[JM article 1] NGS could guide ovarian cancer treatment

The use of next generation sequencing (NGS) could help identify patients with ovarian cancer who would benefit from targeted therapies, according to a small retrospective study from Korea.

The study population comprised 84 patients with ovarian cancer (median age 54 years) who underwent NGS at Yonsei Cancer Center in Seoul, Korea. DNA was extracted from the 84 formalin-fixed, paraffin-embedded tissue samples and sequenced with MiSeq, while the TruSight Tumor 170 gene panel was used for mutational and copy number analyses.

The most common ovarian cancer histological subtype was high-grade serous carcinoma, detected in 65.1 percent of the patients (n=55), followed by clear cell carcinoma (12 percent, n=10). Most of the patients (80.7 percent, n=68) had advanced stage (stage III–IV) disease.

NGS was carried out at diagnosis for 86.7 percent of patients, while the remaining 13.3 percent underwent NGS upon relapse. At least one genomic alteration was detected in all patients, with a mean 10.5 mutations per patient. [Yonsei Med J 2019;60:914-923]

Among single nucleotide variants, TP53, PIK3CA, and BRCA 1/2 were the most common genetic alterations detected in 64, 15, and 13 percent, respectively. Among copy number variations and fusions, MYC, TFRC, and CCNE1 mutations were the most common (27, 24, and 13 percent, respectively).

About 68 percent of patients (n=57) had >1 actionable alteration (signifying potential for targeted therapy with an available agent) aside from TP53; of these, 16 had a mutation in a homologous recombination repair-related gene.

Seven patients were treated with matched therapies, one with immunohistochemistry matched therapy, and 49 with standard chemotherapy.

Among patients treated with matched therapy, five received biomarker-driven therapies and two were enrolled in biomarker matched clinical trials. Five patients received PARP* inhibitors for BRCA 1/2 mutations, one received an AKT inhibitor for PIK3CA mutation, and one received a PD-1** inhibitor for MLH1 mutation with high microsatellite instability.

The patient treated with the PD-1 inhibitor experienced disease progression at 5 months, while the patient treated with the AKT inhibitor has stable disease following 2 months of treatment. Of the five treated with PARP inhibitors, four were as maintenance therapy (three had no recurrence after >5 months and one had disease progression at 7 months) and one as fourth-line monotherapy (stable disease at 7 months of treatment).

Fifty-three patients (63 percent) had potentially actionable alternations. These patients are currently receiving standard therapy or have not progressed or recurred after prior therapy.

Eight patients received genetic counselling, as did their at-risk family members who did not have potentially actionable alterations.

Prior research has shown that the use of NGS could provide, among others, vital information on diagnosis and prognosis, as well as identify suitable treatments in certain cancers, while avoiding inappropriate treatments. [Genome Med 2016;8:133] However, research into the clinical impact of NGS has not extended to ovarian cancer.

“[M]atching susceptible mutations with specific efficacious treatment agents is especially difficult with ovarian cancer patients [due to] heterogeneous cell populations, an extremely complex aetiology, and [the occurrence of further] mutations … as the cancer develops,” said the researchers.

“Nevertheless, the incorporation of NGS into the treatment of ovarian cancer may have a significant clinical impact, including … [identifying] potential candidates for future targeted therapies and genetic counselling,” they added, calling for further research into “the overall clinical utility and feasibility of NGS in ovarian cancer.”