All participants were women with median age 51 (range 31-67 years) and median body mass index 28 (range 23-36). 6 patients (30%) received FEC80, fourteen (70%) received FEC-T chemotherapy and eighteen (90%) received radiotherapy. Two patients treated with the FEC-T received Trastuzumab from the mid-chemo time point. Ten patients had left sided tumours and one had left and right sided tumours. Nine participants were post-menopausal.
All participants attended their pre-chemotherapy MRI scan while 5 were unable to attend the mid-chemotherapy scan due to inter-current illness and 1 was unable to attend the final end-chemotherapy MRI scan.
Cardiac Magnetic Resonance Imaging (CMR)
The mean LVEF for healthy volunteers was 63.6 ± 4.5 % with range 57.6% to 74.3%. Differences in repeated measurements of LVEF for 3 volunteers were 0.5%, 0.6% and -0.5%, indicating a very high degree of repeatability.
LVEF was calculated for all 20 participants prior to chemotherapy, 15 at mid-chemotherapy and 19 at end-chemotherapy.
The mean (± standard deviation) LVEF at pre, mid and end-chemotherapy was 61.6 ± 4.4%, 60.5 ± 5.2% and 56.3 ± 8.1% respectively (Figure 2). There was a significant decrease in LVEF between pre- and end-chemotherapy (p=0.02). There was no significant difference in LVEF between patients receiving FEC80 and those receiving FEC-T at mid (57.7±5.6 vs 61.9±4.7%, respectively, p=0.14) or end-chemo time-points (55.9±3.9 vs 56.5±9.6%, respectively, p=0.94).
In total, 6 patients experienced a significant decrease in LVEF according to agreed criteria . 3 symptomatic patients (with breathlessness) experienced a 5% decrease in LVEF from pre- to mid-chemo. Two of these patients had no further change in LVEF from mid- to end-chemo and one had a significant increase. Three additional patients experienced a decrease of 10% in LVEF from mid- to end-chemo. One patient, receiving FEC-T, became symptomatic during treatment with associated ankle swelling and breathlessness associated with a 30% fall in LVEF between pre- and end-chemo to 30.5%. This patient responded rapidly to low dose diuretics and fluid restriction and was assessed by the cardiology team with full recovery of cardiac function within 2 weeks.
Cardiac energetics assessed by 31P-MRS
The mean PCr/ATP ratio for 13 age-matched female healthy volunteers was 1.94±0.43 (range 1.11 to 2.18). For 3 volunteers with repeat measurements of PCr/ATP the differences in values between scans were 0.58, 0.53 and 0.20. This is consistent with other published work at 3T showing that a change in PCr/ATP of 0.5, with 95% confidence, would require a sample size of 9 patients using a similar protocol to ours .
31P MR spectra were successfully acquired for 19 breast cancer patients pre-chemotherapy, 11 at mid-chemotherapy and 17 end-chemotherapy. Missing scans were due to inter-current illness or technical issues for 1 participant at the pre-chemotherapy scan, 4 mid-chemotherapy and 2 end-chemotherapy. An example patient 31P spectrum is shown in Figure 3.
For the whole cohort there was no significant difference in mean values for PCr/ATP ratio comparing pre-, mid- and end-chemotherapy time-points. However, there was a significant negative correlation between the change in PCr/ATP from pre- to mid- chemotherapy and the subsequent change in PCr/ATP from mid- to end chemotherapy (r=-0.68, p=0.04). The mean change in the PCr/ATP ratio at mid- and at end- chemotherapy relative to the mean baseline value is plotted in Figure 4.
Plasma High sensitivity cardiac Troponin-I
Plasma cardiac cTn-I-I levels (ng/L) were low(<5ng/L) in all patients at baseline prior to starting chemotherapy and increased progressively by mid-chemo with a further rise at the time of the last chemo cycle (figure 4). The threshold cTn-I level for identifying acute coronary syndrome (ACS) in women in our centre is 16ng/L and is based on the 99th upper centile of the normal range for a large sample of patients . In our study, while all participants showed a small but significant rise in mean cTn-I value between baseline and mid-chemo (1.35±0.81 to 4.40±2.64 ng/L, p=0.0001) none of these values exceeded the ACS threshold (16ng/L). By end-chemo there was a further significant increase in mean plasma cTn-I (4.40±2.64 to 14.84±8.73ng/L, p=0.0001) with six cTn-I values above the ACS threshold. These 6 patients, and a further 3 patients with borderline normal cTnI levels at end-chemo, were invited back 2-3 months after end of chemotherapy for longer term follow-up with repeat blood cTn-I. In all cases cTn-I had returned to normal level (mean±SD, 1.55±0.88ng/L).
The specific type of chemotherapy regime had no impact on cTn-I levels. At mid-chemotherapy cTn-I was not significantly higher in patients receiving FEC-T compared to FEC80 (5.0±2.9 vs 3.0±0.89 ng/L, respectively, p=0.12) or at end-chemo in patients receiving FEC80 compared to those receiving FEC-T (18.3±12.0 ng/l vs 13.2±6.7ng/L, respectively, p=0.24). As expected, the side of the cancer had no impact on cTn-I levels at any of the time points studied (end-chemo: left 15.1±8.1 vs right 15.5±10.1, p=0.92).
There were no significant changes in PR interval or QRS duration during chemotherapy. There was a small but significant increase in the corrected QT interval (QTc) from 422±15 to 438±13 ms (p=0.0001) with most of this increase occurring between baseline and mid-chemo. Overall, no patient showed an increase of QTc of >60 ms or a QTc above 500 ms.
Exploratory analysis of possible association between LVEF, PCr/ATP, QT interval and cardiac troponin-I
A significant negative correlation was found between the change in PCr/ATP ratio and the change in LVEF from pre-chemo to end-chemo (r=-0.65, p=0.006, figure 5). A significant negative correlation was also found between the change in PCr/ATP ratio from pre- to end- chemotherapy and the change in LVEF from mid- to end-chemotherapy (r=-0.77, p=0.002). There was no apparent association between cTn-I and LVEF or PCr/ATP any of the time points. There was also no association found between changes in the corrected QT interval in the electrocardiogram and changes in cTn-I or changes in the QT interval and changes in LVEF. There was no apparent effect of trustuzamab treatment on cTn-I levels.
In total, 6 patients displayed cTn-I values above the normal range at the end-chemo timepoint. When examining each of these patients on an individual basis, no clear relationship was observed between cTn-I and baseline clinical data, including pre-existing hypertension or smoking history, LVEF or PCr/ATP ratio.