Title: Mindfulness is associated with improved psychological well-being but no change in stress
biomarkers in breast cancer survivors with depression: a single group clinical pilot study
Version: 2 Date: 12 Feb 2022
Reviewer's report:
Review of Sakki et al.
Overall, the manuscript is well written and has a logical flow. The treatment of psychological
symptoms with behavioral interventions is important, however the use of MBSR to treat
psychological symptoms in breast cancer survivors has been widely explored and published.
It is unclear why the investigators decided to “pilot” this intervention, which has already
demonstrated feasibility and acceptability in many different breast cancer samples. Along these
same lines, the decision to not have a control group was also not justified as the manuscript
was written, and seriously limits the study findings. As the authors point out, positive effects
of MBSR on negative psychological symptoms is well documented. They do include positive
psychological outcomes, such as resilience in this study, which is a contribution to the literature,
however the claim that stress biomarkers have been rarely investigated in response to MBSR
is a weak argument, as there have been studies that have done this. A major design flaw that
weakens the main study findings is that the primary outcome, Beck Depression Inventory score,
was used as a screening tool for inclusion criteria. Participants in a certain range of the BDI were
included in the study, biasing the outcome changes for this variable, which are the main findings.
As written, it is unclear what this study contributes to the literature beyond what has already
been published about MBSR effects on psychological outcomes in breast cancer survivors. I
think a major revision that includes justifications for the “pilot” uncontrolled design, along
with a reframing of the study to emphasize the positive psychological outcomes as the primary
outcomes will strengthen the manuscript.
Abstract: should be revised to reflect manuscript revisions.
Background
Line 88: “with less recent diagnosis”, please rephrase to something like “further from diagnosis
and treatment”
Lines 92-95: This sentence is very hard to believe. Reconsider rationale for focusing on these
outcomes in a ”pilot” study.
What about these citations??:
Reich RR, et al. Biol Res Nurs. 2017. PMID: 28460534 Free PMC article. Clinical Trial.
Lengacher et al. Biol Res Nurs. 2019 Jan;21(1):39-49. doi: 10.1177/1099800418789777. Epub
2018 Aug 5.PMID: 30079756
Bower et al. Cancer. 2015 Apr 15;121(8):1231-40. doi: 10.1002/cncr.29194. Epub 2014 Dec
23.PMID: 25537522
Lines 95-98: Suggest reframing the study aims to emphasize the mental well being outcomes
as primary outcomes and the others as secondary since they have already been thoroughly
investigated in the literature.
Methods:
Line 104: please provide specifics on the sampling method
Line 105: “symptoms related to mental ill- and well-being” please clarify what mental ill- means
Line 107: why were outcomes measured “mid intervention”? Please provide a rationale.
Line 108: please provide more details on the background characteristics that were collected.
Why were these collected by questionnaire not extracted from their medical records? Please
provide a rationale.
Line 112: why was the trial restrospectively registered?
Line 119: how were participants identified and sent letters? Please provide details
Line 123: why was this age range chosen? Please provide rationale
Line 125: exclusion criteria: what about diseases or conditions that are known to impact stress
biomarkers and inflammation (CRP) such as diabetes, or autoimmune conditions? Were people
screened for these comorbidities? Did you account for these in your analyses? If not, this is a
study limitation.
Line 130: inclusion criteria “BDI-II score >13 points”, since this is your screening criteria, it
shouldn’t be your primary outcome (or any study outcome).
Intervention
Lines 138-144: please provide more details on the intervention protocol and how fidelity was
tracked/evaluated
Measures
Line 148: Beck Depression Inventory-II (BDI I-II): as stated above, this is a design flaw, using
the study screening tool as the outcome measure. Since you screened out those below 14, you are
removing the full variability of the outcome measure and biasing your results. Also you say that
the range in BDI-II is 0-63 but you screened out those below 13, so the range should be 14-63.
Line 160: The insomnia sleep index only gets at 1 aspect of the sleep problems concept, so using
this measure has limitations that need to be acknowledged.
Line 173: World Health Organization Quality of Life WHOQOL-BREF–questionnaire: There
are many cancer specific quality of life measures, why was this one chosen. It makes cross study
comparisons difficult. Please provide a rationale or address it as a study limitation
Please provide reliability scores for this study for all the measures rather than cite previous
studies.
Were the Resilience, Self Compasison, Mindfullness Skills tools validated in any previous
cancer survivor populations?
Lines 206+ “The independent mindfulness practice” why was this aspect of intervention
“dosage” emphasized in this study. The focus on this componant of the intervention protocol
seems inconsistent with previous studies reporting on MBSR protocols and warrants a rationale.
Line 208: were onley “daily minutes” tracked? what else was tracked in the at home diaries?
Was study burden assessed at all in this pilot study? The protocol as described seems very time
and resource intensive, how was participant burden, satisfaction, etc. assessed?
Statistical Analysis
Line 225: why was Dunnet’s adjustments used? This is uncommon in clinical trials and I believe
is used when there is a control group which this study had. I think either a family wise error
adjustment or no adjustment (with a rationale) would be more appropriate for the sample size
and the lack of control group.
As written, it is unclear what data were used in your statistical models. Did you do ANOVAs
with data from all 3 time points? if so what models were used to look at differences at time 2 and
time 3, students t tests? Some clarification and justification is needed throughout this section.
Please clarify if changes scores were used for the correlation analyses
Results
Line 241: Please provide details of your sensitivity analysis, did you compare models from the
data with missing data to a dataset with intention to treat data? How did you compare the models?
What method did you use for intention to treat? Carry one forward? How did you interrogate your
missing data? were they missing at random? any differneces in terms of sample characteristics
between those with missing data and those with compelte data?
Table 1: how was social support determined?
Lines 274-286: please revise results to clearly state the findings from the RM-ANOVA
models, along with the sensitivity analysis findings. Then present the mid-intervention and post
intervention findings from the paired t tests.
Lines 288-292: The average min/day for each participant was 47? And this was for 58 days?
This is very high? Any doubts in the validity of these reports?
Please provide more details about other aspects of the MBSR protocol dosage and fidelity. For
example, attendance at all in person classes, engagement with content… the protocol includes
more than the independent mindfulness practice.
Tables 2 and 3: These tables are confusing as formatted. Please provide a column with the F
statistic for the RM-ANOVA and then the T statistics for 4 weeks and 8 weeks. Also please
provide the ADJUSTED p value not just a star indicating that it was adjusted. Then use stars to
indicate level of significance and provide a footnote to explain the stars.
Discussion
Lines 357-358: this is the key contribition of this study and should be highlighted and further
discussed
Lines 362-365: Were any other components of the intervention ”dosage” tracked? What about
attendance at the classes? These ”other” factors could be more flushed out here.
Lines 369-371: “A meta-analysis of 28 studies showed an association (r = 0.26, 95% CI
0.19-0.34) between engaging in home practice (mean 30 minutes daily) and unspecified
psychological and physical treatment outcomes”: what about dividing your group between those
who had 45 or more of daily practice and those that had less then look at group differences in
the outcomes, this could be an interesting post hoc analysis to further interrogate the question
about ”dosage” for MBSR interventions…
Lines380-381: In case there was a threshold-effect of the amount of home practice time and
symptom change, our study could not detect it.” more interrogation is needed here, why do you
think you couldn’t detect it? How about alternative approaches such as the one I suggested in
the previous comment.
Lines 397-399:” To conclude, compared to our study, the vast majority of participants in above
mentioned studies were at earlier stage of recovery 8,28, 29, 33, which is likely contributing
to the conflicting findings.”: This contradicts the previus statements where you say longer term
follow up is needed. Please clarify in the paragraph the elements of ”time” are you referring to
time from MBSR intervention sometimes and time from cancer treatment others. It is confusing
as written.
The discussion is under developed. it seems that all the potential mechanisms (biomarkers,
mindfullness skills, self compassion) were not significant…. what do you think caused the
positive changes in psychological outcomes then?
Other biomarkers? perhaps it was a cellular aging mechanism?
Also need to contextualize your sample. BCS WITH depressive symptoms. Perhaps those with
lower levels of depression could benefit in a positive psychology type of way.
Line 401: a strength is the high study engagement… do you have any thoughts on this? why
depressed patients would be so engaged? It is surprising.
Line 404: “Drop out was acceptable” what does this mean?
Lines 407-408: “Future studies should invest in controlled designs with longer follow-up
periods. “ what about MBSR in person program V MBSR in person + at home program to
determine if the at home portion is needed?
Conclusions
This was a “clinical” pilot study, so what are some clinical implications?