Taking Action to Individualize Ovarian Cancer Care: Somatic Vs Germline Testing

In this second episode of OncChats: Taking Action to Individualize Ovarian Cancer Care, John Nakayama, MD, of the Division of Gynecologic Oncology, Allegheny Health Network, and assistant professor of OBGYN at Drexel University, and Christopher B. Morse, MD, gynecologic oncologist, Allegheny Health Network, explain the differences between germline and somatic testing in patients with ovarian cancer.

Nakayama: The other thing that we need to talk about is that not all ovary cancer is created equal. I like to tell my patients that ovary cancer is kind of like ice cream. All of it is ice cream, but you have different flavors. You have your vanilla, which is your high-grade serous disease; you have your Rocky Road, which is clear cell, or your chocolate, which is endometrioid—whatever your flavor choice may happen to be. Could you tell me a little bit about the histologies, or the flavors, of ovarian cancer, that [are associated with BRCA1 or BRCA2 mutations]?

Morse: The most common histology that we see typically associated with [these] mutations is typically high-grade serous; that is the driver. Then, to a lesser extent, [we see this with] endometrioid [disease]. Other ovarian cancer histologies, such as clear cell or mucinous, are not typically associated with these mutations. When you see patients with a high-grade serious ovary cancer, there is a fair chance that they could carry a mutation in the genes in the homologous recombination repair pathway.

Nakayama: I think that is super important. High-grade serous [cancers] are the ones that you have to be worried about. From the data, approximately 50% of the patients with high-grade serous [disease] could theoretically have some sort of defect in their homologous recombination pathway. The numbers that I see most commonly quoted are a 14% chance [of having] of a germline mutation and somewhere in the neighborhood of a 6% [chance of having a] somatic [mutation]. BRCA methylation has been shown in up to 10% of patients, and there are some other genes that are important.

When you talk about somatic testing in a little bit, maybe you could hit some of the less common genes, like the RAD51 genes, for example. Could you [explain to] the people who are watching, what is the difference between germline and somatic [mutations], and why does it matter?

Morse: When we talk with patients about doing things like tumor testing, where we actually send a portion of their tumor for testing, that is what we refer to as somatic testing. [With this, we try to] see whether there is a mutation that is within their tumor specifically.

The other thing that we talked to them about is germline testing. When we talk about germline testing, that is where the patients go and meet with a genetic counselor. They talk about their family history of cancer, and then they get their blood tested to see whether they carry a mutation that would be in every cell of their body, something that they could pass on to offspring. It is important to have both aspects of genetic testing performed, so that it not only impacts what treatment they might [receive], but also helps with counseling of other family members; [this is] specifically [true for] germline testing.

When we do germline testing, and somatic testing for that matter, we are testing for more than just BRCA1 and BRCA2 genes because there are other genes that increase a patient's risk of ovary cancer, breast cancer, and other cancers. Other mutations, such as ATM mutations, BRIP1 mutations, RAD51C and RAD51D, and also PALB2, are all mutations, that according to National Comprehensive Cancer Network guidelines, put you at increased risk of ovary cancer and consideration for risk-reducing surgery should be made. However, [for] a patient who has 1 of these mutations, the lifetime risk of developing ovary cancer, for example, is generally really less than what we see with BRCA1 or BRCA2; [however, that risk is] still elevated over that 1.5% that you mentioned [for] the average patient without a mutation.

Nakayama: In terms of somatic testing, I would think it would be very similar to BRCA [in that] you would be testing for genes. Is that the way we test for homologous recombination deficiency [HRD]?

Morse: No, so one of the things about HRD is that it is really a phenotype; it is something we are looking for when we do somatic testing. We are looking for evidence of HRD, and typically, we are looking for things like genomic scarring, which shows us that the ability for the tumor to repair things like double-stranded DNA break has been lost. There are several different platforms that are employed for testing for the genomic scarring, which is a sign of HRD.

Nakayama: One of the difficulties is knowing which company to use. All of them use loss of heterozygosity, otherwise known as LOH; however, some of them add additional [factors]. I also know that some companies are expanding what they give.

As such, it is very important for physicians to understand what exactly they are getting when they order something so that they can treat their patients best. [They need] to determine whether [their patients are] homologous recombination deficient or if they are homologous recombination proficient.

Check back next Wednesday to view the next segment in this series.