Imaging Endpoints for Neoadjuvant Therapy

Transcription

1 Imaging Endpoints for Neoadjuvant Therapy Sarah J Vinnicombe Clinical Senior Lecturer Ninewells Hospital and Medical School University of Dundee s.vinnicombe@dundee.ac.uk

2 Objectives What clinical questions should imaging address? Overview of literature Issues in response assessment Research avenues

3 Clinical Questions Can baseline imaging predict response? How good is interim imaging? Response adapted therapy (I-SPY2) Post NACT: Can imaging confidently identify pcr? Avoidance of surgery in exceptional responders Can imaging accurately assess residual disease? Accurate surgical planning

4 Pathological Response: Issues Variable criteria used for pcr in imaging literature: - Minimal residual disease (microscopic foci only) - No invasive disease +/- DCIS - No invasive disease or ductal carcinoma in situ (DCIS) - No invasive disease or nodal disease Choice markedly affects diagnostic accuracy of imaging Marinovich M et al. J Natl Cancer Inst 203;05:32-33

5 Imaging Response: Issues () Criteria used for imaging response vary - WHO or RECIST (.0 or.) criteria - RECIST: rarely enlightening commonly ineffective serial timewasting - MRI size measured on contrast enhanced images no enhancement rcr no enhancement > background - Choice alters response classification Jeh et al. Korean J Radiol 203;4:3-20

6 Imaging Response: Issues (2) Inappropriate analysis: - Correlation confused with agreement! Criteria denoting agreement of imaging with pathology vary widely: - Absolute (0mm, 3mm, 5mm - 2cm!) - Relative (within 30% of pathological size)

7 Imaging Modalities Mammography (XRM) Grey scale ultrasound (US) Magnetic resonance imaging (MRI) (PET/CT) (Novel modalities)

8 What do Oncology experts recommend? Imaging: baseline Mammography and ultrasound (breast and axilla) MRI: consider for dense breasts, invasive lobular ca (ILC), inflammatory breast cancer (IBC) Imaging: post treatment Mammography and ultrasound MRI: only in certain instances Kaufmann et al. Ann Surg Oncol 202;9:508-6

9 ACR Appropriateness Criteria Baseline and interim or post treatment MRI is appropriate (as well as conventional imaging) Enhancement pattern on pre treatment MRI indicates how reliable it will be in evaluating response J Am Coll Radiol 207;4:S

10 XRM and U/S Response criterion: uni- or bidimensional diameter Keune et al.: 04 cancers XRM could only size 52% cancers pre-rx Prediction of pcr similar (sensitivities 54 & 46%) Sizing residual tumour: U/S more accurate (60% vs. 32%) XRM and U/S CR: probability of pcr 80% Am J Surg. 200;99:477-84

11 CBE, XRM, U/S, MRI & prediction of response Method CBE FFDM U/S MRI Accuracy 57% 74% 79% 84% PPV 9% 85% 85% 93% NPV 3% 4% 44% 65% Synthesis of 6 studies pts. comparable in each modality MRI: highest PPV for residual disease (93%) Croshaw et al. Ann Surg Oncol 20;8;360-3

12 Conventional Imaging: Problems XRM US - mammographically occult tumours - persistent residual masses, distortion,2 - DCIS and persistent microcalcification - greater accuracy for tumour size - poor for microcalcification - adds little to CBE and XRM 3 Vinnicombe et al. Radiology 996;98: Feliciano Y. et al. Ann Surg Oncol 207;24: Schultz-Wendtland Eur J Radiol 202;8 Suppl :S47-8

13 Mammographic microcalcification Malignant microcalcification: - Can increase, decrease, condense, remain stable,2,3 - Changes do not correlate with changes in MR enhancement 4 - Changes do not correlate with pcr 4,5 Vinnicombe S. et al. Radiology 996;98: Jochelson M. et al. Ann Surg Oncol 205;22: Adrada B. et al. Ann Surg Oncol 205;22:-7 4 Feliciano Y. et al. Ann Surg Oncol 207;24: Goldberg H. et al. Eur J Surg Oncol 207;43:45-20

14 MRI: Assessment of Response More accurate assessment tumour size/volume at end R x cf. XRM and U/S Closer correlation with histology cf. XRM and U/S - r Higher PPV for residual disease than NPV for pcr Rieber 997, Esserman 200,Rosen 2003, Londero 2004, Warren 2004, Martincich 2004

15 MRI versus U/S: End R x 23 patients with MRI and U/S post NAC (2006-9) MRI: within 0mm pathological size in 54% U/S: 64% Overestimation: 28% for MRI, 20% for U/S Underestimation: 8% for MRI, 7% for U/S NPV for ER+ tumours: 26% and 33% for MRI and U/S) Vriens B et al. Eur J Cancer 206;52:67-76

16 MRI: Assessment of response Systematic review from 203 : 35 studies - Sensitivity for pcr 25-00%, specificity 50-97% - PPV 47-73%, NPV 7-00% Review of meta-analyses 2 : sensitivity for pcr Lobbes M. et al. Insights Imag 203;4: Fowler A et al. Radiology 207;285:

17 MRI: influences on response (2) Morphology of primary tumour (mass vs. non-mass) Shrinkage pattern induced by CT (concentric, dendritic) 2 Type of chemotherapy (anti-angiogenic agents) 3 Molecular subtype,4,5 - Greater pre-test probability of response Mukhtar R. et al. Ann Surg Oncol 203;20: Kim et al. Acta Oncol 2007;46: Schrading &Kuhl Radiology 205;277: Hayashi et al. Oncol Lett 203;5: Houssami et al. Eur J Cancer 202;48:

18 MR Phenotype and response pattern Rounded/oval mass Lobulated masses Irregular masses Non mass (nme) Septal spread Michishita S. et al. The Breast 205;24:59-65

19 MRI in identification of pcr NPV highest for TNBC, HER2+,2,3 - accurate prediction pcr in 95% HER2+, 50% HER2- - accurate prediction pcr in 60-90% TNBC 2,4 Less accurate in HR+ and low grade tumours 2 N.B. overall accuracy can be v. high for HR+ ca s because of high PPV 2 Chen JH. et al. 2008, De Los Santos J. et al. Cancer 203;9: Mukhtar R. et al Kim et al. Acta Radiol 205

20 Tumour Subtype and response Leeds experience: - 7y, n=278, overall pcr rate 28.%: significantly improved survival, fewer recurrences - pcr rate; 6% (luminal A) 2% (luminal B, HER2-), 35% (lum B HER2+) 72% (HER2+) 32% (TNBC) - Mid R x MR predicted pcr with sens 77.6%, spec 53.3% - End R x MR; rcr predicted pcr (82.6%, p <0.00) but sensitivity only 32%, specificity 97.6% Dave R. et al. Brit J Surg 207;04:77-87

21 MRI and FDG PET/CT Prospective n=88 over 3 yrs - MRI and PET pre and post Rx. - HER2 + : pcr 76% MRI AUC (sens 36%); PET/CT AUC ER+: pcr 2.6% MRI AUC 0.742; PET/CT AUC 0.79 (sens 56%); combined 0.88 (nsd) - TNBC: pcr 56.4% MRI AUC 0.855, (sens 45.4%), PET Schmitz A. et al. PLoS One 207;2:e076782

22 MRI and response HER2 positive ca s, n=297 (43 HR+, 54 HR-) rcr 69%, pcr 6% NPV of rcr better in HR- disease (88% vs 57%) PPV better in HR+ disease (78% vs 50%) rcr associated with improved long term outcome Van Ramshorst M. et al. Breast Cancer Res Treat 207

23 MRI changes and Outcomes 272 HR positive patients MRI pre, during and post NAC: median FU 4m. MVA: MR CR predicted RFS (HR 4., p 0.006) pcr was not significant (HR 2.2, p 0.096) Loo C. et al Breast Cancer Res Treat 206;8:82

24 MRI in detecting residual disease Marinovich et al. 203 : 44 studies (2,050 pts) Overall AUC for MRI median sensitivity 0.92, median specificity 0.60 Altered by definition of pcr or near-pcr (AUC 0.83 vs. 0.9) Specificity (i.d. of pcr) depended on definition of rcr MRI more accurate than XRM, but not U/S J Natl Cancer Inst 203;05:32-333

25 MRI in sizing residual disease Marinovich et al. 203 : 9 eligible studies (958 pts.) Pooled mean difference between MRI & path 0.cm (LOA +/ cm) US gave comparable performance XRM and CBE poorer % agreement higher for MRI Wide range of Pearson s/spearman s correlations Br J Cancer 203;09:

26 MRI post NAC: Surgical guidance Bhattacharyya et al : n=32, locally advanced cancer MRI correlated best with pathology ( r 2 0.7) Mammographic assessment post R x not possible in 60% of patients Breast conserving surgery possible in 9/2 patients with single operation Br J Cancer 2008;09:

27 MRI post NAC: Surgical guidance Marinovich et al., 205 : Individual patient data meta-analysis (n=300, 8 papers) Pooled mean difference for MRI 0cm (LOA +/- 3.8cm) US underestimated size cf. MRI (MD -0.3cm) Pts. with pcr: MRI - measurements > 5cm seen in 5% XRM - measurements > 5cm seen in 46% Overall: MRI performed best BMC Cancer 205;5:662-73

28 Early changes in Size & Volume at MRI Early changes in size can predict response Significant changes shown after cycle,2,3,4 Other studies: changes only after 2 cycles 5,6,7 Padhani et al. Radiology Cheung et al. Breast Cancer Res Treat Johansen et al. J Magn Reson Imag Yu et al. J Magn Reson Imag Baek et al. Radiology Pickles et al. Magn Reson Imag Sharma et al. NMR Biomed 2009

29 Response Prediction: tumour volume changes ACRIN 6657 I-SPY trial : 26 women, ca s >3cm MRI: baseline, post # NAC, pre taxane, pre surgery Functional tumour volume: derived with enhancement threshold of 70% Early Δ FTV best predicted response FTV better predictor of RFS than pcr 2 - post # and pre surgery - optimal timepoint variable (post # for TN, HER2+) Hylton N. et al. Radiology 202;263: Hylton N. et al. Radiology 206;279:44-55

30 Does measurement method affect ability to predict response? FTV utilises a fixed enhancement threshold - Volume could be erroneously low if slowly or mildly enhancing or pixels are excluded Might user defined semi-automated thresholding techniques be more accurate?

31 Signal Intensity ITK-Snap 50% Time 78 consecutive patients Baseline (pre-nac) & interim MRI Enhancing tumour volume analysed offline Compared with final RCB score

32 % Volume Reduction Volume Reduction- ETV p<0.05 Mann-Whitney U % 66.6% 62.9% % pcr RCB-I RCB-II RCB-III n=2 n=0 n=39 n=7

33 % Volume Reduction Volume Reduction- FTV p<0.05 Mann-Whitney U 88.8% 70.6% 54.6% 20.8% pcr RCB-I RCB-II RCB-III n=2 n=0 n=39 n=7

34 ROC curve analysis AUROC for FTV AUROC for ETV FTV Optimal Threshold: 76% ETV Optimal Threshold: 90% Sensitivity 80.0% 8.0% Specificity 76.8% 9.8% Accuracy 77.4% 89.8% PPV 42.% 68.0% NPV 77.4% 95.7%

35 Importance ETV changes differentiate pcr from any residual disease Could facilitate optical surgical management post NACT Good intra and inter-observer repeatability - could be a potentially useful clinical tool Henderson, Vinnicombe et al. in press

36 Effect of MR Imaging Thresholds Subgroup analysis of ACRIN 6657 I-SPY cohort, n=6 Early enhancement % and SER threshold varied: effect on AUROC observed Significant effects seen in different tumour subtypes HR+: AUC 0.90 vs HER2+: 0.75 vs. 0.6 TNBC: AUC 0.85 vs Li W. et al. Tomography 206;2:

37 Dynamic contrast-enhanced MRI Enhancement after i.v. Gd. - microvessel no s, density - capillary permeability - interstitial space Qualitative analysis Physiological: Δ [Gd] (Toft s model) S.I. Type II Type III Type Ia, Ib 20 s Time

38 True DCE-MRI Fully quantitative pharmacokinetic parameters Gd-DPTA injection K trans transfer constant Blood plasma renal excretion k ep rate constant V e extravascular extracellular space K trans, k ep high in tumours; 35% in responding LABC 2-4 K trans most promising biomarker in phase I/II studies 5 Tofts P et al. J Magn Reson Imaging Ah-See M et al. Clin Cancer Res Pickles MD et al. Breast Cancer Res Treat Padhani A et al. Radiology O Connor J et al. Br J Cancer 2007

39 Early Prediction of Response 3 eligible studies (605 patients imaged at baseline and post -2#) Variable MRI & pathology response parameters meta-analysis Sensitivity/specificity pairs highest: k trans, early contrast uptake, tumour volume (thresholds > 50%) Recommendations: standardisation of MR thresholds & pcr definition Marinovich et al. Breast 202;2:669-77

40 Challenges for DCE MRI Quantitative DCE is impractical in the clinic Standarisation! Pre-treatment parameters don t predict outcomes U/S after 2 cycles may be just as good Marinovich et al. 204; Int J Cancer Nov 2. doi: 0.002/ijc.29323

41 Woolf et al., 204 : Challenges for DCE MRI 58 women R x with NAC: DCE MRI at baseline, post 2 cycles K trans : correlated with T-I curves at baseline & post 2 cycles Δ curve shape correlated with Δ k trans Δ curve shape correlated with clinical & pathological response (p 0.005) Breast Cancer Res Treat 204;47:335-43

42 DCE as a Prognostic Biomarker Curve shape change after 2 cycles NAC are associated with DFS and OS K trans min - K trans min - Woolf et al., Breast Cancer Res Treat 204;47:335-43

43 Marinovich meta-analysis, interim US GeparTrio study: US post 2 cycles, WHO D, 2D, RECIST US and XRM together good at pcr Highest sens. for pcr with WHO 2D, ypt0 ypn0 82% spec (for residual dis) 80% Neo-Alto : - at 6/52: XRM and US response (RECIST.) assoc. with pcr - Pre surgery: only XRM response associated with pcr - pcr rates 57% for US rcr, 53% for XRM rcr - NB. Many HR positive patients in study Di Cosimo S et al. Eur J Cancer 208;89:42-8

44 Results: end of treatment n=70 pcr: 5 (2%) Sensitivity Specificity Diagnostic accuracy SWE 50 kpa SWE % US % SWE and US MRI

45 End of treatment response assessment 00 Significant differences in AUROC for MRI and all US and SWE parameters p 0.03 p 0.04 p 0. percent change us size percent change in stiffness % change in stiffness and US diameter percent change in MRI diameter Sensitivity AUC Sensitivity AUC Sensitivity AUC AUC Specificity Specificity Specificity Specificity

46 Diffusion Weighted Imaging Sensitive to factors affecting microscopic motion of water Random Brownian Motion Free diffusion Low signal intensity DWI High signal ADC Restricted diffusion High signal intensity DWI Low signal ADC cell water molecule ADC = Apparent diffusion coefficient

47 DWI and Response Assessment Early studies: rise in ADC correlated with response Larger rises in patients achieving pcr Baseline ADC generally not predictive of response - but immunophenotype not considered ADC ratios (post R x ADC/pre R x ADC) may be more useful Higher sensitivity for pcr & lower specificity cf. DCE 2,3 Santamaria G. et al. Radiology 207;283: Wu L. et al. Breast Cancer Res Treat 202;35: Park S. et al. Eur Radiol 202;22:8-25

48 Diffusion-weighted imaging & NAC DWI: increase in ADC in response to treatment,2 Δ ADC prior to changes in breast tumour size,2 Pickles MD et al. Magn Reson Imaging 2006;24: Sharma et al. NMR Biomed 2009;22:04-3

49 Sub-study of I-SPY ACRIN Quantitative DWI in early response assessment - 0 sites, 227 patients in final cohort, different vendors - ADC measured at baseline, post #, mid & end R x ADC at baseline & post # NOT predictive ADC mid & end, ADC from baseline did correlate ER+, HER2+ tumours: in mid R x ADC was better Partridge S et al. JCO 207

50 DWI in Response Prediction Meta-analysis of DCE-MRI, DWI and PET/CT 57 studies (54 CE-MRI, 8 DWI) Overall AUC and Q* index: CE-MRI 0.88, 0.8 DWI 0.94, 0.85 Pooled sensitivity for pcr: CE-MRI 0.64 DWI 0.93 Pooled specificity: CE-MRI 0.92 DWI 0.85 Gu YL. Et al. Clin Breast Cancer 207;7:245-55

51 MR Spectroscopy: A promising research tool for the last 2 decades! Presence of choline (tcho) at.5t indicates tumour - reflects membrane turnover & therefore proliferation Lip=Lipid Lac=Lactate Cho=Choline Bartella L et al. Radiographics 2007;27 S;S24-52 Magnified spectrum: positive Cho peak at a frequency of 3.2 ppm

52 MRS & Early Response Prediction Presence of tcho before R x and reduction/absence after -2 cycles,2 Changes can occur as early as 24 hours 2 Larger reductions in tcho seen in responders 3 Changes after 2 cycles reflect response before change in tumour size seen 4 Jagannathan et al. Br J Cancer 200;84: Meisamy et al. Radiology 2004;233; Baek et al. Radiology 2009;25: Tozaki et al. J Magn Reson Imag 200;3:

53 MRS and Response Prediction Sub study of ACRIN 6657 n=9, MRS -4d post R x Analysable data only obtained in 29/9 (24%!!) No reliable changes found in tcho from baseline to post # Too difficult for multi-centre studies Bolan P. et al. J Magn Reson Imaging 207;46:

54 The Future: Radiogenomics Correlation of radiomics with genomics (GEP) Integration of data with clinical features & outcomes Gillies R. et al. Radiology 206;278:563-77

55 Conclusions Combination of modalities seems most useful MRI performance not sufficient to obviate the need for confirmatory biopsies in cases of rcr Who should get MRI? - Anyone in a clinical trial - Anyone where a good response might enable BCS - Anyone where omission of surgery is contemplated - Anyone where response adapted therapy is utilised

56 Conclusions The future: - Big data and radiogenomics - Standardisation of techniques, data collection - Novel technologies - Subtype-specific use of modalities and response criteria

57 Acknowledgments Shelley Henderson Andy Evans Iain Lyburn Anwar Padhani The Tayside patients