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Why Do Some DCIS Cases Turn Invasive? Researchers Look to Germline Genetics for Answers

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NEW YORK – Scientists are working to better understand the role of germline pathogenic variants in the development of ductal carcinoma in situ (DCIS) and whether germline variants influence which patients later progress to invasive cancer.

Researchers led by Fergus Couch, chair of the Mayo Clinic's Division of Experimental Pathology and Laboratory Medicine, have found that some pathogenic variants in known breast cancer risk genes appear linked to a higher risk of DCIS patients developing invasive disease. These findings, based on a large-scale analysis of clinical and population-based cohorts, and published in Clinical Cancer Research earlier this month, reinforce present testing guidelines and lend support to testing DCIS patients alongside invasive breast cancer patients for germline genetic risk variants.

For their analysis, Couch and colleagues collected data from a set of 12 population-based and family-based breast cancer studies in the US, a clinical testing cohort of DCIS and breast cancer patients from Ambry Genetics, and the UK Biobank. Researchers performed the analysis of germline variants in DCIS samples based on 3,876 samples from the population-based study cohort, 9,887 DCIS samples from the clinical testing cohort, and 2,339 samples from the UK Biobank. The datasets separately included samples from patients with other forms of breast cancer and those unaffected by cancer.

The researchers looked for pathogenic variants in DCIS patients in the known breast cancer predisposition genes: ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, PALB2, RAD51C, and RAD51D.

One in every five new breast cancer diagnoses is DCIS, which is often called stage 0 breast cancer. Most people with DCIS can be cured with treatment. However, studies have found that between 20 percent and 40 percent of patients with DCIS will experience local recurrence, depending on their initial treatment.

According to Couch, the senior author of the study, researchers have not specifically focused on evaluating cancer predisposition in DCIS before or the role of cancer predisposition in DCIS patients developing second cancers. "Maybe there's something different about these DCIS [cases], because in the clinical outcomes so few of them actually progress to invasive cancer," Couch said. "[We thought] there's maybe something about the inherited genetics that could explain it."

Overall, the pooled frequency of pathogenic variants in these breast cancer predisposition genes was 6.5 percent in the clinical cohort and 4.6 percent in the population cohort. In both datasets, the most common pathogenic variants occurred in CHEK2 and BRCA2, followed by ATM and PALB2.

Among DCIS patients with a family history of breast or ovarian cancer, the frequency of pathogenic variants in cancer predisposition genes was higher. In the clinical cohort, the frequency was 7.1 percent in patients with a family history of cancer versus 5.1 percent among patients without a family history of these cancers. The population cohort had an even wider spread, with pathogenic variants occurring in 7.7 percent of DCIS cases with first-degree relatives with breast or ovarian cancer compared to 3.8 percent of women without a family history.

Patients who were diagnosed with DCIS at 50 years old or younger, another indicator of hereditary cancer, also had higher frequencies of pathogenic variants in the cancer predisposition genes, 6.9 percent in the clinical testing cohort and 6.3 percent in the population-based cohort versus 5.9 percent and 4.1 percent in each cohort, respectively, for those diagnosed at an older age.

When compared to samples from patients with invasive ductal breast cancer in these same datasets, DCIS patients had lower frequency of pathogenic variants in breast cancer predisposition genes. In the clinical cohort, 9.3 percent of invasive ductal breast cancer patients had these variants compared to 6.5 percent of DCIS patients, and in the population cohort, pathogenic variants occurred in 6.2 percent of invasive ductal breast cancer patients versus 4.6 percent of DCIS patients.

There was a twofold or greater chance that pathogenic variants in BRCA1/2 and PALB2 would occur in invasive ductal breast cancer cases than in DCIS cases in both cohorts. However, patients with grade 2/3 DCIS had higher frequencies of pathogenic variants in BRCA1/2 and PALB2 compared to patients with grade 1 invasive ductal breast cancer.

DCIS patients with pathogenic variants in breast cancer predisposition genes also had a higher risk of developing a second breast cancer. Among patients with germline pathogenic variants in BRCA1/2 or PALB2 in the population cohort, the incidence of a second contralateral breast cancer was 11 percent in five years, 17 percent in 10 years, and 23 percent in 15 years. Patients without these pathogenic variants had a second breast cancer incidence of 3 percent in five years, 5.5 percent in 10 years, and 8 percent in 15 years.

Couch noted that these findings confirm that the same germline variants play a role in the risk of developing both DCIS and invasive breast cancer. "That [finding] suggests that DCIS really is on the continuum of cancer risk from normal risk to DCIS to invasive cancer risk. That's why the genetics are the same, because they're all heading in the same direction," he said.

He added that the findings suggest DCIS patients could benefit from genetic testing for germline variants in cancer predisposition genes. Currently, the National Comprehensive Cancer Network (NCCN) recommends in its guidelines that oncologists consider clinical factors alongside information about a patient's family history of cancer to determine the need for genetic testing for breast cancer susceptibility genes in DCIS. The guidelines do not differentiate between testing needs for DCIS and invasive breast cancer.

According to Couch, DCIS patients should qualify for such testing, as they harbor germline mutations that are likely driving their disease. "They are at elevated risk of additional breast cancers, ovarian cancers. It suggests that DCIS patients should get genetic testing just as much as invasive patients should get genetic testing," Couch added.

Understanding a DCIS patient's genetic cancer predisposition could also guide their treatment and disease management. Most DCIS patients undergo surgery and radiation treatment, but some previous research has sought to find genetic signatures in DCIS patients to reduce overtreatment for patients at low risk of recurrence.

"At least for that subset of DCIS patients that have mutations, they would probably have better precision medicine and a more precise understanding of their risks and management of that [with germline testing]," Couch said. "We believe that it's important for as many people as possible to have information about their genetic risk."

Couch added that mutations in certain breast cancer predisposition genes confer only a low or moderate risk of cancer, such as mutations in ATM and CHEK2, while others, like BRCA2, appeared linked to a higher incidence of cancer recurrence in this analysis.

His group is also involved in ongoing research to evaluate different biomarkers to explain why some DCIS patients progress to invasive cancer while others don't. "Certainly there are differences in these people in that some of them do progress," Couch said. "Looking at the subset [of patients] that have predisposition genes might be the window into understanding those biomarkers and patients."