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Two tests for homologous recombination deficiency have been FDA approved for patients with ovarian cancer, including myChoice CDx and FoundationOne CDx, and they produce important information that can be used to guide treatment decisions.
Two tests for homologous recombination deficiency (HRD) have been FDA approved for patients with ovarian cancer, including myChoice CDx and FoundationOne CDx, and they produce important information that can be used to guide treatment decisions, according to Thomas C. Krivak, MD. However, differences between these assays can make standardization of their use difficult.
The myChoice CDx, developed by Myriad Genetics, was approved by the FDA in May 2020 as a companion diagnostic for olaparib (Lynparza) plus bevacizumab (Avastin) in patients with advanced ovarian cancer, while the FoundationOne CDx, developed by Foundation Medicine, was approved in November 2017to identify molecular abnormalities in several solid tumors, including ovarian cancer.1,2 Although both tests are useful, the clinical data to support myChoice CDx may be more compelling, according to Krivak.
Importantly, both tests define HRD in differently. FoundationOne CDx identifies HRD based on deleterious or suspected deleterious mutations in BRCA1/2 and/or a positive Genomic Instability Score.3 In comparison, FoundationOne CDx defines HRD as patients with tumor tissue BRCA positivity and/or a high loss of heterozygosity.4 Because approved and prospective HRD tests have different definitions, standardization may not be possible, according to Krivak.
“I do not believe there is going to be standardization,” Krivak said. “I would have to say HRD is this concept that each company is going to define, and then it is going to be up to the individual clinician, whether that is a pathologist or someone who specializes in genetics and cancer, who will say, ‘We think this is the best test for these reasons and this is what we are going to do in our practice.' I do not think there is a perfect test out there.”
In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on Ovarian Cancer, Krivak, director of the Ovarian Cancer Center for Excellence and co-chair of the Society of Gynecologic Oncology Research Institute at Allegheny Health Network, discussed the significance of HRD in ovarian cancer, approved and prospective HRD tests, and considerations for genomic testing in this population.
Krivak: For patients with advanced ovarian cancer, you have to always think about germline testing. We do not want to have everyone focused on tumor testing. First, think about a good surgery, chemotherapy for the majority of patients, and then the germline genetic testing component. That is important because that will help us to determine who may qualify for medications after chemotherapy.
However, also, an ounce of prevention is better than a pound of cure. [If] we can identify patients who have germline mutations that place their family members at a higher risk for ovarian cancer, then we can intervene in those patients with risk-reducing surgery. With technology these days, if you have a patient who has a daughter who is 21 [years and] tested positive, obviously, we are going to make interventions at that point for her. However, even [in terms of] reproductive capabilities, there are [institutions] in the country where you can do prenatal genetic testing before you implant the embryos.
Also, we really have to do some type of molecular interrogation to classify and select our medications. We have numerous medications that we can use to treat these patients; now, we have to figure out what the optimal timing is to initiate these medications, as well as what sequence [they should be given in]. Hopefully, some of this molecular information will help.
Someone who has HRD and is known to be BRCA normal is going to triage to some type of maintenance strategy. If patients have a germline mutation, testing them for HRD up front probably is not a great use of resources because you are going to use an oral medication. If that patient recurs, you may want to test them later on or you may want to actually use a different test; you may not want to use an HRD test. You may say, 'I want to get more molecular information, such as true mutation and DNA mismatch repair [MMR] status.’ This other type of information may be gained through molecular interrogation.
[We should] test up front. If someone is going to receive chemotherapy followed by maintenance in the recurrent setting, if they have not received a PARP [inhibitor and] have not been tested, especially the platinum-sensitive [patients, testing] may help triage [what] to use: oral medications or potentially intravenous medications; or, they may not use any if [the patient is] considered [to be] HRD proficient.
What we are really testing is the tumor. To me, that can be looked at as unfavorable if you do not have any tumor [tissue] available and maybe the patient did not undergo debulking. If I am going to test a patient, I want to test the most recent biopsy because chemotherapy may potentially induce some changes within the tumor itself. Most of us would say, if someone has recurred [for] the third or fourth [time], and you are going to do some molecular interrogation at that time, you would want to biopsy that patient and use the most recent tumor [specimen] that you can get. If you cannot get that, then you go back to the initial specimen.
As to why [we] want to test, [it is] so we can get more information on how to best treat patients. Certain medications may only be indicated for 3% to 5% of patients. Microsatellite instability or deficient MMR may only be present in 3% to 5% of patients with ovarian cancer, but those patients now qualify for checkpoint inhibition. That may open up that strategy for that patient who may not otherwise be [considered for it].
We do not have all the answers and we do not know how to sequence chemotherapy appropriately. This is another piece of information that will help guide us through how we are going to sequence treatments. How we [choose to] treat our patients will be based upon curability and non-curability, prior treatment-related adverse effects, and possibly cost and distance to [the institution]. If we look at the molecular profile of the tumor, that may [present] us [with] other ideas for someone who may have not experienced any response in the past.
Each company is developing a test [and are defining what] HRD is. We, as clinicians, need to be able to say, 'This patient is homologous recombination deficient [according to] this test,' whether it is the Caris Life Sciences test or the Tempus test. The 2 tests that are FDA approved are Myriad, as well as Foundation Medicine. All those companies I mentioned are very solid companies with good research, but there is no doubt that Myriad has really done a tremendous amount of research to develop their test. Foundation Medicine [has, as well,] in very different ways. However, when someone calls me and says, 'Hey, listen, I have this patient who has this, this, and this, and they are HRD positive.' My immediate reflex is to answer, 'Wait a second, how do you define that? Is that by Myriad or Foundation Medicine?'
I wish it was standardized. I wish we could say, 'HRD is defined as this.' If you were to talk to me 3 years ago, I would have said that I define HRD as any molecular alteration within that homologous recombination pathway…I do not want to say that I have no data, [but we] have very limited data. It is mostly intuition. The way I defined [HRD back then is not how I define it now]. We are probably never going to have a standard definition for [HRD]; it probably just boils down to economics. All companies want to say that their test is [best].