Study: Genetic testing for inherited mutations may be helpful for all people with advanced or metastatic cancer

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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?

This study looked at how many cancer patients had inherited mutations and whether that changed their cancer treatment.

 

Why is this study important?

A growing number of treatments for advanced or metastatic cancer may benefit individuals with inherited mutations in genes that affect cancer risk. Genetic test results might guide these patients’ treatment decisions and improve their care. Despite this, metastatic cancer patients are not always offered genetic testing for inherited mutations. This study looked at people with metastatic cancer across different cancer types and measured the following:

  • how common inherited mutations are in this group of people.
  • how often that knowledge was “actionable” (might be used to guide treatment).

 

Study findings

How frequent are inherited mutations?

Researchers enrolled 11,947 patients from across the United States, including 9,079 participants (76 percent) who had metastatic or recurrent cancer. DNA from each participant was tested for inherited mutations in 76 to 88 genes that are associated with cancer risk.

  • 17% of participants tested positive for an inherited mutation in a gene linked to cancer.

Which inherited mutations may guide treatment?

Researchers listed all of the harmful (pathogenic or likely pathogenic) mutations found in participants and categorized them according to OncoKB knowledge base. OncoKB is a large database, which lists mutations that could potentially be used to guide treatment. 

  • Level 1 were mutations in genes with an FDA-approved drug treatment for the person's cancer type.
  • Level 3B were mutations in genes with an FDA-approved or investigational treatment for a different type of cancer than the participant's cancer.
  • Level 4 were mutations linked to response in a drug that was still being tested in clinical trials.

A potential treatment based on genetic test results existed for 10% of patients in this study.

  • 2,037 harmful inherited mutations were found among the participants.
  • 10% of patients had a harmful mutation with an actionable treatment:
    • 4% were Level 1 (linked to an approved-FDA drug treatment for their cancer).
    • 4% were Level 3B (linked to an approved-FDA drug treatment for a different tumor type).
    • 1% were level 4 (linked to evidence for a response to drug treatment in a clinical trial).

71% of participants did not know they had an inherited mutation; this knowledge might have guided their treatment.

  • Awareness of inherited mutation status differed by a gene mutation.
    • Of those who knew that they had an inherited mutation, most had a BRCA or Lynch syndrome gene mutation.
    • 20% of people with an ATM mutation knew of their mutation.
    • 19% of people with a PALB2 mutation knew of their mutation.
    • 4% of people with a RAC51C/D mutation knew of their mutation.
    • 4% of people with a BRIP1 mutation knew of their mutation.

How often do metastatic or recurrent cancer patients with an actionable inherited mutation have a gene-directed treatment that may be effective for someone with their mutation?

Researchers looked at medical records for all patients with metastatic or recurrent cancer who had Level 1 or 3B mutations to see if they had treatment based on their inherited mutation status.

  • 41% of patients with metastatic or recurrent cancer who had actionable inherited mutation received the corresponding gene-directed treatment.
    • 227 of 371 (61%) of patients with Level 1 mutations received a drug that was FDA-approved for their type of cancer.
    • 62 of 339 (18%) of patients with Level 3B mutations received a drug that was FDA-approved for a different type of cancer.
       

Strengths and limitations

Strengths

  • This was a large study that looked at multiple types of cancer.
  • All participants had DNA testing for known cancer genes regardless of the type of cancer they had.
  • The researchers determined whether the identified mutation had an approved treatment for that cancer or a different cancer and whether the participant received that treatment. This provided insight into gaps in gene-directed treatment.

Limitations

  • For some of the genes included on the actionable list, data supporting effectiveness for people with different cancer types is limited. The authors note this as a limitation and suggest that more research is needed to understand which treatments are most appropriate based on mutation and tumor type.
  • Many more patients had metastatic cancer than early-stage cancer. The selection and enrollment criteria were not entirely described. Because the participants did not represent a random sampling of cancer patients, it is unclear whether these findings will hold up for the general population.
  • The study looked at the medical records of patients who received care at the researchers’ institution. Care received by patients at other hospitals was not included in the study.
  • Nearly 20% of the participants were non-white; however, no information was given about whether the findings were the same or different for white and non-white participants. Sixteen percent of the participants were of Ashkenazi Jewish heritage; no additional racial or ethnic information was provided.
     

What does this mean for me?

If you have any type of metastatic or recurrent cancer, you may want to have genetic testing for inherited mutations. Test results may change your treatment plan or make you eligible for a clinical trial. For this reason, NCCN guidelines recommend that all patients with metastatic pancreatic, breast, ovarian or prostate cancer have genetic testing because this information may change their treatment plan. Genetic counseling is recommended before and after genetic testing to ensure that you have information about the risks and benefits and that you understand what that information means for your situation.

If you know you have an inherited mutation in a cancer gene, consider discussing with your doctor how that information affects your treatment options.

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

posted 9/30/21

 

Reference

Stadler ZK, Maio A, Chakaravarty D, et al. Therapeutic Implications of Germline Testing in Patients With Advanced Cancers. Journal of Clinical Oncology. 2021; 39(24): 2698-2709. Published online June 16, 2021.

 

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 metastatic or recurrent cancer

This article is also relevant for:

People with metastatic or advanced cancer

People with breast cancer

Men with breast cancer

People with colorectal cancer

People with endometrial cancer

People with ovarian cancer

People with pancreatic cancer

People with prostate cancer

Be part of XRAY:

Expert Guidelines

The National Comprehensive Cancer Network has guidelines on who should undergo genetic counseling and testing. If you have metastatic or advanced cancer, you should speak with a genetics expert about genetic testing if any of the following apply to you:     

  • Tumor testing found a mutation or another result that suggests you may have an inherited mutation linked to cancer. 
  • You have a blood relative who has tested positive for an inherited mutation. 
  • You have been diagnosed with breast, ovarian, pancreatic or prostate cancer. 
  • You had previous genetic testing prior to 2014 and your test was negative. 

This list is not comprehensive; other cancers may also be hereditary. If you are uncertain if you meet the guidelines above and you are interested in or considering undergoing genetic testing, you should speak with a cancer genetics expert

Updated: 11/12/2021

Questions to Ask Your Doctor

  • With my personal and family cancer history, should I consider genetic testing?
  • What are the risks and benefits of genetic testing?
  • How do I receive genetic counseling?
  • I have been newly diagnosed with an inherited mutation in a cancer gene. What options or changes would you suggest for my cancer treatment?
  • I have an inherited mutation in a cancer gene. What are my risks of different types of cancer given my mutation status?

Open Clinical Trials

Updated: 11/11/2021

Find Experts

Health care providers who are specially trained in genetics can help you more clearly understand your risk for hereditary cancer. The following resources can help you locate a genetics expert in your area.

  • The National Society of Genetic Counselor website offers a searchable directory for finding a genetic counselor by state and specialty. To find a genetic counselor who specializes in cancer genetics, choose "cancer" under the options "Area of Practice/Specialization." 
  • InformedDNA is a network of board-certified genetic counselors providing this service by telephone. They can also help you find a qualified expert in your area for face-to-face genetic counseling if that is your preference. 
  • JScreen is a program from Emory University that provides low-cost genetic counseling and testing. 
  • Grey Genetics provides access to genetic counselors who offer genetic counseling by telephone. 
  • The Genetic Support Foundation offers genetic counseling with board-certified genetic counselors. 
  • FORCE's toll-free helpline at: 866-288-RISK, ext. 704, can connect you with a volunteer board-certified genetic counselor who can answer general questions about genetic testing and hereditary cancer and help you find a genetic counselor near you. 
  • FORCE Peer Navigator Program will match you with a volunteer who has undergone genetic counseling and can help you navigate resources to find a genetic counselor near you.
  • Ask your doctor for a referral to a genetics expert. 

Updated: 11/12/2021

Who covered this study?

GU Oncology Now

Germline Sequence Analysis in Advanced Cancer This article rates 2.5 out of 5 stars

Cancer Therapy Advisor

Germline Testing Reveals Actionable Mutations in Advanced Cancers This article rates 1.0 out of 5 stars

How we rated the media

IN-DEPTH REVIEW OF RESEARCH

 

Study background

Genetic testing for inherited mutations has been used to identify high-risk people before they have cancer (previvors) or those with early-stage cancer to help guide risk-reducing treatment decisions. Historically, genetic testing for inherited mutations in metastatic cancer patients was uncommon. As new cancer treatments have been developed for people with inherited mutations, the need to understand when this information is most useful has grown. Over the last several years, research has shown that a substantial number of patients with metastatic ovarian, prostate or pancreatic cancer have inherited mutations and may benefit from targeted treatments. The National Comprehensive Cancer Network (NCCN) recommends genetic testing for inherited mutations for all of these patients.

While biomarker testing of tumors for mutations is common, metastatic cancer patients do not always have genetic testing for inherited mutations. Knowing about an inherited mutation might guide treatment decisions and improve care in metastatic cancer patients. This study focused on understanding the frequency of inherited mutations among metastatic patients regardless of cancer type and how often that knowledge was used to provide targeted cancer treatment.

 

Researchers of this study wanted to know

Researchers wanted to know the frequency of metastatic cancer patients who have inherited mutations and what portion of those had treatment tailored to their mutation status.

 

Populations looked at in this study

Researchers enrolled 11,947 patients from across the United States from January 2015 to May 2019. Among participants, 53.2 percent were female. While 60 percent were non-Ashkenazi Jewish, white patients, 16.3 percent were Ashkenazi Jewish and 19.5 percent were non-white, non-Ashkenazi Jewish. Race and ethnicity were unknown for the remaining 4.3 percent of participants. No additional information regarding race was given. The average age at cancer diagnosis was 55. The majority of participants (9,079 or 76 percent) had metastatic or recurrent cancer.

Participants had many different cancers:

Cancer type

Percent of participants

Percent with metastatic cancer

Breast

14%

73%

Prostate

14%

77%

Pancreatic

12%

88%

Colorectal

10%

72%

Uterine

7%

60%

Ovarian

6%

95%

Kidney

4%

70%

Bladder

3%

68%

Brain or CNS

3%

29%

Sarcoma

3%

74%

Other

22%

81%

 

Study design

DNA from tumor samples and normal blood samples of each participant was tested for inherited mutations in any of 76 to 88 genes that are associated with elevated cancer risk (4,593 patient samples were tested with a 76-gene panel; 7,354 were tested using an updated 88-gene panel).

Researchers listed all harmful (pathogenic or likely pathogenic) mutations.  Variants of uncertain significance were not included.

Mutations were then categorized according to their actionability in the OncoKB Knowledge base as of Sept 17, 2020:

  • Level 1: Mutations in genes with an FDA-approved drug treatment for that tumor type.
  • Level 1-MSI-H: Indicated mutations in Lynch Syndrome genes (MLH1, MSH2, MSH6 or PMS2) from patients whose tumors were also classified as having microsatellite instability (MSI-H) or DNA mismatch repair deficiency (dMMR). This category was independent of tumor type and was included with other Level 1 mutations.
  • Level 3B: Mutations in genes with an FDA-approved or investigational treatment in a different type of cancer.
  • Level 4: Evidence that the mutation is linked to drug response in an investigational drug
     

If a patient had multiple mutations, the highest level of those mutations was used.

Researchers looked at medical records for all patients with metastatic or recurrent cancer who had Level 1 or 3B mutations to determine whether they had a treatment based on their inherited mutation status.

 

Study findings

A substantial portion of participants had an inherited mutation in a gene that is linked to cancer risk.

  • 17% of participants  (77% with metastatic or recurrent cancer and 23% with early-stage cancer) had an inherited mutation.
  • 10% of all participants (with any stage cancer) had a harmful (pathogenic or likely pathogenic) inherited mutation in a gene with a high or moderate risk of cancer.
  • 4% of participants had an inherited mutation in BRCA1 or BRCA2.
  • 1% of participants had an inherited mutation in a Lynch Syndrome gene.

An actionable gene-directed treatment exists for 10% of patients.

  • 2,037 harmful inherited mutations were found among the participants.
  • 10% of patients had a harmful mutation with an actionable treatment:
    • 4% were Level 1 mutations that are linked to an FDA-approved drug treatment for that person's cancer.
      • Level 1 mutations occurred most commonly among those with nerve sheath tumors, prostate, ovarian, pancreatic or small bowel cancer.
    • 4% were Level 3B mutations that are linked to an approved-FDA drug treatment for a different type of cancer than the participant had.
    • 1% were level 4 mutations that are linked to evidence for a response to a drug treatment being tested in a clinical trial.

Most participants did not know they had an actionable inherited mutation.

  • 1,042 participants had an actionable inherited mutation. In other words, they were eligible for a cancer treatment that is designed to specifically target their cancer but would not have known that they were eligible for that treatment.
  • 71% of participants with an inherited mutation did not know they had an inherited mutation.
  • 29% of participants knew they had a harmful inherited mutation as a result of prior personal or family genetic testing.
    • Most people who knew their inherited mutation status had BRCA or Lynch syndrome mutations.
    • Among those with a BRCA1 or BRCA2 mutation, awareness of inherited mutation status differed by cancer type:
      • 75% of people with ovarian cancer knew their mutational status.
      • 69% of people with breast cancer knew their mutational status.
      • 40% of people with pancreatic cancer knew their mutational status.
      • 18% of people with prostate cancer knew their mutational status.
    • Awareness of inherited mutation status differed by gene mutation:
      • 20% of people with an ATM mutation knew their mutational status.
      • 19% of people with a PALB2 mutation knew their mutational status.
      • 4% of people with a RAC51C/D mutation knew their mutational status.
      • 4% of people with a BRIP1 mutation knew their mutational status.

Only half of the patients with metastatic or recurrent cancer who had an actionable inherited mutation received the corresponding gene-directed treatment.

Researchers asked how many of the 9,079 participants with metastatic or recurrent cancer received gene-directed cancer treatment. Participants with stage 3C ovarian cancer and inoperable nerve sheath tumors were included in this group.

  • 710 participants (8%) with metastatic or recurrent cancer had a level 1 or 3B inherited mutation.
  • 289 participants received treatment that was gene-directed.
    • 3.2% of the patients with metastatic/recurrent cancer (289 of 9,079 patients) received gene-directed treatment.
    • Only 41% of eligible patients (289 of 710 patients) received gene-directed cancer treatment:
      • 227 of 371 (61%) of patients with Level 1 mutations received gene-directed treatment.
      • 62 of 339 (18%) of patients with Level 3B mutations received gene-directed treatment.
  • 244 participants had cancer of an unknown primary, meaning that the location of the original tumor was undetermined. Of these, 22 (nearly 10%) people had an inherited mutation:
    • 11 had a mutation in BRCA1 or BRCA2
    • 2 had a mutation in a Lynch syndrome gene
    • 3 had a mutation in ATM
    • 3 had a mutation in PALB2
    • 2 had a mutation in CHEK1
    • 1 had a mutation in BARD1
       

Strengths and Limitations

Strengths

  • This was a large study that looked at multiple types of cancer. The size of the participant group means that observations are more likely to reflect the general population and less likely to occur by chance.
  • All participants had DNA testing for known cancer genes regardless of the type of cancer they had. This differs from panel testing that may have otherwise been specific to genes that are linked to their type of cancer.
  • The researchers associated whether the mutation identified had an approved treatment (for that cancer or a different cancer) with whether the participant received that treatment. This provided insight into gaps in gene-directed treatment.

Limitations

  • For some of the genes included on the actionable list, data supporting effectiveness for people with different cancer types is limited. The authors note this as a limitation and suggest that more research is needed to understand which treatments are most appropriate based on mutation and tumor type.
  • Many more patients had metastatic cancer than early-stage cancer. Because participants did not represent a random sampling of cancer patients—the selection and enrollment criteria were not entirely described—it is unclear whether these findings will hold up for the general population.
  • Nearly 20% of the participants were non-white people; however, no information was given about whether the findings were the same or different for white and non-white participants. No additional racial or ethnic information was provided other than that 16% of participants were of Ashkenazi Jewish heritage.
     

Context

Genetic testing for inherited mutations has become more available in recent years. Its use to help inform risk-reducing decisions for early-stage cancer patients has become more common. In contrast, people with metastatic cancer may not have had genetic testing for inherited mutations, despite the growing number of gene-directed treatment options that are now available. Prior studies of particular types of cancer (e.g., pancreatic or prostate) have shown that a substantial number of those with metastatic cancer have inherited mutations. This is the first study that looked at metastatic cancer patients with any type of cancer. These findings suggest that a portion of patients with unrecognized inherited mutations would be eligible for actionable treatments. Identifying these patients may allow them to take advantage of treatments that are otherwise unavailable to them.

 

Conclusions

A substantial portion of people with metastatic cancer in this study had inherited mutations with actionable gene-directed treatment options. Most people with metastatic cancer did not know that they had an inherited mutation; only 40% percent received gene-directed treatment for which they were eligible. The authors suggest that genetic testing for inherited mutations should be considered in addition to standard tumor testing for all patients with advanced or metastatic cancer.

 

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

Posted 9/30/21

 

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