Precision medicine and companion diagnostics join the battle against ovarian cancer

The American Cancer Society estimates that 22,280 women will be diagnosed with ovarian cancer in 2016. However, the lack of accurate screening tests for ovarian cancer means that 70 percent to 80 percent of all ovarian cancers will be diagnosed at a late stage, with a 10-year survival rate of only 35 percent.^1-3 As a result, approximately 14,240 women will die of ovarian cancer in 2016, accounting for five percent of all female cancer deaths.³

The standard treatment for most women with ovarian cancer is surgery, followed by a platinum-based chemotherapy regimen. Despite initial remission, up to 80 percent of women treated with platinum-based therapies will experience disease recurrence within years, or even months.^4,5 While progress has been made in ovarian cancer treatment over the last 10 years, these therapies have historically aimed to accommodate all patients. However, we now know that ovarian cancer is a heterogeneous disease with many distinct pathologies and etiologies.^6,7

In the emerging era of precision medicine, clinicians hope to replace the traditional “one-size-fits-all” treatment approaches with individualized care based on underlying disease biology. With advances in genetics research and sequencing technologies, healthcare providers are now poised to utilize the information garnered from genetic testing for cancer predisposition genes both to determine hereditary cancer risks and to evaluate possible treatment options based on those results.

Defects in DNA repair pathways

Mutations are known to accumulate more rapidly in cells that are unable to repair the damage that arises in their DNA. Breaks limited to single strands of DNA are fixed by processes known as base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). Double-strand breaks are predominately repaired by two mechanisms; template-directed high fidelity homologous recombination (HR) and low fidelity non-homologous end joining (NHEJ). The loss of the error-free HR repair mechanism contributes significantly to the accumulation of mutations in ovarian cells and ultimately promotes ovarian tumor growth.

Researchers estimate that 30 percent to 50 percent of ovarian cancers are associated with this HR deficiency.⁴ DNA-damaging agents that instigate additional DNA damage in cells that are already HR-deficient will lead to cell death through the rapid accumulation of genomic aberrations from low fidelity DNA repair. Pathogenic variants in two critical HR genes, BRCA1 and BRCA2, are among the first genetic markers of HR deficiency. As such, many studies have now documented an improved response to platinum therapy among women with ovarian cancer who carry pathogenic variants in BRCA1 and BRCA2.^8-10 Although platinum therapy is currently the standard of care, these studies suggest that different therapies may need to be developed to target HR-intact ovarian tumors.

A more recent treatment strategy involves the use of a class of small molecules developed to inhibit poly ADP ribose polymerase (PARP).^6,11 These PARP inhibitors disrupt the secondary pathways for DNA repair that rely upon proper PARP1 and PARP2 function (NHEJ, BER). Non-tumor cells are equipped with the full repertoire of repair mechanisms and are therefore not sensitive to PARP inhibition. This treatment strategy is therefore specifically directed toward tumor cells, resulting in a reduction in overall toxicity.

As with platinum, previous studies have shown that PARP inhibitors selectively benefit individuals with pathogenic variants in BRCA1 or BRCA24,^11-13 and, as such, illustrate the benefits of personalized medicine in the selection of therapies based on individual tumor biology and patient characteristics. Cells that possess at least one normal BRCA1 and BRCA2 copy are relatively resistant to PARP inhibition. BRCA1 or BRCA2 dysfunction, defined as mutant cells lacking wild-type BRCA1 or BRCA2, sensitizes cells to PARP inhibition, leading to chromosomal instability, cell cycle arrest, and apoptosis.^14,15

Although both platinum and PARP inhibitors target cells with HR deficiency, many tumors eventually become “platinum-resistant.” Studies have shown the benefit of treatment with PARP inhibitors following platinum among women with ovarian cancer who have pathogenic variants in BRCA1 or BRCA2.^16,17 Such findings are significant, as maintenance therapy in ovarian cancer is becoming more desirable due to the high rate of disease recurrence.^6,16

Companion diagnostics

Companion diagnostic tests are used to identify patients who are most likely to benefit from a particular therapy, and their growing number has the potential to transform medical practice. One such commercially available companion diagnostic test is paired with AstraZeneca’s drug Lynparza (olaparib), which is a PARP inhibitor. The assay is intended to detect germline BRCA1 and BRCA2 variants and provide a clinical interpretation of the identified variants. Single nucleotide variants and small insertions and deletions are identified by polymerase chain reaction (PCR) and Sanger sequencing. Large deletions and duplications are detected using multiplex quantitative PCR. Results of this test are used as an aid in the identification of ovarian cancer patients who may be considered for treatment with Lynparza.

Notably, the companion diagnostic test for Lynparza was the first laboratory-developed in vitro companion diagnostic test approved by the FDA.¹⁸ Achieving FDA approval for this test was no small undertaking. The specific performance characteristics of the assay were established by 10 categories of studies and supported by over 4,000 pages of documentation. These studies were performed using whole blood samples from ovarian cancer patients, as well as samples from breast cancer patients and unaffected individuals from families that have a high risk for hereditary breast and ovarian cancer. Table 1 provides a brief description of all the studies performed.

The use of companion diagnostic tests will form the foundation for the precision medicine revolution. The increasing number of collaborations between genetic testing laboratories and biopharmaceutical companies bodes well for the development of a varied menu of treatment options for cancer patients, targeted specifically to their own underlying disease etiology.  The benefits of such personalized treatment strategies are numerous and far-reaching, leading to reductions in healthcare costs and treatment time by not pursuing ineffectual therapies, and ultimately resulting in improved clinical outcomes.

REFERENCES

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16. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011;12(9):852-861.
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Debora Mancini-DiNardo is a board certified Laboratory Director at Myriad Genetics Laboratories. She holds a PhD in Molecular Biology and is a fellow of the American College of Medical Genetics (FACMG).

Krystal Brown is a medical writer at Myriad Genetics Laboratories. She holds a PhD in
Biophysical Chemistry from the University of Utah.