Sheth v1 (1)

Interventional Radiology for Metastatic Breast Cancer Rahul A. Sheth Associate Professor Department of Interventional Radiology MD Anderson Cancer Center

MD Anderson

IR For Advanced Breast Cancer

Disclosures • Trisalus (consultant) • Boston Scientific (clinical and preclinical research funding) • Replimune (consultant) • Medtronic (consultant) • Varian/Siemens (consultant) • Johnson and Johnson (EAB)

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IR For Advanced Breast Cancer

Overview • Rationale for local therapies in patients with metastatic breast cancer • Biopsy/tissue sampling • Pain palliation (e.g. bone lesions, venous disease) • Chemo holiday • Oligometastasis (e.g. liver lesions)

• The IR toolkit • Thermal ablation • Transarterial embolization • Stabilization • Neurolysis • Vascular interventions • Histotripsy

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Liver Metastases • The IR toolkit for treating liver metastases is extensive • Percutaneous (heat, cold, electricity) • Transarterial (embolization, radiation, chemotherapy) • Histotripsy • Roles for both local control as well as palliation • For lesions < 2cm, local control rates are similar to surgery in some malignancies (e.g., colorectal cancer)

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IR For Advanced Breast Cancer

Liver Metastases

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IR For Advanced Breast Cancer

Liver Metastases

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Liver Metastases

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Liver Metastases

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Liver Metastases

Pre

Post

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Liver Metastases

Deipolyi AR et al. Radiology, 2022, 220158.

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Liver Metastases

Choi, Jin Woo et al. JVIR 2024 (35), 203 – 212.

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IR For Advanced Breast Cancer

Liver Metastases

Deipolyi AR et al. Radiology, 2022, 220158.

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IR For Advanced Breast Cancer

Liver Metastases

Deipolyi AR et al. Radiology, 2022, 220158.

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Liver Metastases

Deipolyi AR et al. Radiology, 2022, 220158.

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Histotripsy

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Originated from basic science research at U of Mich in 2004

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Differentiated from HIFU by using short bursts of ultrasound energy to initiate mechanical cavitation within tissue

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Cavitation thresholds are tissue-dependent, so the power settings are adjusted to suit the target tissue

Verma, Arachchige. Radiology: Imaging Cancer 6, no. 3 (2024).

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Histotripsy Study (Year) & Reference Question investigated

Feasibility Findings

Vlaisavljevich et al (2013)

Proof of concept

Successfully created ~1-cm³ ablation zones in No damage to ribcage or overlying tissue; vivo through intact chest and rib blockage; ablation well-confined. Vessels and preserved major vessels and gallbladder. gallbladder remained intact.

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Smolock et al (2018)

Feasibility of clinical robotic arm; injury to body wall

Created clinical-sized 3-cm ablation zones Damage to body wall in animals with using clinically-relevant robotic arm; ablation limited acoustic windows or operator error zone resorbed 4 weeks post-treatment.

29381870

Longo et al (2020)

Respiratory compensation

Modified ablation volumes prescribed to No significant safety concerns reported; compensate for respiratory motion, improving ablation zones matched prescribed shapes. ablation zone shape.

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Knott et al (2021)

Ablation zone size; off-target injury

Prolonged cooling time prevented severe Human-scale transcostal ablations feasible; 3- thermal body wall damage; edema in body cm spherical ablation zones created. wall and hemorrhage in lung noted, however.

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Longo et al (2019)

Robotic arm, ablation zone size

Robotically assisted sonic therapy (RAST) created 3-cm spherical ablation zones.

Thrombosis of portal/hepatic veins noted

31041527

Vlaisavljevich et al (2017)

Histotripsy around vessels

Histotripsy performed around hepatic vein; ablation sizes similar in anticoagulated and normal pigs.

No increased risk of hemorrhage; all animals survived treatment. No thrombosis on 28318889 Doppler imaging of hepatic vein. No need for heparinization?

Mauch et al (2023)

Histotripsy in setting of anticoagulation

Histotripsy performed in anticoagulated pigs; ablation zones created at organ surface.

No elevated risk of hemorrhage in the setting of anticoagulation

Khokhlova et al (2019)

Treatment time

Transabdominal and transcostal boiling histotripsy feasible; well-demarcated lesions generated.

Shorter pulses with larger peak power (1% duty cycle) decreased treatment time without 31882870 affecting efficacy

Verma, Arachchige. Radiology: Imaging Cancer 6, no. 3 (2024).

Safety Findings

PMID

36503074

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Histotripsy Immunologic ramifications of histotripsy Study (Year

Qu et al (2020)

Pepple et al (2023)

Murine Model

Key Findings

PMID

Melanoma, HCC (C57BL/6 mice)

Histotripsy ablation stimulated strong local and systemic antitumor immune responses, including increased infiltration of innate and adaptive immune cells, release of immunogenic tumor antigens, and abscopal inhibition of distant tumor growth. Histotripsy enhanced the efficacy of checkpoint inhibitor immunotherapy.

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Melanoma, HCC (C57BL/6 mice)

Unilateral histotripsy ablation triggered local immunogenic cell death and systemic tumor growth inhibition. Early innate immune activation and delayed CD8+ T cell 36756111 infiltration were observed, with ferroptosis features in abscopal tumors. Histotripsy-generated cell-free tumor fractions conferred partial protection from tumor challenge.

Verma, Arachchige. Radiology: Imaging Cancer 6, no. 3 (2024).

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Histotripsy

Trial Name

Study Design & Population

Key Outcomes

THERESA

First-in-human, multicenter, phase I feasibility study Acute technical success in all procedures (zone of in Spain; 8 patients with unresectable, end-stage tissue destruction matched planned volume by No device-related adverse multifocal liver tumors (CRLM, breast, MRI 1-day post-procedure); 2 patients had events through 2 months cholangiocarcinoma, HCC); 11 tumors treated; continuous decline in tumor markers over 8 weeks median age 60.4 years; mean tumor diameter 1.4 cm

Prospective, multicenter, single-arm pivotal trial Technical success in 95% (42/44) of tumors; 1(US, EU, UK); 44 patients with primary (HCC) or year local control 63.4% (primary assessment), HOPE4LIVER metastatic liver tumors; up to 3 tumors <3 cm treated 90% (post hoc); 3.6cm average size of treatment per patient zone

Safety Profile

References (PMID)

36002243

Major complications in 7% (3/44) within 30 days; 6 39225612, serious device-related 40201962, events within 30 days; 36380155 minimal late adverse events

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Histotripsy • •

US and European nonrandomized, single arm prospective pivotal study Co-primary endpoints = technical success (treatment volume greater than or equal to target volume,

evaluated on 36 hour post-imaging) and safety (CTCAE > 2 at 30 days) • •

Technical threshold = 70%, safety threshold of 25%

Secondary endpoint = technical efficacy (lack of enhancement at 30 days)

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Histotripsy

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Histotripsy •

Major complications (CTCAE 3 or greater) that classified as primary safety end-point failures occurred in 3 out of 44 patients (7%) • •

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Additional major complications that were not counted towards the primary safety end-point •

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Grade 3 x 2 (sepsis, pleuritic pain requiring admission) Grade 5 x 1 (liver failure on day 12 -> death on day 37 in a patient with extensive liver mets) Splenic hematoma, melena, procedural pain, progression of metastatic colorectal cancer

Minor complications • • •

Abdominal pain (10/44, 23%) Pyrexia (4/44, 14%) Fatigue (5/44, 11%)

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Histotripsy • • •

Update on 1 year clinical outcomes for patients enrolled on the HOPE4LIVER study Imaging outcomes assessed by a core lab at each time point. A post hoc analysis was also performed to allow for a learning curve of interpreting the imaging findings 47 patients, 52 lesions

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Histotripsy

Local control rate @ 1 year = 63.4% on primary assessment, 90% on post hoc

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Histotripsy Table 4: Qualitative Tumor Assessment (Core Lab Assessed) Variable Tumors at follow-up Primary Assessment (n) Nodular or mass-like area of enhancement along the edge or margin of the treatment volume

30-Day 52 48

6-Month 41 35

1-Year 30 24

• Yes • No • Unknown Post-Hoc Assessment (n) Treatment area of another locoregional therapy confounds the read

8 (16.7%) 38 (79.2%) 2 (4.2%) 48

7 (20%) 28 (80%) 0 (0%) 36

2 (8.3%) 22 (91.7%) 0 (0%) 25

• Yes • No • Indeterminate Area of enhancement that is representative of a vessel within the treated area

5 (10.4%) 41 (85.4%) 2 (4.2%)

3 (8.3%) 32 (88.9%) 1 (2.8%)

1 (4%) 23 (92%) 1 (4%)

• Yes • No • Indeterminate Nearby tumors that may introduce ingrowth into the targeted area

10 (20.8%) 36 (75%) 2 (4.2%)

9 (25%) 26 (72.2%) 1 (2.8%)

5 (20%) 20 (80%) 0 (0%)

• Yes • No • Indeterminate In your opinion, based on this visit’s images, is there residual targeted tumor or progression of the targeted tumor?

11 (22.9%) 37 (77.1%) 0 (0%)

7 (19.4%) 29 (80.6%) 0 (0%)

4 (16%) 21 (84%) 0 (0%)

• Yes • No • Indeterminate

2 (4.2%) 43 (89.6%) 3 (6.3%)

1 (2.8%) 33 (91.7%) 2 (5.6%)

1 (4%) 24 (96%) 0 (0%)

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Histotripsy • •

All adverse events occurred within 30 days of the procedure, with 1 exception: biloma on day 188 Minor adverse events attributable to the therapy: •

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Serious adverse events attributable to the therapy (6/47, 12.8%): • • • • • •

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Pain (24.5%), pyrexia (12.2%) Liver failure x 1 Portal vein thrombosis x 1 Post-operative thrombosis x 1 Procedural pain x 1 Sepsis x 1 Pleuritic pain x 1

Additionally, 1 death on day 37 attributable to the therapy (hepatic failure)

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Histotripsy •

Local control outcomes are ambiguous given post-hoc analysis. At face value, they do not yet match current curative intent locoregional therapies (MWA, Y90, etc.) at their best (i.e. COLLISON, RASER, DOORwaY90)

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However, there is certainly a learning curve to this procedure, and outcomes will likely improve with operator experience

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Though noninvasive, it still has high procedure requirements, and visibility of the lesions is a major hurdle for treatment eligibility

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No procedure is without risk or toxicity, and this is true for histotripsy as well

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Thus far, there are very limited published data on ‘abscopal’ responses to histotripsy

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Bone Metastases Bone metastases can lead to devastating morbidity •

Pain from bone metastases is due to: • Biological causes due to the tumor itself • Mechanical failure due to weakening of the bone

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Bone metastases can lead to compromised functional status • Not weight-bearing • Taking prescription pain meds daily • Not getting through normal daily activities

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Bone Metastases 1.

Wallace AN, Greenwood TJ, Jennings JW. Radiofrequency ablation and vertebral augmentation for palliation of painful spinal metastases. J Neuro Oncol. 2015;124(1):111-118.

2.

Spiegel D, et al. Pain and depression in patients with cancer. Cancer. 1994;74:2570-2578.

3.

Levy J, Hopkins T, Morris J, et al. Radiofrequency Ablation for the Palliative Treatment of Bone Metastases: Outcomes from the Multicenter OsteoCool Tumor Ablation Post-Market Study (OPuS One Study) in 100 Patients. J Vasc Interv Radiol.

2020;31(11):1745-1752.

4.

Goetz et al. Percutaneous image-guided radiofrequency ablation of painful metastases involving bone: a multicenter study. J Clin Oncol.

2004;22:300-306.

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Spine Metastases

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Stringam J et al. Radiology. Imaging Cancer 7, no. 3 (2025): e240122.

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Bone Metastases • Multidisciplinary decision-making (Radiation, Surgery) • IR interventions can be combined safely with XRT (either before or after) • IR stabilization procedures can be done at the same time as the local tumor intervention (e.g. ablation) • Comprehensive treatment plan • Ablation for tumor control • Neurolysis for pain relief • Embolization for devascularization • Percutaneous stabilization for mechanical pain generators

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Bone Metastases

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Bone Metastases

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Bone Metastases

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Bone Metastases

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Bone Metastases

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Cryoneurolysis

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Cryoneurolysis

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Venous Interventions • Breast cancer patients are at increased risk for venous thromboembolism (VTE) • ER+ cancers are thrombogenic • SERMs increase VTE risk • Surgery (including axillary lymph node dissection), XRT, etc. can affect adjacent veins • Implantable devices such as chest ports can increase thrombosis risk

• Symptomatic VTE is associated with significant reductions in global, cancer-specific, and VTEspecific quality of life (QOL) in the oncologic population • National Comprehensive Cancer Network (NCCN) guidelines for cancer-associated venous thromboembolic disease support the use of endovascular therapy for acute DVT in appropriate patients with proximal DVT that are candidates for anticoagulation • Endovascular therapies have been shown to improve physical function and QOL in prospective trials performed in a non-oncologic patient population as well as small retrospective studies in the cancer population.

Kishore, S. A., Bajwa, R., Doren, L. V., Wilkins, C. & O’Sullivan, G. J. Curr Oncol Rep 1–12 (2022)

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Venous Interventions Not all ‘lymphedema’ is truly lymphedema, and there may be an underlying cause that can be intervened upon •

Subacute/chronic thrombus

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Obliterated venous return

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Tumor thrombus

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External compression by tumor, fluid collections, etc.

8 year old venous occlusion

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Venous Interventions • L breast CA s/p mastectomy + lymphadenectomy p/w severe L arm swelling, decreased mobility, heaviness • On Eliquis

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Venous Interventions

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Take Home Points • Interventional Radiology offers a diverse toolkit for treating metastatic breast cancer patients • Consider calling your friendly neighborhood IR for limb swelling, painful bone lesions, and solid organ metastases • IR therapies can be integrated into other existing treatment plans including chemotherapy and radiation

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Thank you!

rasheth@mdanderson.org

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