Study: Cancer risks of people with inherited PALB2 mutations

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Contents

At a glance Clinical trials
Study findings Guidelines
Strengths and limitations Questions for your doctor
What does this mean for me? Resources
In-depth  

 

STUDY AT A GLANCE

What is this study about?

In this study, researchers wanted to estimate the risks of breast, ovarian, pancreatic, male breast, and colorectal cancers for people with inherited mutations.
 

Why is this study important?

People with an inherited mutation need to know their risks for cancer so that they can make informed healthcare decisions. Knowledge of individual risk may inform decisions about cancer surveillance, risk-reducing medicine or surgeries and possible family planning. Having a cancer diagnosis may also alter treatment options.

 

Study findings

Among 17,906 individuals in families with an inherited mutation, the risk of breast, ovarian and pancreatic cancers was greater than the risk of family members without a mutation. Increased risk levels among the mutation carriers included:

  • A 7-fold greater risk of breast cancer for women
  • A 7-fold greater risk of breast cancer for men
  • 3-fold greater risk of ovarian cancer
  • 2.4-fold greater risk of pancreatic cancer (women and men)
  • These increased risks are based on a model in which risk is constant over a person's lifetime. Researchers also tested whether the models in which risk varies with age were a better fit. A model that allowed risk to vary with age showed that women’s breast cancer risk declined with age. This model suggests that ovarian cancer risk may increase with age, but a constant age model described the data just as effectively.
     

The study identified the risks of cancer by age 80 for people with mutations:

  • Breast cancer
    • 53% risk for women with no family history
    • Up to 76% risk for women with two close female relatives with breast cancer by age 50
    • 1% risk for men
  • Ovarian cancer
    • 5% risk for women with no family history of ovarian cancer
    • Up to 16% risk for women with two close female relatives with ovarian cancer by age 50.
  • Pancreatic cancer
    • 2.2% risk for women
    • 2.8% risk for men
  • The risks for or colorectal cancer were not higher among people with mutations.

 

Strengths and limitations

Strengths

  • This is the largest group of people with mutations to be studied. The size of the group provides greater confidence that the findings are accurate.
  • By looking at only clearly deleterious mutations, the findings are more robust and interpretable than prior studies that included missense mutations.

 

Limitations

  • This study relies on self-reporting of information (past events). studies may be biased by participants’ recall of information.
  • The risk of cancer for people with missense mutations in was not determined.
  • The cancer risk of people who had a mutation in both a and a gene was not determined. Because proteins and the protein work together to perform repair, the combined effect of mutations in these genes is difficult to predict.
  • No information is provided about participants’ race or ethnicity or whether any differences in risk vary by race or ethnicity.


What does this mean for me?

  • If you are a woman with an inherited mutation, you have an increased risk of breast, ovarian and pancreatic cancer. Your risk of breast cancer may be higher if you also have close female relatives who have had breast cancer by 50.
  • If you are a man with an inherited mutation, you have an increased risk of breast and pancreatic cancer. This study suggests that you may not have an increased risk of cancer, but the results of other studies suggest that some level of risk may be elevated.
  • You may consider talking to a genetic counselor and your doctor about surveillance or risk-reducing strategies for these cancers.
  • If you have been diagnosed with cancer and have a mutation, discuss with your doctor whether your mutation status alters your treatment options or recommendations.

 

Share your thoughts on this XRAY review by taking our brief survey.  

posted 7/1/21

 

Reference

Yang X, Leslie G, End M, et al., Cancer Risks Associated with Germline Pathogenic Variants: An International Study of 524 Families. Journal of Clinical Oncology; 2021: 38:673-685.  

 

Disclosure

FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

This article is relevant for:

people with inherited PALB2 mutations

This article is also relevant for:

People with breast cancer

Men with breast cancer

Previvors

People with a genetic mutation linked to cancer risk

People with a family history of cancer

People with ovarian cancer

People with pancreatic cancer

Be part of XRAY:

Expert Guidelines Expert Guidelines

The National Comprehensive Cancer Network (NCCN) provides risk management guidelines for people with mutations. We recommend that you speak with a genetics expert who can look at your personal and family history of cancer and can help you to determine the best risk management plan. 

Breast cancer screening and prevention

  • Clinical breast exams every 6-12 months beginning at age 30.
  • Annual  (consider 3D if available) and breast with contrast beginning at age 30.
  • Women should have a discussion with their doctors about of the advantages and disadvantages of risk-reducing mastectomy.

Ovarian cancer prevention 

  • The National Comprehensive Cancer Network (NCCN) guidelines recommend that ovarian cancer risk be managed based on family history.  
  • Some experts recommend risk-reducing salpingo-oophorectomy after age 50 to their patients with mutations.

Pancreatic cancer screening for people with a family history

  • For  mutations carriers with a first- or second- degree relative with pancreatic cancer consider screening beginning at age 50 or 10 years younger than the age of diagnosis of the relative. 
  • For mutation carriers who choose pancreatic cancer screening, NCCN recommends that the screening be performed in an experienced facility. Before undergoing screening, people should have a conversation with their doctor about the potential benefits, risks, costs and limitations of screening.
  • Consider annual screening with contrast-enhanced MRI/MRCP (magnetic resonance cholangiopancreatography) and/or EUS (endoscopic ).
  • Consider enrolling in a research study looking at methods to screen for cancer, or agents to lower risk. 

There has not been enough research to show a benefit from screening and prevention for other cancers in people who have a  mutation. For this reason, experts recommend managing these risks based on family history of cancer. Cancer screening and prevention research studies may be available for people with  mutations. 

Updated: 11/26/2021

Questions to Ask Questions to Ask Your Doctor

  • I have an inherited mutation. What is my risk of cancer?
  • Given my inherited mutation, what preventive options should I consider?
  • I have been diagnosed with cancer; does my mutation status alter treatment recommendations?
  • I have a family history of cancer but I have not had genetic testing; should I consider genetic testing?
  • How do I contact a genetic counselor?

Open Clinical Trials Open Clinical Trials

The following are risk-management studies enrolling people with inherited mutations. Check study listings or contact the study team to see if you are eligible. 

Multiple cancers

cancer

  • NCT03805919: Men at High Genetic Risk for  Cancer. This is a  cancer screening study using  in high risk men. This study is open to men with , , , , , HOXB13, , , ,  and other inherited mutations.
  • NCT05129605: Cancer Genetic Risk Evaluation and Screening Study (PROGRESS).  This study will look at how well  MRI works as a screening tool for men at high risk for cancer. This study is open to men with inherited mutations in , , , , , , HOXB13, , , , , , , , , and other genes. 

Ovarian cancer

Pancreatic cancer

Additional risk-management clinical trials for people with inherited mutations may be found here.

Updated: 03/14/2022

Peer Support Peer Support

FORCE offers many peer support programs for people with inherited mutations. 

Updated: 03/12/2022

Who covered this study?

Cancer Therapy Advisor

PALB2 Linked to Increased Risk for Breast, Ovarian, and Pancreatic Cancer This article rates 3.0 out of 5 stars

How we rated the media

IN-DEPTH REVIEW OF RESEARCH

Study background

Inherited mutations in the gene were first linked to an increased risk of breast cancer in 2007. The protein made by the gene interacts with proteins to help cells repair (thus its name: Partner And Localizer of BRCA2). A large international research group estimated the risk of breast cancer among women with a mutation to be 14 percent by age 50 and 44 percent by age 80, based on a study of 154 families. Currently, is included in genetic testing for inherited mutations that increase breast cancer risk.

Mutations in have also been implicated in an increased risk of pancreatic and stomach cancers and possibly with ovarian and colorectal cancers as well. However, these previous studies were small and statistically unconvincing.

This study is the largest research of people with inherited PALB gene mutations to date. Because of the large number of participants, researchers could more accurately estimate the risk of multiple types of cancer for people with these mutations.
 

Researchers of this study wanted to know

Researchers wanted to estimate the risks of male and female breast cancer and ovarian, pancreatic, and colorectal cancers for people with inherited mutations.

 

Populations in this study

This study looks at cancer information from the largest group of people with mutations in the Interest Group. Participants included 524 families with inherited, deleterious mutations from 44 study centers in 21 countries. Families had at least one living family member with a . For this study, families with or mutations were excluded; only families with deleterious mutations that cause shorter or absent proteins were included. Families with missense mutations were excluded (due to a less certain impact of these mutations on protein function).

The family members included 8,830 women and 9,076 men. In this group, 852 women and 124 men had a mutation. The remaining family members did not have mutations. The makeup of this group allowed researchers to compare individuals with and without mutations who were from similar environmental and genetic backgrounds.

 

Study design

A modeling test called “complex segregation analysis” was used to estimate . Family members were followed from birth until diagnosis with a first cancer (excluding non-melanoma skin cancer), age of death, age of the last follow-up, age of risk-reducing mastectomy (for breast cancer estimates), age of risk-reducing salpingo-oophorectomy (RRBSO for ovarian cancer estimates), or age 80, whichever happened first.

 

Study findings

Models

Several genetic models were considered. Risk estimates were reported for the model with the best fit, which was plus some variable impact of additional family history for breast and ovarian cancer risk. This means that risk estimates may differ depending on whether there is no family history of that cancer or more family history.

For most cancer, the model reported was a constant lifetime risk. However, for breast and ovarian cancer, a model that varied by decade of life fit better or as well as a constant risk model.

Breast cancer risk in women

Women with an inherited mutation had a 7-fold greater risk of breast cancer compared to women without a mutation. This estimate assumes that a woman’s risk is constant over her lifetime.

A better fitting model varied risk by the decade of life. In these estimates, women with a mutation had their highest risk of breast cancer at age 25—a 13-fold greater risk of breast cancer compared to women without a mutation at the same age. The risk then declined by age 75, when women with a mutation had a 4.7-fold greater risk of breast cancer compared to women without a mutation at the same age.

The lifetime risk of breast cancer in women with a mutation was:

  • 17% by age 50
  • 53% by age 80 (for a woman with no family history of breast cancer)
    • The breast cancer risk for a woman with a mutation who has two close female relatives, e.g., mother and/or sisters who had breast cancer by age 50, is up to 76%.

Breast cancer risk in men

Men with an inherited mutation had a 7-fold greater risk of breast cancer compared to men without a mutation. This estimate assumes that their risk is constant over their lifetime.

The lifetime risk of breast cancer in men with a mutation was:

  • 1% by age 80

Ovarian cancer risk

Women with an inherited mutation had a 3-fold greater risk of ovarian cancer compared to women without a mutation. This estimate assumes that risk is constant over their lifetime.

In the model in which risk varied by the decade of life, a woman with a mutation had a lower risk of ovarian cancer by age 50, 2-fold greater than women without a mutation. Her risk increased to 4.7-fold by age 75 compared to women without a mutation. The constant model and this age-specific model were likely to be statistically equal.

The lifetime risk of ovarian cancer for women with a mutation was:

  • 0.6% by age 50
  • 5% by age 80 (for women with no family history of ovarian cancer)
    • The ovarian cancer risk for a woman with a mutation who has two close female relatives with ovarian cancer e.g., mother and/or sisters with ovarian cancer by age 50, is up to 16%.

Pancreatic cancer risk

People with inherited mutation had a 2.4-fold greater risk of pancreatic cancer compared to family members without a mutation. This estimate assumes that their risk is constant over their lifetime.

The lifetime risk of pancreatic cancer for individuals with a mutation was:

  • 2.2% by age 80 for women
  • 2.8% by age 80 for men

This study found no increase in the risk for or colorectal cancer.

 

Strengths and limitations

Strengths

  • This is the largest group of people with mutations to be considered to date. The size of the group means that there is greater confidence that the findings are accurate.
  • The models considered and the resulting range of risk estimates are clearly presented.
  • By looking at only clearly deleterious mutations, the findings are more robust and interpretable than prior studies that included missense mutations.

Limitations

  • This is study relies on self-reporting of information (past events). studies may be biased by participants’ recall of information.
  • The risk of a second primary breast cancer in women with mutations could not be determined.
  • Only people with known deleterious mutations were included. The risk of cancer for people with missense mutations in was not determined.
  • The cancer risk of people who had a mutation in both a and a gene was not determined. Because the proteins and the protein work together to perform repair, the combined effect of mutations in these genes is difficult to predict.
  • No information is provided about participants’ race or ethnicity or whether any difference in risk varies by race or ethnicity.

 

Context

Prior studies involving 154 families estimated the risk of breast cancer in women with an inherited mutation to be 14 percent by age 50 and 44 percent by age 80. As a result, genetic testing panels include when testing for inherited breast cancer genes. This study's results agree with the smaller, less certain prior studies on breast cancer in both men and women.

Links to pancreatic and stomach cancer have been reported with less clear links to ovarian and colorectal cancers. Overall, not much information was available about these cancers among people with known mutations. Prior studies of PALB2-related ovarian cancer risk produced inconsistent results. Some studies showed no increase, while others found substantial risk but these were small and not statistically significant. As the most extensive to date, this study included 524 families, nearly 18,000 individuals and provides more definitive results.

Although prior studies suggested that mutations may be linked to increased cancer risk, this study found no such increased risk.

 

Conclusions

mutations substantially increase the risk of breast cancer in women and men. The risk of ovarian cancer and pancreatic cancer in men and women is also higher. Establishing the lifetime risk of cancer for people with inherited mutations allows this information to be incorporated into risk models for healthcare decision-making.

 

Share your thoughts on this XRAY review by taking our brief survey.
posted 7/1/21

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