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Neoadjuvant chemotherapy induces mutational, molecular shifts in ovarian cancers

 

Key clinical point. Neoadjuvant chemotherapy was associated with changes in gene expression and associated pathways in high-grade serous ovarian carcinomas. Some mutations in tumors were also present in plasma cell-free DNA.

Major finding: Pathway analysis confirmed that the cell cycle and apoptosis pathway was the most up-regulated after neoadjuvant chemotherapy, while the DNA damage repair pathway was the most down-regulated. Among 38 baseline mutations in tumor specimens, 15 of 38 appeared in plasma cell-free DNA. At interval debulking, tumor specimens yielded 36 mutations, of which 11 were detected in cfDNA.

Data source: Gene expression profiling, pathway analysis, and next-generation sequencing of 19 patients with high-grade serous ovarian carcinomas.

Disclosures: Dr. Arend cited no funding sources and reported having no conflicts of interest.


 

– Treatment of high-grade serous ovarian carcinomas with platinum-based neoadjuvant chemotherapy led to significant changes in the expression of genes encoding “canonical” cell cycle and DNA damage pathways, said Rebecca C. Arend, MD.

Analyses of cell-free (plasma) DNA also revealed mutations that matched those in tumor specimens obtained before and after platinum-based neoadjuvant chemotherapy, Dr. Arend reported at the annual meeting of the Society of Gynecologic Oncology. “Understanding the effect of chemotherapy on gene expression profiles may help guide therapy, and plasma cfDNA could provide a noninvasive approach for monitoring tumor mutations,” said Dr. Arend of the University of Alabama at Birmingham.

Dr. Rebecca Arend of the University of Alabama, Birmingham Amy Karon/Frontline Medical News

Dr. Rebecca Arend

High-grade serous ovarian carcinoma is genetically heterogeneous, and chemotherapy further alters gene expression profiles and causes molecular derangement, Dr. Arend noted. “Neoadjuvant chemotherapy provides a unique opportunity to evaluate biospecimens before and afterward,” she added.

Both gene expression and mutational profiles have been used to characterize HGSC, but researchers lack solid methods to evaluate tumor heterogeneity and clonal evolution. To begin filling this gap, Dr. Arend and her associates analyzed plasma and tumor specimens from 19 patients with stage 3 or 4 high-grade serous ovarian carcinoma before and after they underwent three to six cycles of neoadjuvant chemotherapy. Biopsies yielded the baseline tumor specimens, and follow-up specimens were obtained during interval debulking.

The investigators used the NanoString PanCancer 770 gene pathway panel, the Ingenuity Pathway Analysis tool, and nSolver Analysis software to assess changes in gene expression. To quantify mutations, they performed longitudinal next-generation sequencing of 50 genes in tumor and plasma specimens with a 50-gene Ion Torrent panel.

After neoadjuvant chemotherapy, the most up-regulated genes included NR4A1 and NR4A3, which regulate cellular proliferation, differentiation, and apoptosis, and SFRP2, which promotes resistance to chemotherapy by modulating Wnt signaling, Dr. Arend said. The most down-regulated genes included E2F1, which helps mediate the cell cycle and the activity of tumor suppressor genes, and BRCA2, the tumor suppressor gene that encodes a DNA repair protein.

Pathway analysis confirmed that the cell cycle pathway was most up-regulated after neoadjuvant chemotherapy, and that the DNA damage repair pathway was the most downregulated, Dr. Arend reported. Within the DNA damage repair pathway, no gene was significantly up-regulated, while RAD51C, BRCA1, BRCA2, and the FA core complex genes were down-regulated.

Next-generation sequencing of baseline plasma cfDNA identified 57 mutations, of which 6 persisted after neoadjuvant chemotherapy. In contrast, of 38 mutations in tumor at baseline, 33 persisted after chemotherapy.

Only 15 of the 38 mutations in tumor also appeared in cfDNA before treatment. At the time of interval debulking, tumor specimens yielded 36 mutations, of which 11 were detected in cfDNA.

At baseline and after treatment, all patients had TP53 mutations either tumor alone, or in both tumor and plasma. Among four patients whose cancer recurred, three had mutations in cfDNA that were previously detected in tumor. Implicated genes included PIK3CA, TP53, KIT, and KDR.

Overall, the study suggests that gene expression profiling of ovarian HGSC tumor tissue taken at interval debulking could someday help guide treatment decisions after neoadjuvant chemotherapy, Dr. Arend said. “To be able to use cfDNA as liquid biopsy, more studies like this one, which match tumor and cfDNA from multiple time points, are needed,” she added.

Dr. Arend cited no funding sources and reported having no conflicts of interest.

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