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Inching Toward Market, Myriad Growing Evidence Base for NGS HRD Companion Test

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Originally published Dec. 23.

Myriad Genetics recently presented data from a study on its homologous recombination deficiency test at a major medical conference, showing that the next-generation sequencing assay could accurately predict which triple-negative breast cancer patients would respond to the chemotherapy cisplatin.

In the study, presented at the San Antonio Breast Cancer Symposium earlier this month by researchers from Myriad, HRD test score predicted with a sensitivity of 100 percent all triple-negative patients who had a complete response to platinum chemotherapy before surgery. Additionally, the researchers concluded that the test score can predict drug response in all breast cancer subtypes, not just for triple-negative breast cancer patients.

Myriad's NGS-based HRD test gauges germline and somatic BRCA1/2 gene mutations, as well as a number of other markers involved in DNA repair. In a poster presentation at SABCS, researchers led by Kirsten Timms and others from Myriad evaluated 213 invasive breast tumor samples and matched normal tissue samples spanning all breast cancer subtypes defined by estrogen receptor, progesterone receptor, and HER2 status. In the study, researchers detected somatic and germline BRCA1/2 mutations "at significant levels" and depending on the breast cancer subtype, the frequency of mutations ranged from 7.8 percent to 16.4 percent.

However, BRCA1 promoter methylation showed up most frequently in triple-negative cancers, and BRCA deficiencies were present in 36 percent of triple-negative tumors compared to 10 percent in estrogen receptor-positive, HER2-negative cancers.

Myriad's HRD test provides three scores based on whole-genome tumor loss of heterozygosity (LOH) profiles, telomeric allelic imbalance (TAI), and large-scale state transitions (LST). According to Jerry Lanchbury, Myriad's chief scientific officer, the company developed the HRD test initially with the LOH score, but came up with the two other scores in the past year. With the addition of the TAI and LST scores, the company is hoping to increase the sensitivity of the test ahead of commercial launch for platinum therapies in 2015 and for PARP inhibitors in 2017.

All three scores are "highly correlated" with defects in BRCA1/2 and other pathway genes in breast or ovarian cancer, and can predict whether patients will respond to platinum agents, Timms and colleagues note in their SABCS abstract. "In this dataset all three scores showed significant association with BRCA1/2 status for the entire dataset," and "significant association was observed between the scores and BRCA1/2 status in each of the individual tumor subtypes," they reported. "The three scores were found to be highly correlated with one another, but all three were still significant in multivariate."

Although the current study is too small to definitively conclude this, based on the data presented at SABCS, Timms and colleagues believe that a combination of the three scores will likely be the "best predictor" of homologous recombination deficiency and treatment response in patients.

The correlation between the quantitative measures gauged by all three scores is approximately .7 or .8, Lanchbury told PGx Reporter. "So, they're all seeing something in common because if they weren't you wouldn't see a correlation," he explained. "But there is still .2 or .3 [of the quantitative measures] that the individual scores are seeing."

Lanchbury compared the HRD test scores to primary colors making up a picture that one sees on a television. "Each of the scores work" on their own, he noted. "But to see the whole picture, you need all of them."

At the moment, Myriad has two publicly announced partnerships with drug developers using the HRD test to identify best responders to investigational drugs. PharmaMar is studying Myriad's HRD test in a Phase II trial of PM1183, an agent that causes double-stranded DNA breaks to kill cells. BioMarin is also using it to investigate how different tumor types respond to the PARP inhibitor BMN-673. The company also has two undisclosed companion diagnostic partnerships involving the HRD test.

Because drug developers are interested in investigating generic cisplatin only in combination with their investigational agents, Myriad itself will likely market the HRD test as a predictive diagnostic that doctors can use to gauge which breast cancer patients will respond to platinum therapy. "Platinum is a very widely used drug. It is a very effective drug in the right people," Lanchbury said. "We're moving from generic chemotherapies that have all kinds of consequences to targeted agents. And one thing that the HRD test does is it makes drugs like platinum targeted agents."

He noted that platinum currently is not as widely used in breast cancer as it can be. "There are doctors who really like platinum and there are doctors who don't like it so much," Lanchbury said. "The ones who don't like it so much obviously have given it to patients who weren't the right patients and they haven't seen the appropriate benefit. I think with the right test, we could make platinum much more acceptable to more doctors."

A year ago, also at SABCS, Myriad presented data from a study that showed that 70 percent of triple-negative breast cancer patients with a high HRD test score had a response to carboplatin-based therapy compared to 20 percent of those with a low score. In that trial, using the HRD test helped researchers identify three times as many breast cancer patients who would benefit from platinum therapy than if they had gauged only BRCA mutation status.

Myriad researchers and collaborators also published data in the British Journal of Cancer last year showing that the HRD test can gauge whether ovarian tumor cells have impaired homologous recombination ability. The investigators noted in the paper that "a substantial fraction" of tumors with intact BRCA1, BRCA2, and RAD51C have elevated homologous recombination deficiency scores. "Two possible explanations are that there is a substantial rate of defects in other genes in the HR pathway in many of these samples, or that the HRD score is non-specific," the researchers wrote.

Currently, the majority of Myriad's companion diagnostic collaborations with pharmaceutical companies are around its flagship BRACAnalysis test. In total, Myriad has announced collaborations with six drug developers advancing PARP inhibitors, half of which have now advanced their drugs into late-stage development. The closest to market is AstraZeneca's olaparib, which along with BRACAnalysis as a companion test, is slated for launch in Europe by 2015.

Drugmakers "are willing to adopt what is known and recognized first," Lanchbury said. "That's going to get them to market, because the barriers of adoption are much lower there. But they also know that the market [for their drugs] would be bigger if they could expand the companion diagnostic to include more people."

While drug developers recognize the value of the HRD test and NGS-based testing in general, they balk at the uncertain regulatory and reimbursement landscape for NGS platforms. "There is a gentle evolution in terms of getting the data and also in terms of acceptability to regulatory authorities," Lanchbury said. "So, it's a relatively slow process but it's a process that has an order and a strategy to it."

The FDA has accepted Myriad's investigational device exemption application for BRACAnalysis to allow it to be studied in Phase III olaparib trials. Lanchbury said that the FDA is also aware of the HRD test and the company will continue to educate and have dialogue with the agency about the NGS-based diagnostic.

Currently, there is no FDA-cleared or approved NGS companion test. However, the agency recently approved Illumina's MiSeq platform, two diagnostic tests for cystic fibrosis that run on the NGS platform, and a reagents kit. Clovis Oncology, meanwhile, is aiming to launch an FDA-okayed NGS-based companion test to predict which high-grade serous ovarian cancer patients will respond to its PARP inhibitor rucaparib.

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