Study: What is the risk for a new breast cancer diagnosis in the other breast for women with a BRCA1, BRCA2 or TP53 mutation?

IN-DEPTH REVIEW OF RESEARCH

Study background:

The risk of breast cancer is greater among woman with an inherited mutation and depends on which gene is mutated. Mutations in BRCA1 and BRCA2 are associated with an increased risk of breast, ovarian and other cancers. The lifetime risk of breast cancer in women with BRCA1 or BRCA2 mutations is estimated to range from 55 to 85 percent. Inherited mutations in the gene TP53 lead to a disease called Li-Fraumeni Syndrome (LFS) that is associated with increased risk of several types of cancer at young ages. The number of people with TP53 mutations is much lower (about 1 in 5,000 to 20,000 people) than those with BRCA1 or BRCA 2 mutations (about 1 in 500 people). However, the lifetime risk of cancer for those with TP53 mutations is high—up to 85 percent—akin to BRCA mutations. Diagnosis of breast cancer at an early age is known to indicate high risk of an inherited mutation.

The presence of an inherited mutation also increases the risk of a second breast cancer in the opposite (contralateral) breast. A review of multiple studies reported that the 10-year cumulative risks of contralateral breast cancer were 27 percent and 19 percent, respectively, among women with BRCA1  and BRCA2 mutations. Data on contralateral breast cancer among women with TP53 mutation is lacking, although the National Cancer Institute’s LFS Study observed that half of individuals developed a second primary cancer, with breast cancer being the most common second cancer diagnosis.

Contralateral breast cancer is generally thought to be a second primary cancer. These contralateral breast cancers may be have metastasized from the first primary cancer, although metastases typically have other patterns. Women who have an inherited mutation in a gene that predisposes them to breast cancer are predicted to have higher rates of second cancers in the breast or other susceptible organs. This study examined the frequency of inherited mutations and contralateral breast cancer with a focus on women under age 36 with BRCA1, BRCA2 and TP53 mutations.

Researchers of this study wanted to know:

What the risk of breast cancer is in the other breast of women diagnosed with breast cancer at a young age (under 36) who had a harmful mutation in BRCA1, BRCA2 or TP53.

Populations looked at in this study:

A total of 397 women diagnosed with breast cancer under age 36 participated in this study. Participants were identified from three groups in Britain: a North West England population study that enrolled participants from 1980 to 1997, referrals from St. Mary's Hospital from 1990 to 2018 and the Family History Clinic at Wythenshawe Hospital in South Manchester.

Study design:

Researchers confirmed the breast cancer diagnosis and family history of each participant from hospital and other records. Participants were defined as having a family history if they had one or more close relative under age 65 with breast cancer or ovarian cancer at the time of the participant's diagnosis.

Researchers sequenced the DNA of participants to identify mutations in the BRCA1, BRCA2 or TP53 genes (including copy number variations). For the purpose of this study, researchers only considered pathogenic or likely pathogenic mutations. Researchers tested genes based on prior information of genes that are most likely to be present among women with very early breast cancer; researchers did not test for other known breast cancer genes. (For example, women with mutations in genes such as CHEK2 or PALB2  typically have breast cancers at ages over 36).

Researchers tracked health information about each participant from the time of their initial diagnosis up to 20 years later, including history of contralateral breast cancer, last healthcare assessment and whether they were living or dead or had undergone risk-reducing mastectomy.

Participants diagnosed with contralateral breast cancer within three months of their original breast cancer diagnoses were defined as having synchronous bilateral breast cancer (two or more primary tumors in different breasts during the same time period).

Annual rates for contralateral cancer were calculated as a proportion of the total years of follow-up until the contralateral breast cancer occurred or until the participant either had risk-reducing mastectomy, left the trial or died.

Study findings:  

60% of women diagnosed before age 36 had an inherited mutation in BRCA1, BRCA2 or TP53 (see table).

• BRCA1/BRCA2: 53% of women under age 36 who were diagnosed with breast cancer had a mutation in either BRCA1 or BRCA2. This matches prior reports of BRCA mutations in young women.
• TP53: 7% of women (approximately 1 in 14) in this study had TP53 gene mutations compared to 1 in 5,000-20,000 of unselected people in the general population. As expected, the number of women with breast cancer diagnosed before age 36 included many more women with TP53 mutations than in the general population. This reflects the high risk of breast cancer in young women who have a TP53 mutation.

• 25% of women with an inherited mutation had contralateral breast cancer during the study. The average time to diagnosis was 7 years, 7 months (ranging from 0 to 29.5 years after their first diagnosis).
• The time to diagnosis of contralateral breast cancer was similar for women in all three mutation groups:
  • BRCA1/BRCA2
    • 23% of women with a BRCA1 mutation had a contralateral breast cancer.
    • 25% of women with a BRCA2 mutation had a contralateral breast cancer.
    • Among 6 women (4 with BRCA 1 and 2 with BRCA2 mutations), contralateral cancer was detected within 3 months of their original diagnosis and was therefore considered to be a synchronous cancer. These rates match prior reports of BRCA mutations in young women. One woman who had a mutation in both BRCA1 and BRCA2 was omitted from the analysis.
  • TP53
    • 30% of women with a TP53 mutation also had a contralateral breast cancer. Two women had synchronous contralateral cancers.
    • This high rate of contralateral breast cancer is consistent with the observations that TP53 increases the risk of breast diagnosis at a young age.

• 5% of women with no identified mutation had a contralateral breast cancer. This includes women (7%) with a known family history of breast and ovarian cancer who have contralateral breast cancer, similar to the group (8%) with no family history. These women may have had no mutation in their family, may not have inherited their family's mutation but developed an early sporadic cancer, or they may have had a mutation in another gene that increased breast cancer risk (e.g., CHEK2), but at a lower rate or typically later onset. The average time to diagnosis was 9 years, 9 months (ranging from 1 year, 7 months to 18 years after their first diagnosis). Among women without a mutation, none of the contralateral breast cancers were synchronous.

• The annual rate of contralateral breast cancer was almost 10 times higher in women who had an inherited mutation (3.4 percent) than among women who had no mutation (0.4%). In other words, on an annual basis, a woman with an inherited mutation was more likely to have contralateral breast cancer diagnosed than a woman without an inherited mutation (see table below). The cumulative risks of breast cancer for women with a BRCA1, BRCA2 or TP53 mutation at 5, 10 and 15 years are shown below.

• BRCA1/BRCA2: 53% of women under age 36 who were diagnosed with breast cancer had a mutation in either BRCA1 or BRCA2. This matches prior reports of BRCA mutations in young women.
• TP53: 7% of women (approximately 1 in 14) in this study had TP53 gene mutations compared to 1 in 5,000-20,000 of unselected people in the general population. As expected, the number of women with breast cancer diagnosed before age 36 included many more women with TP53 mutations than in the general population. This reflects the high risk of breast cancer in young women who have a TP53 mutation.

*Excludes synchronous breast cancers that occurred within 3 months of original diagnosis
** Adjusted for women who had risk-reducing mastectomy, left the study or died.
n.d. = not reported numerically

• BRCA1/BRCA2: The annual rate of contralateral breast cancer was 3.6% for women with a BRCA1 mutation and 2.6% for women with a BRCA2 mutation. The cumulative risks of having breast cancer in the other breast 10 years after diagnosis were 32% and 21% for women with a mutation in BRCA1 and BRCA2, respectively, in this study. This is similar to prior studies that observed 27% and 19% rates for BRCA1 and BRCA2, respectively. The study authors suggest that the slightly higher rates observed may reflect increased surveillance given the knowledge about mutation status.
• TP53:  The annual rate of contralateral breast cancer was 7% for women with a mutation in the TP53 gene, twice the annual risk of women with a BRCA mutation and almost 18 times the risk of women without a TP53 mutation. Among study participants with TP53 mutations, 45 developed a contralateral breast cancer within 10 years, while 82% developed contralateral breast cancer within 20 years of their original diagnosis. This matches the 85% rate of any cancer by age 60 observed among people with TP53 mutations. These observations strongly suggest that women with TP53 mutations may want to consider bilateral prophylactic mastectomy or hormone-modulating drugs such as tamoxifen, and at minimum, have a robust surveillance plan.

• Women with TP53 mutations (6%) were less likely to have risk-reducing mastectomy than their counterparts with BRCA mutations (16 to 17%), despite having a risk of contralateral breast cancer that was 18 times more likely than women without a mutation and twice as likely as women with a BRCA mutation.

At time of original diagnosis, women with BRCA or TP53 mutations should discuss their risk of contralateral breast cancer with their healthcare providers for fully informed decision making.

Strengths and limitations:

Strengths of this study include:

• A considerable group of participants with breast cancer under age 36, including a large number of participants with BRCA1 and BRCA2 mutations.
• Long-term follow-up of the participants.

Limitations of this study include:

• A limited number of TP53 participants. While larger than many studies, the number of participants with TP53 mutations limits the possible subgroup analyses.
• Lack of pathology details on medical records limited analysis for grade or receptor status, particularly in patients who were diagnosed before 1990.
• Limited information about cancer treatment. The authors note that endocrine therapy may impact the rate of contralateral breast cancer observed, likely reducing it. Similarly, radiation therapy may increase rate of second cancers in people with TP53 mutations.
• Lack of information about menopausal status or risk-reducing oophorectomy, which may impact rates of breast cancer.
• This study took place in one region of Britain, therefore it is not clear how generally the results can be applied to other populations in terms of the rates of mutations among young women with breast cancer. Furthermore, participants in this study were selected from a mixture of a population study and more selected high-risk families in Britain. Other populations may have a different rate of mutations in these particular genes.

Conclusions:

In this study of a selected, high-risk sample of the British population, the majority of women diagnosed with breast cancer under age 36 have an inherited mutation. The rate of contralateral breast cancer is high for women with mutation in the BRCA1, BRCA2 or TP53 genes; this risk increases each year from the time of first diagnosis.