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At ASCO, Small Victories, Challenges in Characterizing Inherited Cancer Susceptibility

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NEW YORK (GenomeWeb) – Presenters at this week's annual meeting of the American Society of Clinical Oncology shared new data highlighting incremental steps toward a more comprehensive understanding of the genetic variants that confer a greater risk of cancer.

However, participants also recognized that much of the complexity of heritable cancer risk still remains unknown.

During two science sessions at the meeting on cancer prevention, genetics, and epidemiology, clinicians and researchers presented new data on cancer risk genetics in several disease areas.

In one oral abstract session, Judy Ellen Garber from the Dana-Farber Cancer Institute presented results of a study in which she and her colleagues used Myriad Genetics' 25-gene hereditary cancer panel to study the prevalence of BRCA1/2 mutations specifically in women with ER-positive, HER2-negative breast cancer.

The study took the first steps toward establishing whether a BRCA mutated subgroup of ER-positive breast cancers actually shares more in common with BRCA mutant triple negative cancers.

In the study, Garber and her colleagues collected 104 biobank samples from women under 50 years old and tested them with Myriad's hereditary cancer panel. Mutations were found in 11 women in total, about 10 percent. BRCA1/2 mutations specifically were present in 6.7 percent of the cohort.

Following Garber's presentation, Geoffrey Oxnard, another Dana Farber researcher, presented results from his study, called INHERIT, in which he, Garber, and colleagues at several other institutions have been evaluating lung cancer patients to attempt to identify germline EGFR T790M mutations in order to establish whether this alteration confers an increased susceptibility to non-small cell lung cancer akin to the influence of BRCA in breast cancer.

Oxnard and his team started the INHERIT registry in 2013 working from the hypothesis that an underlying, inherited T790M mutation significantly increases the chances of some never smokers developing lung cancer.

In an earlier analysis Oxnard and colleagues had found that in a group of 10 NSCLC patients with EGFR T790M at diagnosis, five had a germline mutation, raising the hope that the mutation might explain a substantial percentage of familial lung cancer risk.

Between December 2012 and December 2014, Oxnards team went on to recruit a total of 46 NSCLC subjects to INHERIT who either had a T790M mutation discovered in routine cancer genotyping, or had a relative who had been found to have a germline EGFR mutation.

This cohort included 16 probands, 23 relatives, and six germline-negative patients with T790M-positive NSCLC.

Germline T790M mutations were present overall, in 16 of 22 patients with T790M-positive NSCLC. In addition, 10 of 14 first-degree relatives also had germline mutations.

Among 12 total relatives with germline T790M mutaitons, one had previously been diagnosed with NSCLC, one was diagnosed with NSCLC post-germline testing, and another four had small lung nodules. Six have not yet undergone CT imaging,Oxnardsaid.

Meanwhile, in 18 germline carriers with NSCLC, the median age at diagnosis was 56. When the team created pedigrees for 14 probands, it found that eight had one to two first-degree relatives with NSCLC and six had none. The team concluded that the penetrance of the variant is variable, but in some individuals germline T790M is associated with lung nodules or advanced NSCLC at a young age.

During his talk, Oxnard said that to estimate the population prevalence of the T790M allele the team also queried an institutional database of ongoing NGS cases. Based on this analysis of almost 9,000 cancers, there were only 11 EGFR T790M mutations. Three of these were present prior to, and not after therapy, and only one was germline-positive. This puts the estimated overall population prevalence at 0.01 percent.

Reflecting on both presentations, Stanford University oncologist James Ford said they take some critical steps forward, especially when, "even with BRCA 1 and 2 having been studied intensively for more than a decade, we still don't understand much of hereditary cancer risk in common cancers."

According to Ford, the results of the two studies also address several important issues in the field, namely, when and how newer multigene panels like those offered by Myriad Genetics and Invitae can best be used, and the question of the germline implications of tumor testing, as illustrated by Oxnards success in identifying hereditary T790M mutations by recruiting patients with somatic T790M mutations.

RegardingOxnard's results in the INHERIT study, Ford highlighted several immediate implications. Based on the data, he said, it looks like clinicians should consider germline testing in patients whose somatic test results show a T790M mutation.

The results also support germline testing for families with multiple non-smoking lung cancers; though identifying these rare groups may be difficult. Also, testing for first-degree relatives should be considered, with implications for screening strategies to potentially identify early cancers and improve patient outcomes, he advised.

"My highly anecdotal experience is that though these [cancers] are often stage four, they can be more indolent and potentially approachable," he said.

Remaining questions

The remaining questions raised by the results are what the true population prevalence and penetrance are for this variant, as well as whether and how the biology and outcomes differ among carriers versus those with spontaneous lung cancers, Ford added.

Additionally, it will be important to try to discover whether the mutation is associated with elevated risk for any other types of cancer, and whether treatment can be tailored for patients using novel T790M-targeted drugs.

In the case of BRCA1/2 mutated ER-positive breast cancers, Ford said that the critical questions for the field are: Do these tumors show the same sensitivity to things like platinum chemotherapy and PARP inhibitors as do triple negative cancers? What is the freqency of these mutations in this population? And how can further investigating these questions better inform genetic testing guidelines?

According to Ford, current NCCN guidelines do not necessarily conflict with the results of Garber's study. They recommend BRCA1/2 testing in any breast cancer in a woman under 45 years old, or in any triple negative cancer in a woman less than 60 years old.

However, clinicians may be more aware of the "triple negative plus less than 60" guideline than they are of the "any cancer less than 45" recommendation.

"I think these results reinforce the guidelines, and potentially further results may lead to changes in guidelines to be more inclusive," Ford said.

The remaining question, Ford stressed, is whether targeted treatment of BRCA1/2 mutant ER-positive breast cancer has a distinct outcome from BRCA wild-type ER-positive cancer, or from BRCA mutant ER-negative cancer. "Hopefully [ongoing] studies will have enough numbers to ask these questions," he said.

Another interesting aspect of Garber's results, Ford said, is the presence of mutations other than BRCA in a significant proportion of the women tested.

Using Myriad's 25-gene hereditary cancer panel, Garber and colleagues found that out of 100 overall subjects, about 10 percent had at least one mutation. The majority of these were in BRCA1/2, but nearly half were in other genes on the panel, including ATM, PALB2, and CHEK2.

"At this meeting we've seen a number of studies of panels … that show very similar patterns," Ford said.

One of these, a poster by Myriad Genetics, reported on the clinical utility of its 25-gene hereditary cancer risk panel in over 75,000 cases.

According to the company investigators, the results indicate that compared with BRCA1 and BRCA2 testing alone, the panel resulted in a 2.3-fold increase in the percentage of individuals identified with a cancer risk mutation.

Moreover, 2 percent of the cohort appeared to have two simultaneous cancer susceptibility gene mutations, a finding that would not have been possible without a broad panel-based strategy.

Interestingly, a significant number of subjects, especially those with alterations in lower-penetrance genes, had no family history linked to their identified mutation, suggesting that the use of broader panels like Myriad's could help identify cancer risks that are not easily assessable by current methods of assessing familial and clinical history.

In a separate poster, researchers from City of Hope working with Myriad looked more closely at the occurrence and clinical presentation of dual or multiple mutation carriers. Among about 80,000 patients tested using Myriad's 25-gene panel, the team found that 7 percent had a single mutation, and 0.19 percent had multiple mutations, which were spread over 19 of the 25 genes tested.

Among the 154 multiple mutation carriers, 40 had two mutations in high-penetrance genes, 24 had two mutations in moderate-penetrance genes, and another 67 had mutations in both a high- and low-penetrance gene. In addition, 23 had biallelic MUTYH mutations and were excluded from the analysis.

Almost 70 percent of the remaining cases had at least one BRCA mutation as one of their multiple mutations. The most common second mutations were in PALB2, CHECK2, and ATM. Six subjects had a mutation in both BRCA1 and BRCA2.

Among the 40 patients with mutations in two different high-penetrance genes, more than half showed a mixed phenotype consistent with both. Patients with multiple mutations were also found to be statistically significantly more likely to be affected by cancer, but not to have multiple primary cancers, or cancer earlier in life than those with a single mutation.

There was no obvious effect on phenotype of moderate-penetrance genes present in addition to higher-penetrance genes in the 67 patients with this pattern.

Clinical impact

In another poster presented at the meeting, scientists working with Invitae, which also offers a broad panel-based test for cancer risk mutations, recruited more than 1,000 women with breast or ovarian cancer who were negative for BRCA1/2.

They found that 3.8 percent of this cohort had a risk-associated mutation, including less prevalent breast cancer-associated mutations like PALB2 and CHEK2, as well as mutations in genes associated with Lynch syndrome.

As part of the study, physicians were asked prior to and after testing how they would manage their patient, and changes in these prescribed actions were recorded. Among the 63 mutation carriers, the majority had a mutation that would change the recommendations for additional screening and/or prevention measures above what would be indicated by family and clinical history alone, the study authors wrote.

Susan Domchek, from the University of Pennsylvania reflected on these, among other abstracts, in a session at the conference.

"At the end of the day, what we are trying to get out of genetic information is how to use it to improve patient care. And two of the major issues we've been dealing with are how to find new genes … and how to confirm the findings are critically important," Domchek said. "In the last several years we've seen a significant uptake in panel testing and yet we still have some unanswered questions."

Regarding the Invitae clinical management results, Domchek said that the data suggests that "doctors think we should do something when we have this information." However, she added, neither what is actionable nor how to act are well-defined in some cases.

"The things that keep me up at night are CDH1 and P53 in families that don't meet syndromic criteria," she said.

In the Invitae data, four families with CDH1 mutations were recommended for gastrectomy. "I was extremely relieved to hear that three of these four actually had gastric cancer," Domchek said. "The challenge is the gastrectomy in the family that didn't."

Though these larger panel-based strategies demonstrate benefits, it's important to remember that the risk associated with classic syndrome-causing genes like CDH1 are unclear in cases where that classic syndromic phenotype is not present.

Moreover, Domchek said, the risk associated with many of the genes in these panels is still poorly defined, and may be modified by other factors like clinical and family history. "We need to recognize the limitation of the data, and be careful in counseling patients that the data are evolving," she concluded.

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