Building on a legacy of pioneering and validating advances in spinal metastasis care, neurosurgeons and radiation oncologists with the Memorial Sloan Kettering Cancer Center (MSK) Multidisciplinary Spine Tumor Service have been investigating the clinical utility of genomic data as the next frontier for improving patient outcomes.
The spine is the most common site of metastatic disease, a significant source of cancer-related morbidity. Up to 40% of people with cancer develop spine metastases, and this percentage is expected to grow as newer biologics and checkpoint inhibitors improve survival. These systemic therapies are significantly more effective for visceral tumors like lung and liver lesions than spine tumors arising from bone. (1)Treatment serves a mostly palliative function by improving or preserving quality of life, spinal stability, and neurologic function.
“At MSK, our group is recognized worldwide as the driving force behind many advances that have dramatically improved local tumor control, survival, and quality of life for patients with spinal metastasis. For example, hybrid therapy — separation surgery, followed by stereotactic spinal radiosurgery — achieves durable control in more than 90% of patients,” says spine neurosurgeon Mark Bilsky, MD, Chief of the Multidisciplinary Spine Tumor Service, William E. Snee Endowed Chair, and Vice Chairman of Clinical Affairs in Neurosurgery at MSK. “The next generation of spinal metastasis care will incorporate genomic information with proven prognostic significance into predictive modeling.”
Genomic Data From Spinal Tumors Is Clinically Reliable
Recently, spine neurosurgeon Ori Barzilai, MD, Director of Minimally Invasive Spine Oncology at MSK, and colleagues were the first to demonstrate the reliability of spine tumor samples for patient-specific genomic-based decision-making. For their study published July 1, 2022, in Neuro-Oncology, they analyzed spine tumor samples and matched primary or metastatic tumors obtained during routine clinical care at MSK from 2013 to 2019 using MSK-IMPACT (2), a next-generation sequencing assay.
“The clinical reliability of genomic data from spinal tumors had never been investigated scientifically before,” says Dr. Barzilai, lead author of the study. “We know that mutations may differ between a primary tumor and a spine tumor, but when we looked at driver mutations that inform decision-making, the differences were minor. Our findings suggest that many patients can forgo additional biopsies and genomic analyses of primary tumors.”
The MSK researchers found high concordance rates in driver mutations between spinal metastases and primary tumors in a cohort of 54 matched primary tumors and spinal metastases of mixed histologies. The average concordance rates were 96.97% for all genetic events, 97.17% for mutations, 100% for fusions, 89.81% for deletions, and 97.01% for amplifications. The average concordance rates in driver mutations were especially high in three common cancer types: 96.99% for prostate cancer, 96.43% for breast cancer, and 95.69% for non-small cell lung cancer (NSCLC). (1)
Genomic Insights From Spine Tumors May Inform Prognosis
Most recently, MSK investigators analyzed clinical and prognostic predictors of outcomes for adult patients with metastatic epidural spinal cord compression (ESCC) or nerve root compression secondary to NSCLC after undergoing hybrid therapy. They examined histology, tumor location, mutational status when available, and systemic treatment regimens for a cohort of 103 patients treated at MSK between 2012 and 2019. They also evaluated mechanical instability using the Spinal Instability Neoplastic Score (2) and the degree of ESCC using the ESCC scale, which was developed by Dr. Bilsky and colleagues. (3)
The median overall survival (OS) for 103 patients in the cohort was 6.5 months, and the local control rate was 95% two years post-surgery. The improvement in progression-free survival from the time of surgery for patients harboring an EGFR exon 21 mutation was from 7 months to a median of 19 months. Notably, the investigators found a significant survival advantage for treatment-naive patients who began EGFR-targeted therapy after hybrid therapy, a 53% reduced risk of death, compared with patients who began EGFR-targeted therapy before hybrid therapy. The study was published online ahead of print December 8, 2022, in Neurosurgery. (4)
“Mutation data is helpful for determining optimal treatment plans,” says Dr. Barzilai, senior author of the study. “However, our novel finding also underscores the importance of considering where a patient is in their disease course and how that affects prognosis.”
A Legacy of Pioneering Advances in Spinal Metastasis Care
MSK spine care experts developed the Neurologic, Oncologic, Mechanical, and Systemic (NOMS) disease decision framework in 2004 and update it every two years to incorporate advances in evidence-based treatment. This system — the most used worldwide — considers the patient’s neurological function, the radiation sensitivity of their tumor, their degree of mechanical instability, and their systemic disease issues, including the extent of disease and medical comorbidities, to inform treatment options and the development of individual treatment plans. (5)
MSK researchers recently reviewed 20-year survival trends for 1,515 patients who underwent surgery at MSK for metastatic ESCC or tumor-related mechanical instability. Patients with spinal metastases secondary to renal, breast, lung, and colon cancers experienced a statistically significant improvement in OS of 40% to 100% between 1998 and 2017, based on the year of surgery, whereas the trend for the entire cohort was not statistically significant. The extended survival results reflected the integration of biologics and checkpoint inhibitors. (6)
Hybrid therapy was pioneered at MSK. It involves separation surgery, followed by spine stereotactic radiosurgery. In contrast to traditional gross total resection, separation surgery involves a simple epidural decompression, with the goal of creating a 2 mm margin between the spinal cord and tumor, thus creating a safe target for spine stereotactic radiosurgery (sSRS). SSRS uses highly conformal delivery techniques to target the tumor with a precise ablative radiation dose.
Dr. Bilsky and colleagues published a validated, standardized ESCC scoring system for assessing the feasibility of delivering a cytotoxic sSRS dose to spinal tumors within spinal cord constraints in 2010. (3) They also evaluated the effectiveness of hybrid therapy using different dose strategies in 186 patients with high-grade metastatic ESCC of mostly radioresistant tumor histologies and published their findings in 2013. The one-year cumulative recurrence rate was 16.4%. However, patients who received high-dose single fraction (24 Gray) or high-dose hypofractionated radiation (24 to 30 Gray in three fractions) had much lower local recurrence rates of 9% and 4%, respectively. (7)
This data compares very favorably to aggressive surgical resection followed by conventional external beam radiation therapy, demonstrating 30% local tumor control at one year. (8) These hybrid therapy results were validated further this year in two subsequent histology-specific studies examining renal cell carcinoma and NSCLC. (3), (9)
Overall, hybrid therapy has demonstrated more than 90% local tumor control at two years in radioresistant histologies. The extraordinary tumor control afforded by sSRS has allowed surgeons to employ increasingly minimally invasive techniques for separation surgery, which continues to reduce operative morbidity.
Future Research Directions
Drs. Bilsky and Barzilai and colleagues continue to investigate the utility of genomic insights from spinal tumors for predicting quality of life and survival and informing the development of individualized treatment plans. Current research avenues include evaluating genomic data for patients with spinal metastasis secondary to colorectal cancer and applying an artificial intelligence–based algorithm across the landscape of spinal metastasis for deeper insights.
The following authors also contributed to the paper “Clinical reliability of genomic data obtained from spinal metastatic tumor samples,” published July 1, 2022, in Neuro-Oncology: Axel Martin, MS; Anne S. Reiner, MPH; Ilya Laufer, MD; and Adam Schmitt, MD. All study authors reported no conflicts.
The following authors also contributed to the paper “Targetable Mutations MESCC NSCLC Hybrid Therapy,” published online December 8, 2022, in Neurosurgery: Vikram B Chakravarthy, MD; Benjamin Schachner, MPH; Anubhav Amin, MD; Anne S. Reiner, MPH; Yoshiya Yamada, MD; Adam Schmitt, MD; Daniel S. Higginson, MD; and Ilya Laufer, MD. All study authors reported no conflicts.