Scarcity of Actionable Oncogenes Should Not Preclude Testing in Breast Cancer

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 and PI3CA. 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 or BRCA2 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 Mutation.”

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.

In very rare cases, gene panels will find germline mutations in more than 1 gene. Results from research to date suggest that women with 2 mutations face about as much breast cancer risk as women who carry only the riskier of the 2 mutations, but uncertainty remains. A meta-analysis that compared gene panels and outcomes in 150,000 women did not have enough multiple-mutation carriers to reach statistically significant conclusions about any particular pair of mutations.

Greater certainty would allow surgeons and physicians to provide better guidance to patients, and that’s another reason all patients with breast cancer should receive germline genetic testing panels now. Doctors who order such panels can facilitate patient enrollment in registries that track outcomes. The greater the number of patients whose information gets tracked, the sooner investigators can calculate definitive risks.

Investigators are only just beginning to get enough data to make precise risk calculations, in part because knowledge of many genes and their role in tumor development is limited and partly because genetic testing has only recently become cheap enough for widespread use. Equally important, there is limited evidence about the effectiveness of screening or prevention regimens in the moderate-risk gene setting.

Rising competition in the genetic testing space has brought about a reduction in pricing, particularly for breast cancer genetic testing. This has been attributed to a 2013 Supreme Court decision that invalidated certain patents held by Myriad Genetics. Weitzel estimated that prices have fallen from about $2000 per sequenced gene to about $100 per sequenced gene. Utilization has skyrocketed, registry participation has done likewise, and investigators have been getting an ever-increasing flow of data to parse.

“There’s still a lot we don’t know about genes other than BRCA,” Weitzel said, “but each patient who undergoes testing and participates in a registry helps us learn more. They also help themselves make better decisions about their own treatment and follow-up.”

Weitzel believes that tests are already cheap enough and informative enough to justify germline genetic panels for all patients with breast cancer. Professional societies are not in full agreement with that just yet. Guidelines from the NCCN recommend germline panels for more patients with breast cancer than they did a few years ago, but they do not recommend universal testing.

The NCCN’s most recent standards⁴ call for germline testing in an individual with a breast cancer diagnosis who meets any of the following criteria:

1. A known mutation in a cancer susceptibility gene within the family.
2. Breast cancer diagnosed in those ≤50 years.
3. Triple-negative breast cancer diagnosed at ≤60 years.
4. Two primary breast cancer episodes in a single individual.

The guidelines also call for germline testing in any man with breast cancer, any patient of Ashkenazi Jewish descent, any patient with a family history with 3 or more cancers, and any woman with breast cancer at any age and at least 1 of the following:

• ≥1 close blood relatives with breast cancer ≤50 years
• ≥1 close blood relatives with invasive ovarian cancer at any age
• ≥2 close blood relatives with breast cancer, prostate cancer (Gleason score ≥7 or metastatic), and/or pancreatic cancer at any age Personal history of pancreatic cancer at any age From a population at increased risk

The current guidelines from the US Preventive Services Task Force call for testing in fewer women, but those guidelines are several years old and in the process of being updated.⁵ The most recent published guidelines from the National Society of Genetic Counselors,⁶ which date to 2013, also called for less testing than the far newer NCCN guidelines, which are only a few months old.

References

1. Antoniou AC, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371(6):497-506. doi: 10.1056/ NEJMoa1400382.
2. Hofstatter EW, Domchek SM, Miron A, et al. PALB2 mutations in familial breast and pancreatic cancer. Fam Cancer. 2011;10(2):225-231. doi: 10.1007/s10689-011-9426-1.
3. Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18(2):400-407. doi: 10.1158/1078-0432.CCR-11-2283.
4. NCCN. NCCN clinical practice guidelines in oncology (NCCN guidelines). Genetic/familial high-risk assessment: breast and ovarian. Version 1.2018—October 3, 2017. https://www.genomeweb.com/sites/ default/files/nccn_2017.pdf. Published October 3, 2017. Accessed February 15, 2018.
5. Final research plan for BRCA-related cancer: risk assessment, genetic counseling, and genetic testing. US Preventive Services Task Force website. uspreventiveservicestaskforce.org/Page/Document/final-research-plan/ brca-related-cancer-risk-assessment-genetic-counseling-and-genetictesting1. Updated August 2017. Accessed February 15, 2018.
6. Berliner JL, Fay AM, Cummings SA, et al. NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. J Genet Couns. 2013;22(2):155-163. doi: 10.1007/s10897- 012-9547-1.