Oncologists are getting a handle on BRCA1/2 in breast cancer, becoming more adept at treating and counseling patients with these mutations. But the BRCA mutation is only one example of a host of genetic variations that can increase breast cancer risk, according to James M. Ford, MD, Associate Professor of Medicine and Genetics and Director of Clinical Cancer Genetics Program at Stanford University School of Medicine, Palo Alto.
With next-genome sequencing and genome-wide association studies will come new paradigms for genetic testing and counseling, said Dr. Ford, who discussed the topic at the Best of ASCO Meeting in Los Angeles.
Penetrance Matters
BRCA1/2 mutations are high-penetrance mutations that are very rare but confer a greatly elevated risk of breast cancer. Less is known about the moderate-penetrance gene mutations, such as those found in the Fanconi anemia pathway, associated with a two- to threefold increased breast cancer risk. Even less has been established regarding the low-penetrance mutations, which are common in the population but confer only a minimal increased risk.
“The completion of many genome-wide association studies is yielding information about the moderate- and low-penetration mutations,” said Dr. Ford. “These studies have identified common genetic changes—mostly SNPs [single nucleotide polymosphisms]—in a high proportion of the population, but their effect size is small. This knowledge is helping us close in on the unexplained heritability in cancer.”
BRCA1/2 mutations account for about 25% of familial breast cancers, and a small percentage are explained by SNPs, TP53, and PTEN alterations, with a smattering due to half a dozen or so other rare mutations. Approximately 65% of familial breast cancer risk remains unexplained.
The goal of genetic testing is to render either a clearly positive answer (showing disease association) or negative answer (no sequence change consistent with the mutation). However, in 5% to 20% of cases (depending on ethnicity) the result is a “variant of uncertain significance.” These are changes in sequences that cannot be determined to be deleterious.
“If you multiple the risk of a variant by the number of genes we will be looking at on multiplex panels—up to 40 or so—you can see the challenge in interpreting these results,” Dr. Ford said.
Familial Syndromes and Testing
The National Comprehensive Cancer Network revised its guidelines this year for BRCA1/2 mutation testing to advise screening when there is a:
- Family member with known BRCA1/2 mutation
- Personal history of breast cancer with:
—Triple-negative breast cancer and age ≤ 60
—Onset at age ≤ 45 (7% prevalence)
—Onset at age ≤ 50 if two primaries, or ≥ 1 affected close relative ≤ 50
—Onset at any age, if ≥ 2 close relatives with breast/ovarian cancer
—High-risk ethnicity, such as Ashkenazi (20%–25% prevalence) - Personal history of ovarian cancer (10%–15% prevalence)
- Personal history of male breast cancer (12%–16% prevalence)
- Close family member meeting the above criteria
While the BRCA-associated hereditary breast and ovarian cancer syndrome is certainly the most common familial breast cancer syndrome, there are others that clinicians should be familiar with and that help guide screening.
More and more susceptibility loci are being described as genetic testing becomes more sophisticated. Family studies have revealed the rare to very rare, high-risk alleles to include TP53, PTEN, CDH1, and STK11, which are observed in far less than 1% of the population but convey a relative risk of 10.0 or higher. The rare, moderate-risk alleles, found by sequencing studies, appear to be BRIP1, ATM, PALB2, and CHEK2; they occur in about 1% of the population and carry a relative risk of around 2.0. The common, low-risk alleles, identified on genome-wide association studies, include 6q, TOX3, FGFR2, 2q, MAP3K1, LSP1, Sp, 8q, AKAP9, and CASP8. These are observed in about 25% to 50% of the population, but the relative risk ranges from 1.1 to 1.5.
“What is unclear is whether the risks associated with these multiple SNPs, when they occur within a single patient, are additive,” he said.
The recommendation for genetic testing is also informed by breast cancer molecular phenotype and certain patient characteristics. Dr. Ford might advise testing under the following circumstances:
- Triple-negative breast cancer and age ≤ 60: Consider BRCA1/2 testing.
- Triple-positive and age ≤ 35: consider p53 testing for Li-Fraumeni syndrome
- Lobular breast cancer with a family history of gastric cancer: Consider CDH1 testing for hereditary diffuse gastric cancer syndrome.
- Breast cancer plus mucocutaneous lesions, macrocephaly, endometrial cancer, nonmedullary thyroid cancer: Consider PTEN testing for Cowden syndrome.
- Microsatellite-high breast cancer and family history of colorectal or endometrial cancer: Consider mismatch repair gene testing for Lynch syndrome.
Risk Modifiers Can Help Refine Treatment
Not all BRCA-associated breast cancers carry the same magnitude of risk, according to research done by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a global collaboration. The group has stored more than 15,000 BRCA1/2 samples from which they have begun to identify modifiers from common alleles. CIMBA has concluded that certain genetic factors can modify the individual risk of a BRCA mutation carrier. Depending on the particular mutations identified, aside from BRCA, risk may be greater or lesser than the oft-quoted numbers, he said.
Ten influential genes or regions have been found to modify risk associated with BRCA1, and 12 have been found for BRCA2. These modifiers occur at a frequency ranging from 7% to 52% and carry hazard ratios ranging from 0.75 to 3.18.
“These modifiers are multiplied against a very high baseline risk, and they can be used to stratify patients at relatively low risk (21%–50%) from those at extraordinarily high risk (81%–100%),” he explained. “These can help us with risk assessment and counseling regarding screening and prophylactic surgeries. We determine the individual risk, as compared with the population risk.”
Future Directions
Increasingly, more susceptitility loci and modifier genes will be identified through advanced SNP array technology, and the challenge of interpreting the data and incorporating it into clinical management will be formidable, Dr. Ford concluded.
Multiplex panels, which examine 20 to 40 genes, are arriving in the clinic and are capable of revealing moderate-penetrance genes. But there are currently concerns about their implementation, as the proper way to deal with incidental findings and uncertainty is unknown, and as yet there is no clear strategy for counseling patients regarding the results.
“How will we discuss these test results with patients within a reasonable time frame?” he asked. “And how will we interpret and deal with nonsyndromic changes, and variants of uncertain significance, which we cannot identify as deleterious or not? The role of professional judgment will be indispensable.” ■
Disclosure: Dr. Ford reported no potential conflicts of interest.
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