Changes in Physical Activity, Functional Capacity, and Cardiac Function during Breast Cancer Therapy.

PURPOSE: Functional capacity and cardiac function can decline during breast cancer (BC) therapy. In non-cancer populations, higher physical activity (PA) is associated with better physical function and cardiac health. This study compared baseline PA, functional capacity, and cardiac function between women with and without BC and tested if greater PA participation was related to higher functional capacity and/or better heart function after three months of BC therapy. METHODS: Data was collected in 104 women without BC (82% Caucasian, baseline only) and 110 women with stage I-III BC (82% Caucasian) before therapy and after three months of treatment. Participants self-reported PA and underwent six-minute walk distance (6MWD) testing to measure functional capacity and cardiovascular magnetic resonance to assess left ventricular ejection fraction (LVEF). Analyses were adjusted for age, race, body mass index (BMI), and medication use. RESULTS: The BC group was older (56.2 ± 10.7 vs 52.1 ± 14.7 yrs, P=0.02) with a higher average BMI than the non-cancer group (30.3 ± 6.8 vs 27.7 ± 6.2 kg/m2, P<0.01). Pre-treatment, BC participants reported lower PA scores (27.9 ± 2.8 vs 34.9 ± 2.8, P=0.04) with similar 6MWD and LVEF relative to those without cancer (485 ± 11 vs 496 ± 11 m, P=0.4 and 59.7 ± 0.7 vs 58.9 ± 0.8%, P=0.37, respectively). After three months of BC therapy, declines were observed for PA scores (27.9 ± 2.8 vs 18.3 ± 2.5, P=0.02), 6MWD (485 ± 11 vs 428 ± 10 m, P<0.001), and LVEF (59.7 ± 0.7 vs 56.1 ± 0.7%, P<0.001). Compared to BC participants who reported no PA at three months (n=24, 22%), BC women who reported any PA (n=78, 86%) had higher 6MWD (442 ± 11 vs 389 ± 17 m, P=0.006) but similar LVEF (56.5 ± 0.9 vs 55.3 ± 1.5%, p=0.5). Women who reported any PA were less likely to exhibit an LVEF below normal (<50%) or decline in LVEF of 'â•10 points compared to inactive women (BMI-adjusted, OR [95% CI]: 0.27 [0.09, 0.85]). CONCLUSIONS: These preliminary results indicate that self-reported PA, LVEF and 6MWD decline in the first three months of BC treatment, but PA participation during BC treatment may mitigate declines in functional capacity and cardiac function. Further research is needed to identify barriers and facilitators of PA participation during BC therapy. FUNDING: Data collection was funded by the Wake Forest NCORP Research Base grant 2UG1CA189824 with support of the NCI Community Oncology Research Program (NCORP). Additional funding for this study was provided by grants from the National Institutes of Health, National Cancer Institute (1R01CA199167 and 5T32CA093423). CLINICAL TRIAL ID: NCT02791581 for WF97415 UPBEAT.

Proliferation-induced decline of primitive hematopoietic progenitor cell activity is coupled with an increase in apoptosis of ex vivo expanded CD34+ cells.

We examined the decline in hematopoietic potential observed when human CD34+ cells are cultured in vitro by evaluating the association between proliferation history and the fate of long-term hematopoietic culture-initiating cells (LTHC-ICs) as well as the onset of programmed cell death. The membrane dye PKH2 was used to track ex vivo expanded human CD34+ cells from bone marrow, cord blood, and mobilized peripheral blood, and to identify and isolate CD34+ cells that had divided once, twice, three, or four times or more, as well as cells that had remained cytokine nonresponsive and therefore failed to proliferate. These isolated groups of cells were assayed for their hematopoietic potential, cell cycle status, and percentage of apoptotic cells. A gradual decline in the content of LTHC-ICs, as well as in their ability to initiate and sustain in vitro hematopoiesis, was found to correlate with the number of in vitro cellular divisions, such that the hematopoietic potential of CD34+ cells dividing four or more times was nearly depleted. DNA analysis revealed that cells dividing more than three times resided predominantly in G0/G1 phases of the cell cycle. In addition, the percentage of CD34+ cells undergoing apoptosis was found to increase concomitantly with the number of in vitro cellular divisions; less than 10% of cells dividing once were apoptotic, whereas more than 25% of CD34+ cells dividing four or more times underwent programmed cell death. Together, these data suggest that a proliferation-associated, and possibly activation-induced, loss of hematopoietic potential among dividing CD34+ cells may result from an increase in programmed cell death among dividing primitive hematopoietic progenitor cells.

Orderly process of sequential cytokine stimulation is required for activation and maximal proliferation of primitive human bone marrow CD34+ hematopoietic progenitor cells residing in G0.

Bone marrow (BM) CD34+ cells residing in the G0 phase of cell cycle may be the most suited candidates for the examination of cell cycle activation and proliferation of primitive hematopoietic progenitor cells (HPCs). We designed a double simultaneous labeling technique using both DNA and RNA staining with Hoechst 33342 and Pyronin Y, respectively, to isolate CD34+ cells residing in G0(G0CD34+). Using long-term BM cultures and limiting dilution analysis, G0CD34+ cells were found to be enriched for primitive HPCs. In vitro proliferation of G0CD34+ cells in response to sequential cytokine stimulation was examined in a two-step assay. In the first step, cells received a primary stimulation consisting of either stem cell factor (SCF), Flt3-ligand (FL), interleukin-3 (IL-3), or IL-6 for 7 days. In the second step, cells from each group were washed and split into four or more groups, each of which was cultured again for another week with one of the four primary cytokines individually, or in combination. Tracking of progeny cells was accomplished by staining cells with PKH2 on day 0 and with PKH26 on day 7. Overall examination of proliferation patterns over 2 weeks showed that cells could progress into four phases of proliferation. Phase I contained cytokine nonresponsive cells that failed to proliferate. Phase II contained cells dividing up to three times within the first 7 days. Phases III and IV consisted of cells dividing up to five divisions and greater than six divisions, respectively, by the end of the 14-day period. Regardless of the cytokine used for primary stimulation, G0CD34+ cells moved only to phase II by day 7, whereas a substantial percentage of cells incubated with SCF or FL remained in phase I. Cells cultured in SCF or FL for the entire 14-day period did not progress beyond phase III but proliferated into phase IV (with <20% of cells remaining in phases I and II) if IL-3, but not IL-6, was substituted for either cytokine on day 7. G0CD34+ cells incubated with IL-3 for 14 days proliferated the most and progressed into phase IV; however, when SCF was substituted on day 7, cells failed to proliferate into phase IV. Most intriguing was a group of cells, many of which were CD34+, detected in cultures initially stimulated with IL-3, which remained as a distinct population, mostly in G0/G1, unable to progress out of phase II regardless of the nature of the second stimulus received on day 7. A small percentage of these cells expressed cyclin E, suggesting that their proliferation arrest may have been mediated by a cyclin-related disruption in cell cycle. These results suggest that a programmed response to sequential cytokine stimulation may be part of a control mechanism required for maintenance of proliferation of primitive HPCs and that unscheduled stimulation of CD34+ cells residing in G0 may result in disruption of cell-cycle regulation.