Jeffrey Weitzel, MD
There are many unanswered questions about oncogenes. The practical understanding of these is limited to a handful of genes such as BRCA1/2
. However, broad genetic assays typically yield an amount of data that dwarfs the actionable oncogene subset, based on concrete medical and scientific knowledge. It might be tempting, therefore, to skip the sort of germline DNA test that maps more than a dozen such genes—tempting but, according to leading experts in the field, unwise. Although much remains unknown about many mutations and test results rarely clarify the need for any particular response, panel testing has already demonstrated its cost value, which continues to increase every day. Each new paper has the potential to transform today’s obscure results into tomorrow’s actionable intelligence.
“It’s unusual for mutations in anything but the BRCA1
genes to justify preventive surgery, but mutations in an ever-growing list of genes justify frequent checkups, MRI scans, and/or genetic tests for close relatives,” Jeffrey Weitzel, MD, director of the Division of Clinical Genomics at City of Hope, said in an interview with OncLive
. At the recent 2018 Miami Breast Cancer Conference, Weitzel delivered a presentation titled, “When Genetic Testing Reveals Something Other Than a BRCA
Though rare, one of the most important non-BRCA
mutations is a mutation in the TP53
gene, which carries a 90% lifetime risk of developing cancer, and bilateral mastectomy is a common preventive approach for adult women. Researchers have been studying the gene a long time, but its rarity makes it difficult to quantify its exact impact on the risk of developing a tumor, especially in tissues exposed to radiation therapy.
Several mutations that increase the risk of breast cancer also increase the risk of ovarian cancer, but TP53
mutations seem to have no effect on ovarian cancer rates, so they do not necessitate increased ovarian monitoring.
Mutations in the PALB2
gene appear to produce the next-highest lifetime risk of breast cancer. A study of 362 women from 154 families found that individuals with PALB2 mutations have a 14% risk of developing breast cancer by 50 years of age (95% CI, 9%-20%) and a 35% risk of developing it by 70 years of age (95% CI, 26%-46%). As with other genetic mutations, the risks associated with PALB2
mutations vary from woman to woman. “By 70 years of age, breast-cancer risk ranged from 33% [95% CI, 25%-44%] for a female carrier with no affected relatives to 58% [95% CI, 50%-66%] for a female carrier with 2 first-degree relatives [parent, sibling, child] who had breast cancer diagnosed by 50 years of age,” the study authors wrote, noting that mutations also seemed to increase cancer by a greater degree in more recent birth cohorts than they did in older cohorts.1
Though an association was suspected, the PALB2
study was not large enough to conclude that such mutations also increased the risk of ovarian cancer. Several studies suggest a very modestly increased risk (<5%, lifetime) of pancreatic cancer.2
The authors of the PALB2
study declined to make any recommendations about enhanced surveillance or risk-reducing surgery for patients with such mutations, except to say that both strategies should be evaluated by future research. “We should have better data on that gene mutation soon,” said Weitzel, who will go into more depth today during his presentation.
“Those 154 families represented our total experience with that mutation in breast cancer back when that study was published in 2014. There are now 600 families in the study cohort, and data are coming out. New ovarian risk numbers are about ready for publication now,” he added.
The other mutations that have been definitively linked to elevated breast cancer risk are those that disable the ATM
, the PTEN
, or the CHEK2
genes. Again, research has yet to quantify the level of risk elevation with any degree of exactitude. The current best guess, according to Weitzel, is that women with either mutation probably have a 20% to 30% chance of developing breast cancer at some point in their lives.
That’s probably not enough to justify preventive surgery, perhaps not even for the most risk-averse woman, but it’s significantly more than the 12% lifetime invasive breast cancer rate among American women as a whole. These risks do warrant enhanced surveillance and genetic testing for close relatives. And, again, the enhanced surveillance should be tailored to the types of cancer associated with the specific gene. For example, studies have already linked PTEN
mutations with increased risk of uterine and thyroid cancers,3
and future work may well find other risk increases.