Abstract Secretory variant invasive ductal carcinoma is not well described in the literature but is defined by its unique histopathology. These tumors stain positive for S100 and are typically triple negative hormonal cancers with an overall good prognosis. There is speculation that secretory carcinoma in adults is more aggressive with a greater likelihood for tumor recurrence. We present two case studies of this rare histopathologic diagnosis. First, a 76-year-old female with a recurrent secretory variant, invasive ductal carcinoma of the left breast. Second, a 68-year-old male who presented with invasive and in situ secretory carcinoma. A thorough chart review of all available institutional and outside institution records was performed from initial diagnosis to current treatment. Background information and de-identified patient information was summarized for this case series. This is a 76-year-old female who presented to her physician in 2011 with a palpable left breast and axillary mass. Her workup demonstrated ER+/PR+/HER2- invasive ductal carcinoma with lobular features of the left breast measuring 2.3 cm, along with a 1.5 cm malignant axillary lymph node. She underwent a left breast lumpectomy with axillary dissection. She underwent adjuvant whole breast radiation, axillary nodal radiation, and was placed on anastrozole therapy for 5 years. Seven years later a recurrence was noted in the superior aspect of the left breast. MRI guided biopsy revealed recurrent left breast cancer with pathology of invasive ductal carcinoma, secretory variant. She elected to undergo lumpectomy alone. Final pathology demonstrated invasive ductal carcinoma, secretory variant, ER negative (0%), PR negative (0%), HER2 negative (0%), pT1bNx. She underwent accelerated adjuvant partial breast radiation. Follow up and surveillance with bilateral breast MRI two years later demonstrated a new left breast mass, found to be triple negative, recurrent secretory variant invasive ductal carcinoma. She underwent definitive treatment with a left skin sparing mastectomy, right sentinel lymph node biopsy, and a latissimus dorsi flap with implant placement. Final pathology demonstrated multifocal recurrent secretory carcinoma, two foci measuring 6 and 11 mm. Our second patient was a 68-year-old male who initially presented to the clinic for evaluation of a ventral incisional hernia. During his initial assessment, a palpable retro-areolar nodule was noted on physical exam. Subsequent mammography demonstrated a hypoechoic mass with irregular margins measuring 2.8 x 2.3 x 1.7 cm along with increased vascularity and calcifications. An ultrasound guided biopsy demonstrated invasive secretory carcinoma. Initial pathologic testing of the tumor demonstrated ER positive (5%), PR positive (1%), and HER2 negative. The patient was taken to the operating room for a total mastectomy with sentinel lymph node biopsy. His postoperative pathology demonstrated negative margins, and invasive secretory carcinoma with lymph nodes negative for metastatic disease. Secretory variant of invasive ductal carcinoma is rare and is determined by its unique immunohistochemical features. We present two cases of secretory carcinoma at our institution. Data suggests that local recurrence is common in patients with secretory breast cancer, occurring in 33-44% of cases. Ki-67 index has been used as a prognostic indicator for metastases and recurrence of disease. Current treatment regimens are diverse; however, surgery is favored as the primary method. This report shows that although indolent, multifocality and recurrence is plausible. Given the limited data on this subset of carcinoma, more investigation is warranted to describe the effectiveness of adjuvant treatment options. Case 1 –insert figure image– Histopathologic examination at 200x shows invasive carcinoma with dense eosinophilic secretory material. By immunohistochemistry, the cells are negative for ER (0%) and PR (0%) with a HER2Neu score of 0, supporting the diagnosis of invasive secretory carcinoma. Case 2 –insert figure image– Histopathologic examination at 200x shows invasive carcinoma with dense eosinophilic secretory material. The tumor cells are positive for CK5/6 (patchy), CD117, ER (focal and weakly), and S100; negative for p63 and calponin, supporting the diagnosis of invasive secretory carcinoma. NTRK3 gene rearrangement was detected on fluorescence in situ hybridization (FISH). Citation Format: Lauren Geisel, Hemanth Venkatesh, Alyssa Obermiller, Quyen Chu, Jessica Gielow, Danielle Henry. Case Series: Invasive Secretory Carcinoma [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-20-10.