META-ANALYSIS ON THE DIAGNOSTICS ACCURACY OF DIFFERENT SCREENING MODALITIES IN LOW AND HIGH RISK OF

Akriti Chahar, Mohammad Zoheb, Shashwat Sharma, Mohammad Ameel, Ajai Basil, Anjaney, Vigneshwaran, SB Sinha

Division of Healthcare Technology National Health Systems Resource Centre (NHSRC), New Delhi

BACKGROUND

¨ Breast cancer is the most commonly occurring cancer among females in the world (American Cancer Society). ¨ Estimated 627,000 women died from breast cancer in 2018 (WHO, 2018). ¨ Annual incidence of breast cancer is approximately 1,44,000 making it most commonly occurring cancer in females in India (WHO, 2012). Screening Modality: ¨ - X ray technique that captures the image of the breast on an x – ray film. ¨ Clinical Breast Examination – Clinical Examination of breast by a trained Healthcare professional to detect any lumps or warning signs of breast cancer. ¨ – Uses sound waves to produce images of the breast. ¨ Magnetic Resonance Imaging – An imaging technique in radiology. Used to visualize internal structures in detail by using magnetic radiation. ¨ Piezoelectric finger – Works on the technique of piezoelectric palpitation to enhance the Clinical Breast Examination Objective

To assess diagnostic accuracy of different screening modalities in women at low and high risk of breast cancer.

PICO

• Population: Women

• Intervention: CBE, Mammography, MRI, Piezoelectric finger, Ultrasonography

• Comparator: No screening

• Outcome: Diagnostic Accuracy

PRISMA Flowchart Summary of characterstics of the included studies

S.N Author, Year Country, No. Women Mean Study Population of o of sites (completed Age, Design Interest screening) Years (Range) 1. Broach, 2016 USA 78 42 (21-79) Prospective Adult patients cohort study presenting for diagnostic work up 2. Kuhl, 2005 Germany 529 41.7 (27 – 59) Prospective Lifetime risk> 20 % observational based on family history cohort study 3. Ozulker, 2010 Turkey 46 46.1 ± 13.31 Prospective Women with suspicious (22 – 82) cohort study lesions detected in their by palpitation, imaging modalities or clinically 4. Pediconi, Italy 238 47.5 ± 9.3 (16 – Retrospective Women with dense 2009 77) cohort study breast parenchyma who were suspicious for breast cancer Summary of characterstics of the included studies

S.No Author, Year Country, Women Mean Age, Study Population of No. of sites (complete Years (Range) Design Interest d screens) 5. Riedl, 2016 Austria 559 Median 44 (22 Prospective * BRCA1 or BRCA2 – 83) non – mutation *Lifetime randomized risk>20 % comparison study 6. Schwarz, Germany 99 Median 50 (30 Prospective Patients underwent 2010 – 66) multicentre one or more breast trial imaging modalities before in addition to clinical examination

7. Somashekhar, India 916 Women above Prospective Asymptomatic 2016 40 and under three arm women 40 triple blinded comparative study Summary of characterstics of the included studies

S.No Author, Country, No. Women Mean Age, Study design Population of interest Year of sites (complete Years d screens) (Range)

8. Vassiou, Greece 69 53 (39 – 68) Prospective Women with focal breast 2008 comparative lesions study

9. Warner, Canada 236 46.6 (26.4 – Prospective Women with BRCA 1 or 2004 64.8) observational BRCA 2 mutations who study underwent 1 to 3 annual screening examination

10. Weinstei USA 609 Median 49 Prospective multi Asymptomatic high –risk n, 2009 – modality cohort women study

11. Malur, Germany 413 58 (19 – 85) Prospective Abnormal breast findings 2000 cohort study Summary of characterstics of the included studies

S.No Author, Year Country, No of Women Mean Study Population of sites (completed Age, designs interest screens) Years (Range) 12. Huang, 2012 China 3028 25 years or Randomize Females seeking older d organized and controlled opportunistic trials screening women with existing untreated malignancies, known metastatic disease or psychiatric condition 13. Sankarnaraya India 50366 30 – 69 years Cluster Healthy women n, 2011 randomize aged 30 – 69 d years with no controlled history of breast trial cancer Methodological quality of the included studies – Risk bias and applicability concerns graph

Fig: Risk of bias and applicability CLINICAL EFFECTIVENESS REVIEW Table: Diagnostic accuracy of single and combined screening modalities obtained from the results of systematic review and meta – analysis.

Screening Positives Negatives Sensitivity Specificity Predictive value modalities (95 % CI) (95 % CI) True False True False Positive Negative (95 (95 % CI) % CI) Ultrasonography 379 357 6320 136 0.730 (0.657 – 0.946 (0.948 0.51 0.97 0.794) – 0.9444) Mammography 361 273 6356 144 0.715 (0.673 – 0.959 (0.954 0.56 0.97 0.754) – 0.963) MRI 438 346 3313 52 0.894 (0.863 - 0.905 (0.895 0.55 0.98 0.920) – 0.915) CBE 127 2881 5043 47 0.730 (0.657 – 0.946 (0.948 0.04 0.99 8 0.794) – 0.944) Piezoelectric 183 119 933 35 0.839 (0.784 – 0.887 (0.866 0.62 0.96 finger 0.886) – 0.905) MMG paralleled 130 226 2533 6 0.956 (0.906 – 0.918 (0.907 0.36 0.99 with MRI 0.984) – 0.928)

MMG paralleled 119 285 5465 50 0.704 (0.629 – 0.950 (0.945 0.29 0.99 with USG 0.772) – 0.956)

MRI paralleled 36 162 1163 4 0.90 (0.76 – 0.88 (0.86 – 0.18 0.99 with USG 0.97) 0.89) CLINICAL EFFECTIVENESS REVIEW

Screening Positives Negatives Sensitivity Specificity Predictive value modalities (95 % CI) (95 % CI) True False True False Positive (95 Negative % CI) (95 % CI) CBE paralled 30 36 2959 3 0.91 0.99 0.90 0.99 by USG (0.76-0.98) (0.98 – 0.99) CBE followed 20 10 2985 13 0.61 (0.42 – 1.00 (0.99 – 0.66 0.99 by USG 0.77) 1.00) CBE followed 23 17 2978 10 0.70 (0.51 – 0.99 (0.99 – 0.57 1.03 by MMG 0.84) 1.00)

USG paralleled 30 36 2959 3 0.91 (0.76 – 0.99 (0.98 – 0.90 0.99 with CBE 0.98) 0.99)

MMG 28 60 5 2935 0.85 (0.68 – 0.98 (0.97 – 0.84 0.99 paralleled with 0.95) 0.98) CBE Sources: 1. WHO, Radhakrishnan et al, 2018 (Role of MRI in ) & Broach RB 2016, (A cost effective handheld device breast scanner for use in low – resource environments). 2. Broach RB, Geha R, Englander BS, Delacruz L, Thrash H and Books AD (2016), A cost-effective handheld breast scanner for use in low – resource environments: a validation study, World Journal of Surgical 14:277, DOI 10.1186/s12957-016-1022-2 Health Technology Assessment of medical devices, WHO Medical Device Technical series 3. Kuhl CK, Schrading S, Leutner CC, Spitz NM, Wardelmann E, Fimmers R, Kuhn W and Schild HH (2005), Mammography, Breast Ultrasound, and Magnetic Resonance Imaging for Surveillance of Women at High Familial Risk for Breast Cancer, Journal of Clinical Oncology, DOI: 10.1200/JCO.2004.00.4960 4. Ozulker T, Ozulker F, Ozpacaci T, Bender O, Degirmenci H (2010), The efficacy of 99m Tc – MIBI scintimmammography in the evaluation of breast lesions and axillary involvement: a comparison with X – rays mammography, ultrasonography and magnetic resonance imaging, Hell J Nucl Med; 13 (2): 144 – 149 5. Pediconi F, Catalano C, Roselli A, Dominelli V, Cagioli S, Karatasiou A, Pronio AM, Kirchin MA and Passariello R (2009), The Challenge of Imaging Dense Breast Parenchyma, Is Magnetic Resonance Mammography the Technique of Choice? A Comparative study with X-Ray Mammography and Whole – Breast Ultrasound, Invest Radiol; 44: 412 – 421. 6. Riedl CC, Luft Nikolaus, Bernhart C, Weber M, Bernathova M, Tea M-K M, Rudas M, Singer CF and Helbich TH, Triple – Modality Screening Trial for Familial Breast Cancer Underlines the importance of Magnetic Resonance Imaging and Questions the Role of Mammography and Ultrasound Regardless of Patient Mutation Status, Age, and Breast Density, Journal of Clinical Oncology, Vol 33, No. 10, DOI: 10.1200/JCO.2014.56.8626 7. Schwarz JD, Tiling R, Sassen SA, Mahner S, Lebeau A, Weber C, (2010) Schwaiger M, Janicke F, Untch M and Avril N, Assessment of residual tumour by FDG- PET: conventional imaging and clinical examination following primary of large and locally advanced breast cancer, British Journal of Cancer, 102, 35 -41.8. 8. Somashekhar SP, Vijay R, Ananthasivan R, Prasanna G (2016), Non-invasive and low – cost technique for early detection of clinically relevant breast lesions using a handheld point of care medical device (iBreast Exam): Prospective three – arm triple – blinded comparative study, Indian Journal of Gynecol Oncolog 14:26. 9. Vassiou K, Kanavou T, Vlychou M, Poultsidi A, Athanasiou E, Arvanitis DL and Fezoulidis IV (2009), Characterization of breast lesions with CE – MR multimodal morphological and kinetic analysis: Comparison with conventional mammography and high – resolution ultrasound, European Journal of Radiology 70, 69 – 76 Warner E, Plewes D.B, Hill K.A, Causer P.A, Zubovits J.T, Jong R.A, Cuturara M.R, Deboer G, Yaffe M.J, Messner SJ, Meschina WS, Piron CA and Narod SA (2004), Surveillance of BRCA1 and BRCA2 mutation carriers with Magnetic Resonance Imaging, Ultrasound, Mammography, and Clinical Breast Examination, JAMA, Vol 292, No. 11 10. Weinstein SP, Localto R, Conant EF, Rosen M, Thomas KM and Schnall M.D, (2009), Multimodality screening of high – risk women: A prospective cohort study, Vol 27. No. 36 11. Malur S, Wurdinger S, Moritz A, Michels W and Schneider A (2000), Comparison of written reports of mammography, sonography and magnetic resonance mammography for preoperative evaluation of breast lesions, with special emphasis on magnetic resonance mammography, Breast Cancer Res, 3:55 – 60 12. Huang Y, Kang M, Li H, Li J.Y, Zhang J.Y, Liu L.H, Liu X.T, Zhao Y, Wang Q, Li C.C and Lee H (2012), Combined performance of physical examination, mammography, and ultrasonography for among Chinese women: a follow – up study, Curr Oncol, Vol 19, pp eS22-30. 13. Sankaranarayanan R, Ramdas K, Thara S, Muwonge R, Prabhakar J, Augustine P, Venugopal M, Anju G and Mathew BS (2011), Clinical Breast Examination: Preliminary Results from a Cluster Randomized Controlled Trial in India, J National Cancer Inst;103:1476-1480. 14.Okonkwo QL, G Drasima G, der Kinderen A, Brown ML, de Koning HJ (2008), Breast cancer screening policies in developing countries: a cost – effectiveness analysis for India, J Natl Cancer Inst. 2008 Sep 17;100(18):1290-300. 15. Laxminarayan R, 2006, Chapter 2, Intervention cost – effectiveness: overview of main messages, Disease control priorities in developing countries 2nd edition

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