Staging and restaging for distant metastatic disease in breast cancer: Has anything changed?

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1 Staging and restaging for distant metastatic disease in breast cancer: Has anything changed? Sarah J Vinnicombe Clinical Senior Lecturer in Cancer Imaging Dundee Cancer Centre s.vinnicombe@dundee.ac.uk

2 Outline Review of guidance and conclusions from 2012 Evolution of guidance Imaging modalities of choice Staging in recurrent disease New imaging modalities

3 Whole body staging Screening for metastases in early stage breast cancer (ESBC) Staging patients who present with de novo MBC Restaging patients who present with local recurrence or who are suspected of having it

4 Why should we screen? Should it influence 1 treatment of the breast? - NO? Will it influence systemic therapy? - POTENTIALLY (eg. bisphosphonates) Will early detection improve prognosis? - NO Are there survival benefits? - NOT SHOWN

5 Will it influence primary treatment? Retrospective studies: improved survival of pts. with metastatic breast cancer (MBC) if 1 treated (risk mortality approx. 40%) 1,2 Improved OS: - younger pts (<50y), pts. with bone/soft tissue MBC 3 Pts. presenting with occult 1 do better if 1 is treated 4 RCTs: SUBMIT, ECOG E2108, JCOG 1017, POSYTIVE 1 Ruiterkamp et al. Breast Cancer Res Treat Nguyen et al. Int J Radiat Oncol Biol Phys Shien et al. Oncol Rep Wang et al. Breast J 2010

6 When and whom?

7 When and whom? Overall: 4-6% of pts. newly diagnosed with breast cancer will have stage IV disease Most of those with MBC have symptoms 1 Prognosis for MBC poor (25% 5 y OS) but site dependent 1 Ravaioli et al. Breast Cancer Res 2002

8 When and Whom? Prevalence of asymptomatic MBC - Increases with T stage and N stage Asymptomatic women, ES breast cancer 1 : - Stage I median prevalence 0.2% - Stage II median prevalence 1.2% Stage III median prevalence 14% Inflammatory breast cancer 40% 1 Brennan and Houssami Breast 2012

9 Does T or N stage matter more? Chu et al. 1 : 256 pts. with N2/3 disease 16% had stage IV disease (N2, 15%; N3, 16%) Stage IV disease: T0/1 0% T2 6% T3 22% T4 36% MVA: T stage & grade independent predictors of OS 1 J Am Coll Surg 2012

10 Do Guidelines help? Not a lot. Even less than before!

11 TNM Staging of Breast Cancer (AJCC 7 th Ed) Stage T N M 1a 1b 1 0, 1 N0 N1mi 0 11a 11b T0, 1 or 2 T2 or 3 N1 or 0 N1 or a 111b 111c T 0-2, 3 T4 T any N2, 1 or 2 N0-2 N3 0 1V T any N any 1

12 TNM Staging of Breast Cancer (AJCC 7 th Ed) Stage T N M 1a 1b 1 1 N0 N1mi 0 11a 11b T0, 1 or 2 T2 or 3 N1 or 0 N1 or a 111b 111c T 0-2, 3 T4 T any N2, 1 or 2 N0-2 N3 0 1V T any N any 1

13 Guidelines NICE CG81: updated in Use plain radiography, US, CT, MRI for visceral mets - Bone scan or CT or MRI for bone mets - PET/CT only when imaging is suspicious, not diagnostic of MBC Scottish intercollegiate guidelines (SIGN 134, 2013): excludes diagnosis, staging and follow-up! NCCN: not for ESBC unless symptoms or Stage IIIa (T3N1)

14 i-refer B11: What does RCR say? - High pre-test probability (Stage III or above) - Suggestive symptoms Modality: - CXR/US/BS or CT depending on local preference - PET only in certain specific circumstances

15 RCR recommendations for cross sectional imaging in breast cancer, 2014 For patients with T3/4 disease, including IBC, routine CT is not generally done - Bone scan with liver U/S performed by most centres Really???

16 Are clinicians adhering to guidelines? US SEER data, : - Increased % of pts. having CT & PET scans for stage I & II BC CT PET Crivello et al. Ann Surg Oncol 2013

17 US Practice Clinicians don t follow guidelines! ASCO top 5 inaugural Choosing Widely guideline, 2012: no CT, PET or BS for ESBC Charts of 200 women with ESBC reviewed pre and 100 post publication (85%) had 1 imaging test (mean 3.6/pt) - 77% not in keeping with guidelines - 51/169 (30%) needed further imaging to clarify; NONE had metastases 1 Simos et al. J Eval Clin Pract 2015

18 Collective opinion of UK surgeons Survey sent to ABS on local policy on staging 1 26% response rate ESBC: 36% obtained CXR, only 2% liver U/S, 1% CT Decision to obtain CT - Very variable - 46% would obtain CT for T3/4 tumours - 86% would do CT with any evidence LN involvement! 67% obtain CT prior to neoadjuvant, but only 19% prior to adjuvant chemotherapy 1 Chand et al. Int J Breast Cancer 2013;2013:506172

19 Criteria for pre- and post-operative CT

20 Consequences Increased detection of incidentalomas 1 Patient and clinician anxiety 2 Radiological burden Excessive economic costs of 781 pts. with ESBC had bone scan - 42 (16%): metastases - 2/42 asymptomatic bone metastases - 50,850 Eu per case 1 Berland et al. White paper, ACR Incidental Findings Committee J Am Coll Radiol Han et al. J Health Commun Morris et al. Ir Med J 2009

21 When is pre-operative staging indicated? T3 tumours (> 5cm) T4? - possibly not T4 a or b - T4c - definitely T4d inflammatory carcinomas N2-4 obviously involved axillary nodes

22 Postoperative Staging Does the NPI help? 67 pts. with post-op NPI > /67 (3%) had MBC on CT CAP - 18/67 (27%) had indeterminate CT requiring 21 further tests - 1/18 had metastases ie. FP rate of 25% - 2 of 3 had N3 and 1 had N2 disease 1 James et al. Breast 2012

23 Should we adapt staging by risk? Biology, phenotype affect metastatic behaviour TNBC, HER2+ tumours: more visceral MBC TNBC have early metastatic capacity 1 Should we screen more aggressively? - No good evidence for this to date - Rates of DM at PET/CT not shown to be affected by receptor status 2 1 Rosa Mendoza et al. J Cancer Res Clin Oncol Riedel et al. J Nucl Med 2014

24 How should we screen?

25 How should we screen? Commonest 1st sites MBC: - Bone (median 6%) - Lungs (median 3%) - Liver (median 1.5%) Modality used should be accurate in these sites Historical low prevalence of occult MBC reflects poor performance of CS tests

26 What modality? Breast clinicians still request CXR, liver U/S and BS despite low detection rates 1 - CXR % - Liver U/S % - BS % - Very low specificity: most series report FP rates for BS 10-30%; liver U/S 33-52%; CXR 0-23% 1 Schneider et al. Arch Gynec Obstet. 2003

27 Role of bone scan in addition to CT Barrett et al. 1 : Stage II 3 nodes: 0.3% MBC (n=2 prob. both FP) 4 nodes: 6% MBC (13% FP) Stage III: 14% MBC (13% FP) Stage IV: 57% (no FP) Bone scans (BS): 6.2% TP (n=23), 13.7% FP CT: 26.9% TP, 3.8% FP All pts with + BS had at > 1 metastasis shown at CT 1 BJC 2009

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29 Visit poster 58! Retrospective study of 113 asymptomatic pts. 22 had DM CT missed 1 metastasis BS missed 5, overcalled 1 Cost of CT: 147 Cost of BS: 246 Extended coverage CT would have avoided miss

30 Role of Bone Scan in addition to CT Review of prospective database, n = Included proven node pos. axilla & pre NAC - 52% were CS II 69 had MBC; - 49 bone alone, 47 in axial skeleton 5 FN CTs, 3 FN bone scans Inclusion of proximal femur at CT would have reduced FN to 3 Omission of BS would have saved 250,000 Eu 1 McCartan et al. Br J Surg 2016

31 Suspected bony metastases Houssami & Costelloe 1 : PET +/- CT vs. BS: sens. 92% vs 82% spec. 92% vs. 82% Discordant results: PET more often correct Not enough data on MRI or MRI vs. PET/CT (2 studies) 1 Ann Oncol 2011

32 FDG-PET/CT PET/CT better than BS for lytic or mixed mets CT component detects purely sclerotic mets - Hence NCCN amendment of guidelines - BS can be omitted if PET/CT performed Confirmatory prospective studies needed

33 PET/CT in Clinical Stage III and IIB Groheux et al. 1 : Prospective study of 254 pts Changed stage: 30% (77) overall (N3, 16%; M1, 21%) 10.7% of stage IIB pts (T3N0, T2N1) 17.5% of stage IIIA pts 36.5% of stage IIIB pts 47% of stage IIIC pts 3 y DSS of the 47 M1 pts 57% vs. 88% for M0 pts. MVA: only M1 on PET and TNBC prognostic 1 J Natl Cancer Inst 2012

34 FDG-PET/CT Detects N3 disease (56% with N2 became N3) 1 Changes R x (XRT fields) May obviate need for bone scan 2-1 misclassification for PET/CT, 8 for BS Stage IIb or higher: - PET/CT 100% sens., 98% spec. - CI inc. CT 60% sens., 83% spec. 1 Groheux et al. J Nucl Med Morris et al J Clin Oncol 2010

35 FGD-PET/CT

36 Inflammatory Breast Cancer (IBC) MBC at presentation frequent (20-40%) CT: identifies asymptomatic MBC in 25-30% PET/CT: 30-50% (mediastinal LN, bone, liver) 1,2-20% incremental detection rate cf. conventional tests 1 May improve prognosis (stage migration) 1 Carcaki et al. J Nucl Med Alberini et al. Cancer 2009

37 Check out poster 49! 40 IBC in Leeds between Only 28 had initial staging CT 4 (14%) had DM 5 had indeterminate findings Of the 19 who were DM(-): - 50% developed DM at F/U, 6 within 1 yr - 2/5 with indeterminate findings developed DM PET/CT at initial staging warranted

38 FDG-PET/CT One-stop shop for high risk pts. - T3-4, N 2, IBC - Regional lymph node involvement - Occult distant metastases eg. bone 1 1 Groheux et al. J Nucl Med 2013

39 Suspected Local Recurrence OS with LRR depends on presence/absence distant metastases (DM) - 5 y relative survival 80% vs. 25% Robust detection of DM prognostically critical Number of sites and nature of DM determines treatment intent and modality Appropriate imaging modality is important

40 Known Local Recurrence Value of CT CAP in proven local recurrence: - DM commoner with axillary cf breast recurrence 1-21/65 recurrences had MBC (chest > bone > liver) - 3/21 with IBTR, 18/44 with axillary/scf/mastectomy flaps - More likely for patients under 50 at time of diagnosis and under 60 at time of recurrence 1 Tennant et al. Clin Radiol 2009

41 Guidelines for? Local Recurrence RCR: no specific advice for? recurrence NCCN: - CT CAP or MRI first - PET/CT optional, BS optional (level 2B) ESMO: - PET/CT: equivocal or conflicting conventional imaging

42 RCR recommendations, 2014: PET/CT best for - Small volume nodal disease - Lytic bone metastases - Equivocal imaging/clinical findings - Confirmation of oligometastatic disease

43 PET/CT in Suspected Recurrence 1 - n=63, all with suspicion of relapse and comparative conventional imaging (CI) - 42 confirmed relapse, 37 +ve CI, 40 +ve PET/CT - PPV 95% vs. 70% - NPV 86% vs. 54% - PET/CT changed management in 36 of 42 - Strongly associated with outcome (OS) cf. CI 1 Cochet et al. Cancer Imaging 2014

44 Role of PET/CT Recent metaanalysis of 26 studies (1,752 pts.) 1 - Pooled sens. 91%, spec. 81%, SROC BUT most studies retrospective - Info needed cf. WB-MRI and PET/MRI 1 Xiao et al. Nucl Med Commun 2016

45 PET/CT in suspected LR Very high NPV Differentiates IBTR from DM Useful with increased tumour markers Major effect on management (48-57%) - Identifies oligometastatic disease - NB with new local control strategies

46 PET/CT in local recurrence (c) Copyright 2014 SNMMI; all rights reserved From: Groheux et al. J Nucl Med 2016;57:17S-26S

47 DWIBS in whole body staging Metaanalysis of 13, studies, 1067 pts. 1 Equivalent AUC to PET/CT (0.966 vs ) Equivalent pooled sensitivity and specificity Heterogeneity; - Sequences (DWIBS alone or others) - lesion type (single or multiple) - data analysis (per lesion or per patient) 1 Li et al. Eur J Radiol 2014

48 Role of DWIBS in Assessment of MBC From: Woolf et al. Ann Oncol 2015;26: The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please

49 Conclusions WB screening is harmful and wasteful for ESBC High T, N stages or symptoms should prompt screening should we look more at tumour biology?? Extended CT obviates the need for BS PET/CT as first choice: IBC, some LABC? LRR: CT CAP or PET/CT for some groups? Follow-up: DWIBS?