Associations of pre-diagnosis physical activity with treatment tolerance and treatment efficacy in breast cancer patients with neoadjuvant chemotherapy

Abstract

Purpose

Higher pre-diagnosis physical activity (PA) is associated with lower all-cause mortality in breast cancer (BCa) patients. However, the association with pathological complete response (pCR) is unclear. We investigated the association between pre-diagnosis PA level and chemotherapy completion, dose delay, and pCR in BCa patients receiving neoadjuvant chemotherapy (NACT).

Methods

180 stage I-III BCa patients receiving NACT (mean [SD] age of diagnosis: 60.8 [8.8] years) in the Sister Study were included. Self-reported recreational and total PA levels were converted to metabolic equivalent of task-hours per week (MET-hrs/wk). The pCR was defined as no invasive or in situ residual in breast or lymph node (ypT0 ypN0). Multivariable logistic regression analyses estimated odds ratios (ORs) and 95% confidence intervals (CIs) for treatment outcomes.

Results

In this sample, 45 (25.0%) BCa patients achieved pCR. Higher pre-diagnosis recreational PA was associated with lower likelihood of chemotherapy completion (highest vs. lowest tertile: OR=0.87, 95% CI=0.30–2.56; P_trend=0.84) and greater dose delay (OR=1.45, 95% CI=0.54–3.92; P_trend=0.46), but greater odds of pCR (OR=1.28, 95% CI=0.49–3.34; P_trend=0.44), albeit with no significant trends. Associations were similar for total PA. Meeting the recommended level of recreational PA was modestly associated with pCR overall (≥7.5 vs. <7.5 MET-hrs/wk: OR=1.33, 95% CI=0.59–3.01).

Conclusions

Although small sample size and limited information on exercise closer to time of diagnosis limit interpretation, pre-diagnosis PA was not convincingly associated with treatment tolerance or treatment efficacy in BCa patients receiving NACT. Future investigations are needed to better understand the impact of pre-diagnosis PA on BCa treatment.

Introduction

Breast cancer is the most commonly diagnosed cancer and is the second leading cause of cancer death among women in the United States (US) [1, 2]. Neoadjuvant chemotherapy (NACT), a systemic therapy given before surgery, is the standard of care for locally advanced breast cancer, which constitutes 10% to 20% of all breast cancer cases in the US [3, 4]. NACT has also been widely used among patients with more aggressive tumor types, such as human epidermal growth factor receptor 2 positive (HER2+) or triple-negative tumors (TNBC) [5, 6]. The absence of disease in surgically resected tumor tissue following NACT, referred to as a pathological complete response (pCR), is associated with higher disease-free survival (DFS) and overall survival (OS) [7–9]. However, research has shown that the achievement of pCR only occurs in 19–40% of breast cancer patients with NACT, and varies depending on tumor types and node status [10, 11]. To achieve the full benefit of NACT, with greater likelihood of pCR, completing the full planned treatment course is important. Therefore, understanding factors that may contribute to improved treatment tolerance (completing the planned treatment course) and treatment efficacy (pCR) are critical.

Patients who do not tolerate their chemotherapy often have dose reduction, dose delay, or stop chemotherapy early. Therefore, these factors are often used as surrogates for treatment tolerance. Chemotherapy dose reduction, dose delay, and discontinuation result in worse survival in cancer patients [12–14]. In addition, relative dose intensity [RDI], defined as the ratio of the actual to the planned dose intensity (dose of chemotherapy administered per unit time) [14], is a summary measure commonly used to describe treatment tolerance throughout the chemotherapy course. An RDI of 85% is a clinically meaningful threshold, as breast cancer patients who achieve this threshold have an optimized DFS and OS [14–16]. Earlier studies observed that a higher pretreatment physical fitness level was associated with higher odds of achieving ≥85% RDI in breast cancer patients receiving adjuvant chemotherapy [17, 18]. Physical fitness level reflects individuals’ ability to perform physical activity and activities of daily living [19]. However, evidence for whether amount of physical activity, the primary indicator of physical fitness, before diagnosis, or before treatment, can predict treatment tolerance and treatment efficacy in NACT settings is limited.

Recently, the CANcer TOxicities (CANTO) cohort study (N=1,075) found that recreational physical activity level prior to treatment (at diagnosis or shortly after diagnosis) was not associated with dose reduction, dose delay, or pCR in breast cancer patients with NACT [20]. As physical activity levels increase, rates of dose reduction, dose delay, and pCR remained relatively stable. These results contradicted a smaller breast cancer study (n=67) which observed that a higher pre-diagnosis recreational physical activity level was associated with a higher chemotherapy completion rate, defined as the proportion of patients receiving full doses of all prescribed chemotherapy, with or without cycle delays [21]. No association between pre-diagnosis recreational physical activity and pCR was observed in their study [21]. To our knowledge, associations of pre-diagnosis recreational physical activity level with treatment tolerance and treatment efficacy among breast cancer patients receiving NACT have only been examined in this single study. No research has yet investigated the association between total physical activity level (the combination of recreational physical activity and other activities) before breast cancer diagnosis and treatment outcomes in NACT settings. Evidence suggest that the type of physical activity before diagnosis may contribute to breast cancer survival differently [22]. More studies, especially in prospective cohorts, are needed to further explore the effect of pre-diagnosis recreational and total physical activity levels on treatment outcomes for NACT breast cancer patients. Since the prospective design ensures that physical activity information is collected before breast cancer diagnoses occur, recall bias is less of a concern and any inaccuracies in reporting physical activity levels should be independent of disease stage and pre-diagnostic symptoms.

In this study, we sought to evaluate the association between pre-diagnosis recreational and total physical activity levels and treatment tolerance and treatment efficacy in breast cancer patients receiving NACT in a population-based prospective cohort. We hypothesized that both higher pre-diagnosis recreational and total physical activity levels would be positively associated with a better treatment tolerance and a higher pCR rate. The 2018 Physical activity Guidelines for Americans and American Cancer Society (ACS) both recommend 150–300 minutes of moderate or 75–150 minutes of vigorous aerobic physical activity per week for adults [23, 24], as that level of physical activity is sufficient to reduce risks of chronic disease, such as cancer, and reduce mortality rates [25, 26]. Therefore, we further hypothesized that engaging in 150 min/wk or more of recreational physical activity before breast cancer diagnosis would be associated with a higher treatment tolerance and a higher pCR rate for breast cancer patients receiving NACT.

Materials and methods

Study population

The Sister Study is a prospective cohort of more than 50,000 women residing in the US, including Puerto Rico, aged 35 to 75 years at enrollment between 2003 and 2009 [27]. Eligible participants could not have had breast cancer themselves at the time of enrollment but must have had a biological sister who had a diagnosis of breast cancer. Participants were asked to complete computer-assisted telephone interviews that assessed demographics, medical history, and potential risk factors for breast cancer and other health conditions at enrollment. During follow-up, participants were recontacted to complete either a short questionnaire about any major health changes, including any breast cancer diagnoses (annually), or a detailed questionnaire on changes in health, lifestyle, and environmental exposures (approximately every three years) [27]. Participants reporting a breast cancer diagnosis during follow-up were asked to provide authorization to retrieve their medical records [28].

The sample used in this analysis included Sister Study participants who had an incident breast cancer diagnosis at stage I-III and had documented NACT treatment in their medical records up to September 30^th, 2021 (n=190). For the purpose of this analysis, we further excluded women who 1) had breast cancer diagnosis < 6 months after enrollment (n=1), 2) were missing information on pCR in medical records (n=6), or 3) were missing information on physical activity level at baseline (n=3), leaving 180 participants remaining in the analysis. The research was approved by the Institutional Review Boards of Penn State University and the National Institutes of Health. All participants provide written informed consent.

Physical activity measurement

For the Sister Study cohort, recreational (primary predictor) and total (secondary predictor) physical activity levels were collected at baseline interview. Recreational physical activity for the past 12 months was assessed during the interview through a series of questions where participants were asked to report: 1) all sports/exercise activities that they had participated in at least once a month during the past 12 months, 2) the number of months they did each activity, 3) the number of days per week they did each activity, and 4) the amount of time spent per day on that activity [29]. The average duration of recreational physical activity (hrs/wk) was calculated based on the collected information. Metabolic equivalent of task (MET) score was assigned to standardize each activity based on the 2011 Compendium of Physical Activities [30]. MET-hrs/wk was then calculated to measure recreational physical activity level that incorporate the intensity of the activity in addition to the duration [29].

Total physical activity was the combination of recreational physical activity and daily activities, not including occupational activity. Similar to recreational physical activity, daily activities for the past 12 months, including walking, climbing stairs, moderately strenuous chores, and strenuous chores, was collected at the baseline survey. The average MET-hrs/wk for total physical activity were assessed. Both recreational and total physical activity levels are categorized into tertiles based on the distribution of MET-hrs/wk among all eligible participants (Recreational: <3.0 MET-hrs/wk, 3.0 – <13.2 MET-hrs/wk, ≥13.2 MET-hrs/wk; Total: <33.0 MET-hrs/wk, 33.0 – <55.7 MET-hrs/wk, ≥55.7 MET-hrs/wk).

There are currently no physical activity guidelines for cancer patients during treatment. The 150 min/wk of moderate aerobic physical activity recommended by national guidelines for all American adults and ACS for the reduction in cancer risk is equivalent to 7.5 MET-hrs/wk of recreational physical activity level. Therefore, in addition to categorizing into tertiles, recreational physical activity level was also dichotomized using the 7.5 MET-hrs/wk threshold to assess whether meeting physical activity guidelines was associated with better treatment outcomes (Recreational: < 7.5 vs. ≥ 7.5 MET-hrs/wk).

All follow-up questionnaires included detailed assessments of physical activity. Over 80% of participants who developed breast cancer were diagnosed after the 1^st follow-up physical activity questionnaire and reported their total physical activity levels at subsequent follow-up surveys. The follow-up questionnaires asked participants’ total physical activity level in the past seven days, including activities from work, house and yard work, transportation, and spare time for recreation, exercise or sport. For participants who had breast cancer diagnosis ≥ 6 months after a most recent follow-up questionnaire, their total physical activity levels reported at this follow-up questionnaire were defined as the “recent pre-diagnosis total physical activity level”. The 6-month interval was selected to reduce reverse causation bias from undiagnosed breast cancer, which could be differential by symptom severity. MET-hrs/wk for recent pre-diagnosis total physical activity levels were assessed.

Treatment tolerance outcomes

Treatment information for breast cancer patients was collected from their medical records. Neoadjuvant chemotherapy was defined as receiving chemotherapy before the first post-diagnosis surgery (lumpectomy or mastectomy). Sister Study team members abstracted chemotherapy variables including planned chemotherapy regimens, cycles, and dosage intervals (days/cycle) prescribed by oncologists, as well as actual received chemotherapy regimens, cycles, and dosage intervals. The duration of NACT varies by regimens. The most common chemotherapy regimen our population received was doxorubicin (A) and cyclophosphamide (C) every two weeks for four cycles, followed by either paclitaxel (T) weekly for 12 cycles or docetaxel (T) every three weeks for four cycles (AC/T; N=67, 37.2%). The second most common regimen our patients received were docetaxel (T) and carboplatin (Cb) every three weeks for six cycles (TCb) (N=43, 23.9%).

Treatment tolerance was not directly measured. However, patients who do not tolerate their treatment may stop early or delay one or more of their doses. Thus, we defined two endpoints to capture treatment tolerance: 1) completion of chemotherapy treatment, and 2) having one or more dose delays. Chemotherapy completion was defined as the completion of the planned treatment cycles. The chemotherapy completion status was defined as “completed” if 1) actual chemotherapy regimens patients received were the same as planned chemotherapy regimens, and 2) the number of actual treatment cycles equals to the number of planned treatment cycles. Otherwise, chemotherapy completion status was defined as “not completed”. Treatment duration (days) was calculated by summing dosage intervals across all chemotherapy cycles. Dose delay was defined as the actual duration of treatment more than 7 days longer than the planned treatment duration [20]. The dose delay was categorized as “delayed” or “not delayed”.

Treatment efficacy

Treatment efficacy was evaluated by pCR. The pathologic examination of surgically resected tissue was performed to determine the presence and extent of residual invasive disease after the completion of NACT. The pCR was defined as no invasive or in situ residual in breast or lymph nodes (ypT0 ypN0) following the completion of NACT, as this is one of the most widely used definitions of pCR [31]. The pCR was categorized as “achieved pCR” or “not achieved pCR”. Because there is no uniform clinical definition of pCR [7], other two commonly used pCR definitions were also adopted for supplemental analyses: 1) No invasive residual in breast or lymph nodes, in situ breast residuals allowed (ypT0/is ypN0), and 2) No invasive residual in breast, in situ breast residuals and positive lymph nodes allowed (ypT0/is ypN0/+) [31].

Statistical analysis

Characteristics of participants were described overall and by the level of recreational pre-diagnosis physical activity. Multivariate logistic regression analysis was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between recreational and total pre-diagnosis physical activity levels and treatment tolerance and treatment efficacy. Covariates in regression analyses included variables known to be associated with breast cancer outcomes. The first model (Model 1) was adjusted for age at breast cancer diagnosis (continuous) and BMI (<25.0, 25.0-<30.0, and ≥30.0 kg/m²). The multivariable-adjusted model (Model 2) was additionally adjusted for race/ethnicity (Non-Hispanic White and others), alcohol consumption (non-drinkers, <1 drink/day, and ≥1 drinker/day), menopausal status (premenopausal and postmenopausal), and hormone replacement therapy use (never use, estrogen use only, progestin use only, and estrogen plus progestin use), tumor stage (I, II, and III), tumor receptor status (hormone receptor [HR]+HER2+, HR+HER2-, HR-HER2+, and HR-HER2-), and receiving neoadjuvant biological therapy (NABT; yes and no). Hormone receptor-positive (HR+) can be estrogen receptor positive (ER+), progesterone receptor positive (PR+), or both. NABT was considered as a covariate because biological therapy (i.e. Trastuzumab, Pertuzumab, and Bevacizumab) is often used with chemotherapy concurrently for breast cancer that is HER2+ or TNBC, and the addition of biological therapy to NACT improves pCR [32, 33]. Information on demographics, alcohol consumption, menopausal status, and hormone therapy use was collected at baseline interview. Clinical characteristics and treatment information were obtained from medical records. Trend tests were conducted by using the median value for each category of pre-diagnosis physical activity as a continuous variable. Whether the association between meeting physical activity guidelines and treatment efficacy differs according to breast tumor types (HR+ vs. HR-; and HER2+ vs. HER2-) was further examined.

Because of some uncertainty in medical record data, a sensitivity analysis was conducted by excluding participants who ended biological treatment after the surgery or had unknown biological treatment end time. For participants who had breast cancer diagnosis ≥ 6 months after a follow-up questionnaire and had available “recent pre-diagnosis total physical activity level”, a sensitivity analysis was further conducted on this sub-population to examine the association between recent pre-diagnosis total physical activity and treatment outcomes. In addition, for all participants, we utilized their total physical activity data from the latest report prior to diagnosis, which included either baseline activity levels (for participants developed breast cancer before the 1^st follow-up questionnaire) or the most recent follow-up data (for participants developed breast cancer after the 1^st follow-up questionnaire) to examine the recency effect of total physical activity level. The models were stratified by months from last report to diagnosis (6 – 12, >12 – 24, and >24 months). All statistical analysis was conducted in SAS 9.4 (Cary, NC). Statistical significance was assessed as a two-sided P value < 0.05.

Results

Characteristics of the 180 participants were described (Table 1). The average age at enrollment was 53.4 (standard deviation [SD]: 8.0) years. The average age of initial breast cancer diagnosis was 60.8 (SD: 8.8) years. Compared to participants with the lowest level of pre-diagnosis recreational physical activity, those with the highest level of pre-diagnosis recreational physical activity (≥13.2 vs. <3.0 MET-hrs/wk) were more likely to be Non-Hispanic White (81.7% vs. 68.3%), less likely to be obese (≥30 kg/m²; 11.7% vs 35.0%), and more likely to drink more alcohol (≥1 drink/day; 55.0% vs 33.3%). Other risk factors for breast cancer (age, smoking, parity, menopausal status, and hormone replacement therapy use), clinical characteristics (tumor grade, tumor stage, tumor receptor status), and treatment patterns (chemotherapy and biological therapy) did not differ across pre-diagnosis recreational physical activity levels.

Table 1.

Baseline characteristics of the study population by pre-diagnosis recreational physical activity level, the Sister Study.

Baseline characteristics	Overall (n=180)	Pre-diagnosis recreational physical activity, MET-hrs/wk
		<3.0 (n=60)	3.0 – <13.2 (n=60)	≥13.2 (n=60)
Pre-diagnosis recreational physical activity, MET-hrs/wk mean ± SD	13.4 ± 17.8	0.8 ± 1.0	8.2 ± 3.3	31.6 ± 21.8
Pre-diagnosis total physical activity, MET-hrs/wk mean ± SD	48.4 ± 31.6	31.0 ± 21.8	44.0 ± 19.8	70.2 ± 36.9
Age at baseline, yr mean ± SD	53.4 ± 8.0	52.2 ± 7.2	54.0 ± 7.5	54.1 ± 9.1
Age at BCa diagnosis, yr mean ± SD	60.8 ± 8.8	59.2 ± 8.0	61.9 ± 8.3	61.3 ± 10.0
Interval from baseline to BCa diagnosis, n (%)
0.5 – <5 yrs	49 (27.2)	16 (26.7)	14 (23.3)	19 (31.7)
5 – <10 yrs	80 (44.5)	33 (55.0)	21 (35.0)	26 (43.3)
≥10 yrs	51 (28.3)	11 (18.3)	25 (41.7)	15 (25.0)
Race/Ethnicity, n (%)
Non-Hispanic White	139 (77.2)	41 (68.3)	49 (81.7)	49 (81.7)
Non-Hispanic Black / African American	24 (13.3)	12 (20.0)	7 (11.7)	5 (8.3)
Hispanic / Latina	13 (7.2)	5 (8.3)	3 (5.0)	5 (8.3)
Other	4 (2.2)	2 (3.3)	1 (1.7)	1 (1.7)
* BMI, n (%)
<25 kg/m2	68 (37.8)	18 (30.0)	20 (33.3)	30 (50.0)
25 – <30 kg/m2	62 (24.4)	21 (35.0)	18 (30.0)	23 (38.3)
≥30 kg/m2	49 (27.2)	21 (35.0)	21 (35.0)	7 (11.7)
Alcohol intake, n (%)
Nondrinker	39 (21.7)	18 (30.0)	9 (15.0)	12 (20.0)
<1 drink/day	61 (33.9)	22 (36.7)	24 (40.0)	15 (25.0)
≥1 drink/day	80 (44.4)	20 (33.3)	27 (45.0)	33 (55.0)
Smoking status, n (%)
Ever smokers	110 (61.1)	41 (68.3)	35 (58.3)	34 (56.7)
Never smokers	70 (38.9)	19 (31.7)	25 (41.7)	26 (43.3)
Parity, n (%)
Nulliparous	36 (20.0)	11 (18.3)	9 (15.0)	16(26.7)
Parous	144 (80.0)	49 (81.7)	51 (85.0)	44 (73.3)
Menopausal status, n (%)
Premenopausal	85 (47.2)	32 (53.3)	26 (43.3)	27 (45.0)
Postmenopausal	95 (52.8)	28 (46.7)	34 (56.7)	33 (55.0)
Hormone replacement therapy, n (%)
Never use	118 (65.6)	40 (66.7)	36 (60.0)	42 (70.0)
Estrogen use only	24 (13.3)	8 (13.3)	8 (13.3)	8 (13.3)
Progestin use only	7 (3.9)	2 (3.3)	3 (5.0)	2 (3.3)
Estrogen plus progestin use	31 (17.2)	10 (16.7)	13 (21.7)	8 (13.3)
* Tumor grade, n (%)
Low	10 (5.6)	2 (3.3)	5 (8.3)	3 (5.0)
Moderate	63 (35.0)	22 (36.7)	20 (33.3)	21 (35.0)
High	97 (53.9)	32 (53.3)	32 (53.3)	33 (55.0)
Tumor stage, n (%)
Stage I	36 (20.0)	13 (21.7)	12 (20.0)	11 (18.3)
Stage II	95 (52.8)	28 (46.7)	29 (48.3)	38 (63.3)
Stage III	49 (27.2)	19 (31.7)	19 (31.7)	11 (18.3)
* Tumor receptor status, n (%)
HR+ HER2+	42 (23.3)	13 (21.7)	15 (25.0)	14 (23.3)
HR+ HER2-	66 (36.7)	23 (38.3)	22 (36.7)	21 (35.0)
HR- HER2+	17 (9.4)	7 (11.7)	5 (8.3)	5 (8.3)
HR- HER2-	48 (26.7)	14 (23.3)	16 (26.7)	18 (30.0)
Receiving Anthracylines chemotherapy, n (%)	96 (53.3)	33 (55.0)	30 (50.0)	33 (55.0)
Receiving Taxanes chemotherapy, n (%)	169 (93.9)	58 (96.7)	54 (90.0)	57 (95.0)
Receiving Platinum agents chemotherapy, n (%)	56 (31.1)	18 (30.0)	20 (33.3)	18 (30.0)
Receiving neoadjuvant biologic therapy, n (%)	64 (35.6)	22 (36.7)	20 (33.3)	22 (36.7)
Trastuzumab + Pertuzumab	35 (19.4)	15 (25.0)	11 (18.3)	9 (15.0)
Trastuzumab only	23 (12.8)	6 (10.0)	8 (18.3)	9 (15.0)
Bevacizumab	2 (1.1)	1 (1.7)	0	1 (1.7)
Unknown	4 (2.2)	0	1 (1.7)	3 (5.0)

MET=metabolic equivalent task, BCa=breast cancer, SD=standard deviation, BMI=body mass index, HR=hormone receptor, HER2= human epidermal growth factor receptor 2

^*Missing: BMI n=1 (0.6%), tumor grade n=10 (5.5%), tumor receptor status n=7 (3.9%)

Of 153 participants had available chemotherapy completion data, 115 (75.2%) completed planned chemotherapy. In addition, of 140 participants had available dose delay data, 46 (31.5%) experienced dose delay. Treatment tolerance according to pre-diagnosis recreational physical activity levels were examined (Table 2). Participants with a higher pre-diagnosis recreational physical activity level were less likely to complete their planned chemotherapy (Model 2: ≥13.2 vs. <3.0 MET-hrs/wk: OR=0.87, 95% CI=0.30–2.56; P_trend=0.84) and were more likely to experience dose delay (Model 2: ≥13.2 vs. <3.0 MET-hrs/wk: OR=1.45, 95% CI=0.54–3.92; P_trend=0.46), although these associations were not statistically significant. Of the 180 patients, 45 (25.0%) achieved pCR (ypT0 ypN0) at the time of surgery. No significant association was observed between pre-diagnosis recreational physical activity level and pCR (Model 2: ≥13.2 vs. <3.0 MET-hrs/wk: OR=1.28, 95% CI=0.49–3.34; P_trend=0.42). Associations were consistently null when different pCR definitions were adopted (data not shown). Similar to recreational physical activity, pre-diagnosis total physical activity was not associated with chemotherapy completion (Supplemental Table 1; P_trend=0.63), dose delay (P_trend=0.21), and pCR (P_trend=0.13).

Table 2.

Odds ratio (ORs) and 95% confidence interval (CIs) for treatment tolerance and treatment efficacy by pre-diagnosis recreational physical activity levels (n=180).

	Pre-diagnosis recreational physical activity level, MET-hrs/wk
	<3.0	3.0 – <13.2	≥13.2	P trend
* Chemotherapy completion (n=153)
No. population	54	48	51
No. cases (%)	42 (77.8)	37 (77.1)	36 (70.6)
OR (95% CI) a	1.00 (reference)	1.02 (0.39, 2.66)	0.82 (0.33, 2.04)	P trend = 0.64
OR (95% CI) b	1.00 (reference)	0.86 (0.27, 2.75)	0.87 (0.30, 2.56)	P trend = 0.84
* Dose delay (n=140)
No. population	52	39	49
No. cases (%)	15 (28.8)	12 (30.8)	19 (38.8)
OR (95% CI) a	1.00 (reference)	1.06 (0.42, 2.69)	1.32 (0.56, 3.10)	P trend = 0.51
OR (95% CI) b	1.00 (reference)	1.17 (0.39, 3.54)	1.45 (0.54, 3.92)	P trend = 0.46
pCR (ypT0 ypN0) (n=180)
No. population	60	60	60
No. cases (%)	14 (23.3)	11 (18.3)	20 (33.3)
OR (95% CI) a	1.00 (reference)	0.74 (0.30, 1.81)	1.52 (0.66, 3.50)	P trend = 0.22
OR (95% CI) b	1.00 (reference)	0.67 (0.22, 2.01)	1.28 (0.49, 3.34)	P trend = 0.42

MET=metabolic equivalent task, OR=odds ratio, CI=confidence interval, pCR=pathological complete response

^*Missing: chemotherapy completion n=27 (15.0%), dose delay n=40 (22.2%)

^aAdjusted for age at diagnosis and BMI.

^bAdditionally adjusted for race/ethnicity, alcohol intake, menopause status, hormone replacement therapy use, tumor stage, tumor receptor status, and receiving neoadjuvant biological therapy.

Before breast cancer diagnosis, 91 (50.6%) of the 180 patients met recommended 7.5 MET-hrs/wk or more of recreational physical activity. Meeting physical activity was not associated with chemotherapy completion (Table 3; ≥7.5 vs. <7.5 MET-hrs/wk: OR=0.91, 95% CI=0.37–2.26) nor dose delay (≥7.5 vs. <7.5 MET-hrs/wk: OR=1.19, 95% CI=0.50–2.79). In addition, no significant associations were observed between meeting physical activity guidelines and pCR for either the overall cohort (≥7.5 vs. <7.5 MET-hrs/wk: OR=1.29, 95% CI=0.56–2.97) or upon stratification by tumor subtypes (≥7.5 vs. <7.5 MET-hrs/wk: HR+: OR=2.46, 95% CI=0.73–8.24; HR-: OR=0.65, 95% CI=0.19–2.17; HER2+: OR=0.60, 95% CI=0.11–3.17; HER2-: OR=1.93, 95% CI=0.68–5.52).

Table 3.

Odds ratio (ORs) and 95% confidence interval (CIs) for treatment tolerance and treatment efficacy by meeting physical activity guidelines.

	Meeting guidelines of 7.5 MET-hrs/wk or more of exercise
	No	Yes
Total tumors (n=180)
*Chemotherapy completion (n=153)
No. population	76	77
No. cases (%)	59 (77.6)	56 (72.7)
OR (95% CI)a	1.00 (reference)	0.91 (0.37, 2.26)
*Dose delay (n=140)
No. population	71	69
No. cases, n (%)	21 (29.6)	25 (36.2)
OR (95% CI)a	1.00 (reference)	1.19 (0.50, 2.79)
pCR (ypT0 ypN0) (n=180)
No. population	89	91
No. cases, n (%)	19 (21.3)	26 (28.6)
OR (95% CI)a	1.00 (reference)	1.29 (0.56, 2.97)
HR+ tumors (n=112)
No. population	58	54
pCR (ypT0 ypN0), n (%)	6 (10.3)	13 (24.1)
OR (95% CI)b	1.00 (reference)	2.46 (0.73, 8.24)
HR- tumors (n=67)
No. population	30	37
pCR (ypT0 ypN0), n (%)	13 (43.3)	13 (35.1)
OR (95% CI)b	1.00 (reference)	0.65 (0.19, 2.17)
HER2+ tumors (n=59)
No. population	31	28
pCR (ypT0 ypN0), n (%)	10 (32.3)	9 (32.1)
OR (95% CI)b	1.00 (reference)	0.60 (0.11, 3.17)
HER2- tumors (n=114)
No. population	53	61
pCR (ypT0 ypN0), n (%)	8 (15.1)	16 (26.2)
OR (95% CI)b	1.00 (reference)	1.93 (0.68, 5.52)

MET=metabolic equivalent task, OR=odds ratio, CI=confidence interval, pCR=pathological complete response, HR=hormone receptor, HER2= human epidermal growth factor receptor 2

^*Missing: chemotherapy completion n=27 (15.0%), dose delay n=40 (22.2%)

^aAdjusted for age at diagnosis, BMI, race/ethnicity, alcohol intake, menopause status, hormone replacement therapy use, tumor stage, tumor receptor status, and receiving neoadjuvant biological therapy.

^bAdjusted for age at diagnosis, BMI, race/ethnicity, alcohol intake, menopause status, hormone replacement therapy use, and tumor stage.

In sensitivity analyses, results were similar when excluding participants with biological treatment end date after the surgery or with unknown biological treatment end date (Supplemental Table 2). In addition, 154 participants completed a most recent follow-up questionnaire ≥ 6 months but < 3 years prior to breast cancer diagnosis and reported their recent pre-diagnosis total physical activity level. Recent pre-diagnosis total physical activity was not associated with treatment tolerance or pCR in this sub-population either (Supplemental Table 3). Similarly, non-significant associations were noted when analyzing the total physical activity data from the last report before diagnosis, encompassing either activity levels at baseline or at the latest follow-up (supplemental Table 4).

Discussion

This study investigated the association between pre-diagnosis physical activity level and treatment tolerance and treatment efficacy in 180 stage I-III breast cancer patients receiving NACT within the Sister Study cohort. Neither recreational physical activity nor total physical activity levels before breast cancer diagnosis were convincingly associated with chemotherapy completion, dose delay, or pCR. Meeting at least the recommended levels of recreational physical activity (7.5 MET-hrs/wk, equivalent to 150 min/wk of moderate aerobic physical activity) before a breast cancer diagnosis was not associated with pCR overall or by tumor subtypes. Observations of our study suggest that an individual’s level of physical activity prior to breast cancer diagnosis may not directly impact their ability to tolerate NACT or their tumor response to NACT.

Although the results were not statistically significant, participants with higher levels of pre-diagnosis recreational physical activity tended to have a lower treatment tolerance than those with lower levels, as evidenced by a lower rate of chemotherapy completion and a higher rate of dose delay. This differed slightly from the CANTO cohort, where the rates of chemotherapy completion and dose delay remained relatively stable as physical activity levels increased [20]. However, as mentioned earlier, a small prior study of this topic reported a positive association between pre-diagnosis physical activity level and treatment completion rate [21]. It is notable that in this study, a significantly higher percentage of participants met the recommended physical activity level before breast cancer diagnosis (67%), compared with the Sister Study (51%). The limited research in this topic, together with the small sample sizes and lack of diversity in existing studies, suggest that further work may still lend to insights into the association between pre-diagnosis physical activity level and treatment tolerance.

In addition to chemotherapy completion rate and dose delay, other clinical outcomes, such as dose reduction and RDI, have also been utilized to measure chemotherapy tolerance in breast cancer patients in previous research [17, 18, 20]. Breast cancer patients who reach an RDI of 85% have an optimized DFS and OS [14–16]. Recently, two retrospective analyses conducted by distinct research groups, utilizing pooled data from randomized trials, showed that breast cancer patients with higher levels of physical fitness, assessed either before or shortly after initiating chemotherapy, were more likely to achieve a RDI ≥85% [17, 18]. These observations of physical fitness provided the rationale for exploring the potential association between pre-diagnosis or pre-treatment physical activity levels and chemotherapy tolerance in breast cancer patients undergoing chemotherapy.

One of the advantages of using NACT in the clinical care of breast cancer patients is the ability to evaluate the tumor’s response to a particular chemotherapy regimen through the achievement of pCR. Further, because the primary tumor remains intact during therapy, the NACT strategy allows for monitoring of treatment response and discontinuing of therapy in the event of disease progression [34]. Pre-diagnosis recreational or total physical activity level was not associated with pCR for the overall cohort, or in analyses stratified by tumor subtypes in our study. Notably, our null findings are generally consistent with earlier observations of both pre-diagnosis [21] and pre-treatment [20] recreational physical activity levels and pCR. However, direct comparisons across studies are challenging due to different study designs (prospective vs. retrospective), and the setting of study populations (US vs. French breast cancer populations).

It should be noted that our study measured baseline physical activity level years before diagnosis, whereas the CANTO study assessed physical activity level in a typical week around the time of diagnosis and closer to when treatment began. This could be an important difference between these two studies. Physical activity levels in our study population may have changed between baseline and the time just prior to breast cancer diagnosis. Therefore, to explore the impact of more recent pre-diagnosis physical activity on NACT outcomes, we used “recent pre-diagnosis physical activity” obtained from follow-up questionnaires. A similar null association with this recent pre-diagnosis physical activity level was revealed. Instead of focusing on earlier patterns of physical activity, as captured in our study, future research considering the time-varying effects of pre-diagnosis or pe-treatment physical activity maybe lend further insight. The observed positive association between pre-treatment physical fitness and RDI in adjuvant chemotherapy contexts [17, 18] suggests that pre-habilitated exercise prior to the initiation of chemotherapy would improve treatment response. This aligns with findings from animal studies and some human studies showing that exercise working in synergy with the cytotoxicity of treatment for an improved tumor response [35, 36].

Key strengths of this study are worth mentioning. First, we conducted our analysis using a prospective cohort of US women. Information on physical activity levels was collected at baseline, prior to any breast cancer diagnoses. As a result, errors in pre-diagnosis physical activity level reporting between those who achieved pCR and those who did not would likely be non-differential in our study. Second, the standardized protocols and procedures for data collection in the Sister Study have been extensively validated in previous studies [28, 29]. Detailed information on physical activity allowed us to assess the effect of pre-diagnosis recreational and total physical activity levels respectively [29]. Third, by obtaining medical records from breast cancer patients within the Sister Study, we were to capture comprehensive treatment outcomes, as evaluated by specialized professionals. To our knowledge, no other prospective cohort has examined pre-diagnosis physical activity level and treatment tolerance and treatment efficacy in breast cancer patients receiving NACT.

This study was subject to several limitations. First, self-reported physical activity is likely inaccurate, meaning that non-differential exposure misclassification may exist in our study. However, a self-administered physical activity questionnaire similar to our study that assessed the duration and frequency of physical activity over the past one year has been demonstrated to have reasonable reproducibility and validity [37]. Second, because of the concern about potential bias in physical activity assessment due to the use of different questionnaires at baseline and follow-up, our assessment of main exposures – pre-diagnosis recreational and total physical activity levels – were confined to data collected solely from the baseline questionnaire. Among women with baseline physical activity information, some were diagnosed relatively soon after baseline but some further away. To address this issue, we then used “recent pre-diagnosis physical activity level” reported from the most recent follow-up questionnaire, which at most 3 years prior to diagnosis, to look at the recency effect of physical activity in a sub-population. In addition, for all women we used their latest reported physical activity data prior to diagnosis – either physical activity levels at baseline or at the most recent follow-up – and stratified by time before diagnosis to look at the effect of total physical activity on NACT outcomes to diminish the informative bias. Third, the Sister Study participants are all US women who have at least one biological sister with breast cancer at the time of enrollment. This means that the participants have, on average, an elevated risk of breast cancer relative to the general population [27]. Therefore, the observations in our study may not be generalizable to other samples of women with breast cancer in the US. Fourth, because medical records were acquired from facilities across the US, the type and amount of treatment information received varies tremendously. Abstracted chemotherapy data was derived mainly from summary descriptions in clinic notes provided by oncologists. Certain cases may feature precise chemotherapy dosage information (e.g., milligrams administered for each drug per cycle), while others may lack chemotherapy dosage information entirely. This restriction reduced the availability of certain proxy measures of treatment tolerance, such as dose reduction and RDI, which were not obtainable in this study. In addition, because of the limited study population, the statistical power to test the association of interest is insufficient. Future investigations with large sample sizes are needed to further explore the association between pre-diagnosis physical activity level and treatment outcomes.

In conclusion, we did not observe meaningful associations between pre-diagnosis physical activity level and treatment tolerance and treatment efficacy in breast cancer patients receiving NACT. Our results did not support the hypothesis that meeting the recommended guideline of at least 150 min/wk of physical activity level prior to breast cancer diagnosis is associated with better NACT outcomes. Though future research may provide different insights, our results suggest that physical activity levels before breast cancer diagnosis may not directly impact on treatment tolerance or tumor response to NACT.