Ramez N. Eskander, MD: The management of patients who have advanced-stage metastatic ovarian cancer hinges on systemic treatment. In the context of disease recurrence, what we’ve clearly established is that with each subsequent line of therapy the disease-free interval progressively shortens. So when patients have their initial primary treatment and have a remission, and when that remission is followed by a recurrence, that subsequent recurrence usually [happens within a shorter period] than what we achieved at primary systemic treatment.
So prognostically, the goal of therapy is to re-establish disease remission with an intent to keep the disease in remission for as long as possible, preserving platinum sensitivity. If the patient develops a subsequent relapse, there are greater opportunities for therapeutic intervention. Cure may not be anticipated in this setting, although thankfully with the evolution of our treatment strategies, particularly in patients with BRCA mutations, that may change in the future. Nonetheless, in this setting the goal is to achieve an acceptable quality of life, while subsequently and in parallel, getting these patients to achieve a remission.
Molecular testing is emerging as a really important part of anticancer therapy across disease sites. Specifically, in the ovarian cancer arena, we have known for several years the importance of evaluating for germline BRCA alterations. This is quite important, both for patients, with respect to prognosis and assessment of response, but also so family members can be evaluated for a genetic aberration in BRCA1 or BRCA2. Then, they can have an early risk-reducing surgical intervention that could be life-saving and could prevent cancer altogether.
Also, if we identify a BRCA mutation in patients with ovarian cancer, if that’s germline, inherited, or somatic in the tumor, those patients will be eligible for maintenance PARP therapy in the front line based on the SOLO-1 clinical trial. SOLO-1 explored olaparib as a maintenance monotherapy, which showed a significant improvement in median progression-free survival and a 70% reduction in the risk of disease progression in that setting. So germline testing is incredibly important, both for the patient and the family. Somatic testing of the tumor is equally important. We know that germline testing does not capture all of the BRCA mutations. Five percent to 7% of patients may have a somatic BRCA mutation, meaning in the tumor or acquired rather than inherited. We want to capture those patients as well, because we know from studies like ARIEL2 that those patients with a somatic or a germline BRCA mutation respond equally well to PARP inhibition.
In addition, we expand the molecular assessments beyond BRCA. As many of you are aware, BRCA is a member of a family of genes that are important for DNA repair or homologous recombination. When there is an abnormality in any member of these family of genes, you can develop something called homologous recombination deficiency [HRD], which we are learning, based on both prior studies and recently published clinical trials, is potentially informative regarding the magnitude of response a patient may achieve with a PARP inhibitor in the frontline setting or in the platinum-sensitive recurrent setting.
The timing of molecular testing for patients with ovarian cancer is important and relevant. In the front line, I test all of my patients for germline BRCA mutations. I also evaluate for somatic BRCA aberrations. Thankfully, we now have molecular testing paradigms that allow us to do both of those in panel testing. So we can get a germline assessment of the BRCA status, exclude hereditary breast-ovarian cancer syndrome, evaluate the tumor to determine whether there is a somatic BRCA alteration, and also look at other family members and the homologous recombination pathway, RAD51C or RAD51D, for example, or potentially alternate actionable mutations. This also gives me the assessment of HRD, homologous recombination, and an LOH [loss of heterozygosity] score.
And I do this for my patients: the germline assessment, the somatic assessment, and the loss of heterozygosity or homologous recombination assessment in the frontline setting. The germline assessment does not need to be repeated, because that will not change over time. But certainly, if patients develop disease recurrence, I advocate for resampling of the tumor, if it can safely be done with limited risk, because we know there can be an evolution in the tumor genomics over time with exposure to prior therapy. By biopsying at the time of recurrence, we can send a contemporary sample, get those data back, and that will hopefully inform treatment based on the disease that’s present at that time.
Transcript edited for clarity.
Case: A 71-Year Old Woman With High-Risk Ovarian Cancer
Treatment and Follow-Up