Carleton, Neil
(2024)
Understanding Hormone Disposition and Innate Immune Biology to Right-Size Treatment in Older Women with ER+ Breast Cancer.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Age is one of the most important risk factors for the development of breast cancer. Nearly a third of all breast cancer cases occur in older women (aged ≥ 70 years), with most cases being estrogen receptor-positive (ER+). However, our understanding of why so many estrogen sensitive tumors develop and grow in older, postmenopausal women despite low circulating estradiol remains limited. In this work, we sought to better understand the interplay between age-related changes in estrogen disposition and chronic inflammation to shed light on the age-related incidence of ER+ breast cancer. We show that aged F344 rats treated with the DMBA/MPA carcinogen develop more tumors at faster rates than their younger counterparts, suggesting that the aged environment accelerates tumor growth. Across a broad cohort of specimens from patients with ER+ breast cancer and age-matched donors of normal breast tissue, we observe that even with E1-predominant estrogen disposition in the systemic circulation, tumors in older patients upregulate HSD17B7 expression to convert E1 to E2 in the TME. Age-related accumulation of tumor-associated macrophages serve as signaling hubs that integrate the E2 and chemokine-driven chronic inflammatory signaling in the TME, which polarize TAMs towards a CD206+/PD-L1+, immunosuppressive phenotype. These findings suggest that chronic inflammation and hormonal disposition are critical contributors to the age-related nature of ER+ breast cancer development and growth. Clinically, we go on to show that many of these older patients are overtreated given the biology of their disease. We thus deployed an intervention to reduce unnecessary axillary surgery for older patients with ER+ clinically node negative disease and showed that targeting the surgeons in the outpatient setting is an effective way to reduce SLNB. Lastly, we evaluated outcomes for those patients who forego surgery altogether and are treated with ET alone. We prospectively enrolled patients to a ctDNA surveillance protocol to better identify those patients who are at risk for tumor progression. Overall, this work contributes significantly to our understanding of breast cancer development and how to best right-size treatments for older patients with ER+ breast cancer.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
| Title | Member | Email Address | Pitt Username | ORCID |
|---|
| Committee Member | Wells, Alan | | | | | Committee Chair | McAuliffe, Priscilla | | | | | Committee Member | Zervantonakis, Ioannis | | | | | Committee Member | Lotze, Michael | | | | | Committee Member | Coffman, Lan | | | | | Thesis Advisor | Lee, Adrian | | | | | Thesis Advisor | Oesterreich, Steffi | | | |
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| Date: |
14 October 2024 |
| Date Type: |
Publication |
| Defense Date: |
10 May 2024 |
| Approval Date: |
14 October 2024 |
| Submission Date: |
23 May 2024 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
205 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Integrative Systems Biology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
breast cancer, aging, estrogen receptor positive breast cancer, breast cancer in older women, overtreatment |
| Date Deposited: |
14 Oct 2024 14:27 |
| Last Modified: |
14 Oct 2024 14:27 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46433 |
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