The Role of Dedicated Single Photon Detectors in Breast Cancer Detection Iraj Khalkhali M.D., F.A.C.R., F.A.C.N.M. Professor of Radiological Sciences David Geffen School of Medicine at UCLA Director, Breast Diagnostic Center Harbor-UCLA Medical Center, Torrance, CA MEDAMI 2014, Sardegna ,Italy

Breast Cancer Screening Modalities Mammography Digital Mammography Tomosynthesis Clinical Breast Exam Breast Self-exam Ultrasonography Magnetic Resonance Imaging Molecular Breast Imaging

Systematic Assessment of Benefits and Risks MEDLINE search from 1960-2014. Overall mortality reduction of BC, 19%. Women in 40’s, only 15%. Women in 60’s, 32%. Risks; 19% of CA in 10-year period are not clinically apparent. Conclusion: Benefit of screening decisions should be individualized based on risk profiles. JAMA. 2014: 311 (13):1327-1335.

Screening Mammography in Older Women PubMed search for 1990-2014. The major risk factor for BC: AGE Age at first birth or age at menarche, less predictive. Recent hormonal exposure & obesity more predictive. No randomized trial enrollment over 74. JAMA. 2014: 311 (13): 1336-1347.

Screening Mammography in Older Women, continued. Potential harms of screening for 10 years after 69, 200/1000 screened have false positive. 13/1000 screened are over-diagnosed, (finding breast cancer that would not have clinically surfaced otherwise). Conclusion: women less than 10 year life expectancy, no mammogram. Over 10 year life expectancy, screening outweighs harm (possibly).

SNM Guideline for Breast Scintigraphy with Breast-Specific Gamma Camera June 4, 2010 SNM Evaluation of patients with recently detected BC. High risk patients for BC. Indeterminate breast abnormalities. Patients with difficult breast imaging. Patients with indication for MRI but unsafe or difficult to do.

Indications of Molecular Breast Imaging – Lahey Clinic Siegal, E. et al. The Breast Jour. 2012; 18 (2): 111-117.

Molecular Breast Imaging- Lahey Clinic Experience In 416 MIBI scans Sensitivity = 93% Specificity = 78.9% Only 2 false negatives Siegal, E. et al. The Breast Jour. 2012; 18 (2): 111-117.

Molecular Breast Imaging Sensitivity of MIBI is the function of tumor size. 97% for tumors 6-9mm. 69% for tumors < 5mm. Brem, R. et al. Breast Journal.

Breast-Specific Gamma Camera Imaging 2004-2012: 19 manuscripts, 3093 patients. 95% of all cancers were detected. Cancer < 1cm sen. : 84% DCIS sen. : 88% ILC sen. : 93% BSGC is as sen. as MRI with spec. 80% Suny et al., Eur J Nucl Med Mol Img 2013; 40: 450-463.

Meta Analysis of 64 Studies with MIBI 5,340 patients Sen. : 85% Spec. : 87% PPV. : 88% NPV. : 82% Accuracy : 86% Schillaci, O., et al. Q J Nucl Med Mol Imaging 2013; 57:340-351.

Can MBI find small breast tumors? These studies were all done in women with known mammographic abnormalities, although as seen here, MBI frequently found additional foci of tumor. We then set out to determine if MBI performed as a screening tool in women with dense breast parenchyma and additional risk factors for breast cancer.

Can these technologies find lesions not visible on mammogram? These studies were all done in women with known mammographic abnormalities, although as seen here, MBI frequently found additional foci of tumor. We then set out to determine if MBI performed as a screening tool in women with dense breast parenchyma and additional risk factors for breast cancer. 2 x 1 cm IDC with multiple satellite lesions confirmed as DCIS at surgery

MBI in the preoperative workup of breast cancer patients Ongoing prospective trial of preop MBI 98 patients accrued to date MBI identified additional disease in 13 cases compared to mammography Surgical management altered in 12 cases

Infiltrating Lobular Carcinoma – index lesion detected on mammography Multifocal cancer detected by MBI and MRI 3585519 cc Screen Mammogram MBI Breast MRI

R CC R MLO R CC R MLO Ultrasound: 2.3 cm irregular hypoechoic mass MBI: Uptake in 2 foci, 2.5 cm and 0.9 cm Mammogram: irregular nodule in upper outer quadrant at site of palpable abnormality satellite Final Pathology: Infiltrating ductal carcinoma, grade III, forming 2 masses: 2.2 cm, and 0.9 cm index MRI: index carcinoma -1.6 x 2.4 cm irregular enhancing mass; satellite lesion - 0.8 x 1.4 cm

Who is “High Risk”? All women are not at high risk! Lifetime risk of one in seven by age 85 14% lifetime risk at age 85 Lower if younger age (2% lifetime risk at age 50) Women with a personal history of breast cancer have ~ 3 fold increased risk “Increased” risk is most published screening MRI studies (> 20% lifetime risk) Known genetic mutation BRCA 1 / BRCA 2 Strong family history First degree relatives, premenopausal onset

Effect of density, p < 0.001 Diagnostic Mammography in the Breast Cancer Surveillance Consortium (BCSG): Modeled Receiver Operating Characteristics (ROC) Curves for Adjusted Breast Density Effect of density, p < 0.001 J Natl Cancer Instit 2002; 94: 1151

Low-Dose MBI for Screening in Dense Breasts Funded by Susan G Low-Dose MBI for Screening in Dense Breasts Funded by Susan G. Komen for the Cure MBI - 240 MBq Tc-99m sestamibi Eligible women: Asymptomatic Presenting for routine screening mammography Heterogeneously or extremely dense breasts >1600 enrolled between 2009-2012 Screening mammogram and MBI read blindly We have completed two large screening studies, both funded by the Komen foundation, comparing screening mammography with screening MBI in women with dense breasts. Dr. Conners will show you some MBI images in a few minutes and explain how this modality compares with other options for supplemental screening in the dense breast. But I’d like to leave you with this summary slide of our data. 19

Example of incident MBI screen at 4 mCi March 2010 MBI with 300 MBq Tc-99m sestamibi July 2012 MBI with 150 MBq Tc-99m sestamibi 18 x 13 mm IDC Mammogram negative “subtle” appearance on US

Diagnostic Performance Characteristics of Screening MMG and MBI at Participant Level Incident MMG No. % Prevalance MBI No. % Sensitivity 5/21 24 17/21 81 Specificity 1465/1639 89 1530/1639 93 Recall rate 179/1649 11 126/1649 8

Case 1: Mammographically Occult Invasive Ductal Carcinoma Dense Breast MMG March 2009 MMG March 2011 MBI March 2011 5282632 – another good example of a large cancer hiding in dense tissue. After this many cases, it’s kind of amazing there are so many in such a small group screened! DO NOT CROP MMG Grade II Invasive Ductal Carcinoma, 1.9 cm

Case 4: Mammographically Occult DCIS MMG January 2010 MMG January 2011 MBI January 2011 Patient unable to have MRI due to implanted device Right Breast: Multifocal DCIS

MBI Screening Data: the Mayo experience Data from ~2700 women with dense breasts Number of cancers detected Sensitivity Cancers detected per 1000 screened Incident Mammography 8/32 25% 3.1 Prevalent MBI 26/32 81% 10.1 Incident Mammography + Adjunct MBI 29/32 91% 11.3 To date, we have screened over 2600 women at Mayo. We have found that the sensitivity of digital mammography is 25% compared to 81% for MBI, and a sensitivity of 91% for the combination. As we’ve seen, the reported sensitivity of mammography varies widely depending on which study you consult in which country. But our study gives us a unique window on the performance of screening mammography for our patients at Mayo Clinic with dense breasts. Put in other words, for women with dense breasts presenting for screening mammography at Mayo, the detection rate for breast cancer is 1 out of 4 tumors. And these tumors were not all small tumors that could be dismissed as overdiagnosis or could wait until next year for detection – rather, the median tumor size exceeded 1 cm, with a range of 4 mm to over 6 cm. It is essential to point out that this is not a problem with the radiologists – who in my opinion are the best in the field. Rather, this is an inherent limitation of the technology in the dense breast. So – I would like to introduce my research collaborator, Dr. Amy Conners, who will discuss the relative advantages and disadvantages of the current options to improve detection of breast cancer in the dense breast. Median size of tumors not detected on mammography = 12 mm (range 4-62 mm)

Comparing Screening Modalities in the Dense Breast Imaging Modality Additional diagnostic yield /1000 Recall rate for additional imaging Biopsy rate (% of total screened) PPV (% biopsies +ive for cancer) Mammogram* 3 10 % 1 % 4 % Tomosynthesis ? ~5-7% US (Conn. Study)** 25 % 5 % 6 % US (ACRIN 6666)*** 5 21 % 9 % MBI* 10 8 % 3 % 13 % MRI*** 15 26% 23% MRI calculated by subtracting 6.2 from 13.2 MBI from our data: Recall rate: Study 1 – 71/936 Combined = 9.5% Study 2 – 175/1639 Biopsy rate: Study 1 – 36/936 Combined = 3.3% Study 2 – 49/1639 Mammogram from our data: Recall rate 10.2% Biopsy rate: Study 1 – 17/936 Study 2 – 19/1639 CT US data: Had to base it on final assessment rather than assessment of US alone b/c that was not reported Adding BI-RADS 3-4 (there were no 5) = 187+47/935 = 25% Biopsy (per patient) = 47/935 = 5.0% PPV = 3/47 = 6/4% * Based on data from Mayo screening trial comparing mammogram and MBI ** Hooley et al. Screening US in Patients with Mammographically Dense Breasts: Initial Experience with Connecticut Public Act 09-41. Radiology 2012. ***Berg et al. Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk. JAMA 2012. 25

Frequency of Screening Mammographic Results and Beast Cancer BI-RADS Assessment Assessment Percent of Mammogram Breast Ca Risk 1 or 2 Negative or benign finding 87-93 0.0005-0.001 3 Probably benign finding 1-2 0.003-0.018 Need additional imaging evaluation 6-8 0.02-0.10 4 Suspicious abnormality 0.3-1.4 0.10-0.55 5 Highly suggestive of malignancy 0.1 0.6-1.0 Kerlikowske Ann Intern Med 2003; 139: 274

Future Direction Toward Screening, I New Radiopharmaceutical Dedicated N.M. breast fusion imager with co-registration with FFDM, Tomo, UT, and MRI. Adequate breast compression. Development of robust core BX devices for N.M.

Future Direction Toward Screening, II Understanding of false positive and false negative results. Tissue culture, specimen imaging after biopsy and high risk lesions, etc. Conducting large scale clinical trials. Allocation $$$/€€€!!