A patient with newly diagnosed breast cancer found to have mosaic <i>TP53</i> likely pathogenic variant

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. Initial biopsies demonstrated bilateral high-grade DCIS, both of which were ER-positive (90%–95%; strong). A separate biopsy of a left breast mass revealed a malignant fibroepithelial lesion containing a benign epithelial component and a high-grade malignant spindle cell component with lipoblastic differentiation. The spindle cell component was positive for CD34 and SMA (smooth muscle actin) and was negative for numerous cytokeratin stains and p63. Moreover, fluorescence in situ hybridization analysis was negative for amplification of MDNW (mouse double minute 2 homolog), excluding a dedifferentiated liposarcoma. Bilateral mastectomies were performed, and 22 mm of DCIS was found in the right breast, whereas the left breast contained a small (5.6 mm) malignant phyllodes tumor with lipoblastic differentiation; no residual DCIS was identified in the left breast (Figure 1, Figure 2, and Figure 3). The left breast mass biopsy contained a fibroepithelial lesion with overtly malignant, high-grade spindle cells and a benign epithelial component. Lipoblastic differentiation is present in the bottom right of the biopsy. The left mastectomy specimen contained a small (5.6 mm), malignant phyllodes tumor with lipoblastic differentiation, which was remote from ductal carcinoma in situ. Numerous ducts containing high-grade ductal carcinoma in situ, solid pattern, were identified in the right mastectomy specimen. Several years before presentation, the patient was diagnosed with a large left breast cyst and underwent excision. After that, she was recommended by her gynecologist to undergo annual mammographic screening alternating with whole-breast ultrasound in the setting of fibrocystic changes and dense breasts. Thus the patient began annual mammography screening before age 40 years and had four prior normal mammograms, with normal imaging 1 year before diagnosis. Of note, she did not undergo high-risk MRI screening, which would have been recommended annually starting at ages 25–30 years had her high-risk status been known.2 In patients with a new diagnosis of breast cancer, contrast-enhanced breast MRI is appropriate to evaluate for locoregional disease and can accurately assess tumor size and detect additional cancers in the ipsilateral or contralateral breast.3 The screening guidelines for breast disease depend on risk, and high-risk includes patients with genetic-based increased risk, those with a calculated lifetime risk of breast cancer ≥20%, and those exposed to chest radiation at young ages. Patients with genetic-based increased risk of breast cancer, annual breast MRI is recommended.1 If performed, such patients can delay mammographic screening until age 40 years rather than starting earlier than those with average risk. All women should undergo breast cancer risk assessment by age 25 years so that those at high risk can be identified and appropriate screening can be initiated earlier than age 40 years when appropriate.2 Her mammogram showed new calcifications in both breasts (Figure 4) and dense breast tissue, which limits the sensitivity of mammography.4 (A) Right and (B) left mediolateral oblique screening mammogram images and (C) right and (D) left craniocaudal screening mammogram images show extremely dense breast tissue and grouped calcifications in the right breast at 5 o'clock, posterior depth, and in the left breast at 12 o'clock, posterior depth (arrows). (E) Right craniocaudal magnification view also shows the right breast calcifications, which measure up to 7 mm (arrow). (F) Left craniocaudal magnification view also show the left breast calcifications, which measure up to 19 mm (arrow). Bilateral stereotactic biopsies with clip placement were performed. (G) Maximum-intensity projection image from a subsequent contrast-enhanced MRI shows minimal enhancement at the biopsy sites and a separate, 1.0-cm, irregular, enhancing mass in the left breast at 10 o'clock far posterior depth (arrow), which had suspicious washout enhancement kinetics. (H) A subsequent MRI-directed, targeted ultrasound showed a 0.8-cm mass at 10 o'clock, posterior depth, corresponding to the MRI finding (arrow). Ultrasound-guided biopsy with clip placement was performed. Subsequent whole-body MRI was performed without contrast and revealed no other suspicious findings. 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