Abstract P1-10-27: NTHL-1 Syndrome in a Breast Cancer Survivor: Malignant Pleural Effusion Unveils Metastatic Colon Adenocarcinoma

Abstract NTHL1-associated tumor syndrome is an autosomal recessive disorder stemming from mutations in the NTHL1 gene, initially linked with colorectal cancer but now recognized to elevate risks for various malignancies like breast, bladder, and endometrial cancers. This syndrome, characterized by NTHL1-associated polyposis and multiple adenoma development in adults, affects an estimated 0.014% of the population. NTHL1 encodes a DNA glycosidase crucial in repairing oxidatively damaged DNA via the base excision repair pathway. We present a case which highlights the complex and diverse nature of NTHL1-associated tumor syndrome in a 40 year old premenopausal woman who developed ER+PR+HER2- invasive ductal carcinoma of the left breast in 2021. Subsequently, she underwent a left mastectomy and sentinel lymph node biopsy in May 2021, with one out of three sentinel lymph nodes positive for metastatic carcinoma. Post-operatively, she completed four cycles of docetaxel and cyclophosphamide chemotherapy followed by radiation therapy and tamoxifen. Post-surgical staging was determined as (m)pT2pN1a(sn)Mx. Two years after her breast cancer diagnosis, she developed new-onset dyspnea. Further investigation revealed a pleural effusion with pathology consistent with colon adenocarcinoma, despite no primary lesions being identified during subsequent EGD and colonoscopy. Genetic testing uncovered a heterozygous NTHL1 recessive mutation. The patient was initiated on first-line therapy for metastatic colon cancer and eventually passed within 6 months of therapy. Heterozygous carriers of NTHL1 mutations face cancer risks, with emerging evidence suggesting increased breast cancer susceptibility, though precise risk estimates and management changes remain unclear. Recognition of NTHL1 syndrome's clinical heterogeneity and overlaps with other hereditary cancer syndromes underscores the importance of early genetic testing for accurate diagnosis and management. Despite its rarity, increasing awareness and research are vital to comprehending and managing this complex syndrome. Recent studies highlight that heterozygous NTHL1 carriers may confront notable cancer risks, such as colorectal and breast cancers. However, current literature lacks surveillance guidelines for these individuals. Understanding the prevalence and clinical implications of both heterozygous and homozygous NTHL1 mutations is critical for effective risk assessment, genetic counseling, and clinical management. Further research into molecular mechanisms and gene-environment interactions is essential to delineate how these mutations influence disease progression. Citation Format: Marian Varda, Lauren K Lewis, Charity A Huang. NTHL-1 Syndrome in a Breast Cancer Survivor: Malignant Pleural Effusion Unveils Metastatic Colon Adenocarcinoma [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-10-27.