Germline Testing in Stage IIIc Ovarian Cancer

Jubilee Brown, MD:It’s important to talk to the patient about her prognosis and why we do the surveillance we do, because of course this patient is at very high risk for recurrent disease. We know that about 75% to 80% of patients with epithelial ovarian cancers, when they’re advanced stage like this patient, will eventually recur. These patients need to know that and they need to know what we’re going to do to try to delay, or decrease, or prevent that. They also need to know how we’re going to be looking to see if the patient does recur.

I think it’s important in this patient to note that she did not have a pleural effusion and that she did not have parenchymal liver involvement. Those are things that keep her from being stage IV, and that’s important to know because it’s going to help us determine does she need neoadjuvant chemotherapy or should she have an upfront cytoreduction. This patient is a IIIc because she didn’t have those things. She did have bulky disease and she did have the lymph node involvement.

This is important because it impacts outcome so greatly, and it impacts everything that we do in terms of talking with the patient and making different recommendations for the appropriate therapy for the patient. It’s really important now in our management of patients with epithelial ovarian cancer to take into account both germline and somatic testing because it impacts everything we do in terms of treatment decisions, as well as counseling for the patient and her family.

The first thing to consider is germline testing. Every one of these patients at diagnosis should be referred for germline testing to identify any type of hereditary mutation that could be responsible for her ovarian cancer. Those can be things likeBRCA1, BRCA2,BRIP1mutations, and of course we’re learning more about this all the time. It’s very much a dynamic field, and we’ll see lots of changes in this in the next several years I’m sure. In the meantime, that really impacts how we counsel patients in terms of their family members. If someone is positive for aBRCA1mutation, not only are they at risk for other malignancies, but their family members should be tested, what we call cascade testing, to make sure that they don’t develop any of those cancers that could be related to their mutation.

Patients who have what we call homologous recombination deficiency, so patients who haveBRCA1orBRCA2or a related mutation, or have mutations that can cause that kind of DNA repair change, we can identify those patients and alter their therapy. These patients are very much susceptible to PARP [poly ADP ribose polymerase] inhibitors, and that can not only improve their outcomes but even yield cures in these patients. It’s super important to identify those patients.

Now, we can identify germline mutations or inherited mutations even just by a blood sample or a cheek swab. But we also don’t want to miss the additional perhaps 7% of ovarian cancers that may have somatic mutations in those genes. That’s important because if we can identify those patients, we can treat them the same way. They’re not hereditary mutations. If a patient has a somatic mutation in her tumor, she can still benefit from a PARP inhibitor as therapy, but her family members wouldn’t be at risk for cancers related to it.

One thing that has come to light in the recent couple of years is the importance of identifying multiple other types of mutations, either within the tumor that help you identify and target the tumor, or other mutations that could be germline or inherited. For example, patients with Lynch syndrome, you may see microsatellite instability or a defect in repair, MMR [mismatch repair]. With those patients, you’re going to identify that in order to identify other syndromes and also to identify them as potential candidates for immunotherapy. A lot of the times we’ll find PD-L1 [programmed death-ligand 1] overexpression, and when patients may have PD-L1 overexpression, that may indicate to us that they’re a candidate for immunotherapy. That’s really changed the field as well.

Transcript edited for clarity.

Case: A 59-Year Old Female With Stage IIIC Ovarian Cancer

Initial Presentation

• A 59-year old female presented with new onset early satiety, abdominal bloating and discomfort
• PMH: unremarkable, postmenopausal
• SH: schoolteacher; no tobacco, alcohol or drug use
• PE: abdominal distention, left lower quadrant tender on palpation, shifting dullness noted on percussion

Clinical work-up

• Pelvic exam with transvaginal ultrasound showed a left ovarian mass
• Chest/abdomen/pelvis CT with contrast revealed a left adnexal 4.8-cm mass, extension to liver capsule without parenchymal involvement; retroperitoneal lymph node involvement and ascites noted; no pleural effusion
• Lymph node, adnexal mass biopsy, and paracentesis (2000 cc) cytology confirmed high-grade epithelial ovarian cancer
• Diagnosis: high-grade epithelial ovarian cancer; stage IIIC — T3cN1M0
• Germline/molecular testing showed HRD-,BRCA1/2wild—type
• CA-125, 385 U/mL
• ECOG PS 1

Treatment

• Patient underwent TAH/BSO, lymph node dissection, with optimal debulking; R0
• IP/IV paclitaxel/carboplatin + bevacizumab every 3 weeks for 6 cycles
  • Followed by bevacizumab for 6 more cycles
  • Complete response; post treatment CA—125, 48 U/mL

Follow-up

• 3-months CA-125, 30 U/mL
• Chest/abdomen/pelvis CT showed no gross pelvic masses or nodes
• Pelvic exam, unremarkable
• ECOG PS 0