-) HR(+) HR(-) Ki-67>=40% Ki-67<40% Sen 76; spe 100; acc 83 Sen 88, spe 88, acc 88 1.6 (2.8) 0.6 (0.9) (P=0.05 for mean; P <0.0001 for range) 0.4 (0.8) 1.2(2.0) (P=0.05 for mean; P=0.002 for range)

Pathologic complete response

pCR Definition Typical definition for pCR: absence of invasive CA (in situ may be present) Near-pCR: minimal residual invasive cancer Some studies: neither invasive nor DCIS pCR rates: 2.6- 54.9%, median 16%. MR accu for pCR varied with definition Higher when DCIS excluded, lowest for standard def (detecting RD as true positive)

Other Factors– pCR Rates Higher in younger (<40), larger (>4cm), higher grade (gr 3), higher Ki-67, ER neg, basal-like, HER2 pos. Lower in lobular ca, lower grade, lower Ki-67, ER pos, Lum A Higher with taxane based C/T than anthracycline based, Herceptin for HER2 pos.

MRI Acc- pCR / Molecular Subtypes HER2 pos > HER2 neg HER (-): more likely scattered foci Herceptin for HER2 (+): clear peripheral foci Antivascular (Avastin) for Her2 (-): increased scattered foci Best accu for pCR in TNBC cancer: sen/spe/acc 60, 100, 82%; PPV in TNBC (100%)> non-lum/HER2 pos 92% > Lum/Her2 pos (45.5%)/ lum/HER2 neg (33.3%) Hayashi, et al. Oncol Lett 2013

Conclusion MRI for RD: more accurate than Mam, US Over and underestimation still occur Accuracy (RD and pCR) affected by tumor pattern on MRI, histology type and grade, molecular subtypes and NAC regimen, targeting therapy Understanding the factors affecting MRI accuracy in RD evaluation can help modify the clinical management for breast cancer patients after NAC.

Thank you!!