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Comprehensive Genomic Profiling May Identify Select Subsets in Ovarian Cancer

Angelica Welch
Published: Monday, Aug 07, 2017

In an evaluation of 4114 ovarian tumor specimens, researchers aimed to identify the different molecular changes that can occur within these specimens in an effort to better group them into relevant targetable populations, according to lead investigator, Julia A. Elvin, MD, PhD.

According to Elvin, who presented the results at the 2017 ASCO Annual Meeting, these samples were analyzed for classes of genomic alternations through a hybrid capture based next-generation sequencing platform of up to 315 genes. Tumor subtypes were separated as high-grade serous (n = 2770), difficult to classify (n = 807), and nonserous (n = 537).

In an interview with OncLive at ASCO, Elvin, who is vice president and senior associate medical director of Foundation Medicine, discussed this genomic research in ovarian cancer and how it could potentially impact treatment decisions for patients.

OncLive: Can you provide an overview of this research?

Elvin: The study that I performed in conjunction with my collaborators was to look at the largest set of ovarian tumor specimens—over 4100 ovarian cancers, peritoneal tumors, and fallopian tube tumors. The way that we do this is that we use comprehensive genomic profiling. This is a hybrid capture based next-generation sequencing platform where we looked at 315 different oncogenes and cancer-related genes and fully sequenced them. We were able to capture all 4 categories of genomic alterations, including mutations, inserting/deletion events, and copy number changes, as well as rearrangements. This is incredibly important to this study because the depth and comprehensiveness of the sequencing approach is required for the next level of observations that we are now able to make.

The first level is identifying mutations in any 1 of these more than 300 genes. Then, the second level is to get almost a global genomic-wide landscape of how well the cell's double-strand repair process works—their homologous recombination pathway. We know that, in ovarian cancer, a large portion of these tumors have loss of the ability to repair breaks in their DNA. Gynecologic oncologists have been taking advantage of this Achilles heel, but didn’t know why it was working for a long time. Platinum-based chemotherapies actually introduce additional double-strand breaks, and it is partially for this reason that it’s believed that these chemotherapies are so effective in many patients with ovarian cancer. 

One of the great things about our technology is that we can observe a signature called "loss of heterozygosity” [LOH]. This is when a cell loses its ability to use homologous recombination, which is the high-fidelity repair pathway for double-stranded breaks. It has to go through a collateral channel that is a low-fidelity way of correcting these errors. As this pathway is used over and over again in the tumor cell, a certain specific type of mutational pattern accumulates that we can observe in our sequencing. We cannot only just observe this, but we can quantitate the amount of the genome that is experiencing this type of LOH effect. 

The ARIEL2 and ARIEL3 trials with the PARP inhibitor rucaparib (Rubraca) showed that patients who have homologous recombination deficiency respond to the synthetic lethality of the PARP inhibitors because they block the collateral circulation through other repair pathways. We have both ways to identify patients with this biomarker as well as have some clinical data to show that this is an important way of stratifying patients.

We applied this approach to 4000 mixed ovarian cancers. Generally, the [samples] that come to us are late-stage and often treatment refractory, at that point. We found that 41% of this mixed population of ovarian tumors had either a BRCA1 or BRCA2 mutation or this observable pattern of LOH. This means that 4 out of 10 patients could potentially benefit from a PARP inhibitor.

People tend to think about platinum sensitivity in this PARP inhibitor approach as it pertains to a certain subset of ovarian cancers—the serous cancers. A lot of the clinical trials are specifically designed to exclude patients that have the less common, but incredibly difficult-to-treat nonserous tumors. It is actually these patients who have the highest unmet clinical need because they do not respond to platinum therapy as readily. We looked specifically at the nonserous patients, and found that 19%—nearly 1 in 5 nonserous patients—had either a BRCA mutation, or this pattern of LOH. So, [there were] not as many as the serous patients, but it was still a reasonable thing to consider for these patients who often run out of options. 

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