HRD Mutations Propel New Approaches in Uterine Cancer

Significant rates of homologous recombination deficiency (HRD) somatic gene mutations were found in patients with uterine serous cancer, resulting in possible implications for future testing and treatment for the patient population, according to the results of a research study.¹

Presenter Muhammad Danyal Ahsan, a medical student at Weill Cornell Medicine, said at the European Society for Medical Oncology (ESMO) Gynaecological Cancers Congress 2023 that “these data support the development of clinical trials to evaluate the efficacy of PARP inhibitors in this patient population.” He also suggested that testing should become more commonplace for patients with uterine serous cancer.

PARP inhibitors have demonstrated significant improvements in survival for patients with advanced ovarian cancer. For example, olaparib (Lynparza) led to a progression-free survival rate at 3 years of 69% compared with 35% with placebo in patients with advanced high-grade serous or endometrioid ovarian cancer and a mutation in BRCA1/2 (HR, 0.28; 95% CI, 0.20-0.39; P < .001).²

The possible benefit of this cclass of therapy has not been tested in patients with uterine serous cancer, where standard treatment includes surgery, chemotherapy, radiation, and trastuzumab (Herceptin).

The investigators combed through the American Association for Cancer Research’s Project Genomics Evidence Neoplasia Information Exchange database for next-generation sequencing genomic profiles of patients with uterine serous cancer and high-grade serous ovarian cancer to compare rates of HRD mutations in both populations. They looked to the frequencies of 9 HRD genes: ATM, BRCA1, BRCA2, BRIP1, BARD1, CHEK2, PALB2, RAD51C, and RAD51D.

Among the uterine serous cancer samples (n = 844), HRD gene mutations were found in 15.7% of samples compared with 28.4% of high-grade serous ovarian cancer samples (n = 3304; P < .001).

The most common somatic gene mutations in uterine serous cancer samples were observed in BRCA2 (5.2%), ATM (3.3%), BARD1 (1.8%), PALB2 (1.6%), and BRCA1 (1.5%). Comparatively, the most common among high-grade serous ovarian cancer samples were BRCA1 (10.0%), BRCA2 (7.0%), ATM (3.7%), BARD1 (2.1%), and BRIP1 (1.9%) (TABLE¹).

Mutation frequencies were significantly higher for metastatic vs primary samples in BRCA2, BRCA1, BRIP1, and PALB2 genes. On the other hand, mutation frequencies were significantly lower for metastatic samples over primary samples in ATM, BARD1, and CHEK2.

In addition to the possible therapeutic implications for the high rates of HRD gene mutations in patients with uterine serous cancers, Ahsan noted that there were also other considerations, including preventive factors.

“From a preventive standpoint, uterine serous cancer could be a phenotype of hereditary breast and ovarian cancer syndrome. And if so, germline mutation carriers opting for surgical risk reduction could be offered hysterectomy at the time of risk-reducing bilateral salpingo-oophorectomy,” he said.

In terms of study limitations, Ahsan noted a lack of clinical outcome data reported in the database as well as a lack of assessment of functional HRD status.

The investigators were also unable to differentiate between heterozygous and homozygous mutations.

Nonetheless, the study warrants further research into HRD gene mutations found in patients with uterine serous cancer, and whether PARP inhibitors could benefit these patients.

REFERENCES

1. Ahsan MD, Levi SR, Webster EM, et al. Homologous recombination deficiency gene mutations in uterine serous cancer. Presented at: ESMO Gynaecological Cancers Congress 2023; February 23-24, 2023; Barcelona, Spain. Abstract 22MO. Accessed March 2, 2023. http://bit.ly/3mePxVb

2. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495-2505. doi:10.1056/ NEJMoa1810858