Risk of Secondary Cancer After Radiotherapy in Patients With TP53-Mutant Breast Cancer

Radiotherapy, a frequently used and effective treatment for breast cancer, may nevertheless increase the risk of developing other types of cancer after treatment in patients with certain genetic variants.

NOTE: A genetic variant refers to a difference in the DNA sequence and can occur in different forms in each individual. A mutation is a permanent change in genetic material; every mutation is a variant, but not every variant is a mutation, because some variants may be harmless.

In particular, patients with pathogenic TP53 variants may face a risk of developing secondary cancers such as sarcoma after radiotherapy. On September 12, 2024, JAMA Oncolgy published a study examining the risk of secondary cancers after radiotherapy in patients with breast cancer who carry pathogenic TP53 variants, and discussing how these findings should be taken into account when planning treatment.

The Importance of TP53

A TP53 mutation occurs when TP53, an important tumor suppressor gene that controls cell growth and division, is altered. People with pathogenic mutations in this gene have an increased tendency for their cells to become cancerous, because TP53 loses its ability to repair DNA damage or eliminate the cell. TP53 mutations substantially increase not only the risk of one type of cancer but also the risk of multiple cancers, making lifelong cancer screening essential for these patients. In particular, individuals with this mutation may have an even higher risk of developing second cancers following treatments such as radiotherapy.

The JAMA Study

The risk of developing secondary cancers after radiotherapy in patients with breast cancer who carry germline (inherited) TP53 variants had not previously been fully understood. To clarify this issue, researchers evaluated carriers of germline TP53 variants: 91 patients with breast cancer. Some of these patients received radiotherapy, while others did not.

• Of the 91 patients, 40 received radiotherapy and 51 did not.
• Patients who received radiotherapy had more advanced tumors and high-grade tumors with greater axillary lymph node involvement.
• The researchers observed the development of secondary cancers in these patients over a median follow-up of 14 years.
• The study specifically examined the risk of developing sarcoma among patients who had received radiotherapy.

Striking Findings: The Effect of Pathogenic TP53 Variants

The study's main finding was that patients carrying pathogenic TP53 variants had an estimated 8.8% risk of developing sarcoma within 15 years after radiotherapy. No sarcomas developed in patients who did not receive radiotherapy. Sarcoma is a specific type of cancer, and the study emphasizes that this type of cancer is seen more frequently after radiotherapy.

Risk of Any Secondary Cancer: Among patients carrying pathogenic TP53 variants, the estimated risk of developing any secondary cancer within 10 years was 22.5% in those who received radiotherapy and 38% in those who did not. This is a broader measure and includes types of secondary cancer other than sarcoma.

In summary: Radiotherapy appears to increase the risk of a specific type of cancer, such as sarcoma (8.8%). Overall, however, when secondary cancers other than sarcoma are included, the risk is even higher in those who did not receive radiotherapy (38%). The lack of a statistically significant difference among those who received radiotherapy suggests that the effect on patients' overall cancer risk is limited. In other words, there is a risk of sarcoma after radiotherapy, but the difference in overall secondary cancer risk is not very pronounced.

There was also no significant difference in overall survival rates between carriers of pathogenic TP53 variants who received radiotherapy and those who did not.

The Importance of Balancing Treatment and Risk

These findings show that the benefits and risks of radiotherapy must be carefully weighed in patients carrying pathogenic TP53 variants. The authors emphasize that these patients are at high risk of developing secondary cancers and that most of these cancers are not related to radiotherapy. The therapeutic benefits of radiotherapy must be weighed against the risk of secondary cancer, particularly in patients with high-risk breast cancer.

Limitations of the Research

This study has several limitations:

• The study involved a limited number of patients, which may restrict the generalizability of its findings.
• Analyses based on retrospective, de-identified data may introduce certain biases.
• In addition, there are insufficient data to capture all long-term outcomes.

Conclusion: Personalized Treatment Approaches

This study shows that secondary cancer risks must be considered when planning treatment for patients with breast cancer who carry pathogenic TP53 variants. The balance between the therapeutic benefits of radiotherapy and the risk of secondary cancer plays a critical role, particularly for patients with these genetic variants. Personalized treatment approaches are therefore expected to become increasingly important in minimizing such risks.