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  • Research article
  • Open Access

Association between C-reactive protein and radiotherapy-related pain in a tri-racial/ethnic population of breast cancer patients: a prospective cohort study

Breast Cancer Research201921:70

https://doi.org/10.1186/s13058-019-1151-y

  • Received: 18 December 2018
  • Accepted: 6 May 2019
  • Published:

Abstract

Background

Post-surgery adjuvant radiotherapy (RT) significantly improves clinical outcomes in breast cancer patients; however, some patients develop cancer or treatment-related pain that negatively impacts quality of life. This study examined an inflammatory biomarker, C-reactive protein (CRP), in RT-related pain in breast cancer.

Methods

During 2008 and 2014, breast cancer patients who underwent RT were prospectively evaluated for pre- and post-RT pain. Pre- and post-RT plasma CRP levels were measured using a highly sensitive CRP ELISA kit. Pain score was assessed as the mean of four pain severity items (i.e., pain at its worst, least, average, and now) from the Brief Pain Inventory. Pain scores of 4–10 were classified as clinically relevant pain. Multivariable logistic regression analyses were applied to ascertain the associations between CRP and RT-related pain.

Results

In 366 breast cancer patients (235 Hispanic whites, 73 black/African Americans, and 58 non-Hispanic whites), 17% and 30% of patients reported pre- and post-RT pain, while 23% of patients had RT-related pain. Both pre- and post-RT pain scores differed significantly by race/ethnicity. In multivariable logistic regression analysis, RT-related pain was significantly associated with elevated pre-RT CRP (≥ 10 mg/L) alone (odds ratio (OR) = 2.44; 95% confidence interval (CI) = 1.02, 5.85); or combined with obesity (OR = 4.73; 95% CI = 1.41, 15.81) after adjustment for age and race/ethnicity.

Conclusions

This is the first pilot study of CRP in RT-related pain, particularly in obese breast cancer patients. Future larger studies are warranted to validate our findings and help guide RT decision-making processes and targeted interventions.

Keywords

  • Breast cancer
  • Radiotherapy
  • Pain
  • C-reactive protein
  • Inflammatory biomarker

Background

Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death among American women [1]. Compared to breast-conserving surgery (BCS) alone, adjuvant radiotherapy (RT) has significantly reduced loco-regional recurrences [2]. However, RT-induced adverse responses negatively impact patient overall quality of life (QOL). Breast erythema, pain, retraction at the tumor-bed site, fibrosis, cardiac morbidity, lymphedema, and telangiectasia are among the known adverse responses to RT [36]. Pain is one of the most prevalent symptoms and is an important QOL issue in breast cancer survivors [710].

A recent study reported the presence of racial-ethnic disparities in pain experience upon completion of RT [11], indicating the heterogeneity in the RT responses. The identification of a biomarker that can predict treatment-related symptoms is an important research question in the field of radiation oncology. Exposure to ionizing radiation induces immune/inflammatory responses to promote tissue repair [12], and elevated pro-inflammatory cytokines are potential biomarkers for RT-induced toxicities [1315]. However, very few studies have examined biomarkers for RT-related pain. Recently, our lab reported that RT-induced skin toxicity was associated with an increase in plasma C-reactive protein (CRP) levels [15, 16]. This may suggest a potential relationship between inflammatory responses and RT-induced skin toxicities, which can be another source of treatment-related pain for patients with breast cancer.

CRP has been widely used as a robust inflammatory biomarker for many health conditions in both clinical and research settings, and several studies have shown a positive correlation between plasma CRP levels and pain intensity in cancer patients [1719]; however, these results were from cross-sectional studies, which were often limited by uncertain temporal relationships or from the univariate analysis without adjustment for confounding variables [20, 21]. In addition, the study samples were limited to a specific racial/ethnic group, resulting in limited generalizability of the findings.

Therefore, we aimed to examine the associations between CRP levels and RT-related pain among breast cancer patients who underwent adjuvant RT using a prospective study design. We hypothesized that breast cancer patients with elevated CRP levels would be more likely to report pain, which may identify CRP as an inflammatory biomarker for pain. We also hypothesized that patients with elevated pre-RT CRP may be at higher risk in developing RT-related pain. Pain sensitization is one of the most important risk factors for persistent pain [22, 23]; thus, identifying potential biomarkers or mediators will be a critical strategy to identify those at risk of RT-related pain and targeted interventions among breast cancer patients.

Methods

Study design and patient population

Data for the current analysis was obtained from a prospective cohort study (University of Miami, FL, USA) where the goal was to examine the disparity of RT-induced early adverse skin reactions in a racially and ethnically diverse population of breast cancer patients. Briefly, the study recruited breast cancer patients from the Radiation Oncology clinics at the University of Miami Sylvester Comprehensive Cancer Center and Jackson Memorial Hospital in Miami, Florida, between December 2008 and August 2014. Patients were followed up for up to 12 months after the completion of RT. At the time of enrollment, each participant completed a self-administered baseline questionnaire. In addition, participants completed QOL questionnaire on the first day before initiation of RT, on the last day immediately after completion of RT, and at each follow-up visit (1, 2, 6, and 12 months). The current study only used QOL data collected on the first day of RT (i.e., pre-RT) and on the last day of RT (i.e. post-RT). The treating radiation oncologist met patients each week during the radiation treatment and evaluated adverse skin reactions at week 3 (mid-treatment), at week 6 (completion of RT), and at each follow-up visit. We collected blood samples (20 mL) at pre- and post-RT for biomarker data. Blood samples were processed within 2 h of phlebotomy, and the aliquoted plasma samples were stored at − 80 °C until assay. The study was approved by Institutional Review Boards of the University of Miami and Jackson Memorial Hospital, and all patients provided written informed consent.

The inclusion criteria were adult (≥ 18 years old at the time of diagnosis) female patients, newly diagnosed with breast cancer (AJCC stage 0–III) who had undergone BCS and planned to receive adjuvant RT to the whole breast with or without regional lymph nodes (total dose ≥ 40 Gy, dose per fraction ≥ 2.0 Gy). Other criteria included patients belonging to one of three racial/ethnic groups [self-reported non-Hispanic whites (NHW), black/African Americans (AA), and Hispanic whites (HW)] and being able to speak English or Spanish. The exclusion criteria were patients diagnosed with stage IV breast cancer and those that received partial breast irradiation and/or concurrent chemoradiation. Patients with missing pain score and/or CRP level at pre- or post-RT were excluded. To increase the validity of RT-related change in pain score, patients who reported pain due to other acute health conditions unrelated to cancer or radiation (such as shingles or fracture) were also excluded from the analysis after medical record verification.

Radiation treatment

RT was delivered using standard or partially wide photon tangents using 6 and/or 10MV photons with forward planned field-in-field technique to maximize dose homogeneity. Patients received RT to the whole breast ± regional lymph nodes with conventional fractionation (2.0 Gy/day over 5–6 weeks, mostly 50 Gy in 25 fractions) or hypo-fractionation (> 2.0 Gy/day over 3 weeks, most commonly 42.4 Gy in 16 fractions). An additional boost dose of 10–20 Gy without bolus was delivered to the tumor-bed site in most patients. Radiation oncologists contoured target volumes, including the breast and lumpectomy cavity. The treatment plan was completed on the Eclipse or Pinnacle planning systems.

Assessment of pain

All women enrolled in the study filled out the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39/RTOG 0413 protocol QOL questionnaire pre- and post-RT. This questionnaire measured QOL relating to breast cosmesis, fatigue, treatment-related symptoms, and perceived convenience of care. The section pertaining to treatment-related symptoms included four pain severity items, which were extracted from the Brief Pain Inventory (BPI): “Rate your pain at its worst, at its least, on average in the past four weeks, and now (0 = no pain to 10 = pain as bad as you can imagine).” The pain score was measured as a mean of these four pain severity items; a pain score of 4–10 was used to define the presence of clinically relevant pain because pain ≥ 4 indicates a moderate to severe level of pain, as used in previous studies [7, 24, 25]. In addition, patients who reported an increase in pain level from pre- to post-RT (i.e., pain score changed from < 4 to ≥ 4) was defined as having RT-related pain as previously reported [11] and compared to patients with pain score < 4 at both pre- and post-RT.

Assessment of plasma CRP

Plasma CRP levels were measured using a high-sensitivity CRP enzyme-linked immunosorbent assay (ELISA) kit (Calbiotech, Spring Valley, CA) according to the manufacturer’s protocol, as previously described [16]. A standard curve was generated for each batch of samples based on CRP concentrations, which ranged from 0.2 to 10.0 mg/L. To ensure that the diluted samples were within the linear range of the standard curve, we re-ran the assays by adjusting the dilution ratio if samples were outside the detection range. The average coefficient of variation was 8.3%, and the inter-assay variation was less than 10%. The cut-off value of CRP level was determined based on clinical usage and literature review where CRP ≥ 10.0 mg/L is a prognostic biomarker for breast cancer survival [26]. For CRP change, we used 1.0 mg/L as the cut-off value because it has been significantly associated with RT-induced skin toxicity in the same patient population [16]. Considering that CRP is an acute-phase protein with a half-life of 18 h, we collected post-RT blood samples immediately after RT on the last day consistently among all sample patients.

Assessment of covariates

Demographic information, self-reported race and ethnicity, comorbidities, and smoking history/status were obtained from a self-administered baseline questionnaire at the time of enrollment. A high correlation was found between the comorbidities reported on the questionnaires and those extracted from medical records [27, 28]. Tumor characteristics, such as tumor stage, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and detailed information on treatments were ascertained from medical records.

Statistical analysis

We first examined the distributions and frequencies of patient-, tumor-, and treatment-related characteristics overall and by race/ethnicity using the Pearson’s chi-square test or the Fisher’s exact test. The analysis of variance (ANOVA) was used to compare CRP levels by patient characteristics. The Pearson's chi-square test or the Fisher's exact test was used to compare the frequencies of elevated CRP or pain by patient characteristics. Univariable and multivariable logistic regression analyses were used to test whether elevated pre-RT CRP and/or obesity (BMI ≥ 30 kg/m2) were significantly associated with RT-related pain. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were reported. In addition, we performed the receiver operating characteristics (ROC) curve analysis to evaluate whether pre-RT CRP level and/or obesity contribute to RT-related pain. A two-tailed P value < 0.05 was considered statistically significant, and all statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, USA).

Results

Patient population characteristics

The study population consisted of 366 breast cancer patients: 64% HW, 20% AA, and 16% NHW. The mean ± standard deviation (SD) of age was 56.0 ± 9.1 years. As shown in Table 1, AA women were more likely to have BMI ≥ 30 kg/m2, advanced stage or triple-negative tumors, larger volume (cc) of the breast, diabetes mellitus, and hypertension compared to HW or NHW women. HW women were more likely to receive hormone therapy (HT) with aromatase inhibitors prior to RT compared to other racial/ethnic groups. For breast cancer surgery, 68% of patients received BCS with or without sentinel lymph node biopsy (SLNB), and 32% received BCS with axillary lymph node dissection (ALND). For systemic therapy, about half of the patients received chemotherapy, 44% initiated HT prior to RT, and 7% began HT during RT. For RT, 84% of patients received conventional fractionation with a mean total dose of 58.2 ± 4.8 (SD) Gy, including an additional boost to the lumpectomy cavity, and 16% were treated with hypo-fractionated regimens. There were no significant differences in RT treatment regimens across the three racial/ethnic groups. Overall, patients reported a significantly higher pain score at post-RT (mean ± SD = 2.8 ± 2.5) compared to pre-RT (mean ± SD = 1.7 ± 2.1). In general, AA and HW patients had significantly higher pre-RT and post-RT pain scores compared to NHW patients.
Table 1

Patient demographic, tumor, and treatment characteristics by race/ethnicity

Variable

Categories

Total

NHW

AA

HW

P 1

N

%

N

%

N

%

N

%

Total

 

366

100

58

16

73

20

235

64

 

Age (years)

< 50

95

26

18

31

19

26

58

25

0.613

≥ 50

271

74

40

69

54

74

177

75

 

Mean (SD)

56.0 (9.1)

55.6 (9.1)

54.9 (9.2)

56.5 (9.1)

 

BMI (kg/m2)

< 25

96

26

29

50

12

16

55

23

<0.0001

25–29.9

124

34

16

28

17

23

91

39

 

≥ 30

146

40

13

22

44

60

89

38

 

Mean (SD)

29.3 (6.4)

26.6 (6.3)

32.6 (8.4)

28.9 (5.2)

 

Smoking status

Never

240

66

37

64

51

70

152

64

0.490

Former

107

29

20

34

17

23

70

30

 

Current

19

5

1

2

5

7

13

6

 

Sum of 12 comorbid conditions2

0

147

40

28

48

19

26

100

43

0.119

1

137

37

20

34

32

44

85

36

 

2

60

16

7

12

18

25

35

15

 

≥ 3

22

6

3

5

4

5

15

6

 

Tumor stage

0

74

20

7

12

14

19

53

23

0.003

IA-B

180

49

37

64

28

38

115

49

 

IIA-B

90

25

13

22

29

40

48

20

 

IIIA-C

22

6

1

2

2

3

19

8

 

ER

Positive

279

76

43

74

49

67

187

80

0.072

Negative

86

23

15

26

24

33

47

20

 

PR

Positive

243

66

36

62

44

60

163

69

0.243

Negative

122

33

22

38

29

40

71

30

 

HER2

Positive

31

8

4

7

6

8

21

9

0.730

Negative

275

75

50

86

56

77

169

72

 

Triple negative

No

294

80

47

81

52

71

195

83

0.005

Yes

54

15

8

14

20

27

26

11

 

Axillary surgery

None/SLNB

248

68

39

67

54

74

155

66

0.439

ALND

118

32

19

33

19

26

80

34

 

Chemotherapy

No

195

53

31

53

39

53

125

53

0.999

Yes

171

47

27

47

34

47

110

47

 

Hormone therapy/initiation time

None/after RT

178

49

37

64

41

56

100

43

0.015

Aromatase inhibitor before RT

98

27

9

16

14

19

75

32

 

Aromatase inhibitor during RT

14

4

3

5

2

3

9

4

 

Tamoxifen before RT

64

17

6

10

12

16

46

20

 

Tamoxifen during RT

12

3

3

5

4

5

5

2

 

RT fractionation

Conventional

306

84

45

78

64

88

197

84

0.298

Hypo

60

16

13

22

9

12

38

16

 

Total RT dose (Gy)

< 60

107

29

21

36

18

25

68

29

0.348

≥ 60

259

71

37

64

55

75

167

71

 

Mean (SD)

58.2 (4.8)

58.4 (4.6)

58.7 (4.9)

58.0 (4.8)

 

Boost

Yes

331

90

56

97

65

89

210

89

0.225

No

35

10

2

3

8

11

25

11

 

Breast volume (cc)

< 892.1 (median)

183

50

38

66

20

27

125

53

< 0.001

≥ 892.1 (median)

179

49

20

34

52

71

107

46

 

Mean (SD)

996 (532)

799 (464)

1254 (645)

965 (479)

 

Pre-RT pain

Mean (SD)

1.7 (2.1)

1.0 (1.3)

2.0 (2.5)

1.8 (2.1)

0.023

Post-RT pain

Mean (SD)

2.8 (2.5)

1.9 (1.7)

3.2 (2.6)

2.8 (2.6)

0.013

1P values from the chi-square test or Fisher's exact test, or ANOVA, excluding missing. Significant findings are in italics

2Sum of 12 patient-reported comorbid conditions: diabetes, hypertension, heart disease, lung disease, thyroid disease, cirrhosis liver, stroke, chronic bronchitis, hepatitis, tuberculosis, and 2 others

Abbreviations: NHW non-Hispanic whites, AA black or African American, HW Hispanic whites, SD standard deviation, BMI body mass index, ER estrogen receptor, PR progesterone receptor, HER2 human epidermal growth factor receptor 2, SLNB sentinel lymph node biopsy, ALND axillary lymph node dissection, RT radiotherapy

Plasma CRP levels at pre- and post-RT and RT-related CRP change

As shown in Table 2, there was no significant difference between pre- (mean ± SD = 6.5 ± 9.3) and post-RT (mean ± SD = 6.1 ± 8.9) plasma CRP levels. The CRP levels were significantly higher in obese patients at both pre- and post-RT. Pre-RT CRP levels were significantly higher in patients with pre- or post-RT pain score ≥ 4. Post-RT CRP levels were significantly higher in patients with smoking history, post-RT pain score ≥ 4, larger breast volume, and tamoxifen treatment during RT.
Table 2

CRP levels by patient, treatment characteristics, and pain status

Variable

Pre-RT CRP (mg/L)

Post-RT CRP (mg/L)

N

Mean

SD

MD

P 1

N

Mean

SD

MD

P 1

Study population

362

6.5

9.3

3.5

 

338

6.1

8.9

3.5

0.6462

Race/ethnicity

 NHW

58

6.1

12.4

2.8

0.879

53

5.2

12.1

2.2

0.541

 AA

71

6.9

8.0

4.4

 

66

7.0

6.7

5.5

 

 HW

233

6.4

8.8

3.5

 

219

6.0

8.6

3.7

 

Age (years)

 < 50

94

6.2

10.7

3.1

0.797

86

5.6

10.1

2.8

0.571

 ≥ 50

268

6.5

8.8

3.7

 

252

6.2

8.5

3.9

 

BMI (kg/m2)

 < 25

94

3.1

6.3

1.2

0.0001

87

3.1

8.4

1.4

0.0009

 25–29.99

124

7.3

11.0

3.7

 

117

6.5

9.5

3.8

 

 ≥ 30

144

8.0

8.8

4.9

 

134

7.7

8.4

5.3

 

Smoking history

 Never

238

5.8

8.6

3.4

0.066

225

5.4

7.8

3.4

0.046

 Ever

124

7.7

10.3

3.7

 

113

7.4

10.7

3.9

 

Pre-RT pain score

 < 4

286

5.9

8.8

3.3

0.014

266

5.6

8.4

3.4

0.054

 ≥ 4

59

9.3

11.8

4.9

 

56

8.1

10.3

4.2

 

Post-RT pain score

 < 4

230

5.4

8.2

3.1

0.007

226

5.3

7.8

3.2

0.014

 ≥ 4

101

8.3

9.9

4.6

 

99

7.9

11.0

4.8

 

Tumor stage

 0

73

6.1

8.2

3.6

0.916

65

6.3

8.3

3.4

0.872

 IA-B

180

6.4

10.0

3.3

 

165

6.3

10.8

3.4

 

 IIA-III

109

6.7

8.8

3.9

 

108

5.7

5.7

4.2

 

Breast volume (cc)

 < 892.1 cc (median)

181

5.2

8.2

2.6

0.011

169

5.0

9.2

2.4

0.021

 ≥ 892.1 cc (median)

177

7.7

10.2

4.6

 

165

7.2

8.6

5.0

 

Hormone therapy

 None/after RT

175

6.7

10.5

3.2

0.736

159

5.7

7.9

3.3

0.032

 AI before

97

6.7

7.7

4.8

 

95

7.2

10.0

4.6

 

 AI during

14

4.5

4.0

3.3

 

14

5.1

5.3

3.8

 

 Tamoxifen before

64

5.5

8.8

2.8

 

59

4.3

6.0

2.4

 

 Tamoxifen during

12

8.2

9.3

5.1

 

11

12.8

21.0

5.1

 

RT fractionation

 Conventional

302

6.4

9.1

3.5

0.632

289

6.2

9.2

3.5

0.575

 Hypo

60

7.0

10.2

3.5

 

49

5.4

7.0

3.7

 

1P values from ANOVA; significant findings are in italics

2Paired t test comparing pre- and post-RT CRP

Abbreviations: NHW non-Hispanic whites, AA black or African American, HW Hispanic whites, BMI body mass index, AI aromatase inhibitor, SD standard deviation, MD median

Clinically relevant pain by selected variables and CRP levels

As shown in Table 3, the proportion of patients who reported clinically relevant pain (pain score ≥ 4) increased from 17% at pre-RT to 30% at post-RT. Pre-RT pain was more prevalent in patients with AA or HW race/ethnicity, BMI ≥ 30 kg/m2, HER2-positive tumor, received trastuzumab alone or taxane+trastuzumab, received ALND, or pre-RT CRP ≥ 10 mg/L, compared to their respective comparison groups. Post-RT pain was more prevalent in patients with AA or HW race/ethnicity, age < 50 years, BMI ≥ 30 kg/m2, at least 2 comorbid conditions, conventional RT fractionation, total RT dose ≥ 60 Gy, or pre-RT CRP ≥ 10 mg/L, compared to their respective counterparts. About 23% of patients had RT-related pain, and it was more frequent in patients with AA or HW race/ethnicity, at least 2 comorbid conditions, conventional RT fractionation, or RT-induced CRP change > 1 mg/L.
Table 3

Pre-RT, post-RT, and RT-related pain by selected variables and CRP status

Variable

Categories

Pre-RT pain1 (N = 349)

Post-RT pain1 (N = 335)

RT-related pain2 (N = 262)

No (< 4)

Yes (≥ 4)

 

No (< 4)

Yes (≥ 4)

 

No

Yes

 

N

%

N

%

P 3

N

%

N

%

P 3

N

%

N

%

P 3

Total

 

290

83

59

17

 

233

70

102

30

 

203

77

59

23

 

Race/ethnicity

NHW

53

96

2

4

0.016

45

88

6

12

0.003

42

89

5

11

0.018

AA

58

82

13

18

 

42

60

28

40

 

37

66

19

34

 

HW

179

80

44

20

 

146

68

68

32

 

124

78

35

22

 

Age (years)

< 50

75

81

17

19

0.639

51

60

34

40

0.027

46

69

21

31

0.045

≥ 50

215

84

42

16

 

182

73

68

27

 

157

81

38

19

 

BMI (kg/m2)

< 25

84

88

11

12

0.009

68

81

16

19

0.001

63

85

11

15

0.075

25–29.99

101

88

14

12

 

85

74

30

26

 

73

78

20

22

 

≥ 30

105

75

34

25

 

80

59

56

41

 

67

71

28

29

 

Sum of 12 comorbid conditions4

0

114

84

22

16

0.897

103

75

34

25

0.009

87

83

18

17

0.009

1

111

83

22

17

 

88

73

33

27

 

79

81

18

19

 

2

48

83

10

17

 

32

57

24

43

 

28

64

16

36

 

≥ 3

17

77

5

23

 

10

48

11

52

 

9

56

7

44

 

HER2

Positive

18

62

11

38

0.004

16

59

11

41

0.294

10

71

4

29

0.676

Negative

220

84

42

16

 

177

69

79

31

 

155

76

48

24

 

Chemotherapy

None

159

85

27

15

0.140

128

72

50

28

0.455

115

80

29

20

0.416

Taxane

123

79

32

21

 

100

68

48

32

 

83

75

27

25

 

Other

8

100

0

0

 

5

56

4

44

 

5

63

3

38

 

Trastuzumab

No

274

85

49

15

0.005

218

70

92

30

0.281

194

78

55

22

0.497

Yes

16

61

10

39

 

15

60

10

40

 

9

69

4

31

 

Taxane+trastuzumab

None/other chemo only

166

86

26

14

0.012

132

71

53

29

0.558

120

79

31

21

0.667

Either

109

82

24

18

 

87

68

40

32

 

74

75

25

25

 

Both

15

62

9

38

 

14

61

9

39

 

9

75

3

25

 

Axillary surgery

None/SLNB

205

86

33

14

0.027

163

72

63

28

0.141

145

78

40

22

0.590

ALND

85

77

26

23

 

70

64

39

36

 

58

75

19

25

 

RT fractionation

Conventional

240

82

52

18

0.309

190

67

94

33

0.013

165

75

55

25

0.028

Hypo

50

88

7

12

 

43

84

8

16

 

38

90

4

10

 

Total RT dose (Gy)

< 60

92

89

11

11

0.045

74

80

19

20

0.014

66

84

13

16

0.123

≥ 60

198

80

48

20

 

159

66

83

34

 

137

75

46

25

 

Pre-RT CRP (mg/L)

< 10

256

85

45

15

0.006

210

73

79

27

0.001

183

79

48

21

0.056

≥ 10

30

68

14

32

 

20

48

22

52

 

17

63

10

37

 

Post-RT CRP (mg/L)

< 10

234

83

47

17

0.410

203

71

82

29

0.077

175

78

49

22

0.373

≥ 10

32

78

9

22

 

23

58

17

43

 

22

71

9

29

 

RT-related CRP change (mg/L)

≤ 1

192

82

41

18

0.992

170

72

67

28

0.140

151

82

34

18

0.006

> 1

70

82

15

18

 

53

63

31

37

 

43

65

23

35

 

1Pain score ≥ 4 (moderate or severe pain) was considered yes for clinically relevant pain

2Patients with pre-RT pain score < 4 and post-RT pain score ≥ 4 or < 4 were considered yes or no for RT-related pain

3P values were from the chi-square test or Fisher's exact test excluding missing. Significant findings are in italics

4Sum of 12 patient-reported comorbid conditions: diabetes, hypertension, heart disease, lung disease, thyroid disease, cirrhosis liver, stroke, chronic bronchitis, hepatitis, tuberculosis, and 2 others

Plasma CRP levels by pain status

In Table 4, we summarize CRP levels in 4 or 8 groups of patients and identified significantly higher CRP levels (mean ± SD = 10.8 ± 12.1) in 34 patients with pain scores ≥ 4 at both pre- and post-RT. We have also identified 20 patients with pain score ≥ 4 at pre-RT but < 4 at post-RT. In stratified analysis by obesity, we identified 11 non-obese patients with high pre-RT CRP also had pain scores ≥ 4 at both pre- and post-RT. Therefore, we limited subsequent data analysis of RT-related pain to only two groups of patients with pre-RT pain score <  4 and post-RT score either < 4 (no) or ≥ 4 (yes).
Table 4

CRP levels by pre- and post-RT pain stratified by obesity

BMI

Pre-RT pain

Post RT pain

N

Pre-RT CRP

Post-RT CRP

 

Mean

SD

Median

P 1

Mean

SD

Median

P 1

P 2

NA

No

No

194

5.5

8.4

3.3

0.278

5.2

7.9

3.2

0.034

0.675

NA

No

Yes

57

7.1

8.8

3.4

 

7.2

10.8

4.8

 

0.936

NA

Yes

No

20

5.4

9.2

2.2

0.010

5.6

9.5

3.3

0.075

0.807

NA

Yes

Yes

34

10.8

12.1

6.0

 

8.8

10.2

5.6

 

0.278

< 30

No

No

130

5.1

9.2

2.6

0.786

4.4

8.1

2.0

0.169

0.423

< 30

No

Yes

31

5.4

8.1

2.7

 

7.4

14.1

3.2

 

0.366

< 30

Yes

No

10

4.4

7.0

2.2

0.393

3.6

2.4

3.1

0.647

0.676

< 30

Yes

Yes

11

12.1

16.8

3.6

 

7.5

11.5

4.2

 

0.304

≥ 30

No

No

64

6.3

6.3

4.6

0.480

6.9

7.1

4.8

0.368

0.497

≥ 30

No

Yes

26

9.0

9.5

5.9

 

6.9

4.8

5.9

 

0.259

≥ 30

Yes

No

10

6.4

11.3

2.7

0.022

7.7

13.3

3.5

0.142

0.114

≥ 30

Yes

Yes

23

10.1

9.4

6.4

 

9.4

9.7

6.9

 

0.677

1Unadjusted P value from the Wilcoxon two-sample test (comparing 2 groups by pain status)

2P value from the paired t test within each group (comparing pre-RT and post-RT CRP). Significant findings are in italics

Association between pre-RT CRP and RT-related pain

In Table 5, we evaluated the association of elevated pre-RT CRP (≥ 10 mg/L) and/or obesity with RT-related pain. In multivariable model, there was a significant association between high pre-RT CRP and RT-related pain (OR = 2.44, 95% CI = 1.02, 5.85) regardless of obesity status. In obese patients, there was a stronger association between high pre-RT CRP and RT-related pain (OR = 3.71, 95% CI = 1.05, 13.09) than in non-obese patients (OR = 1.36, 95% CI = 0.35, 5.39). Therefore, we conducted a combined analysis to show that patients with BMI ≥ 30 kg/m2 and pre-RT CRP ≥ 10 mg/L had 4.73-fold elevated risk for RT-related pain (95% CI = 1.41, 15.81) compared to patients with BMI <  30 kg/m2 and pre-RT CRP < 10 mg/L. All models were adjusted for age and race/ethnicity.
Table 5

Association between pre-RT CRP and RT-related pain by obesity

BMI

Pre-RT CRP

N

%

RT-related pain

Univariable

Multivariable1

N

%

OR (95%CI)

P

OR (95%CI)

P

< 30

NA

161

64

31

54

Ref

 

Ref

 

≥ 30

NA

90

36

26

46

1.70 (0.93, 3.11)

0.082

1.49 (0.80, 2.78)

0.211

NA

< 10 mg/L

225

90

47

82

Ref

 

Ref

 

NA

≥ 10 mg/L

26

10

10

18

2.37 (1.01, 5.55)

0.048

2.44 (1.02, 5.85)

0.046

< 30

< 10 mg/L

148

92

28

90

Ref

 

Ref

 

< 30

≥ 10 mg/L

13

8

3

10

1.29 (0.33, 4.98)

0.716

1.36 (0.35, 5.39)

0.659

≥ 30

< 10 mg/L

77

86

19

73

Ref

 

Ref

 

≥ 30

≥ 10 mg/L

13

14

7

27

3.56 (1.07, 11.91)

0.039

3.71 (1.05, 13.09)

0.041

< 30

< 10 mg/L

148

59

28

49

Ref

 

Ref

 

< 30

≥ 10 mg/L

13

5

3

5

1.29 (0.33, 4.98)

0.716

1.34 (0.34, 5.26)

0.678

≥ 30

< 10 mg/L

77

31

19

33

1.40 (0.73, 2.72)

0.315

1.22 (0.62, 2.42)

0.567

≥ 30

≥ 10 mg/L

13

5

7

12

5.00 (1.56, 16.03)

0.007

4.73 (1.41, 15.81)

0.012

1All models were adjusted for age (< 50, ≥ 50) and race/ethnicity (NHW, HW, AA). Significant findings are in italics

We also present ROC curves of high pre-RT CRP and/or obesity in predicting RT-related pain for (A) all, (B) NHW, (C) HW, and (D) AA patients and their corresponding area under the curve (AUC). The gray line represents the theoretical performance of the variable equivalent to a coin toss. The blue line is for obesity (BMI ≥ 30 kg/m2), the red line is for pre-RT CRP ≥ 10 mg/L, and the green line shows the combined effect of obesity and pre-RT CRP ≥ 10 mg/L. The results show some improvements of AUC in the combined BMI and pre-RT CRP model for NHW (AUC = 0.6540) and AA (AUC = 0.6524) patients (see Additional file 1: Figure S1).

Discussion

Postoperative adjuvant RT significantly reduces local-regional recurrence and improves breast cancer survival. Therefore, there has been increasing usage of adjuvant RT in early-stage breast cancer patients. However, RT is associated with skin toxicities and other late effects that negatively impact QOL. We evaluated whether the inflammatory biomarker, CRP, was associated with RT-related pain. To the best of our knowledge, this is the first study to date reporting a significant association between pre-RT CRP and RT-related pain.

Consistent with literature, the proportion of patients who experienced clinically relevant pain increased from pre-RT (17%) to post-RT (30%) [7, 29]. Pre-RT pain may be related to other cancer treatments (e.g., surgery and/or chemotherapy). Intriguingly, a higher proportion of patients with at least two comorbid conditions showed an elevated risk for post-RT pain [30]. It is notable that not all patients reported an increase in pain score after RT. Specifically, 194 patients reported pain score < 4 at both pre- and post-RT. A total of 57 patients reported the change of pain score from < 4 at pre-RT to ≥ 4 at post-RT. Twenty patients reported pain score change from ≥ 4 at pre-RT to < 4 at post-RT. Thirty-four patients reported pain score ≥ 4 at both pre- and post-RT. These findings are consistent with another study among breast cancer patients, which reported that cancer pain was not static, but rather could progress or regress [25]. Inter-individual variations in pain may be related to differences in responses to RT, genetic factors, and inflammatory responses.

The CRP level in normal human serum ranges from 0.2 to 10 mg/L; 90% of apparently healthy individuals have CRP levels < 3 mg/L; and only 1% have levels ≥ 10 mg/L. In our study, 13% and 13% of patients had pre-RT and post-RT CRP ≥ 10 mg/L, respectively (Table 3). Radiation sensitivity is a complex and inherited polygenic trait, with many genes in multiple biological pathways. Genetic studies are warranted to elucidate the contribution of genetic variants in racial/ethnic differences of RT-related pain. In addition, a higher proportion of AA patients were obese (60%), compared to 22% of NHW and 38% of HW patients, respectively. Other studies have also reported that a higher proportion of AA women had elevated inflammatory cytokines including CRP and interleukin (IL)-6, relative to NHW women [31, 32]. This may explain, in part, why AA patients experience more cancer treatment-related symptoms such as pain, skin toxicity, nausea/vomiting, and depression compared to NHW patients [11, 3335].

Multiple studies have shown that irradiation increases immune/inflammatory responses [12, 36], and there is evidence showing a positive correlation between elevated inflammatory cytokines and pain severity in both human [17, 19] and animal studies [37, 38]. In addition to pain, elevated pro-inflammatory cytokines, including CRP, after cancer treatment have been associated with persistent fatigue and sleep disturbances in breast cancer patients [18, 39]. These findings may suggest the existence of a shared etiology in cancer treatment-related symptoms. Given that immune/inflammation underscores cancer treatment-related symptoms, the use of anti-inflammatory agents as prophylactic treatment may be considered.

Our current data provides evidence that CRP is associated with RT-related pain in breast cancer patients. Our findings have several clinical implications. First, elevated plasma CRP has been associated with cancer prognosis, vascular atherosclerosis, insulin resistance, and type 2 diabetes mellitus that may impact overall survival. Therefore, patients with elevated post-RT CRP levels should be actively monitored for other medical conditions that may also impact overall survival. Second, considering the involvement of CRP in fatigue and prognosis of breast cancer, future follow-up studies will focus on monitoring CRP levels, QOL, and clinical outcomes. Third, growing evidence suggests that plasma CRP is positively associated with sugar intake but negatively associated with dietary intakes of minerals, vitamins, and polyunsaturated fatty acids [40]. Therefore, modulating CRP concentrations by modifying dietary intakes may be a promising intervention strategy. Lastly, we observed a stronger association between elevated pre-RT CRP and RT-related pain in obese patients. Considering that CRP and BMI are highly correlated, weight reduction may also reduce pre-RT CRP levels and RT-related pain.

Multiple studies have shown the predictive value of CRP in cancer outcomes [4143]. This study further adds to the literature by reporting a significant association between elevated pre-RT CRP level and RT-related pain. However, using a threshold AUC of 0.8 by ROC analysis, combining BMI and pre-RT CRP levels may not be a strong predictor for RT-related pain. With a limited sample size, we did not include many other clinical or treatment variables. Larger studies are warranted to further test our predictive models, which should include other patient/clinical variables and additional promising biomarkers to improve their utilities in predicting RT-related pain.

There are several strengths and limitations of this study. First, we used a prospective study design that is particularly suitable to conduct biomarker research and RT-related pain. We followed patients and collected biological samples over time and recorded patient-reported QOL on the first and last day of RT to minimize recall bias, which provides more precise estimates of biomarkers and pain. This is the first study showing racial/ethnic differences in pre- and post-RT pain, which may help bridge the knowledge gap regarding the mechanisms of racial/ethnic disparities in cancer treatment-related QOL.

Several limitations should also be taken into consideration. First, because CRP is a non-specific inflammatory biomarker, CRP levels can be influenced by multiple factors including anti-inflammatory drug use and/or other health conditions. Second, despite the prospective cohort study design, some covariates (i.e., comorbidities) were collected only one point in time. The lack of repeated measures prevented us from capturing changes in health status, which may influence CRP and pain levels. Third, some variables that may influence individual patient’s pain experience and CRP level (i.e., the use of pain medication and anti-inflammatory agents) were not available for this study, thus should be considered for future studies. Fourth, the nature of pain (nociceptive or neuropathic) may be differently influenced by inflammatory responses; however, the detailed pain quality data was not available in the current analysis. Lastly, we used patient-reported information on comorbid conditions, which might introduce reporting bias. However, many studies have reported high reliability of self-reported information when compared to medical records [27, 28].

Conclusions

In summary, our current data show a significant association between elevated pre-RT CRP and RT-related pain in breast cancer patients. More importantly, we demonstrate for the first time that obese patients with pre-RT CRP ≥ 10 mg/L have a significantly increased risk of RT-related pain compared to non-obese patients with pre-RT CRP < 10 mg/L. Therefore, our current data suggest that there is an association between inflammatory responses and RT-related pain. Our results will need to be validated externally in other study populations. If validated, these results pave the way for testing anti-inflammatory agents in reducing RT-related pain.

Abbreviations

AA: 

African American/black

ALND: 

Axillary lymph node dissection

BCS: 

Breast-conserving surgery

BMI: 

Body mass index

CI: 

Confidence interval

CRP: 

C-reactive protein

ER: 

Estrogen receptor

HER2: 

Human epidermal growth factor receptor 2

HT: 

Hormone therapy

HW: 

Hispanic whites

NHW: 

Non-Hispanic whites

OR: 

Odds ratio

PR: 

Progesterone receptor

QOL: 

Quality of life

RT: 

Radiotherapy

SD: 

Standard deviation

SLNB: 

Sentinel lymph node biopsy

Declarations

Acknowledgements

The authors are thankful to all women who participated in the study and the clinical staff at the radiation oncology clinics for their support.

Funding

This study was supported by two National Institutes of Health grants R01CA135288 and R03CA195643 (J.J.H.) and the University of Miami Sheila and David Fuente Neuropathic Pain Pre-Doctoral fellowship (E.L).

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

EL, CT, JLW, IMR, and JJH designed the study. CT and JLW were in charge of radiotherapy, patient enrollment, and clinical outcome assessment. EL, ON, CP, CT, JLW, and JJH collected the laboratory and questionnaire data. EL, RL, IR, and WZ conducted the statistical data analysis, and EL and JH interpreted results. EL and JJH drafted the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

All women participated in the study provided written informed consent. The study was approved by the Institutional Review Boards of the University of Miami and the Jackson Memorial Hospital.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Health Sciences, University of Central Florida College of Health Professions and Sciences, Orlando, FL 32816, USA
(2)
Department of Public Health Sciences, University of Miami School of Medicine, Miami, FL 33136, USA
(3)
Department of Radiation Oncology, University of Miami School of Medicine, Miami, FL, USA
(4)
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, MD, USA
(5)
Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL, USA

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