Abstract PD14-09: PD14-09 The effect of timing of TP53 genetic testing on treatment and outcomes among women with Li-Fraumeni syndrome and breast cancer
Authors: Sandoval Renata , Bottosso Michele , Polidorio Natalia , Bychkovsky Brittany , Verret Benjamin , Gennari Alessandra , Hyman Sophie , Achatz Maria Isabel , Caron Olivier , Andre Fabrice , Garber Judy 
Published: March 2023

Abstract
Background: Li-Fraumeni syndrome (LFS) is a pan-cancer predisposition syndrome caused by pathogenic germline TP53 variants. Breast cancer (BC) is the most prevalent tumor in women with LFS. The risk of secondary malignancies, including multiple primary BCs, other LFS-related cancers, radiation-induced sarcomas, and local recurrences are important clinical concerns in the LFS setting. The diagnosis of LFS may influence treatment decisions and outcomes. Methods: In this international multicenter study, we analyzed women with pathogenic or likely pathogenic germline TP53 variants and BC (DCIS or invasive breast carcinoma) diagnosed 2002-2022 from three retrospective LFS cohorts (Dana Farber Cancer Institute, USA; Institut Gustave Roussy, France; Hospital Sírio-Libanês, Brazil). We excluded carriers of TP53 unconfirmed possibly mosaic variants, carriers of a 2nd pathogenic variant in another BC susceptibility gene, and those with missing data related to timing of genetic testing (TGT) or date of 1st BC diagnosis (dx). The overall cohort was divided in two groups: genetic testing before or at 1st BC dx (group A) and those with testing ≥1 year after 1st BC dx (group B). In cases with synchronous bilateral BC, we included the tumor of higher risk of recurrence (invasive, higher stage, more aggressive tumor biology) and excluded the other. The chi-square test was used to measure the association between TGT and other categorical variables. Results: 209 patients (pts) met criteria for this analysis. The median age of 1st BC dx was 35 years (IQR, 31-42). BC was the 1st cancer dx in 87.5% of the pts. Among 1st breast tumors, 38 were DCIS, 147 were early-stage BC (61 I, 49 II, 37 III) and 7 stage IV (17 missing). There were no differences between groups A and B regarding staging at dx. Missense TP53 variants were the most common type of germline mutation (n=154, 73.6%), with 60.4% (n=93) in the DNA-binding domain and 38.9% (n=60) in the tetramerization domain. Median follow-up from 1st BC dx was 6 years (IQR, 3-10). 53.1% of pts (n=111) underwent TP53 germline testing only after 1st BC dx. Family history of BC &lt; 50 and non-BC malignancy prior to or synchronous with 1st BC dx were not associated with TGT (p=0.3 and p=0.2, respectively). 35.4% of pts developed a second primary BC (25 ipsilateral; 49 contralateral). Among pts without synchronous bilateral BC or metastatic BC at dx, 97 pts underwent contralateral risk reducing mastectomy (CRRM), 56.7% (55/97) as part of treatment surgery for the 1st BC. CRRM uptake was associated with TGT (A 70.3% vs B 41.6%, p=0.001). Of 194 pts with detailed data on surgical treatment (1st BC), 146 underwent mastectomies and 48 breast conserving surgery (BCS). Group A had more mastectomies (79.5% vs 61.2%, p=0.001) and less radiation therapy (10.2% vs 45.9%, p&lt; 0.001). Among the irradiated pts, 9.8% (n=5) developed sarcomas in the irradiated field. Thirty-eight pts had BC recurrence: 21 loco-regional (A 6 vs B 15, p&lt; 0.05), mostly in-breast, and 17 distant relapses. There was a significant statistical association between TGT and type of BC surgery (p=0.001), radiation-therapy (p&lt; 0.001), CRRM uptake (p=0.001) and local relapses (p&lt; 0.05). Conclusion: This analysis of BC in our sizable cohort of LFS patients with treatment data confirms that, timing of genetic testing affects some treatment options and outcomes, including surgical procedures and use or avoidance of radiation. These decisions appear to influence the risk of local recurrence or additional primary BC and radiation-induced sarcoma. Recognition of germline TP53 variants in breast cancer patients as part of genetic testing at diagnosis appears to have implications for treatment options and outcomes.
Citation Format: Renata Sandoval, Michele Bottosso, Natalia Polidorio, Brittany Bychkovsky, Benjamin Verret, Alessandra Gennari, Sophie Hyman, Maria Isabel Achatz, Olivier Caron, Fabrice Andre, Judy Garber. PD14-09 The effect of timing of TP53 genetic testing on treatment and outcomes among women with Li-Fraumeni syndrome and breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD14-09.