Purpose Age is one of the strongest risk factors for the development of breast cancer, however, the underlying etiology linking age and breast cancer remains unclear. We have previously observed links between epigenetic aging signatures in breast/tumor tissue and breast cancer risk/prevalence. However, these DNA methylation-based aging biomarkers capture diverse epigenetic phenomena and it is not known to what degree they relate to breast cancer risk, and/or progression. Methods Using six epigenetic clocks, we analyzed whether they distinguish normal breast tissue adjacent to tumor (cases) vs normal breast tissue from healthy controls (controls). Results The Levine (p = 0.0037) and Yang clocks (p = 0.023) showed significant epigenetic age acceleration in cases vs controls in breast tissue. We observed that much of the difference between cases and controls is driven by CpGs associated with polycomb-related genes. Thus, we developed a new score utilizing only CpGs associated with polycomb-related genes and demonstrated that it robustly captured epigenetic age acceleration in cases vs controls (p = 0.00012). Finally, we tested whether this same signal could be seen in peripheral blood. We observed no difference in cases vs. controls and no correlation between matched tissue/blood samples, suggesting that peripheral blood is not a good surrogate marker for epigenetic age acceleration. Conclusions Moving forward, it will be critical for studies to elucidate whether epigenetic age acceleration in breast tissue precedes breast cancer diagnosis and whether methylation changes at CpGs associated with polycomb-related genes can be used to assess the risk of developing breast cancer among unaffected individuals.
Purpose: Age is one of the strongest risk factors for the development of breast cancer, however the underlying etiology linking age and breast cancer remains unclear. We have previously observed links between epigenetic aging signatures in breast/tumor tissue and breast cancer risk/prevalence. However, these DNA methylation-based aging biomarkers capture diverse epigenetic phenomena and it is not known to what degree they relate to breast cancer risk, and/or progression. Methods: Using six epigenetic clocks, we analyzed whether they distinguish normal breast tissue adjacent to tumor (cases) vs normal breast tissue from healthy controls (controls). Results: The Levine (p=0.0037) and Yang clocks (p=0.023) showed significant epigenetic age acceleration in cases vs controls in breast tissue. We observed that much of the difference between cases and controls is driven by CpGs associated with polycomb related genes. Thus, we developed a new score utilizing only CpGs associated with polycomb related genes and demonstrated that it robustly captured epigenetic age acceleration in cases vs controls (p=0.00012). Finally, we tested whether this same signal could be seen in peripheral blood. We observed no difference in cases vs. controls and no correlation between matched tissue/blood samples, suggesting that peripheral blood is not a good surrogate marker for epigenetic age acceleration. Conclusions: Moving forward, it will be critical for studies to elucidate whether epigenetic age acceleration in breast tissue precedes breast cancer diagnosis and whether methylation changes at CpGs associated with polycomb related genes can be used to assess the risk of developing breast cancer among unaffected individuals.
Aging is the leading risk factor for cancer. While some have proposed that the age-related accumulation of somatic mutations drives this relationship, it is likely not the full story. Here, we show that both aging and cancer share a common epigenetic replication signature, which we modeled from DNA methylation data in extensively passaged immortalized human cells in vitro and tested on clinical tissues. This epigenetic signature of replication – termed CellDRIFT – increased with age across multiple tissues, distinguished tumor from normal tissue, and was escalated in normal breast tissue from cancer patients. Additionally, within-person tissue differences were correlated with both predicted lifetime tissue-specific stem cell divisions and tissue-specific cancer risk. Overall, our findings suggest that age-related replication drives epigenetic changes in cells, potentially pushing them towards a more tumorigenic state. Citation Format: Christopher J. Minteer, Kyra Thrush, Peter Niimi, Joel Rozowsky, Jason Liu, Mor Frank, Thomas McCabe, Erin Hofstatter, Mariya Rozenblit, Lajos Pusztai, Kenneth Beckman, Mark Gerstein, Morgan E. Levine. Revisiting the bad luck hypothesis: Cancer risk and aging are linked to replication-driven changes to the epigenome [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR009.
Aging is a leading risk factor for cancer. While it is proposed that age-related accumulation of somatic mutations drives this relationship, it is likely not the full story. We show that aging and cancer share a common epigenetic replication signature, which we modeled using DNA methylation from extensively passaged immortalized human cells in vitro and tested on clinical tissues. This signature, termed CellDRIFT, increased with age across multiple tissues, distinguished tumor from normal tissue, was escalated in normal breast tissue from cancer patients, and was transiently reset upon reprogramming. In addition, within-person tissue differences were correlated with predicted lifetime tissue-specific stem cell divisions and tissue-specific cancer risk. Our findings suggest that age-related replication may drive epigenetic changes in cells and could push them toward a more tumorigenic state.
Sacituzumab govitecan has emerged as a promising new therapy in metastatic triple negative breast cancer (TNBC). Sacituzumab govitecan is an antibody-drug conjugate composed of an antitrophoblast cell surface antigen 2 (Trop-2) IgG1 kappa antibody coupled through a hydrolyzable linker to SN-38, a topoisomerase inhibitor and active metabolite of irinotecan. It received full Food and Drug Administration (FDA) approval on April 7th, 2021 for the treatment of unresectable locally advanced and metastatic TNBC after at least two prior lines of therapy based on the confirmatory results of the phase 3 ASCENT trial (1).The ASCENT trial confirmed improved progression free survival (PFS) and overall survival (OS) with sacituzumab govitecan compared to chemotherapy. Accelerated FDA approval was first granted in April 2020 based on phase I/II data from a single group basket trial which showed a response rate of 33% in heavily pretreated 108 patients with metastatic TNBC, PFS of 5.5 months, and a median OS of 13 months (2). Subsequently, the ASCENT phase III trial randomized 468 patients in a 1:1 ratio to either sacituzumab govitecan or chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine). The primary endpoint was PFS and secondary endpoints were OS, objective response, and safety. The median PFS was 5.6 months (95% CI: 4.3-6.3 months) with sacituzumab govitecan vs. 1.7 months (95% CI: 1.5-2.6 months) with physician's choice chemotherapy (HR 0.41, 95% CI: 0.32-0.52, P<0.001). The median OS was
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