Mark Clemens, MD Breast Implant Associated – ALCL MD Anderson Cancer Center Experience FDA Advisory Panel March 25, 2019 Mark W. Clemens, MD, FACS Associate Professor MD Anderson Cancer Center
Mark Clemens, MD Disclosures Mentor Corporation: Clinical investigator for Athena Trial Establishment Labs: Clinical investigator for US Safety/Efficacy Trial Allergan Corporation: Former Consultant 2012 ‐ 2015, Travel expenses for an educational meeting Committee Author, National Comprehensive Cancer Network (NCCN) Lymphoma Guidelines
Mark Clemens, MD Comparison of Databases • Short time interval to development of disease is 2.2 years from implantation • Average time to develop disease 8 ‐ 10 years
Mark Clemens, MD Comparison of Databases • By WHO criteria, are all CD30+ ALK – • CD30 is screening test, ALK differentiates from systemic ALCL
Mark Clemens, MD Comparison of Databases Comparison of PROFILE Data to Published FDA Data • Most common presentation delayed seroma (>1 year) • No testing/screening of asymptomatic patients
Mark Clemens, MD Comparison of Databases Comparison of PROFILE Data to Published FDA Data • No only ‐ smooth implant cases within PROFILE, MDACC, or case series • Even mix of cosmetic/augmentation and silicone/saline
Mark Clemens, MD Smooth Implant ‐ Only Cases?
Mark Clemens, MD No Confirmed Pure Smooth Cases To Date Out of 359 adverse event reports, 28 reports of “smooth implants” cases. Smooth implant reports had either no clinical history or a very superficial unreliable history. 70 to 80 percent of implants sold in North America are smooth. No cases of ALCL were found in patients with documented smooth devices only. 3 Age 71: left breast cancer (1980), treated with radiotherapy and reconstructive breast surgery (device unknown). Right breast cancer (1990) treated with mastectomy and reconstructive surgery (device unknown). 1 58 ‐ year ‐ old woman who had undergone bilateral cosmetic breast augmentation with a smooth silicone gel breast implants 19 years previously. In 2006, her device had already been replaced for the same complication. 2 1. Largent J, et al. Eur J Cancer Prev 2012, 21:274–280; Lazzeri D, et al. Clin Breast Cancer 2011;11(5):283–96; 3. Brody GS, et al. Plast Reconstr Surg 2015; 135:695–705.
Mark Clemens, MD Prosthesis ‐ associated? • Tibial Implant • Dental implant ALCL 2 • Chest port ALCL 3 • Shoulder repair ALCL • Lap Band ALCL • Gluteal Implants x 2 Tibial implant ALCL 1 Dental implant ALCL 2 1. Palraj B, et al. J Foot Ankle Surg 2010;49:561–4; 2. Yoon HJ, et al. Int J Surg Pathol 2015;23:656–61; Chest port ALCL 3 3. Engberg A, et al. J Clin Oncol 2013;31:e87–e89. 4. Kellogg B et al. Annals Plastic Surgery 2013; 73(4).
Mark Clemens, MD Comparison of Manufacturers MD Anderson 2019 Tracking ‐ US 1 Adapted Brody MAUDE FDA 2017 Database 1,2 2015 ‐ World 2 85% US, 15% OUS* Manufacturer n % Manufacturer n % Manufacturer n % Unknown 68 44.7 Unknown 61 35 Allergan/ 78 51.3 Unknown 22 9.6 Allergan/ 97 56 Inamed/ Inamed/ Allergan/ 184 80.3 McGhan McGhan Inamed/ Mentor 6 3.9 McGhan Mentor 3 1.7 Bioplasty 1 0.6 Mentor 20 8.7 Biocell: Biocell: Nagor 3 1.7 Biocell: Silimed PU 1 0.6 CUI 1 0.4 Eurosilicone 0 0 8.3x Vs. All Other 7.1x Vs. All Other 8.1x Vs. All Other Sientra 3 2.0 Sientra 1 0.4 PIP 5 2.9 9.2x vs. Siltex 13x vs. Siltex 32x vs. Siltex Total 228* Sientra/Silimed 1 0.5 Total 152 *Unverified, unconfirmed Total 170 1. Clemens MW, et al. Gland Surgery 2016; doi: 10.21037/gs.2016.11.03; 2. Brody GS, et al. Plast Reconstr Surg 2015;135:695–705.
Mark Clemens, MD CA/CARE Style 410 (Biocell) Prospective Trial • McGuire et al. 2017 • 17,656 patients • 31,985 implants 1 • 8 BIA ‐ ALCL 2 : 1:2207 (95%CI:1120,5112) 1. McGuire P, et al. Plast Reconstr Surg 2017;139:1–9; 2. Clemens MW, McGuire P. Commentary on: Roberts JM et al. A Prospective Approach to Inform and Treat 1,340 Patients at Risk for BIA ‐ ALCL. Plast Reconstr Surg 2019, In press
Mark Clemens, MD Biocell Recall • November 21: ANSM recommends against textured implants • December 17, 2018: CE mark withdrawal and voluntary recall for Biocell and Microcell products • 38 countries: Europe, Israel, Brazil, Russia, Australia • “Allergan cites an incomplete routine review and renewal of the file”
Mark Clemens, MD Global Risk Estimates • US: 1:19,737 (152 cases, 2019) • Mixed market Allergan:Mentor • Netherlands 1:6920 (40 cases) • Textured market • Australia, New Zealand (95 2 cases) 1,2 – Textured Market • Risk 1:1000 ‐ 1:10,000? 1 for textured implants • Allergan Biocell (1:3345) • Silimed polyurethane (1:2832) • Mentor Siltex (1:86029) • 25.7 to 1 ratio of Biocell to Siltex BIA ‐ ALCL risk 1. Therapeutic Goods Administration update, 20 December 2018; 2. Magnusson M, et al. The epidemiology of breast implant–associated anaplastic large cell lymphoma in Australia and New Zealand confirms the highest risk for grade 4 surface breast implants. Plast Reconstr Surg. 2019;143:
Mark Clemens, MD 35 countries Japan: 0 BIA ‐ ALCL Global Mexico: 4 Cases Argentina: 8 cases, 1 death Network Roundtable Netherlands: 40 c, 1 Death Australia: 82 Cases, 3 deaths New Zealand: 13 c, 1 death Belgium: 10 Cases Norway: 3 cases 427 OUS World Cases, Brazil: 12 Cases, 1 death Romania: 0 Unique and pathology Canada: 25 Cases Russia: 2 cases confirmed Chile: 2 Cases Singapore: 0 19 Deaths Worldwide China: 0 South Africa: 1 Case Colombia: 6 Cases South Korea: 0 Czech Republic: 1 case Spain: 29 Cases Denmark: 7 Cases Sweden: 6 Cases, 2 death Egypt: 1 case Switzerland: 4 cases Finland: 10 Case Taiwan: 0 France: 59 Cases, 4 deaths Thailand: 1 Case Germany: 7 cases Venezuela: 2 cases Ireland: 1 case United Kingdom: 45 Cases, 1 death Israel: 8 Cases United States: 152 cases, 5 Italy: 38 Cases deaths
Mark Clemens, MD Published This Month – March 2019 • Supplements in ASJ and PRS journals • 55 authors, 16 peer ‐ reviewed articles on BIA ‐ ALCL Garry Brody Dennis Hammond Andrea Pusic Andrew Feldman Mark W. Clemens Steven Horwitz Gayle Gordillo Eric D. Jacobsen Anand K. Deva Meredith Collins Hinne Rakhorst Greg Lamaris John A. Keech L. Jeffrey Medeiros Tony Connell Ali Qureshi Colleen McCarthy Daphne deJong Kelly Hunt Ahmet Dogan Roberto N. Miranda Charles E. Butler Suzanne Turner Mark Magnusson Marshall Kadin Miles Prince Arianna DiNapoli Peter Lennox Nadim Hallab
Mark Clemens, MD
Mark Clemens, MD
Mark Clemens, MD NCCN Guidelines 1 • Internationally recognised algorithms for the diagnosis and treatment of cancer • Utilized by the majority of oncologists • Adopted by international societies 1. Clemens MW, Jacobsen ED, Horwitz SM. Aesthet Surg J 2019
Mark Clemens, MD 2019
Mark Clemens, MD 2019 BIA ‐ ALCL Diagnosis Symptoms Breast Imaging Finding Effusion Effusion,mass, FNA fluid Ultrasound skin rash/ulcer (>50ml) Or MRI >1year implant Mass Incisional/core (Average 8 ‐ 10y) needle bx mass Inconclusive Further imaging • Effusion 79.3% • Mass 40% • Capsular contracture 8% • Skin rash 2% • Lymphadenopathy 8%
Mark Clemens, MD 2019 Pathology Workup Path Workup Path Results Essential for Dx Indeterminate ‐ 1. Cytology ‐ 2. Flow Negative for cytometry for T Lymphoma cell clone (Normal cells, ‐ 3. IHC for CD30 Scant CD30) Additional CD30 IHC differentiation Confirmation of markers: CD2, Anaplastic cells BIA ‐ ALCL CD3, CD4, CD5, CD7, CD8, CD45, ALK T ‐ cell clone
Mark Clemens, MD Case study: Benign Seroma Vs. BIA ‐ ALCL 3 Normal 4 Benign seroma Wright Giemsa Stain: Lymphocytes/histiocytes 4 CD30 IHC 4 BIA ‐ ALCL Wright Giemsa Stain: anaplastic large cells 3 CD30 IHC 3 Images courtesy of Dr Mark Clemens. 1. Clemens MW, et al. Gland Surg 2017;6:169–84; 2. Personal communication, Dr Mark Clemens, May 2017. 3. NCCN Guidelines. Breast implant ‐ associated ALCL Version 2.2017; 4. Clemens MW, Miranda RN. Aesthet Surg J 2017. doi: 10.1093/asj/sjx040; 4.
Mark Clemens, MD Disease Workup 2019 Treatment BIA ‐ ALCL Disease Workup Surgery H&P En bloc resection: Labs: CBC with diff Total capsulectomy CMP, LDH Explantation Imaging: PET/CT scan Exc mass Recommend multidisc team Exc biopsy node(s) Oncologist lymphoma Consider contralateral Surgical oncologist Consider delayed or Plastic Surgery immediate recon Hemepathologist
Mark Clemens, MD BIA ‐ ALCL As Two Distinct Diseases? • Laurent 2016 • Effusion ‐ limited (in situ) versus massively infiltrative • Based on pathology review 19 BIA ‐ ALCL patients to Lymphopath
Mark Clemens, MD Solid tumor progression 1 1. Effusion only: • 35% of cases • Lymphoproliferative disorder Lymphoma cell 1 2. Cell penetration 2 into capsule: 11% 3 3. Aggregation into mass: 13% Luminal side 4. Mass infiltration Breast 4 2 tissue through capsule: 25% of capsule 5 5. Lymph node mets: 14% 6 6. Organ mets: 3% Thickened 6 Lymph node capsule invasion 5 4 3 BIA ‐ ALCL behaves like a SOLID tumour (like lung or breast cancer) and therefore treated surgically 1 1. Personal communication, Dr Mark Clemens, May 2017. Images courtesy of Dr Mark Clemens.
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