NCCN Guidelines: Recent updates to the Genetic/Familial High-Risk Assessment for Breast, Ovarian, and Pancreatic Cancers (version 1.2021)

Emily Fassi, MS, CGC

On Tuesday September 8, the National Comprehensive Cancer Network (NCCN) released an update to the Genetic/Familial High-Risk Assessment for Breast, Ovarian, and Pancreatic Cancers guidelines, which are heavily relied upon by cancer genetic counselors and other healthcare providers to guide appropriate patient care.

It is important to note that these guidelines are specific for genetic risk assessment regarding cancers of the breast, ovary, and pancreas. They include a lot of language regarding prostate cancer, but prostate cancer is not included in the title of the guidelines. The NCCN Guidelines for Prostate Cancer also touch on recommendations for germline genetic testing in the prostate cancer setting. Additionally, genetic assessment regarding other types of cancer (such as colorectal cancer) is not part of these guidelines. As hereditary factors are implicated in more and more cancer types (and as the importance of germline gene mutations for treatment increases), genetic testing considerations continue to be incorporated into a number of different NCCN Guidelines. How NCCN will ensure that the genetic recommendations among different guidelines are clear and consistent remains to be seen.  

The most up-to-date guidelines can be accessed here. (The guidelines are not behind a paywall, but a login is required.)

Outlined below are some of the more important updates.

What are the updates on who should be offered genetic testing for breast/ovarian cancer risk genes?

Although the updated guidelines do not include “Prostate Cancer” in the title, they broaden the testing criteria in multiple situations related to a personal or family history of prostate cancer. For example, prostate cancer with cribriform histology is now included (in addition to previously added intraductal prostate cancer) as an eligibility criterion for genetic testing. “Cribriform” refers to a particular architectural pattern noted on histopathologic examination of the tumor tissue. Both cribriform and intraductal prostate cancers are thought to be associated with genomic instability and possibly the presence of germline DNA repair gene mutations (see NCCN Guidelines for Prostate Cancer for more details on this). The new NCCN guidelines state that any person with prostate cancer should be offered genetic testing if the prostate cancer is one of the following: metastatic, intraductal/cribriform histology, or are in a high- or very high-risk group. Additionally, with qualifying family history, a person with prostate cancer of any NCCN risk group now qualifies for testing (previously it was only high-grade prostate cancers). The updated guidelines now state that women with breast cancer diagnosed at age 46-50 who have at least one close blood relative with prostate cancer of any type now qualify for testing.

What about genetic testing for people who have a family history of cancer but have not had cancer themselves? 

In the past, NCCNguidelines had suggested that testing may be indicated for people who had a more distant (e.g., second-degree relative) family history of certain categories of pancreatic or prostate cancers. The new guidelines state that the unaffected person must have a first-degree relative with one of these cancer types in order to qualify for testing. Of course, there are other family history situations (ex. family history of breast or ovarian cancer) that could qualify an unaffected person for testing. 

Any updates to cancer risks or management for gene mutation carriers?

Yes, and these updates can be some of the most important for patients, especially if they have already been found to have a mutation in one of these genes. Some genes were “upgraded” (so to speak), meaning that the evidence for association with elevated cancer risks increased or there are new data to support increased screening. Other genes were “downgraded,” meaning the authors now note less concrete evidence of a link with higher cancer risks.

For men with a BRCA1 or BRCA2 gene mutation who also have gynecomastia, it is now recommended to consider annual mammography screening starting at age 50, or 10 years prior to the earliest male breast cancer diagnosis in the family, whichever comes first. This was not recommended previously.

NCCN guidelines now note that there is limited emerging evidence to suggest an increased risk for breast cancer associated with the BARD1 gene, particularly triple-negative breast cancer. Based on this, there are now high-risk breast screening recommendations for BARD1 gene mutation carriers.

For RAD51C and RAD51D, it is now noted that these genes are potentially associated with an elevated female breast cancer risk, including triple-negative breast cancer. Previously there was only noted to be a potential increase in triple-negative female breast cancer risk specifically.

The guidelines now note that NBN gene mutations do not appear to increase the risk for breast cancer other than possibly the 657del5 mutation (Slavic founder mutation), for which there is mixed evidence (some newer studies suggest no increased breast cancer risk). Based on this change, the high-risk breast screening recommendations were removed for NBN gene mutation carriers.

Finally, the guidelines point out that for people with mutations in certain genes (BARD1, BRCA1, RAD51C/D), there is an overrepresentation of triple-negative breast cancers. On the other hand, people with BRCA2 and CHEK2 mutations have an overrepresentation of ER-positive breast cancers. This information can be helpful to keep in mind when determining an appropriate risk reduction and screening plan for patients. 

What do the new guidelines say about polygenic risk scores?

The guidelines indicate that polygenic risk scores should not be used in clinical management at this time. The use of polygenic risk scores is recommended within the context of a clinical trial. Multiple genetic testing labs are offering polygenic risk scores to assess breast cancer risk for patients. Many providers, including genetic counselors, have been struggling with whether it is appropriate to order these tests or incorporate polygenic risk data in risk assessment for their patients, so it is helpful to have this documented in the guidelines.

What do the new guidelines say about how to choose a genetic testing lab?

Although genetic counselors will be intimately familiar with how to choose an appropriate lab, this guidance could be helpful for non-genetics providers. The guidelines point out that not all genetic testing labs have the same methods for DNA and/or RNA analysis, so it is important to be aware of how the lab is performing the testing. Additionally, some labs have the option to reflex to testing more genes, whereas other labs do not. Finally, some labs provide financial assistance for cascade testing for relatives when a mutation is found in their family, and others do not.

Emily Fassi, MS, CGC is a certified genetic counselor, licensed in the state of Idaho. She has special interests in cancer risk assessment, rare disease, and individualized medicine. View Emily’s full profile and schedule an appointment with her here.