Trend Toward Panels, NGS for Breast Cancer-Associated Testing Seen at San Antonio Breast Cancer Symposium
Researchers are forging ahead on utilization of markers across the spectrum of breast cancer (BC) care. At the 2014 San Antonio Breast Cancer Symposium (SABCS; Texas; Dec. 9-13, 2014), researchers presented work showing:
- genetic screening should be expanded for women with certain BC subtypes, regardless of family history;
- multi-gene panels assessing hereditary cancer risk provide incrementally more clinically relevant information than BRCA analysis alone;
- markers are improving prognosis and identification of women who, even when diagnosed with early-stage disease, are at increased risk of recurrence or metastasis and would benefit from more aggressive treatment;
- and blood-based DNA markers identified in "liquid biopsies" improve monitoring for early signs of recurrence or progression.
Two trends underlying these advances in understanding breast cancer risk assessment and prognosis that will impact future BC-associated testing are the shift to panel-based testing and the employment of next-generation sequencing (NGS) technology. A year and a half after the Supreme Court struck down Myriad's exclusive patent on the BRCA gene, it is evident that many laboratories are pushing ahead with multi-gene panels to assess hereditary risk of BC, even while researchers continue to grapple with the clinical significance of lesser-studied variants and work to identify improved parameters for selection of patients for genetic testing.
Expansion of Hereditary Screening
Patients with triple-negative BC (TNBC) should receive BRCA1/2 testing, regardless of age at diagnosis or family history of cancer, according to a study published online Dec. 1, 2014 in the Journal of Clinical Oncology and presented at SABCS.
The Mayo Clinic researchers assessed the frequency of mutations in 122 DNA repair genes, including 17 BC predisposition genes using sequencing in 1,824 patients with TNBC, unselected for family history of breast or ovarian cancer. The researchers found that 271 deleterious mutations were identified in 14.6 percent of all patients. BRCA 1/2 accounted for 57 percent and 18 percent of deleterious mutations, respectively, while 25 percent of the deleterious mutations were found in 12 of the 15 other predisposition genes. The authors say that the prevalence of mutations in the non-BRCA1/2 predisposition genes was stable across all age groups and reported cancer family histories, consistent with lower penetrance of disease for mutations in many of these genes.
"Because a relatively high proportion (7.5 percent) of patients with TNBC with no family history and diagnosed between age 50 and 60 years had mutations, perhaps testing ... all patients irrespective of age or family history, should be considered," writes lead author Fergus Couch, Ph.D., from the Mayo Clinic (Rochester, Minn.).
Couch and colleagues caution that while expanding screening beyond existing guidelines (such as the United Kingdom's National Institute for Clinical Excellence) will identify more carriers, the clinical utility of lower penetrance mutations remains debatable. Clear clinical management guidelines for BRCA1/2 mutation carriers have been developed over the two decades since the genes were identified, but management guidelines for the other predisposition genes are lacking, making the results from broader hereditary gene panels "controversial."
But, other abstracts presented at SABCS are demonstrating emerging evidence of the value of this additional clinical information, in spite of the higher associated rates of variants of unknown significance.
Multi-Gene Hereditary Cancer Risk Panels
Multi-gene hereditary cancer tests deliver comparable performance to traditional BRCA genetic testing, with potentially additional clinically beneficial information.
The 29-gene panel from Invitae (San Francisco) increased the yield of findings with potential clinical impact for almost 8 percent of patients, over BRCA testing alone.
In addition to guideline-directed BRCA testing, 821 patients were also tested using a panel of 29 known cancer risk-associated genes that assessed sequence changes and deletions/duplications. The researchers (some of whom report financial ties to Invitae) found that 13.8 percent of the patients carried BRCA1 or BRCA2 mutations, with greater than 99 percent concordance between the traditional and panel results. Among BRCA-negative patients, 7.6 percent carried mutations in other cancer risk genes that confer a moderately increased risk for breast and ovarian cancer, as well as genes involved in Lynch syndrome (which is not uniformly accepted to be associated with breast and ovarian cancer).
The authors, led by Leif Ellisen, M.D., from Massachusetts General Hospital (Boston), say that the panel identified nearly 40 percent more patients with a deleterious mutation, compared to results reported with BRCA testing alone. Nearly 80 percent of these non-BRCA mutations are not incidental findings, the authors say, and 70 percent of these mutations would "potentially warrant a change" in care for the patient or his or her family, including additional testing or screening and in a few cases, surgical interventions.
tephen Lincoln, Ph.D., from Invitae, in a second abstract says that while concordance is high between the panel and traditional BRCA testing, the details of interpretation are "hampered by the limited reporting of proprietary data by some established laboratories." Lincoln says that efforts to establish large public databases, like ClinVar, "will promote greater transparency and accountability and thus can help improve access to high quality care for hereditary conditions."
Prognosis Predicting Panels
There is also a growing body of evidence that multi-gene panels, coupled with proprietary algorithms, can positively guide treatment decisions by identifying patients at greatest risk of recurrence that would benefit from more aggressive treatment regimens as well as those at low risk of recurrence who could be spared excessive treatment.
In what is one of the first prospective trials utilizing a predictive genetic panel, Genomic Health (Redwood City, Calif.) presented early results from a European study supporting the use of Oncotype DX to guide treatment decisions. The Oncotype DX breast cancer test, which analyzes the RNA expression of a panel of 21 genes (16 cancer genes and five reference genes) from a tumor sample using reverse transcriptase-polymerase chain reaction, was used to identify higher-risk patients who would benefit from the treatment. In the study of 3,198 patients, most patients qualified for chemotherapy under traditional parameters. However, patients with Oncotype DX Recurrence Scores of 12 or higher were randomized to one of two different chemotherapy regimens, while patients with Recurrence Scores of 11 or less (low score) were offered hormonal therapy alone. After nearly three years of follow-up, patients with low Recurrence Score had very high survival rates without evidence of recurrence (98.3 percent), despite having node-positive disease or high-risk node-negative disease by traditional parameters. Researchers will continue to follow patients to assess longer-term outcomes.
Takeaway: While the search is on for additional markers for early-stage diagnosis of BC and those predictive of metastasis, progress is being made in the use of panels to identify BC patients who would benefit from more aggressive treatment. Additionally, panels are being employed for assessment of risk of hereditary BCs, despite limits in understanding the clinical significance of low penetrance variants.
Researchers from Dartmouth-Hitchcock Medical Center (Lebanon, N.H.), Thomas Jefferson University (Philadelphia), Erasmus Medical Center (Netherlands), and the Translational Genomics Research Institute (Phoenix) presented studies at SABCS highlighting the potential of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) as a liquid biopsy for ongoing molecular monitoring of BC.
"We believe our ability to assess cancer DNA in a non-invasive liquid-biopsy sample to monitor the genomic alterations as they occur in response to therapy or simply over the course of the disease will transform the way cancer is treated, monitored, and managed," said Steven Shak, M.D., executive vice president of research and development at Genomic Health, which expects to have a commercially available liquid biopsy-based test in 2016.
Biocept (San Diego) presented data showing the ability of its CTC capture method to identify how a patient's breast cancer can evolve over time and necessitate alterations in the optimal course of treatment. In the study, conducted at Farber Cancer Center (Boston), 22 percent of 311 patients with disease progression, who were previously HER2 negative based on solid tumor biopsy, were subsequently identified as HER2 positive (and eligible for anti-HER2 therapy) using CTC analysis.
eparately, researchers in partnership with Guardant Health (Redwood, Calif.) isolated and analyzed ctDNA for 54 mutations in 35 patients with inflammatory BC (IBC), who failed standard treatment. Based on testing using Guardant360, 94 percent of patients with stage III or IV tumors had identifiable ctDNA alterations (TP53, PIK3CA, ERBB2, NOTCH1, and ALK). The genomic information obtained from ctDNA, NGS (12 patients had NGS analysis of tissue biopsy), or both, was used to select treatments in 11 cases (31 percent), with some evidence of improved outcomes from ctDNA-associated treatment changes.
A number of ongoing studies are trying to further ascertain: the extent of genetic heterogeneity between primary and metastatic tumors and how reflective plasma DNA markers are of these mutations; the role of ctDNA/CTCs in predicting specific treatment response; and ultimately, the association between ctDNA/CTC levels with patient outcomes.
