Third Annual Conference on Brain Metastases Summary

Third Annual Conference on Brain Metastases Summary

Jessica A. Wilcox, MD

The Society for Neuro-Oncology’s Third Annual Conference on Brain Metastases, organized in association with the Section on Tumors of the AANS/CNS, was held virtually from August 19-20th, 2021.  The conference brought together world-class experts in the investigation and treatment of brain and leptomeningeal metastases. The meeting began with a welcome by Dr. Gelareh Zadeh, President of the Society for Neuro-Oncology, and the scientific co-chairs, Dr. Adrienne Boire (Memorial Sloan Kettering), Dr. Paul Kongkham (University of Toronto), Dr. Rohan Ramakrishna (NewYork-Presbyterian Weill Cornell Medicine), and Dr. David Shultz (University of Toronto). This two-day conference featured presentations from pioneers in brain metastasis research, with topics covering basic science, translational research, evolving multidisciplinary treatment paradigms, and clinical trials.

Mechanisms of cancer cell entry and survival in the CNS is a domain of critical importance, as discoveries into metastasis invasion and propagation within the brain may provide novel strategies in brain tumor prevention and treatment. Day 1 of the conference began with Dr. Patricia Steeg (NCI Center for Cancer Research), reviewing her pivotal research regarding the mechanistic aspects of breast cancer access to the CNS, with attention to molecular alterations in the blood-tumor barrier that may be translationally targeted to increase permeability. Dr. Josh Neman (University of Southern California) then discussed how synaptic interactions between neuronal and cancer cells influence the honing and spatial distribution of brain metastases by cancer subtype. These enlightening talks were followed by the keynote speaker, Dr. Kim Margolin (St. John’s Cancer Institute Melanoma Program), on how melanoma genetic alterations and interactions with the CNS microenvironment influence the unique immunopathogenesis of melanoma brain metastases. Emerging preclinical discoveries are critical to our understanding of the success of immunotherapy for patients with melanoma brain metastases, as demonstrated in the Checkmate 204 clinical trial. Molecular biomarkers in melanoma leptomeningeal metastases also hint at differences between treatment responders and non-responders, with increased AKT and TGF-beta signaling in the CSF of patients with more aggressive disease, as discussed by Dr. Keiran Smalley (Moffitt Cancer Center). Dr. Marcus Butler (University of Toronto) highlighted how several known testable biomarkers, including PD-L1 expression, interferon-gamma levels, and tumor mutational burden, help to predict immunotherapy responsiveness, and outlined the vast landscape of immune profiling laboratory techniques.

Several significant advances in just the last year using preclinical models of CNS metastases point to novel therapeutic strategies on the horizon. Dr. Frank Winkler (University of Heidelberg and German Cancer Research Center) refined animal models using in vivo two-photon microscopy to study the dynamic interactions between cancer cells and CNS microvessels, thereby identifying the role of intravascular clot formation in the extravasation of circulating cancer cells into the brain parenchyma. Such findings introduce the concept of anticoagulation and/or von Willebrand Factor inhibitors in the prevention of brain metastases. Dr. Peter Siegel (McGill University) manipulated patient-derived xenografts to identify two different subsets of brain metastases, highly invasive and minimally invasive, and provided molecular insights driving invasive growth patterns. Dr. Adrienne Boire (Memorial Sloan Kettering) discovered how cancer cell growth in the nutrient-sparse CSF is supported by the lipocalin-2 and SLC22A17 iron-scavenging system, a pathway which can be manipulated using intrathecal iron chelation to prolong survival in leptomeningeal metastasis mouse models. New therapeutics are desperately needed for patients with leptomeningeal metastases given their shortened survival and the paucity of available clinical trials. Clinical endpoint validation, enhanced detection of CSF cancer cells, and multi-institutional collaborations are essential towards optimizing clinical trial design for this patient population, as reviewed by Dr. Priya Kumthekar (Northwestern Medicine)

With an understanding of major basic science and translational topics in CNS metastatic disease, the conference then transitioned to modern trends in clinical management. Dr. Kristin Redmond (Johns Hopkins University) highlighted the synergy between immunotherapy and stereotactic radiosurgery through enhanced immune cell recognition of a modulated tumor phenotype. Emerging data suggests a possible survival benefit with such combination therapy for patients with brain metastases, though at the risk of increased radiation necrosis. The concept of brain metastasis prevention was revisited, this time with focus on application to clinical trials. For example, the use of trastuzumab emtansine (T-DM1) versus T-DM1 plus metronomic temozolomide for secondary HER2+ breast cancer brain metastasis prevention was recently studied in a phase I/II study (NCT03190967) led by Dr. Alexandra Zimmer (NCI Center for Cancer Research), results of which are forthcoming. Finally, the data supporting SRS versus WBRT for multiple brain metastases was debated between Dr. Minesh Mehta (Miami Cancer Institute) and Dr. Scott Soltys (Stanford Cancer Center), highlighting the need for prospective comparative trials as well as cognition-preserving WBRT techniques. Day 1 closed with an enlightening multidisciplinary tumor board conference reviewing the incorporation of modern therapies into clinical decision making, and featured experts such as Dr. Manish Aghi (University of California San Francisco),  Dr. Daniel Cahill (Massachusetts General Hospital), Dr. Harriet Kluger (Yale School of Medicine), Dr. Paul Kongkham (University of Toronoto), Dr. Rohan Ramakrishna (NewYork-Presbyterian Weill Cornell Medicine), and Dr. Hany Soliman (Sunnybrook Research Institute).

Day 2 of the SNO Third Annual Brain Metastases Conference continued with a focused discussion on radiologic biomarkers. As patients live longer with CNS metastases, evolving imaging techniques must meet modern demands including the earlier diagnosis of small metastases, consistency in quantitative measurements across institutions, and reliability in measuring therapeutic responses. Dr. Caroline Chung (MD Anderson) discussed how automated tumor segmentation and mathematical imaging biomarkers measuring intra-tumoral growth kinetics aim to support standardization of these domains. Higher order radiomics also hold promise in predicting brain metastasis responses to treatment. Dr. Alexander Shoushtari (Memorial Sloan Kettering) applied these principles to a retrospective patient cohort with melanoma brain metastases treated with immunotherapy and identified several baseline radiomic characteristics that were significantly associated with survival. Several advanced techniques, such as DSC and DCE perfusion, MR spectroscopy, and FDG-PET, are now available to help radiologists adjudicate active tumor from treatment effect in previously-irradiated brain metastases, as reviewed by Dr. Timothy Kaufmann (Mayo Clinic). As the field advances, radiology consensus guidelines are essential to standardizing brain tumor imaging protocols for patient care and clinical trials.

Neurosurgical procedures remain critical in the local control of brain metastases, with trends towards minimally-invasive approaches to improve patient outcomes. Laser interstitial thermal therapy (LITT) is gaining popularity in the treatment of brain metastases that have recurred following SRS. Dr. Sujit Prabhu (MD Anderson) shared his expertise in LITT with examples of impressive local control of refractory cases of admixed tumor and radiation necrosis. Dr. Kaisorn Chaichana (Mayo Clinic) discussed how minimally invasive parafascicular surgery (MIPS) serves as an attractive technique for select deep-seated subcortical lesions, with the advantage of achieving excellent tumor removal while preserving adjacent cortical and subcortical structures. Focused ultrasound (FUS)-enhanced drug delivery aims to combine systemic therapy with non-invasive strategies to transiently open the blood-brain barrier, as reviewed by Dr. Nir Lipsman (Sunnybrook Research Institute). Early phase clinical trials of FUS-enhanced drug delivery show this strategy to be well-tolerated with the ability to target multiple lesions and eloquent cortex.

As scientific advances prolong the lives of patients with cancer, the protection of our patients’ neurocognitive function and quality of life are also essential. Dr. Jeffrey Wefel (MD Anderson) emphasized the high rate of treatment-related cognitive decline in cancer patients, with “chemobrain” afflicting as high as 70-90% of cancer patients. Multiple directly neurologic insults can occur following non-CNS directed therapies as outlined by Dr. Jorg Dietrich (Massachusetts General Hospital), with resulting impaired neurogenesis, neurovascular damage, and demyelination. Following the development of CNS metastases, cognitive dysfunction is directly correlated to brain metastasis lesion volume and quality of life. Dr. Wefel and Dr. Dietrich both outlined potential strategies to combat cancer and treatment-related neurocognitive decline, including standard neurocognitive assessments in clinical trials to balance efficacy with neurotoxicity and prospective testing of cognition-preserving techniques.

Fortunately for our patients, the inclusion of patients with stable brain metastases into clinical trials of systemic therapies is uncovering more treatment options for this patient population. Dr. Carey Anders (Duke Health) highlighted the explosion of HER2 targeting agents in just the last few years, with clinical trials suggesting CNS activity for tyrosine kinase inhibitor-containing combination regimens and antibody-drug conjugates. More novel therapeutics are needed for brain metastases from triple negative breast cancer. The discussion then transitioned to advances in lung cancer treatment with Dr. Bob Li (Memorial Sloan Kettering), who reviewed the encouraging CNS activity of the newly FDA-approved sotorasib, a first-in-class KRAS G12C small molecule inhibitor, from the phase I/II CodeBreak 100 trial. Trastuzumab deruxtecan is currently under investigation in patients with HER2-positive lung cancer in the DESTINY-Lung01 study. Finally, Dr. Michael Davies (MD Anderson) reviewed the tremendous improvements in survival for patients with melanoma brain metastases treated with immunotherapy and shared the 2021 updates from the ABC and Checkmate 204 trials. Among those with BRAF-mutant melanoma, combination dabrafenib and trametinib also constitutes an efficacious CNS-directed therapy, through with shorter intracranial responses compared to the duration of extracranial disease control. Triplet therapy with dabrafenib, trametinib, and nivolumab is now being investigated in the phase II TRIDeNT study.

The final session featured a panelist discussion on emerging controversies and potential solutions related to clinical trials of brain metastases, featuring Dr. Vinai Gondi (Northwestern Medicine), Dr. Isabella Glitza (MD Anderson), and Dr. Rohan Ramakrishna (NewYork-Presbyterian Weill Cornell Medicine). The scientific community has become increasingly cognizant of the need to study pharmacologic agents in patients with brain metastases. Accordingly, investigators should not consider “active” brain metastases as an automatic exclusion from trial eligibility, because doing so excludes the very patient population with the greatest need for evidence-based CNS-penetrant therapies. Additionally, with the knowledge that brain metastases demonstrate branched evolution with potentially targetable genomic alterations, what should be the role of invasive brain metastasis sampling for genomic testing and what is the data that this approach will improve patient outcomes? The phase II Alliance 071701 study aims to shed light on this question. Given the highly complex treatment of patients with brain metastases requiring consistent input from neurosurgeons, radiation oncologists, medical oncologists, and neuro-oncologists, the incorporation of multidisciplinary brain metastasis clinics is advisable to facilitate patient care, organize lesion-specific therapies, and improve long-term outcomes.

Members are encouraged to mark their calendars for the 2022 Brain Metastases Conference, which will have a special focus on clinical trials, scheduled to take place in-person at the Toronto Hilton Hotel, August 11-13, 2022.

About the Author
Jessica A. Wilcox, MD, is a Neuro-Oncologist & Neurologist at Memorial Sloan Kettering in the United States.