THE MOST MUTATED GENE WHEN CONSIDERING ALL CANCERS IS TP53. IS IT EQUALLY IMPORTANT IN BREAST CANCER?

Humans have 23 pairs of chromosomes. The chromosomes house 20 to 25,000 genes with each gene having two copies, one each from the father and mother. Each gene contains a genetic code for a protein. The proteins have specific functions and act as messengers for the cell. They perform duties such as monitoring how quickly cells divide into new cells, repairing mutations in DNA created during cell division, and controlling when a cell dies. The TP53 gene resides on chromosome 17, which can be seen in the accompanying image. When examining the genetic makeup of all cancers, scientists have discovered that the most mutated gene is TP53 (a gene mutation is also called a pathologic variant). More than 50% of cancers involve a missing or damaged TP53 gene. TP53 is a tumor-suppressor gene. In its normal state, it repairs mutations or mistakes made in DNA during cell division that could lead to cancer. The important study that I shall describe involves mutations present only in cancer, and not mutations passed through family members (germline mutations). 

A study by Park et al. was recently published in the Journal of Breast Cancer (2022;25:379-86) from Chung-Ang University, South Korea. The study included patients having surgery for breast cancer (stage I-III), and whose tumors underwent next generation sequencing (NGS) which identifies the genetic code for each cancer. This would be a good point to digress a bit to better define NGS. Before the development of new technology, each gene that researchers were interested in was individually sequenced. The Human Genome Project took 13 years to complete sequencing our entire genome as each gene required individual sequencing. Using next generation sequencing this task can be accomplished in a single day with the Guinness world record being a bit over 5 hours. 

A total of 801 patients had surgery for breast cancer from 2018-2021. Of these 258 had NGS for 50 cancer-related genes, and 219 were included in the study. The genes tested included some of the familiar ones such as BRCA1, BRCA2, CDH1, PTEN, TP53, and STK11 as well as a good number of genes that would be less familiar. TP53 mutations were associated with aggressive histologic features that included high nuclear and histologic grade as well as high Ki67.

PIK3CA was the most mutated gene in the study, identified in 97 patients (44%). There are targeted treatments for patients with PIK3CA who have hormone receptor-positive, HER-2 negative breast cancers, including the FDA-was approved alpelisib (Piqray). TP53 was the second most mutated gene in 79 (36.1%) patients, AKT1 in 23 (10.5%), and GATA3 in 20 (9.1%). PTEN, CDH1, BRCA2, HER2, AND BRCA1 were less commonly mutated.

Mutational characteristics and cancer subtypes
PIK3CA is most associated with the luminal A subtype (low-grade, hormone receptor-positive), whereas TP 53 mutations were more commonly found in cancers that were HER-2-enriched or triple negative. TP 53 mutations were less commonly found in luminal B (high-grade, hormone receptor-positive), both HER-2 positive and negative. GATA3 mutations were exclusively found in luminal (hormone receptor-positive) breast cancers. BRCA1 mutations were more likely to be found in the triple-negative subtype.

Survival
The researchers compared survival outcomes between wild-type TP53 (non-mutant) and mutant tumors. Overall, there were 11(5.0%) recurrences during 31 months of follow-up.  TP53 mutations were associated with significantly worse short-term disease-free survival. For other genes tested, there were no significant differences in survival. Univariate analysis showed that high nodal stage, high nuclear grade, high histologic grade, estrogen receptor negativity, and TP53 mutations were associated with recurrence. However, using multivariate analysis TP53 mutations were independently associated with short-term disease-free survival in breast cancer.

Other studies have shown that TP53 mutations are commonly identified in metastatic breast cancer samples. Other studies have also shown that TP53 mutations were associated with resistance to endocrine therapy, while another study suggested that tamoxifen was effective against breast cancer with a non-mutant TP53 gene. Though no drugs are currently available that target this gene mutation, such drugs are under investigation. In contrast to early breast cancer, mutations in the PIK3CA gene are a poor prognostic indicator in advanced breast cancer. And, as stated earlier there is an FDA-approved oral inhibitor for cancers with this gene mutation.

Conclusion
PIK3CA was the most mutated gene in this study. The second most mutated gene was TP53, which commonly had tumors that were HER-2 positive and triple negative. Most importantly, patients whose tumors had TP53 mutations were found to have worse short-term disease-free survival. Mutations in other genes found in this study were found to have no impact on disease-free survival. Although there are currently no drugs targeting breast cancers with TP53 mutations (though some may be on the horizon), knowledge of this mutation is important for designing future clinical trials.

Dr. Alan Stolier, MD, FACS, clinical breast oncologist, shares his expert medical perspective with a series of educational and scientific articles.