Molecular Testing in Newly Diagnosed Patients

Ramez Eskander, MD: The incorporation of molecular testing in patients with ovarian cancer has been transformational over the last several years. Germline testing of BRCA1/2 alterations should be incorporated as a part of standard care for these patients. There are significant implications for family members of the affected patient, specifically as they relate to risk-reducing surgery and counseling. But there are also very important implications for the patients themselves when it comes to therapeutic options, most specifically as it relates to the data and the approval of olaparib following SOLO-1 in patients who had BRCA1/2 alterations, and the dramatic improvement in progression-free survival with incorporation of a maintenance PARP inhibitor in the frontline setting for these patients. So we believe that germline testing has a defined role, although we can continue to do better in clinical practice.

In the same breath, somatic testing is important because, again, it has potential implications with respect to therapeutic management of the patients in the front line, and will inform how we can counsel patients about how they may respond to treatment. More recently, homologous recombination, which is a term that we use to describe a set of potential molecular aberrations or changes that could reflect in a certain way with respect to the genome, has emerged as a possible predictor of response to PARP inhibition. There are promising data suggesting that patients who have epithelial ovarian cancer and homologous recombination deficiency, may benefit from the addition of PARP inhibitors in the maintenance setting in the front line. It’s a little bit more difficult to determine whether homologous recombination deficiency will emerge as a sufficient biomarker predictive of response in these patients, but this is an active area of investigation.

Building on these—BRCA germline, BRCA somatic, expanding the homologous recombination deficiency—we are also entering an era where we have disease site–agnostic drug approvals. Pembrolizumab was approved in patients who have mismatch repair–deficient or MSI [microsatellite instability]-high recurrent disease, so there may be an opportunity in patients with ovarian cancer to also test for mismatch repair deficiency or MSI status to determine whether these patients would be eligible for pembrolizumab therapy. Most recently, in April of 2020, the FDA granted a breakthrough therapy designation for pembrolizumab in TMB [tumor mutational burden]-high tumors based on data from KEYNOTE-158. So we are determining that there may be multiple molecular targets that we need to test for in patients with these malignancies, and we anticipate that these data will change over time.

Transcript edited for clarity.

Case Overview:

Initial Presentation

• A 68-year-old postmenopausal woman presented with fatigue, urinary frequency, early satiety, abdominal bloating and distention
• PMH: HTN, medically treated with lisinopril
• SH: retired; grandmother of 3; never-smoker; social alcohol use
• PE: abdominal distention, bloating, and a positive fluid wave test; otherwise unremarkable

Clinical work-up

• Pelvic exam with transvaginal ultrasound showed a right ovarian mass
• Chest/abdomen/pelvis CT with contrast revealed a right adnexal 5.3-cm complex mass, a suspicious intraparenchymal liver lesion, retroperitoneal lymph node enlargement and concurrent pleural effusion
• Lymph node and adnexal mass biopsy confirmed high-grade, epithelial ovarian cancer; positive cytology of pleural effusion
  • T1N1M1
• Germline molecular testing showed BRCA1/2 wild-type, HRD+
• CA-125, 438 U/mL
• ECOG: 1

Treatment

• Patient underwent TAH/BSO, lymph node dissection, with suboptimal debulking; residual disease 1.3 cm
• Paclitaxel/carboplatin/bevacizumab + maintenance bevacizumab
  • After 3 cycles, patient underwent second debulking surgery, R0
• Continued on bevacizumab for 6 more cycles
  • Achieved partial response, post treatment CA-125, 40 U/mL
     

Follow-up

• At 3 months
  • CA-125, 18 U/mL
  • Chest/abdomen/pelvis CT showed no gross pelvic masses or nodes
  • Pelvic exam was unremarkable