Cryoablation in the Management of Early Stage Breast Cancer

13 th Annual Pacific Northwest Breast and Gynecologic Care Conference Cryoablation in the Management of Early Stage Breast Cancer Dennis R. Holmes, M.D., Inc. Int. Director, Margie Peterson Breast Center St. John s Health Center Int. Director, Breast Surgery Fellowship Program John Wayne Cancer Institute Santa Monica, CA

Disclosure Sanarus Technologies, Inc. Research Support Consultant Agendia, Inc. In-kind

Overview Discuss Concept of Cryoablation Technical Aspects ACOSOG Z1072 FROST Trial Cryoimmunology

Kamogawa, Japan

Eisuke Fukuma, M.D. (Kamogawa 2009)

Kameda Medical Center Experience (Fukuma) Indications Luminal A Invasive Breast Cancer <15 mm Sentinel node negative Breast Tumor Cryoablation instead of lumpectomy Breast Radiotherapy Endocrine therapy Primary Endpoint: Local recurrence

Lizhi Niu, M.D. Kecheng Xu, M.D.

Cancer Cryosurgery with Cryo Immunology: Today & Tomorrow: Based on Experience of 8000 Cases in a Single Hospital Pancreas Lung Kidney Sarcoma Breast Cancer

Nikolai Korpan, MD Kecheng Xu, MD

Cryoablation Cryo (Ancient Greek) (Kruos, icy cold, chill, frost ) Ablate (Latin) (ablatum, to remove ) Use of extreme cold to destroy tissue.

Cryoablation NCCN guidelines Liver Pancreas Kidney Skin Colon Breast 10 years for fibroadenomas Primary barrier: Cultural

Cryoablation: Mechanism of Action 1. Intracellular Ice formation 2. Osmotic Effect 3. Microvascular damage

American College of Surgeons Oncology Groups ACOSOG Z1072 Clinical Trial Infiltrating Ductal Carcinoma 2 cm 28 days 7-14 days n=99 2 cm MG, US, MR Ultrasound-Guided CRYOABLATION (V2) MRI EXCISION Blood Samples * *

Liquid-Nitrogen Based System Liquid Nitrogen-Based

Cryoprobe 3.4 mm diameter 12.5 cm

Cryoablation Goal: Ablation of 10 mm margin Cancer Cryoprobe Probe 1.0-1.5 cm -185 1 C 10 mm 3-5 cm Iceball

Ultrasound-Guided Cryoablation Cryoprobe Cancer

Ultrasound-Guided Cryoablation with hydrodissection Under Local Anesthesia

Cryoablation of Breast Cancers

ACOSOG Z1072 Results

ACOSOG Z1072 Conclusions Cryo was 100% successful for tumors <1.0cm Cryo was 92% successful for tumors 2cm Multifocal diseases may limit efficacy of cryoablation as stand-alone procedure MRI has 81% Negative Predictive Value Absence of enhancement does not exclude residual disease Presence of enhancement does not indicated presence of residual disease Systemic immune response studies: pending

Which patients are candidates for Breast Cancer Cryoablation as Stand Alone loco-regional therapy?

Rationale Many cancers are not aggressive, and may not require removal Radiation is not required for all patients with invasive breast cancer Lymph node surgery may not be required for all patients with invasive breast cancer Many patients refuse surgery and radiation

F.R.O.S.T. TRIAL Freezing Alone Instead of Resection Of Small Breast Tumors Phase II Single-Arm Study of Cryoablation in the Management of Early Stage Invasive Breast Cancer: A Multicenter Study P.I. Dennis R. Holmes, M.D. Sponsor: Sanarus Technologies, Inc.

F.R.O.S.T. Trial Key Questions Can cryoablation eliminate the need for lumpectomy and radiotherapy? Can we use a core biopsies 6 months after cryoablation to assess the effectiveness of cryoablation? Can sentinel node biopsy be omitted in a subset of patients?

Early Studies of Breast Cancer Cryo J Vasc Interv Radiol 2015;26:1652-1657 Small lesions Clear imaging (US and MRI) Invasive Ductal CA Low % of DCIS

Patient Selection F.R.O.S.T. Trial Inclusion Criteria Age 50 years Invasive ductal carcinoma 1.5 cm Unifocal ER+ (>10%) or PR+ (>10%) HER2/neu negative No Extensive DCIS <25% DCIS on core biopsy Well-visualized by US and MRI

ELIGIBILITY Omission of Radiation CALGB 9343 CALGB 9343 Comparison of Lumpectomy Plus Tamoxifen With and Without Irradiation in Women 70 or Older with Clinical Stage I, ER+ Breast Carcinoma Age > 70 Clinically Node Negative Lumpectomy, Negative Margin Tumor size 2 cm STRATIFICATION Age < 75 75 SNB/ALND Yes No R A N D O M I Z E Radiation + Tamoxifen Tamoxifen ER+ (Luminal A/B)

CALGB 9343 CALGB 9343 CALGB 9343 Comparison of Lumpectomy Plus Tamoxifen With and Without Irradiation in Women 70 or Older with Clinical Stage I, ER+ Breast Carcinoma RT + Tamoxifen Tamoxifen Total treated 317 319 Age >75 176 (56%) 172 (54%) ER Positive 308 (97%) 310 (97%) Size <2 cm 295 (93%) 296 (93%) No Lymph Node Surgery 200 (63%) 203 (64%)

CALGB 9343 CALGB 9343 SURVIVAL WITHOUT LOCAL RECURRENCE 98% (with Radiotherapy) 91% (No Radiotherapy) @ 10 years Axillary Failure (0 vs.1.5%) Ultimate Mastectomy Distant metastasis OVERALL SURVIVAL Death From Breast Cancer Death From Other Causes EQUAL EQUAL EQUAL EQUAL EQUAL EQUAL

CALGB 9343 Radiation can be safely omitted in selected patients Lymph Node surgery can be omitted in selected patients

Society of Surgical Oncology Don t routinely use sentinel node biopsy in clinically node negative women >70 years of age with hormone receptor positive invasive breast cancer.

Society of Surgical Oncology What about omission of sentinel node biopsy in younger in women?

Molecular Profiling (Age 50-69) LOW RISK No SNB HIGH RISK SNBx

F.R.O.S.T. TRIAL Schema (n=210) Cryoablation No Breast Surgery Stratum 1 ( 70 years) Goal n=105 No Axillary Surgery, No Radiotherapy Stratum 2 (50-69 years) Goal n=105 Axillary Surgery if MammaPrint High Risk, Mandatory Radiotherapy, Chemo if indicated 6-month post-cryoablation Core Biopsies Endocrine therapy X 5 years Serial MG, US, MRI X 5 years

Liquid-Nitrogen Based System Liquid Nitrogen-Based

Treatment Algorithm (Two Freeze Cycles)

Molecular Profiling (Age 50-69) LOW RISK No SNB HIGH RISK SNBx

F.R.O.S.T. TRIAL Schema (n=210) Cryoablation No Breast Surgery Stratum 1 ( 70 years) Goal n=105 No Axillary Surgery, No Radiotherapy Stratum 2 (50-69 years) Goal n=105 Axillary Surgery if MammaPrint High Risk, Mandatory Radiotherapy, Chemo if indicated 6-months post-cryoablation Core Biopsies Endocrine therapy X 5 years Serial MG, US, MRI X 5 years

6-month Post-Cryoablation Core Needle Biopsy Cryoablation Zone Suspicious Areas Cryoablated Tumor 4 cores, 14g or greater CNB or VAB Distribution of Needle Biopsies

F.R.O.S.T. TRIAL Schema (n=210) Cryoablation No Breast Surgery Stratum 1 ( 70 years) Goal n=105 No Axillary Surgery, No Radiotherapy Stratum 2 (50-69 years) Goal n=105 Axillary Surgery if MammaPrint High Risk, Mandatory Radiotherapy, Chemo if indicated 6-months post-cryoablation Core Biopsies Endocrine therapy X 5 years Serial MG, US, MRI X 5 years

F.R.O.S.T. TRIAL Follow-up Breast & Axillary Imaging Plan

Primary Endpoint F.R.O.S.T. Trial Study Endpoints To determine the rate of successful tumor ablation (Assessed by absence of residual disease in the 6 month post-cryoablation needle biopsy) Secondary Endpoints assessed over 5 years: To determine the local recurrence rate To determine the rate of axillary failure To document adverse events To assess Cosmesis (BCCT.core) To assess the sensitivity of follow-up imaging

F.R.O.S.T. Trial Indications for Surgical Resection Failure to complete ablation due to technical failure or patient inability (i.e., pain or anxiety) Incomplete ablation of tumor assessed at 6 months Detection of recurrence on follow-up imaging (verified by needle biopsy)

Enrolled subjects: 18 First enrolled 7/22/2017 Treated subjects: 17 F.R.O.S.T. Trial Current Status

F.R.O.S.T. Study Sites Enrolling Blue/Green Interested

Cryoablation Immune Response

Immune Response Tumor Antigen Macrophage Activated and Proliferation of T-Cells T-Cell Tumor Cell Destroyed Tumor Cell

Impact of Cryoablation on Tumor-Specific T-cell Activity MT-901 Cell Lines in BALB/c mice Tumor Cryoablation Harvest Tumor- Draining Nodes Sabel MS et el. Cryobiology. 2006;53(3):360-6.

Tumor-Specific T-cell Activity INF-y Production Cryoablation Surgical Excision No Treatment Sabel MS et el. Cryobiology. 2006;53(3):360-6.

Impact on Cryoablation on Pulmonary Metastasis MT-901 Cell Lines in BALB/c mice Pulmonary Metastasis Tumor Cryoablation Sabel MS et el. Cryobiology. 2006;53(3):360-6.

Pulmonary Metastasis Regression after Cryoablation No Treatment Surgery Cryoablation Sabel MS et el. Cryobiology. 2006;53(3):360-6.

Summary Role of Cryoablation in breast cancer shows promise Available as part of a clinical trial Immune effects of cryoablation is intriguing, further work if needed