03/14/2019

1

IMAGING TO ASSESS

RESPONSE TO

NEOADJUVANT THERAPY

Lisa A. Mullen, MD

Assistant Professor

Breast Imaging Division

The Russell H. Morgan Department of

Radiology and Radiological Science Johns Hopkins Medicine

DISCLOSURES

2/17/19 2

• Research support from IBM

OBJECTIVES

2/17/19 3

• Review options for imaging at diagnosis

• Review options for imaging after NAC

• Review ACR Appropriateness Criteria

• Discuss performance of imaging options

• Discuss future directions

03/14/2019

2

INITIAL EVALUATION

4

• Clinical examination

• Mammography, including DBT

• Breast Ultrasound

• MRI

• PET/CT

• MBI

ACR Appropriateness Criteria Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer

Expert Panel on Bteast Imaging:, Priscilla J. Slanetz. MD, MPH@ B .Unda Mov, MD, Paul Baron, MD, Roberta

M. dtFiorio, MD, MS, Edward 0. Green, MO, Samantha L. Heller, MD, PhD, Anna I. Holbrook, MD,Su..Ju Lee, MO.Alana A. Lewin, MD, Ana P. Lourenco. MD. Bethany Niell, MD, PhD. Ashley R. Stuckey, MD, Sunita

Trikha, MD, Nina S. Vincoff , MD, SyS!!n P, Weinstein , MD, Monica M. Y MD, S. Newell, MD

9

MRI bte

contr

2

1

o D Ity occutt. Thi

mammography!

1 h primary beneftl of this procedure Is evaluat ng systemic dasease..

RRL

9

- - - - - - - - - - - -

1

0

03/14/2019

3

9 2/17/1 7

2/17/19 8

2/17/19 9

03/14/2019

4

EVALUATION OF RESPONSE

10

• Clinical examination

• Mammography, including DBT

• Ultrasound

• MRI

• PET/CT

• MBI

L

2

Com ents RRL

0

, PET and PElleT should ilolft..:ll .r.-i rVt modal ttes.

used

03/14/2019

5

CLINICAL EXAMINATION

2/17/19 13

• Overall accuracy 57%

• PPV 91%

• NPV 31%

• Limited for masses < 2 cm, dense tissue, fibrosis

• Unreliable after NAC for small early stage BC

Croshaw R, et al. Ann Surg Oncol 2011; 18:3160–3163 Keune JD, et al. Am J Surg 2010; 199:477–484

MAMMOGRAPHY

2/17/19 14

• Variable accuracy

• Look for decreased size and density of mass

• Limited due to tumor necrosis, fibrosis, and fragmentation

• Tumor size only moderately correlated with residual

pathologic tumor size

• Calcifications can be misleading

• DBT useful

Chapgar AB et al. Ann Surg 2006;243;257-264

Andrada BE. Ann Surg Oncol 2015;22:1111-1117

ULTRASOUND

2/17/19 15

• More accurate than mammography

• Still relies on size and morphology

• Not better at predicting pCR

• If both US and mammography negative, liklihood of

pCR 80%

Keune JD, et al. Am J Surg 2010; 199:477–484 Rauch GM et al. AJR 2017 Feb;208(2):290-299

03/14/2019

6

2/17/19 16

2/17/19 17

2/17/19 18

03/14/2019

7

19

FUNCTIONAL IMAGING

2/17/19 20

• Evaluate vascular, metabolic, biochemical and /or

molecular changes

• Occur earlier than morphologic changes

• Allow earlier assessment of response to NAC

• MRI, PET, MBI

MRI

2/17/19 21 290-299

• Dynamic, contrast enhanced study

• Detects tumor angiogenesis, changes in

microcirculation, increased permeability of new

vessels

• Earlier and more accurate assessment of tumor

response

• Sensitivity 86-92%, specificity 60-89%, accuracy

76-90% for residual disease

Rauch,GM, et al. Multimodality Imaging for Evaluating Response to Neoadjuvant Chemotherapy in Breast Cancer. AJR 2017 Feb;208(2):

03/14/2019

8

MRI

2/17/19 22

• Accuracy for estimating residual disease varies by

subtype

• Best in triple negative, HER2+, and high grade

tumors

• Highest sensitivity after 2 cycles of NAC

Fatayer H, et al. Eur J Surg Oncol 2016;42:965-972

MRI AFTER CHEMOTHERAPY- WHAT ARE WE LOOKING FOR?

23

• Change in size of the known cancer

– Complete response

– Partial response

– Stable disease

– Progression of disease

• Change in enhancement pattern of known cancer

– Overall enhancement may decrease

– Decreased rate of initial enhancement and flattening of the kinetic curve

• Change in the size of axillary or internal mammary lymph nodes

2/17/19 24

03/14/2019

9

2/17/19 25

2/17/19 26

2/17/19 27

03/14/2019

10

28

2/17/19 29

30

03/14/2019

11

2/17/19 31

CAUSES OF MRI INACCURACY

32

• Treatment related necrosis or fibrosis

• Antiangiogenic therapy can impair delivery of contrast to tumor foci

• Tumor shrinkage may be patchy with intervening necrotic areas

• Small foci of tumor may be scattered over a large area

• Receptor status (best in ER-/HER2+ and TN, worst in HER2-

and receptor positive cancers)

MR FALSE NEGATIVES

33

• No residual enhancement on MRI, but the pathologic specimen

contains residual cancer

• HER2- cancers

• Hormone receptor positive cancers

• Tumors that present initially as non mass enhancement on MR

• Tumors that shrink to multiple tiny foci

• WARNING: residual disease may persist in spite of negative

imaging

03/14/2019

12

MR FALSE POSITIVES

34

• Residual enhancement on MR, no residual

invasive disease at pathology

• Residual DCIS or hyperplasia

• Enhancement of normal tissue

• Scar, necrosis, fibrosis, benign lesions

ADVANCED MRI

2/17/19 35

• Volumetric tumor measurement

• DWI- looks at diffusivity of water, cellularity, cell

membrane integrity-changes can predict response

• Texture analysis-quantitative measure of tumor

heterogeneity based on statistical modeling

• MR spectroscopy

• Multiparametric MRI

Hylton NM, et al. Radiology 2012; 263:663-672 Liu et al. JMRI 2015; 42:779-787

Rauch GM et al. 2017 Feb;208(2):290-299

FDG PET

2/17/19 36

• Metabolic functional imaging

• Can show changes early in NAC

• Change in SUV after second course of NAC higher in patients with pCR

• Sensitivity 84%, specificity 66%, PPV 50%, NPV 91%

for early detection of response

• Limited detection of subcentimeter tumors and ILC

Andrade WP, et al. Eur J Surg Oncol 2013;39:1358-1363 Wang Y, et al. Breast Cancer Res Treat 2012; 131:357-369

03/14/2019

13

FDG PET

2/17/19 Rauch GM et al. AJR 2017 37

• Change in SUV of 55-65%

• More accurate after 1-2 cycles

• Affected by subtype – IDC, high grade, and triple negative, and HER2+ have

higher baseline uptake than ILC and low grade tumors

– Change in max SUV may be most helpful in triple neg, ER+,

and HER2- cancers

– Absolute max SUV after 2 cycles best for HER2+ BC

2/17/19 38

2/17/19 39

03/14/2019

14

ournal of Clinical Oncolo TBCRC026: Phase I I Trial Correlating Standardized

Uptake Value With Pathologic Complete Response

to Pertuzumab and Trastuzumab in Breast

Cancer

Roisin M. Connolly, MD1 0 ; jeffrey P. L l l i BA1 L.llja SOIW- MD1 Chlurut:Yu Huang_ ; ;

Ph01; Ashley Carpenter, MA1; Katy Gaffney, BSN1; Vandana Abramson, MD2; Usa A. Carey,

M03; Minetta c. Llu, Mo•; Mothaffar Rlmawl, M05; Jennifer Specht, MD6; Anna Marla

Stornlolo, MD7; VIcente Valero, MDa; Chrlstos Vaklavas, M09; Jan E. Kroe,. MD. Ph010; Eric P.

Winer, MD1o; Melissa Camp, MD1; RobertS. Miller, MD1; Antonio C. Wolff, MD1; Ashley M01; MD. Ph01; M011; and Vered Stearns,

No pCR

Baseline Follow-up

Images courtesy of Dr. Roisin Connolly

pCR

Baseline Follow-up Images courtesy of Dr. Roisin Connolly

03/14/2019

15

MOLECULAR BREAST IMAGING

2/17/19 43

• 99mTc- sestamibi

• Uptake based on vascularity and mitochondrial

activity in tumor

• Similar sensitivity(88-95%) to MRI

• Better specificity(74-90%) than MRI

Guo C et al. Nuc Med Commun 2016;37:675-688 Mitchell D et al Clin Nuc Med 2013;38:949-956

AXILLARY NODAL IMAGING

2/17/19 44

• Axillary pCR 40-75% with NAC

• Ultrasound useful both for imaging and biopsy

• Overall sensitivity for detection of mets 82%

• Specificity 96%

• Sensitivity for detection of node-positive disease post

NAC

– US 70%, PET/CT 63%, MRI 61%

• Axillary imaging does not preclude surgical staging

FUTURE DIRECTIONS

45

• Imaging early during therapy to assess response

• Diffusion weighted MRI

• MR spectroscopy

• PET/MRI

• Ultrasound- elastography, contrast

• Contrast mammography

• MBI

• AI

03/14/2019

16

CONCLUSIONS

46

• MRI is the most accurate study for monitoring

response to neoadjuvant chemotherapy

• FDG PET and other modalities may have a role

• Evolving literature regarding timing of imaging and which modality will be most useful

Thank you!

2/17/19 47

• lmullen1@jhmi.edu

REFERENCES

2/17/19 48

• Slanetz PJ, et al. ACR Appropriateness Criteria: Monitoring Response to Neoadjuvant Systemic Therapy

for Breast Cancer. JACR 2017;14:S462-475.

Rauch GM et al. Multimodality Imaging for Evaluating Response to Neoadjuvant Chemotherapy in Breast

Cancer. AJR 2017 Feb;208(2):290-299

Croshaw R, et al. Accuracy of clinical examination, digital mammogram, ultrasound, and MRI in determining

post neoadjuvant pathologic tumor response in operable breast cancer patients. Ann Surg Oncol 2011;

18:3160–3163

Keune JD, et al. Accuracy of ultrasonography and mammography in predicting pathologic response after

neoadjuvant chemotherapy for breast cancer. Am J Surg 2010; 199:477–484

Chagpar AB, Middleton LP, Sahin AA, et al. Accuracy of physical examination, ultrasonography, and

mammography in predicting residual pathologic tumor size in patients treated with neoadjuvant

chemotherapy. Ann Surg 2006;243:257-264

Hahn SY, Ko EY, Han BK, et al. Role of diffusion-weighted imaging as an adjunct to contrast-enhanced

breast MRI in evaluating residual breast cancer following neoadjuvant chemotherapy. Eur J Radiol

2014;83:283-288.

Fatayer H, Sharma N, Manuel D et al. Serial MRI scans help in assessing early response to neoadjuvant

chemotherapy and tailoring breast cancer treatment. Eur J Surg Oncol 2016 Jul;42(7):965-72.

Mitchell D, Hruska CB, Boughey JC, et al. 99mTc-Sestamibi Using a Direct Conversion Molecular Breast

Imaging System to Assess Tumor Response to Neoadjuvant Chemotherapy in Women with Locally

Advanced Breast Cancer. Clin Nuc Med 2013;38:949-956.

•

•

•

•

•

•

•

03/14/2019

17

REFERENCES

the clinical management of women with early stage breast carcinoma. J Clin Oncol 2002;20:3413-3423. 49

• Dershaw DD, D’Orsi CJ, Mahoney MC, Monsees BS, Morris EA. ACR Practice Guideline for the Imaging Management of DCIS and Invasive Breast Carcinoma. ACR 2013.

Berg WA, Gutierrez L, NessAiver MS, et al. Diagnostic accuracy of mammography, clinical examination, US and

MR imaging in preoperative assessment of breast cancer. Radiology 2004; 233:830-849.

Gutierrez RL, DeMartini WB, Sibergeld JJ, et al. High cancer yield and positive predictive value: outcomes at a

center routinely using preoperative breast MRI for staging. AJR 2011; 196:W93-99.

Liberman L, Morris EA, Dershaw DD, Abramson AF, Tan LK. MR imaging of the ipsilateral breast in women with

percutaneously proven breast cancer. AJR 2003;180:901-910.

Fischer U, Kopka L, Grabbe E. Breast carcinoma: effect of preoperative contrast-enhanced MR imaging on the therapeutic approach. Radiology 1999;213:881-888.

Hollingsworth AB, stough RG, O’Dell CA, Brekke CE. Breast magnetic resonance imaging for preoperative

locoregional staging. Am J Surg 2008;196:389-397.

Harms SE, Flamig DP. MR imaging of the breast: technical approach and clinical experience. Radiographics

1993;13:905-912.

Lehman CD, DeMartini W, Anderson BO, Edge SB. Indications for breast MRI in the patient with newly diagnosed

breast cancer. J Natl Compr Canc Netw 2009;7:193-201.

Schnall MD, Blume J, Bluemke DA, et al. MRI detection of distinct incidental cancer in women with primary breast

cancer studied in IBMC 6883. J Surg Oncol 2005;92:32-38.

Tillman GF, Orel SG, Schnall MD, Schultz DJ, Tan JE, Solin LJ. Effect of breast Magnetic resonance imaging on

•

•

•

•

•

•

•

•

•

REFERENCES

50

• Le-Petross HC, Hylton N. Role of breast MR imaging in neoadjuvant chemotherapy. Magn Reson Imaging Clin

N Am 2010;18:249-258.

Yuan Y, Chen XS, Liu SY, Shen KW. Accuracy of MRI in prediction of pathologic complete remission in breast

cancer after preoperative therapy: a meta-analysis. AJR 2010;195:260-268.

McGuire KP, Toro-Burguete J, Dang H, et al. MRI staging after neoadjuvant chemotherapy for breast cancer: does

tumor biology affect accuracy? Ann Surg Oncol 2011;18:3149-3154.

Ko ES, Han BK, Kim RB, et al. Analysis of factors that influence the accuracy of Magnetic Resonance Imaging for

predicting response after neoadjuvant chemotherapy in locally advanced breast cancer. Ann Surg Oncol 2013;

20:2562-2568

Kang DK, Kim TH, Han TS, et al. Magnetic Resonanace Imaging enhancement features before and after

neoadjuvant chemotherapy in patients with breast cancer: a predictive value for responders. J Comput Assist

Tomogr 2013; 37:432-439

Williams M, Eatrides J, Kim J, et al. Comparison of breast magnetic resonance imaging clinical tumor size with

pathologic tumor size in patients status-post neoadjuvant chemotherapy. Am J Surg 2013:206:567-573.

Hylton NM, Blume JD, Bernreuter WK, Pisano ED, et al. Locally advanced breast cancer: MR imaging for prediction

of response to neoadjuvant chemotherapy- results from ACRIN 6657/I-SPY trial. Radiology 2012;263(3):663-672.

Ojeda-Fournier H, de Guzman J, Hylton NM. Breast magnetic resonance imaging for monitoring response to

therapy. Magn Reson Imging Clin N Am 2013;21(3):533-46.

Andrade WP, Lima ENP, Osorio CABT, et al. Can FDG/PET predict early response to neoadjuvant chemotherapy in

breast cancer? EJSO 2013;39:1358-1363.

•

•

•

•

•

•

•

•