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44. EFFECT OF STEREOTACTIC RADIOSURGERY ON NON-SMALL CELL LUNG CANCER BRAIN METASTASIS: CONTINUED CORRELATIVE RADIOBIOLOGIC ANALYSIS OF DNA AND RNA GENOMIC PROFILES FROM PHASE-II CLINICAL TRIAL NCT03398694

ABSTRACT: Abstract

BACKGROUND

Stereotactic radiosurgery (SRS) is an increasingly common modality used with or without surgery for the treatment of brain metastases (BM). However, the effects of SRS on tumors in vivo is unknown.

METHODS

Patients were treated with SRS prior to surgery as per clinical trial NCT03398694. Resected tumor was divided into two groups: ‘center’ and ‘periphery’ with respect to SRS treatment. Tissue were analyzed by DNA and RNA sequencing and compared between the two and to non-radiated tumor.

RESULTS

DNA analysis showed at the individual level, matched comparison of SRS samples from the center or periphery of the same tumor had mutational burden differences. RNA analysis revealed no differentially expressed genes between center and periphery, but there were 62 and 192 differentially expressed genes between the center or periphery and non-radiated control, respectively. At an individual level, matched center and periphery tumor had an average of 16641 differentially expressed genes. Comparing total number of up- and downregulated genes with SNP and Indel mutations of matched patient samples, in patients with higher mutational burdens in peripheral tumors as compared to center there was a higher number of upregulated genes. Reciprocally, when mutation burden was higher in center tumor, total number of genes that were either up- or downregulated were about the same. Pooled analysis revealed significant downregulation of oncogenes, such as TP63 and RECQL4, in the SRS group. DO enrichment analysis also revealed pathways related to NSCLC and lung carcinoma significantly altered in radiation cohort.

CONCLUSION

In summary, this study demonstrates that SRS alters the molecular and genomic profile of NSCLC BM. It results in downregulation of oncogenes and pathways related to lung cancer. Additionally, by sampling the tumor at the center and periphery, there are differential effects of the dose gradient on the cellular and molecular response to ionizing radiation.

SUBMITTER: Henriquez M

PROVIDER: S-EPMC7401354 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Project description:Abstract BACKGROUND: Stereotactic radiosurgery (SRS) is an increasingly common modality used with or without surgery for brain metastases (BM). However, biological effect of SRS to tumors in vivois not known. METHODS: Patients were treated with SRS prior to surgery as per the clinical trial protocol. The resected tumor was divided into two groups: ‘center’ and ‘periphery’ with respect to the center of SRS treatment with periphery within 50%-isodose-line. Tissue was analyzed by whole exome sequencing (WES) and compared between the two groups as well as to non-radiated control tissues. RESULTS: All sequenced samples contained greater than 95% clean reads with an average read density of 100 base pairs and mapping efficiency of >99%. Preliminary analysis focused on SNP and Indel detection. In pooled groups with n=7 replicates there was no statistically significant differences in total mutation burden in either SNP’s or Indels compared between controls and both treatment locations. Delving deeper intronic, frameshift, missense, and nonsense mutations all also showed insignificant changes between controls and center or peripheral tumor locations (p >0.5, p >0.1, p >0.4, p >0.3 respectively) hinting that at a pooled biological level there are not significant mutational burdens between treatment locations. However, at the individual level, matched comparison of SRS samples originating from the center or periphery of the same tumor showed total mutational burden differences. 6 out of 7 (86%) patients showed decreased total number of indels in peripheral vs. center and 5 out of 7 (71%) patients showed decreased number of SNP’s in peripheral vs. center locations. CONCLUSION: Ultimately, these data demonstrate the power of matched patient controls over bulk analysis in order to elucidate smaller but possibly biologically meaningful effects, and point to a possible location dependency in treatment associated mutation burden within a single patient and single tumor that may be masked at a population level.

Project description:Abstract Background With improved systemic therapy that has limited impact on the intracranial compartment, the incidence of brain metastasis (BM) from solid cancers is rising and negatively impacting patient’s overall survival (OS). Treatment varies based on presentation, however, for patients with <4 symptomatic BMs current clinical practice involves surgical resection followed by stereotactic radiosurgery (SRS) to the resection cavity. Post-operative SRS is associated with increased risk of leptomeningeal disease (LMD) and local recurrence in the follow-up period. We hypothesize that pre-operative SRS will decrease the incidence of LMD as well as local recurrence and increase patient’s OS by delivering a lethal dose of radiation to tumor cells before they are disturbed by surgical resection. In a Phase II clinical trial (NCT03398694) we are treating patients with 1–4 symptomatic BMs with pre-operative SRS while collecting DNA and RNA sequencing data from core and peripheral edges of the resected tumor to examine the genomic effects of SRS on tumor. Methods Post-SRS resected tumor specimens were divided into two groups: ‘center’ and ‘periphery’ with respect to the center of SRS treatment with periphery within 50% isodose line. Previously resected untreated BMs were used as control. DNA and RNA were isolated from all samples for sequencing. Conclusions Our initial analyses show that pre-treatment with SRS, results in significant genomic changes at DNA and RNA levels throughout the tumor, in both center as well as periphery. Furthermore, significant transcriptomic differences were noted among matched samples between the central and peripheral SRS locations implicating differential effect of SRS dosing within a tumor. Initial gene ontological analysis on non-small cell lung cancer samples demonstrated an overexpression of WNT and BMP signaling pathways (p <.001, p<.01). These pathways are typically involved in neuronal development, hinting that adaptation to the brain microenvironment was occurring post SRS treatment.

Project description:BackgroundStereotactic radiosurgery (SRS) is a frequently chosen treatment for patients with brain metastases and the number of long-term survivors is increasing. Brain necrosis (e.g. radionecrosis) is the most important long-term side effect of the treatment. Retrospective studies show a lower risk of radionecrosis and local tumor recurrence after fractionated stereotactic radiosurgery (fSRS, e.g. five fractions) compared with stereotactic radiosurgery in one or three fractions. This is especially true for patients with large brain metastases. As such, the 2022 ASTRO guideline of radiotherapy for brain metastases recommends more research to fSRS to reduce the risk of radionecrosis. This multicenter prospective randomized study aims to determine whether the incidence of adverse local events (either local failure or radionecrosis) can be reduced using fSRS versus SRS in one or three fractions in patients with brain metastases.MethodsPatients are eligible with one or more brain metastases from a solid primary tumor, age of 18 years or older, and a Karnofsky Performance Status ≥ 70. Exclusion criteria include patients with small cell lung cancer, germinoma or lymphoma, leptomeningeal metastases, a contraindication for MRI, prior inclusion in this study, prior surgery for brain metastases, prior radiotherapy for the same brain metastases (in-field re-irradiation). Participants will be randomized between SRS with a dose of 15-24 Gy in 1 or 3 fractions (standard arm) or fSRS 35 Gy in five fractions (experimental arm). The primary endpoint is the incidence of a local adverse event (local tumor failure or radionecrosis identified on MRI scans) at two years after treatment. Secondary endpoints are salvage treatment and the use of corticosteroids, bevacizumab, or antiepileptic drugs, survival, distant brain recurrences, toxicity, and quality of life.DiscussionCurrently, limiting the risk of adverse events such as radionecrosis is a major challenge in the treatment of brain metastases. fSRS potentially reduces this risk of radionecrosis and local tumor failure.Trial registrationClincalTrials.gov, trial registration number: NCT05346367 , trial registration date: 26 April 2022.

Project description:IntroductionNeoadjuvant stereotactic radiosurgery (NaSRS) of brain metastases has gained importance, but it is not routinely performed. While awaiting the results of prospective studies, we aimed to analyze the changes in the volume of brain metastases irradiated pre- and postoperatively and the resulting dosimetric effects on normal brain tissue (NBT).MethodsWe identified patients treated with SRS at our institution to compare hypothetical preoperative gross tumor and planning target volumes (pre-GTV and pre-PTV) with original postoperative resection cavity volumes (post-GTV and post-PTV) as well as with a standardized-hypothetical PTV with 2.0 mm margin. We used Pearson correlation to assess the association between the GTV and PTV changes with the pre-GTV. A multiple linear regression analysis was established to predict the GTV change. Hypothetical planning for the selected cases was created to assess the volume effect on the NBT exposure. We performed a literature review on NaSRS and searched for ongoing prospective trials.ResultsWe included 30 patients in the analysis. The pre-/post-GTV and pre-/post-PTV did not differ significantly. We observed a negative correlation between pre-GTV and GTV-change, which was also a predictor of volume change in the regression analysis, in terms of a larger volume change for a smaller pre-GTV. In total, 62.5% of cases with an enlargement greater than 5.0 cm3 were smaller tumors (pre-GTV < 15.0 cm3), whereas larger tumors greater than 25.0 cm3 showed only a decrease in post-GTV. Hypothetical planning for the selected cases to evaluate the volume effect resulted in a median NBT exposure of only 67.6% (range: 33.2-84.5%) relative to the dose received by the NBT in the postoperative SRS setting. Nine published studies and twenty ongoing studies are listed as an overview.ConclusionPatients with smaller brain metastases may have a higher risk of volume increase when irradiated postoperatively. Target volume delineation is of great importance because the PTV directly affects the exposure of NBT, but it is a challenge when contouring resection cavities. Further studies should identify patients at risk of relevant volume increase to be preferably treated with NaSRS in routine practice. Ongoing clinical trials will evaluate additional benefits of NaSRS.