Homing in on Brain Mets’ Distinct Alterations Offers Hope for Precision Medicine Approach

Priscilla K. Brastianos, MD

The use of targeted therapies directed at genetic alterations specific to brain metastases is emerging as a viable precision medicine approach to treating brain metastases that have developed from solid tumors rather than using standard-of-care radiation approaches that can lead to significant and long-term cognitive decline and reduced quality of life.

According to Priscilla K. Brastianos, MD, “brain metastases harbor distinct clinically actionable genetic alterations compared to their primary tumors and extracranial sites,” she said in a presentation during the 2020 Society for Neuro-Oncology Conference on Brain Metastases.1 These distinct genetic alterations are potentially able to be targeted with genomically-targeted therapies.

Patients will often develop progressive brain metastases in the setting of stable disease outside of the brain, noted Brastianos, associate professor of medicine and director, Central Nervous System Metastasis Center, Massachusetts General Hospital. Systemic therapies may offer an opportunity to treat patients in this setting as intracranial activity has already been demonstrated with a number of newer systemic therapies, such as osimertinib (Tagrisso), alectinib (Alecensa), dabrafenib (Tafinlar), and more.

“We have a limited understanding of how brain metastases genetically evolve from their matched primary tumors,” she said.

Previously, few studies had looked at the genetics of brain metastases compared with their matched primary tumors.

One such study conducted molecular profiling of patient-matched brain and extracranial metastases from melanoma. The study noted a large number of similarities between the paired samples in each patient in terms of copy number variants, mRNA expression, and protein expression between the intracranial and extracranial metastases. However, increased expression of activation-specific protein markers in the PI3K/AKT pathway was observed in the brain metastases compared with the extracranial metastases.2

Since then, investigators have been creating a tumor bank for the study of the genetics of brain metastases.

Brastianos led an analysis of whole-exome sequencing of 86 matched brain metastases, primary tumors, and normal tissue to identify potentially actionable alterations specific to brain metastases.³ They observed that while there were many overlaps in terms of alterations found in both brain metastases and the primary tumors, there was also branched evolution occurring where the metastases continued to evolve independently from the primary tumor, and thus had some distinct genetic alterations.

She said that this meant that “targeted treatments that are appropriate for the primary tumor may not necessarily be appropriate for the brain metastasis,” as primary tumors and brain metastases are often genetically distinct.

Alterations were detected in the brain metastases that were associated with sensitivity to PI3K/AKT/mTOR inhibitors and CDK inhibitors. Specifically, 43% of cases had alterations that predicted sensitivity to PI3K/AKT/mTOR inhibition.

An RNA sequencing analysis of resected melanoma brain metastases and patient-matched extracranial metastases indicated that the brain metastases had significant immunosuppression and enrichment of oxidative phosphorylation compared with the extracranial metastases. Brastianos noted that this suggested that the brain metastases were evolving independently and compared with the other metastases.⁴

She suggested that in order to treat the brain metastases and not just the primary site of disease, oncologists need to target the genomic drivers of the brain metastases specifically.

Brastianos and co-investigators conducted a study of whole-exome sequencing on patient samples from patients with brain metastases from lung adenocarcinoma. Sequencing was conducted on 73 samples, which were compared with samples from 503 primary lung adenocarcinomas.⁵

The investigators identified genes with a greater frequency of amplifications in the brain metastases samples compared with the primary samples: MYC (12% vs 6%), YAP1 (7% vs 0.8%), and MMP13 (10% vs 0.6%); deletions were also more frequently observed in CDKN2A/B (27% vs 13%).

Cells with these amplifications were then injected into 28 immunodeficient mice and overexpression of MYC, MMP13, and YAP1 significantly increased the incidence of brain metastasis development in 22%, 24%, and 22% of mice, respectively (P <.05).

A biomarker-driven trial was later conducted by Brastianos and co-investigators to assess treatment with a CDK inhibitor as a potential treatment for patients with brain metastases. The phase 2 trial enrolled patients with recurrent or progressive brain metastases from a solid tumor and an alteration in the CDK pathway (NCT02896335). In the study, palbociclib (Ibrance) was administered daily for 21 days per cycle.

The study was conducted with a Simon 2-stage design with a null hypothesis of 10% and an alternative hypothesis of 30% for 30 patients. If 2 patients out of the first 15 had a response, an additional 15 patients were able to be enrolled. The treatment was considered worthy of further investigation if at least 6 of the 30 patients had a response.

The ongoing trial has a primary end point of intracranial clinical benefit rate (CBR) and secondary end points of extracranial CBR, intracranial disease progression rate, extracranial disease progression rate, overall survival (OS), and safety, with a particular focus on grade ≥3 hematologic and neurologic toxicities.

As of the interim analysis, 15 patients were enrolled, including 8 men and 7 women with a mean age of 56 years (range, 33-80). The primary tumor type was breast cancer in one-third of the patients, melanoma in one-third, esophageal in 20%, and non–small cell lung cancer in 13%. More than half of the patients had an ECOG performance status of 1 (53%), and the other half had a performance status of 0 (47%). All patients had previously undergone surgery and systemic therapy, but only 14 of the patients (93%) had received prior radiation therapy. The most common CDK pathway alteration was CDKN2A loss in 80%, and another 2 patients had CCND1 amplification and 1 had CCNE1 amplification.¹

The intracranial CBR was 53% and the extracranial CBR was 40%. The median OS was 6.5 months (90% CI, 3.8-13.6).

In terms of toxicities, the most common events of any grade were gastrointestinal disorders, general disorders and administration site conditions, investigations, metabolism and nutrition disorders, blood and lymphatic system disorders, and nervous system disorders. The most common grade 3/4 treatment-related events were white blood cell count decrease, neutrophil count decrease, and febrile neutropenia.

“Unbiased genome-wide screening can lead to the discovery of putative drivers of metastasis,” Brastianos said.

The results of this study led to the creation of a national biomarker-driven trial for brain metastases, with Brastianos as the study chair. The Alliance A071701 trial is a phase 2 study examining the use of genetic testing to guide treatment for patients with brain metastases from solid tumors (NCT03994796).

Patients with progressive brain metastases from histologically confirmed solid tumors, measurable CNS disease, and available tumor tissue for sequencing are able to enroll in the study. Those who are identified to have alterations in the CDK pathway will receive a CDK inhibitor, those who have an actionable mutation in the PI3K/AKT/mTOR pathway will receive a PI3K inhibitor, and those with an NTRK/ROS1 translocation from a primary lung cancer will receive an NTRK/ROS inhibitor. All treatment will be administered until CNS or systemic progression.

The primary end point is CNS response rate, and secondary end points include OS, CNS and systemic progression-free survival, systemic response, and safety. Exploratory end points also include correlation of response with biomarkers, duration of response, and the first site of progression.

_References:

_{1. Brastianos PK. Genomic evolution of central nervous system metastases: implications for precision medicine. Presented at: 2020 SNO Conference on Brain Metastases; August 14, 2020.}

_{2. Chen G, Chakravarti N, Aardalen K, et al. Molecular profiling of patient-matched brain and extracranial melanoma metastases implicates the PI3K pathway as a therapeutic target. Clin Cancer Res. 2014;20(21):5537-5546. doi:10.1158/1078-0432.CCR-13-3003}

_{3. Brastianos PK, Carter SL, Santagata S, et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov. 2015;5(11):1164-1177. doi:10.1158/2159-8290.CD-15-0369}

_{4. Fischer GM, Jalali A, Kircher DA, et al. Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases. Cancer Discov. 2019;9(5):628-645. doi:10.1158/2159-8290.CD-18-1489}

_{5. Shih DJH, Nayyar N, Bihun I, et al. Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma. Nat Genet. 2020;52:371-377. doi:10.1038/s41588-020-0592-7}