Screening with New Modalities: Breast Ultrasound

Wendie A. Berg, MD, PhD Professor of Radiology

Magee-Womens Hospital of UPMC University of Pittsburgh School of Medicine

Disclosures

No personal financial conflicts of interest Philips Healthcare loaning equipment for

ultrasound clinical trial

Objectives Describe effect on cancer detection from adding

screening US to mammography or tomosynthesis in women with dense breasts

Discuss sources of false positives on screening US and ways to reduce them

Compare outcomes from different methods of screening breast US

Evidence Supporting Screening

Disease-specific mortality reduction Only studied for mammography

Reduction in node-positive disease Increase in node-negative invasive cancers

Reduction in interval cancers Fewer than 10% of all cancers diagnosed

Failure Analysis Webb ML et al Cancer 2013, epub 9/11/13 7301 invasive breast cancer dx 1990-1999 f/u 2007 609 breast cancer deaths; median age 49 yr at dx 29% ca deaths were among women screened

19% screen detected 10% interval cancers

71% deaths among unscreened women

Interval Cancer Cancer dx by clinical symptoms in interval

between recommended screenings Worse prognosis and worse outcome

~1/2 deaths in screened women diagnosed in

their 40s are due to interval cancers

Mammography Failure Analysis

#1 If not performed at all #2 High-risk women #3 Dense breasts

BI-RADS® Density

A. Almost entirely fatty B. Scattered fibroglandular density C. Heterogeneously dense which could

obscure detection of small masses D. Extremely dense, which lowers the

sensitivity of mammography

Breast Density as Function of Age

Kerlikowske et al. JNCI 2007; 99:386-395

40% of women of mammographic age have dense breasts

Masking of cancers with increasing breast density

Increased risk of developing breast cancer

Interval Cancers and Breast Density Density Odds Ratio 95% CI < 10% 1.0 - 10-24% 2.1 (0.9, 5.2) 25-49% 3.6 (1.5, 8.7) 50-74% 5.6 (2.1, 15.3) ≥ 75% 17.8 (4.8, 65.9)

p < .001 Boyd NF, et al. NEJM 2007;356:227-36

Referent “Average” Pt, Hazard Ratios

A B C D Premeno 0.46 1 1.62 2.04 Postmeno no HT 0.57 1 1.35 1.51 Postmeno E+P 0.45 1 1.58 2.09

Kerlikowske K et al J Clin Onc 2010;28:3830-3837

Increased Deaths Chiu SY et al. Cancer Epidemiol Biomarkers Prev 2010;19:1219-28

25 yr f/u Sweden 15,658 women 45-59 12.7% had dense breasts

Increased breast cancer mortality with dense breasts RR 1.91 (95%CI 1.26-2.91) Attributed to higher incidence Shorter sojourn time

www.DenseBreast-info.org 3/13/16

24 States require some sort of density notification

Possible tests to add to mammography Modality vs. Mammography alone

Absolute ↑ Cancer Detection per 1000 screens

Clinical breast exam 0.3 Double Read or CAD 1 Tomosynthesis 1-2 Ultrasound 3-4 Molecular Breast Imaging, CEDM

7-8

MRI 10 Copyright Wendie Berg, MD, PhD

Unable to Tolerate MRI: ACRIN 6666

18.5% (1 in 5.4) (95% CI 16.4 to 20.8%) women who had completed 3 years of screening with US and mammography were unable to undergo an MRI

Berg WA et al. Radiology 2010;254:79-87

Ultrasound

No radiation Not limited by dense tissue No injection of contrast or radioactive

material Inexpensive

US to Replace Mammo? Berg WA et al JNCI 2016; 108, epub 12/18/15 111 breast ca dx among 2809 women ACRIN 6666 129 US to detect one cancer, 127 for mammo Of 89 invasive cancers, 53 (60%) seen on US vs. 41

(46%) on mammography, p = .11 More likely node negative when found by US: 34/53

(64%) vs. 18/41 (44%), p = .003

US but not Mammo Inv Ca Detection Density, % US Mammo US, not

Mammo ≤ 25 0/1 (0) 0/1 (0) 0/1 (0) 26-40 6/10 (60) 6/10 (60) 2/10 (20) 41-60 16/30 (53) 17/30 (57) 8/30 (27) 61-80 22/36 (61) 13/36 (36) 14/36 (39) >80 9/12 (75) 5/12 (42) 6/12 (50) P trend .23 .19 .06

Berg WA et al JNCI 2016; 108, epub 12/18/15

False Positives Over 3 Years US Mammo P-value

Recall Rate 515 (10.7%) 453 (9.4%) .03 Biopsy Rate 266 (5.5%) 97 (2.0%) <.001 PPV Biopsies 31/266 (11.7%) 37/97 (38.1%) <.001

Berg WA et al JNCI 2016; 108, epub 12/18/15

US and Mammo Complementary

Of 22 DCIS, 18 (82%) seen on mammography vs. 5 (23%) on US, p=.002

Sensitivity of mammography + US 0.76 (0.65-0.85) vs. 0.52 (0.40-0.64) mammo alone (p < .001)

Berg WA et al JAMA 2012;307:1394-1404

48F screening

Courtesy Dr. Wei Yang, MD Anderson

RT CC MAG RT ML MAG Courtesy Dr. Wei Yang, MD Anderson

Stereotactic biopsy: High nuclear grade DCIS solid type with comedo necrosis, with microinvasion, ER, PR-, HER2 +

Skin-sparing mastectomy, 0/4 SLN

Supplemental US

Physician Performed Technologist Performed Automated

Handheld US High-frequency transducer, 12-18 MHz linear array Survey scanning transverse and sagittal Document 1 image per quadrant, 1 behind nipple for

negative exam Lesions (all studies to date): Orthogonal views ±

calipers; optional color or power Doppler image Positive test: BI-RADS 3 or higher assessment, or

recommendation for further imaging (BI-RADS 0)

Author N screens

ICDR per

1000

Recall Rate (%)

Bx Rate (% women)

PPV3 Bx Performed

Corsetti 9157 4.0 NS 449 (4.9) 50/623 (8.0)

Berg yr1 2659 5.3 401 (15.1) 207 (7.8) 14/264 (5.3)

Berg yr2-3 4841 3.7 356 (7.4) 242 (5.0) 21/276 (7.6)

TOTAL 16,657 4.4 10% 898 (5.4) 85/1163 (7.3)

Physician Performed US: Multicenter Results

4.9% of women had biopsies for benign findings

Tech-Performed US (USA): Prevalent Screens

Author N ICDR per 1000

Recall Rate (%) Bx Rate (%) PPV3 Bx Performed

Kaplan, 2001 1,862 2.7 176 (9.5) 97 (5.2) 6/96 (6.3)

Hooley, 2012 648* 4.6 154 (23.8) 46 (7.1) 3/58 (5.2)

Weigert, 2012 8,647 2.8 1,196 (13.8) 429 (5.0) 25/418 (6.7)

Parris, 2012 5,519 1.8 680 (12.3) 185 (3.3) 10/181 (5.5)

Overall 16,676 2.5 2,206 (13.2) 757 (4.5) 47/753 (6.2)

*analysis presented for women with negative screening mammograms

Berg WA and Mendelson EB. Radiology 2014;272:12-27

Recalls: Tech-Performed HHUS 2,206/16,676 (13.2%) test positive on prevalence

screen 1,399 (8.4%) all women BI-RADS 3 757 (4.5%) all women BI-RADS 4

44/753 (5.8%) found to have cancer Only 43/16,676 (0.3%) recalled for additional

evaluation (BI-RADS 0) prior to final assessment

Berg WA and Mendelson EB. Radiology 2014;272:12-27

Disease Prevalence Affects Yield

Moderate Risk* No Known Risks P-value

Kolb 2002 14/2914 (4.8 per 1000) 14/7901 (1.8 per 1000) .011

Crystal 2003

4/318 (12.5 per 1000) 3/1199 (2.5 per 1000) <.04

Overall 18/3232 (5.6 per 1000) 17/9100 (1.9 per 1000)

*Personal hx of breast cancer or first-degree relative with breast cancer vs. no risks

Japan Tohno E et al Breast Cancer 2012;19:138-146 2-day educational program; results of

training/testing for 415 technologists and 422 physicians

Observers worse with experience < 100 cases Video sensitivity, still image sensitivity, and

disease agreement for technologists > for MDs

Node-Negative Invasive Cancers

Across 10 series, 475 cancers seen only on US, 415 (87.4%) invasive

273/303 (90.1%) with staging were node negative

22/91 (24%) ILC

By Participant, Yield/1000, ACRIN 6666

Year M+US M Supp. Yield, 95% CI P-value

1 12.8 7.5 5.3 (2.1, 8.4) .0001

2 10.0 6.4 3.6 (0.9, 6.4) .004

3 13.8 9.9 3.9 (0.9, 6.8) .004

Supplemental yield of US is significant each year and similar for incidence and prevalence screens

Berg WA et al JAMA 2012;307:1394-404

Weigert: Recalls Incidence Screens

Year 1 8647 (12%) women screening US Recall rate 13.8% (n=1196): 767 (8.9%) BR 3; 429

(5.0%) BR 4,5; PPV3 5.6% 24 cancers, CDR 2.8 per 1000

Year 2 10,282 (17.9%) women Recall rate 12.7% (n=1310); CDR 2.3 per 1000 (24)

Year 3 4128 (12.8%) women Recall rate 7.7% (n=316); CDR 2.7 per 1000 (11)

Courtesy WP Evans, III, MD

60F, 5-yr risk 2.5%, 24-mo US: 12 mm grade 1 IDC-DCIS, N0

Radial Antiradial

Courtesy Gary Whitman, MD, MD Anderson

75F personal hx Lt cancer 17 mm grade 3 IDC-DCIS, N0 Seen only on 24-month US Seen in retrospect on mammo

Radial Antiradial

70F personal hx rt mastectomy, BRCA-1 mutation carrier 24 mo screen US+ 19 mm grade 3 IDC-DCIS, N0

Courtesy Dr. Mary Mahoney, U Cincinnati

ACRIN 6666: Breast Density Density n Yield per 1000 P-value

≤ 25% 124 0 26-40% 785 6.4 .026 41-60% 2314 3.0 .008 61-80% 2807 4.3 .0006 >80% 1443 5.5 .005

Berg WA, et al., RSNA 2009

Interval Cancer Rate: ACRIN 6666

Yr N Interval N Cancers (%) 1 2 36 5.6 2 4 29 14 3 3 46 6.5

All 9 111 8.1

Interval Ca Rate: 9/7473 screens = 1.2 per 1000 8% of all cancers

Berg WA et al JAMA 2012;307:1394-404

Interval Cancer Rate Italy

Corsetti V et al Cancer 2011;47:1021-6 Interval cancer rate in fatty breasts

1.0 per 1000

Interval cancer rate in dense breasts after adding screening US 1.1 per 1000

J-START Ohuchi N et al Lancet 2015, epub 11/4/2015 Asymptomatic women aged 40-49 at 42 sites Randomized to M+US or M alone twice in 2 yrs 36,869 to intervention and 36,139 to control

group

Results J-START first round Intervention Control P-value

Sensitivity 91.1 (87.2-95.0) 77.0 (70.3-83.7) .0004

Specificity 87.7 (87.3-88.0) 91.4 (91.1-91.7) <.0001

% Stage 0, I 144/184 (71.3) 79/117 (52.0) .019

Interval Cancers 18 (0.05%) 35 (0.10%) .034

Ohuchi N et al Lancet 2015, epub 11/4/2015

Time to Perform US: ACRIN 6666

Bilateral scan, not including time discussing results with patient nor creation of report

Year Median (min) Mean SD 1 17 19.2 11.9 2 15 16.7 10.4 3 13 14.7 9.2

Reducing False Positives BI-RADS 3 lesions

Prevalence of 15-20% of all patients having screening US in prior series (Barr et al; Hooley et al; Chae et al)

Across all series, only 1 lesion had suspicious change yielding malignancy at 6-mo follow-up

12-month follow-up reasonable

Orthogonal Views

Required for any mass for which future comparison is desirable Not necessary for simple cysts

Incomplete characterization without this

RAD ARAD

Berg WA and Mendelson EB Radiology 2014;262:309-315 Courtesy Dr. Christophe Tourasse

53F Papillary DCIS with microinvasion

Berg WA and Mendelson EB Radiology 2014 2014;262:309-315

50F invasive ductal carcinoma; echogenic rim in arad view only

Cysts ACRIN 6666 1255/2662 (47.1%) women over the three years

998 (37.5%) of 2659 year one 537/1363 (39.4%) post-menopausal participants, had cysts

73 using estrogen replacement 48 (66%) had cysts

1290 no HRT 489 (37.9%) had cysts (p<.0001, less common)

516/793 (65.1%) premenopausal women had cysts (p<.0001)

Berg WA, et al Radiol Clin N Amer 2010;48:931-987

Complicated Cysts ACRIN 6666 376 (14.1%) of 2662 participants

301 (80%) had at least one simple cyst 84 (22%) multiple, bilateral

Overall 2/475 (0.42%) such lesions malignant

Berg WA, et al Radiol Clin N Amer 2010;48:931-987

Complicated Cysts N N Malignant (%)

Kolb et al 1998 126 0 Venta et al 1999 308 1 Buchberger et al 1999 133 0 Berg et al 2003 38 0 Chang et al 2007 35 0 Daly et al 2008 228 1 ACRIN 6666 475 2 TOTAL 1343 4 (0.3)

Berg WA et al Radiol Clin N Amer 2010,48:931-987

Cyst or Solid?

Radial Antiradial 53F incidental finding on US, aspirated, cytology: benign cyst with apocrine cells

Radial Antiradial 51F strong FH, incidental finding on US Aspirated to resolution, thick cloudy yellow fluid, cyst

61F with new mass on mammography, prior ipsilateral cancer

Radial Antiradial

12 month follow-up US enlarged: 14-g US-guided bx papillary DCIS

BI-RADS 3

Chae EY et al AJR 2016;206:666-672 With mammographic abnormality, 4/184

(2.2%) malignant Without mammographic abnormality,

4/980 (0.4%) malignant (p=.025)

Clustered Microcysts 3.9 to 5.8% of US examinations 1/235 (0.4%) malignant across 5 series Mean age 48 years (32-71) Short-interval follow-up if uncertainty Caution if new mass on mammogram, post-menopausal

woman not on HRT May merit biopsy

Berg WA AJR 2005;185:952 Berg WA, et al Radiol Clin N Amer 2010;48:931-987

48F new mass on screening mammogram

60F ipsilateral cancer elsewhere US-guided core biopsy DCIS, intermediate grade

Lesions Synchronous to New Cancer

Kim SJ et al AJR 2008;191:653-8 55/482 (11.4%) BI-RADS 3 lesions

malignant 36/170 (21.2%) in same quadrant as 1º 12/122 (9.8%) in different quadrant 8/190 (4.2%) in contralateral breast

M-B Circumscribed Masses: US Berg WA et al Radiology 2013:268:673-683 2172 women in ACRIN 6666 135 (6.2%) participants had 153 unique findings

described as M-B masses on screening US over 3 annual screens 98 complicated cysts with debris 43 solid, circumscribed, oval masses 7 solid masses with 2-3 lobulations 5 clustered microcysts

No malignancies (95%CI up to 2.4%)

Billing

CPT codes 76641, unilateral complete right 76641, unilateral complete left Medicare reimbursement averages $165 Subject to deductible and copays

Billing

ICD-10 92.2 “Inconclusive mammogram” Applicable to dense breasts, NOS Inconclusive mammogram due to dense

breasts

http://www.icd10data.com/ICD10CM/Codes/R00-R99/R90-R94/R92-/R92.2

A – Tower B – Y-axis Gantry & Transducer Carrier C – X-axis Gantry D – Ultrasound Machine Monitor E – Touch Screen / Monitor F – Transducer Holster G – Patient Bed

Automated Arm US

Automated Arm Results Kelly KM et al Eur Radiol 2010; 20:734-742 4419 women, 6425 exams, 8 facilities

40% women at ≥ intermediate risk 23 cancers mammography 46 cancers M+US Supplemental yield 3.6 per 1000 (95% CI 2.3 to 5.4) 10% recall rate 23/75 (31%) biopsies showed cancer

Automated Breast US 12 MHz 15 cm footprint 3 acquisitions per

breast in ~15 minutes 3D dataset

Transverse Created coronal and

sagittal displays

ABUS Results Brem RF et al Radiology 2015;273:663-673 15,318 women BI-RADS 1 or 2 mammo, dense breasts,

automated whole breast US 30 (2/1000) cancers only by ABUS 25 detailed: 23 (92%) invasive, mean size 13 mm, 18

(78%) of those N0 20/23 (87%) ER+ 3/22 (14%) stage IIB or higher 13% absolute increase in recall rate—immediate

additional evaluation, not a final assessment

HHUS vs. AUS HHUS AUS

Time to acquire images 13 min (but range up to 90)

15 min

Training to “ “ Yes, months, technologist

Minimal

Sensitivity ~85% ~74% Number of images 5-20 1000-1700 Time to interpret < 30 sec 5-10 min Recalls 13%

Final assessment typically rendered

13% Incomplete, needs

targeted US Interobserver Variability Κ = 0.53 (SE 0.02) Κ = 0.04 to 0.50

Is screening ultrasound still of benefit after tomosynthesis?

ASTOUND trial Tagliafico AS et al JCO 2016;epub 3/9/2016 3231 women with dense breasts, negative mammogram,

5 centers in Italy DBT 13 cancers (ICDR 4.0/1000 95%CI 1.8 to 6.2) US 23 cancers (ICDR 7.1/1000, 95%CI 4.2 to 10.0,

p=0.006) False positive recall DBT 53 vs. US 65 (p=0.26)

DBTUST study UPMC Pittsburgh UPMC Hamot, Erie Weinstein Imaging 6200 women DBT and technologist-performed

screening US each year for three years NIH and PABCC funding

Three-Step Implementation

1) Does the woman have at least 10-yr life expectancy? No, then CBE only, with mammography only if

warranted by symptoms

2) Is the patient at “high risk” for breast cancer and under age 70? Yes, then MRI annually beginning:

When ascertained to be high risk Age 25 if BRCA1/2 or other pathogenic mutation 8yr after chest XRT if XRT before age 30

If unable to tolerate MRI, then US

3) Dense? Yes: Supplement annual mammography with

US beginning at age 40-45 No: Tomosynthesis beginning at age 40-45

Mam+US

Mammo

MRI