As a genetics trained oncologist, I began taking care of patients with Li Fraumeni Syndrome in 2016. I was learning human genetics and genomics in a postdoctoral fellowship in Dr. Kate Nathanson's lab while starting my clinical practice. In the last nine years, I have seen over 200 patients with this devestating, rare genetic syndrome. Patients with LFS have a near certainity of developing cancer in their lifetimes. Some develop cancer in childhood, and some not until middle age; some patients develop no cancer and some patients can develop five or more cancers.
While there are significant differences in presentation, a nearly universal feature of LFS in females is the development of breast cancer. Developing at a median age of 32 (compared to 60s in the general population), some patients develop breast cancer in their early 20s. Half of the time these breast cancers overexpress HER2, as compared to ~10% of the general population. Because of this, breast cancers in LFS females nearly always require chemotherapy for treatment, even at early stages. There is also an extremly high chance of second breast cancers and individuals with LFS have a secondary cancer risk with radiation; therefore nearly all young women with LFS related breast cancer undergo bilateral mastectomy as treatment.
Because of these characteristics, many young women with LFS are considering prophylactic mastectomy as early as their late teens and early 20s. This decision has a significant impact on their lives. A major goal of my career is to develop either cancer interception strategies or early biomarkers to help women delay this difficult decision. Understanding these breast cancers is also important for developing novel treatments in the cases where early surgery is not sufficient for treatment or when recurrence unfortunately develops.
With the help of the patient advocacy group Li Fraumeni Syndrome Association (LFSA), I formed a multidisciplonary team, incuding Arnie Levine, the scientist who originally dicovered p53. Dr. Levine connected me with Dr. Ben Greenbaum at MSKCC and Dr. Kurt Schalper at Yale, both experienced in cancer immunology. Using DNA and RNA sequencing of tumors along with multiplex immunofluorescence of immune markers in breast cancers from LFS patients compared to age-matched controls, our study reveals two important aspects of germline TP53 driven breast cancer development:
1) LFS breast cancers have specific amplification of short segments of aneuploidy that select for oncogenic amplifications, explaining the frequent HER2+ state in LFS breast ancer patients.
2) LFS breast cancer have increased infiltration by cytoxic T-cells.
As a followup to this study, we are now focused on identifying the mechanism of oncogene amplification in the heterozygous TP53 mutant breast. We are also interested in exploring the potential of immune modulation to intercept early breast cancers in LFS patients.