A patient with newly diagnosed breast cancer found to have mosaic TP53 likely pathogenic variant

Abstract

CASE OVERVIEW

A 36-year-old, nulligravid woman with a history of controlled eosinophilic esophagitis, asthma, and dense fibrocystic breasts was referred to the Breast Health Center after abnormal screening mammography. She reported recent fatigue and intermittent diarrhea but had a negative colonoscopy and food allergy testing this year.

Her family history was significant for a maternal grandmother with a question of uterine cancer, a maternal grandfather who died of renal cancer at age 62 years, a paternal grandmother who died of brain cancer at age 56 years, a paternal grandfather who died of brain cancer at age 80 years, and a history of premalignant changes in the esophagus in her father. She has never smoked tobacco and consumes zero to three drinks of alcohol weekly. She has been physically active in multiple sports, including biking and swimming, and played the cello.

Mammography demonstrated extremely dense breast tissue with new calcifications in both breasts. Diagnostic mammography demonstrated indeterminate grouped calcifications spanning 19 mm in the right breast at 5 o'clock and 7 mm in the left breast 12 o'clock. She subsequently underwent stereotactic needle biopsies of both areas, which revealed right breast ductal carcinoma in situ (DCIS), nuclear grade 3, with 90% estrogen receptor (ER) expression; and left ductal carcinoma, nuclear grade 3, with 95% ER expression, 40% progesterone receptor (PR) expression, negative human epidermal growth factor receptor 2 (HER-2) status, and a Ki-67 index of 40%. Within the left breast biopsy there was an absence of myoepithelial cells, raising concern that the findings reflected an unusual type of invasive carcinoma. She then underwent bilateral breast magnetic resonance imaging (MRI), which revealed the known areas of DCIS in the bilateral breasts and also revealed a 1.0-cm mass inferior to the left breast DCIS at 12 o'clock that was considered suspicious. On subsequent ultrasound, it corresponded to an 8-mm mass in the left breast at 10 o'clock. A biopsy of the mass demonstrated a spindle cell tumor, favoring malignant phyllodes tumor with pleomorphic liposarcomatous differentiation that was negative for ER, PR, and HER2 (triple-negative), with a Ki-67 index of 30%.

At her multidisciplinary consultation, she was referred for genetic evaluation having met National Comprehensive Cancer Network (NCCN) criteria based on her diagnosis of breast cancer when younger than 50 years.¹ Given the concern for invasive left breast cancer and possible need for chemotherapy, she was also referred for fertility preservation.

She completed a comprehensive 76-gene germline genetic test, which revealed tumor protein p53 (TP53) likely pathogenic variant (LPV; c.716A>G; p.N239S). Pathogenic variants (PVs) and LPVs are DNA sequence changes that are associated with increased risk of disease. There is well established evidence that PVs are disease-causing, and LPVs are strongly suspected but have less definitive evidence. Both are considered positive results in genetic testing indicating a diagnostic result.

When TP53 PVs/LPVs are identified in a comprehensive germline panel, this raises concern for Li–Fraumeni syndrome (LFS). However, delineation of the origin of the TP53 PV/LPV is necessary because detection of the TP53 PV/LPV can occur through multiple mechanisms, including clonal hematopoiesis of indeterminate potential (CHIP), mosaicism, or a true germline finding.

She elected to proceed with bilateral skin and nipple-sparing mastectomy with left axillary sentinel lymph node (SLN) biopsy (SLNB) and Magtrace injection (Endomag; A Hologic Company) into the right breast for delayed SLNB. Neurotization of flaps was performed with a nerve graft from the fourth and fifth intercostal nerves to the nipple–areolar complex and placement of prepectoral tissue expanders. She recovered well after surgery, and the final pathology revealed right breast DCIS, no residual left breast DCIS, and a malignant phyllodes tumor excised to negative margins. Left SLNB was negative, and axillary lymph node dissection was not required.