The effect of pre-diagnosis physical activity on breast cancer outcomes
Restricted (Penn State Only)
- Author:
- Lin, Dan
- Graduate Program:
- Epidemiology (PhD)
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- December 01, 2023
- Committee Members:
- Duanping Liao, Professor in Charge/Director of Graduate Studies
Joshua Muscat, Major Field Member
Shouhao Zhou, Outside Field Member
Kathleen Sturgeon, Special Member
Cheryl Thompson, Chair & Dissertation Advisor
Andrea Hobkirk, Outside Unit Member - Keywords:
- breast cancer
physical activity
recurrence
window of susceptibility
neoadjuvant chemotherapy
pathological complete response
white blood cell - Abstract:
- Epidemiological evidence has demonstrated an inverse dose-response association between recreational physical activity level and breast cancer risk. The strength of association varies by the type of hormone receptor (HR) status, being more pronounced for estrogen receptor-positive (ER+) and progesterone receptor-negative (PR-) tumors. The exact nature of this inverse relationship remains unclear. The interval from menarche to first pregnancy is a specific window of susceptibility (WOS), as breast tissue during this phase is relatively undifferentiated and potentially more vulnerable to carcinogenetic exposures. A higher recreational physical activity level during this WOS may be effective in reducing breast cancer risk. However, the extent of this association, particularly in relation to HR status, has not been extensively explored. Epidemiological evidence has demonstrated that a higher recreational physical activity level before breast cancer diagnosis has been associated with a lower all-cause mortality and a lower breast cancer-specific mortality in breast cancer patients. However, the association between pre-diagnosis physical activity level and breast cancer recurrence is unclear. Neoadjuvant chemotherapy (NACT), a systematic therapy given before surgery, is the standard of care for locally advanced breast cancer. Enhanced treatment tolerance and treatment efficacy (defined as pathological complete response [pCR]) following NACT are considered favorable prognostic factors of improved long-term survival. A higher pre-diagnosis physical activity level may positively influence survival through the improvement of treatment tolerance and efficacy. This improvement might stem from reduced cardiotoxicity and enhanced physical fitness, enabling breast cancer patients to better endure chemotherapy. However, the association of pre-diagnosis physical activity level with treatment tolerance and treatment efficacy in breast cancer patients receiving NACT remains unclear. The association between physical activity level and breast cancer outcomes may be attributed to physical activity’s role in reducing inflammation. Epidemiological evidence has demonstrated that higher physical activity level is associated with lower white blood cell (WBC) count, and lower neutrophil-to-lymphocyte ratio (NLR) in both healthy and disease populations, suggesting physical activity may reduce inflammation by altering the cellular composition in peripheral blood. However, associations between physical activity level and other peripheral immune cell populations, such as platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR), are not clear. In addition, the association in females is not well established. The dissertation has four specific aims: 1) examine the association between recreational physical activity level from menarche-to-first pregnancy and breast cancer risk overall and by HR status, 2) examine the association between pre-diagnosis recreational physical activity level and risk of breast cancer recurrence, 3) examine the association between pre-diagnosis physical activity level and treatment tolerance and treatment efficacy (pCR) in breast cancer patients reeving NACT, and 4) examine the association between physical activity level and peripheral immune cell populations in a national representative US female population. Aim 1 utilized the California Teachers Study (a cohort of more than 133,000 women who worked in the educational system in California, n=78,940 for the analysis). Our overall finding was that women with a higher physical activity level during menarche-to-first pregnancy had lower risk of breast cancer overall (≥40 vs. <9 MET-hrs/wk: HR=0.89, 95% CI=0.83-0.97). However, the association went away after additional adjusted for physical activity level after first pregnancy. An inverse association between physical activity level and risk of triple-negative subtype was observed (≥40 vs. <9 MET-hrs/wk: HR=0.53, 95% CI=0.32-0.87). A higher physical activity level was associated with a lower breast cancer risk among women with moderate (15-19 years) menarche-to-first pregnancy intervals (≥40 vs. <9 MET-hrs/wk: HR=0.80, 95% CI=0.69-0.92) only, but not with short (<15 years) or long (≥20 years) intervals. Aim 2 examined stage I-IIIb breast cancer survivors (n=6,479) from the same cohort study. An inverse association between pre-diagnosis recreational physical activity level and breast cancer recurrence was observed in ER-PR- cases (≥26.0 vs. <3.4 MET-hrs/wk: HR=0.31, 95% CI=0.13-0.72), but not in ER+ or PR+ cases. In aim 3, a study of 180 stage I-III breast cancer patients receiving NACT from the Sister Study highlighted that pre-diagnosis physical activity levels were not linked with treatment tolerance or pCR. In aim 4, in 8,730 female participants of NHANES 1999-2018, a higher recreational physical activity level was associated with a lower WBC count (quartile [Q]4 vs. Q1 adjusted mean (95% CI): 7.33 (6.94, 7.71) vs. 7.62 (7.23, 8.02) 1000 cells/μL, Ptrend=0.002) and a lower NLR (Q4 vs. Q1 adjusted mean (95% CI): 1.98 (1.74, 2.23) vs. 2.14 (1.90, 2.38), Ptrend=0.007). These results suggest that understanding timing of physical activity throughout the life course in relationship with breast cancer, particularly with the triple-negative subtype, may be important for cancer prevention strategies. Observations from the California Teachers Study indicate that the benefit of pre-diagnosis physical activity on breast cancer recurrence may differ by tumor characteristics. Understanding pre-diagnosis physical activity level as a predicator for breast cancer recurrence may further help breast cancer patients understand their future risk of recurrence. The research also provides evidence linking physical activity level and peripheral immune cell populations, suggesting that women at higher levels of physical activity may have lower levels of inflammation, which may be important for future breast cancer outcomes.