PS5-06-16: A case of triple negative breast cancer in Lynch Syndrome

Abstract Background: Although there are numerous inherited syndromes that predispose individuals to developing breast cancer, it is inconclusive whether Lynch syndrome (LS) increases the risk of breast cancer. We present a case of a triple-negative breast cancer in a woman with LS. Case Presentation: Our patient is a 73-year-old woman with a past medical history of LS (MSH2 deletion), endometrial cancer status-post TAH/BSO, rectal cancer status-post abdominoperineal resection and end ileostomy, and colon cancer status-post right hemicolectomy/appendectomy and chemotherapy with 5-fluorouracil and leucovorin. A 2.7 cm mass was found in her right breast during a screening mammogram. MRI showed a 3.7 cm right breast mass. CT of the chest, abdomen, and pelvis showed no lymphadenopathy or evidence of metastatic disease. Biopsy of the right breast mass indicated grade 3 invasive ductal carcinoma with ER 10%, PR 2%, HER2 1+. She began neoadjuvant chemoimmunotherapy based on the KEYNOTE-522 trial. Chemoimmunotherapy was discontinued after five cycles due to intolerable side effects, including neuropathy, rash, and musculoskeletal pain. She then underwent a bilateral mastectomy with sentinel lymph node biopsy, which revealed residual invasive ductal carcinoma measuring 6 mm without lymph node involvement, consistent with stage ypT1b pN0. Pembrolizumab was resumed. Adjuvant treatment with dose-reduced capecitabine was initiated following the CREATE-X trial. Discussion: Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is an inherited condition caused by germline mutations in DNA mismatch repair genes, including MLH1, MSH2, MSH6, and PMS2. LS is well known to increase the risk of multiple cancers, such as colorectal, endometrial, ovarian, and stomach cancers. Breast cancer has not been considered a part of the LS spectrum. Despite several studies, a clear link between LS and breast cancer has not been established. A few studies have also looked at the possible association between pathogenic variants of LS and breast cancer risks; however, the data have not been consistent. A cohort study by Sheehan et al. found a significantly higher prevalence of breast cancer in women with PMS2 mutations compared to other genetic alterations, while a study by Scott et al. reported overrepresentation of breast cancer in MLH1 mutations compared to MSH2 mutations. Currently, LS screening guidelines recommend general population-based screening for breast cancer. Immunotherapy with PD-1 blockade has demonstrated profound results with mismatch repair-deficient colorectal cancer as well as other cancers such as endometrial, gastric, pancreatic, ovarian, and cholangiocarcinoma, but whether this translates to breast cancer is unknown. In this case, the patient with triple-negative breast cancer and LS received five cycles of neoadjuvant chemoimmunotherapy, and her mass decreased from 3.7 cm before treatment to 6 mm pathologically. There are no treatment recommendations specific to LS patients with breast cancer. Larger prospective studies are warranted to establish a potential need for intensified breast cancer screening in patients with LS, as well as to study outcomes of breast cancer in LS patients. References: Sheehan, M. et al. Eur J Breast Health 2020; 16(2): 106-109. Schmid, Peter et al. “Pembrolizumab for Early Triple-Negative Breast Cancer.” NEJM vol. 382,9 (2020): 810-821. Masuda, Norikazu et al. “Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy.” NEJM vol. 376,22 (2017): 2147-2159. Scott, R J et al. “Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds.” American journal of human genetics vol. 68,1 (2001): 118-127. Cercek, A et al. “Nonoperative Management of Mismatch Repair-Deficient Tumors.” NEJM vol. 392, 23 (2025): 2297-2308. Citation Format: H. Bhatt, D. A. Rabinovich, M. E. Auster. A case of triple negative breast cancer in Lynch Syndrome [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-06-16.