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

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:

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.
 

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Posted 9/30/21