This study is the first to describe the characteristics of preoperative breast pain in a sample of women prior to breast cancer surgery and to evaluate for genetic variations in pro-and anti-inflammatory genes in women who did and did not report pain. Consistent with previous studies,14,44,63–65
over one quarter of these patients experienced pain prior to surgery. This number is not insignificant given that in 2011 an estimated 230,480 new cases of breast cancer will be diagnosed in the United States.59
While the worst pain scores were in the mild to moderate range, a large amount of inter-individual variability was noted in this sample. In fact, 36.7% of the women reported a worst pain score of ≥ 4. In addition, these women reported that pain interfered with their activities or mood on approximately 3 days per week for about 6 hours per day. In terms of level of interference (), this pain had the largest effect on patients’ mood, sleep, enjoyment of life, and ability to sleep on the affected side. Again, a large amount of inter-individual variability was noted in patients’ interference ratings. Taken together these findings suggest that preoperative breast pain is a significant problem for a subset of women.
Consistent with previous reports, women who reported pain were more likely to be younger1
and have poorer functional status10,39,40,69
than the no pain group. However, while the differences in KPS scores were statistically significant, both groups of women reported high levels of function.
Another interesting but not easily explained finding is that a higher percentage of non-white women reported breast pain prior to surgery. While findings from several studies suggest that members of minority groups report higher rates of chronic pain16–17
and increased sensitivity to painful stimuli,6–8,48
other studies have not demonstrated ethnic differences.17,38
One potential reason for the ethnic differences found in this study is that a higher percentage of non-white women were diagnosed with more advanced disease (61% versus 41%, p=0.035). However, stage of disease was not associated with the occurrence of breast pain in this study. The potential link between ethnicity, stage of disease, and pain warrants investigation in future studies. Finally, women in the pain group were less likely to be post-menopausal, which is consistent with the younger age of this group, and the potential effects of the menstrual cycle and estrogen upon nociception.19,42
These demographic and clinical characteristics suggest a profile of women who are at higher risk for pain prior to surgery.
Possible contributors to presurgical breast pain are tissue injury or nerve damage and inflammation associated with tumor growth, the number of biopsies performed prior to surgery, or both mechanisms. These mechanical injuries could result in the release of inflammatory mediators. This hypothesis is supported by several findings. First, women in the pain group reported a significantly higher number of biopsies. While the total number of biopsies was not normally distributed, 48% of the women in the pain group compared to only 29% in the no pain group had more than one biopsy. Unfortunately, data are not available on the type of biopsy performed, nor when the last biopsy was performed in relationship to completion of the enrollment questionnaire. A higher percentage of patients in the pain group reported swelling, numbness, strange sensations and hardness in their breasts (). However, the exact causes for these differences are not readily apparent. Additional analyses were done within the pain group to evaluate whether women who had mastitis or fibrocystic disease reported higher occurrence rates for these four breast qualities. No differences in occurrence rates were found for any of these qualities between women with or without mastitis who reported pain in their breast prior to surgery. The same negative findings were found for fibrocystic disease (data not shown). Of note, the pain qualities reported by the patients with preoperative breast pain are suggestive of nociceptive pain rather than neuropathic pain.72
These phenotypic findings support the data from the genomic analyses that suggest that some innate differences in inflammatory responses may be influencing the development of pre-surgical pain in breast cancer patients.
The results of the SNP analyses suggest that variation in inflammatory pathways involving IL1R1 and IL13 are involved in preoperative pain. In this study, carriers of the minor allele for IL1R1 (rs2110726) had a 53% decrease in the odds of reporting preoperative breast pain. This finding is consistent with studies of IL1 function in mice, in which removal of IL1R function or blockade of IL1 led to a decrease in inflammation and pain behaviors.67
Additional functional studies are needed to determine if the minor allele of rs2110726 is associated with a decrease in IL1R1 function and therefore a decrease in the pro-inflammatory effects of IL1. The rs2110726 is in the 3’ untranslated region of the IL1R1 gene.29
This SNP analysis supports our hypothesis that genetic variation in anti-inflammatory cytokines may be involved in the development of breast pain prior to surgery. IL13, unlike IL1R1, is a cytokine with anti-inflammatory activity. Therefore, its role in pain may be as a moderator of the inflammatory response. In fact, patients with chronic widespread pain syndrome have reduced levels of a number of anti-inflammatory cytokines (i.e., IL2, IL4, IL8, IL10).68
are known to have antinociceptive effects in mice, independent of endogenous opioid release, possibly through inhibition of TNFα and IL1β release. The SNP rs1295686 is located in intron 3 of the IL13 gene.55
Given that neither tag SNP is in a coding region of the gene nor predicted to impact gene function (i.e., splicing, alteration of transcription factor binding sites), it is likely that each SNP is in linkage disequilibrium with a functional SNP(s).
Several study limitations need to be acknowledged. No direct measurements of systemic levels of inflammatory markers or physical examination for signs of inflammation at the site were performed to provide additional data on the underlying mechanisms for the preoperative breast pain. In addition, type of biopsy, needle size, and time since biopsy were not obtained which would have provided additional information on the pain phenotype. While proportions of African Americans, Asian/Pacific Islanders, and Caucasians were more representative of the United States population than previous studies on pretreatment breast cancer pain,44,63–65
the relatively small number of non-whites (36%) may have limited our ability to detect genotypic differences among the various ethnic groups. However, the rigorous approach used to control for population substructure (i.e., race/ethnicity) makes it unlikely that the genetic associations observed are due to this important source of confounding. Finally, future studies with a larger sample size, would increase the power to detect differences in the other cytokine genes. This hypothesis might be true for those SNPs in this study where genotypic differences approached statistical significance.
In conclusion, findings from this study and others44,63–65
suggest that preoperative breast pain affects a significant proportion of patients. In addition, the genomic data support the hypothesis that this pain problem involves inflammatory processes. This information may help to identify women who are at greater risk for preoperative breast pain. Subsequent studies will need to confirm these findings and evaluate the specific etiologies for this preoperative breast pain. For example, subsequent studies could evaluate whether the severity of pre-existing breast conditions (e.g., fibrocystic disease, mastitis), tumor characteristics (e.g., size, specific type of breast cancer), or preoperative biopsies contribute to the pain, numbness, hardness, and strange sensations reported by women in the pain group. In addition, future research needs to determine whether preoperative pain influences the severity of postoperative pain and/or the development of chronic pain following breast cancer surgery.
In women with breast cancer, preoperative pain may be associated with increases in inflammatory responses associated with an increased number of biopsies. In addition, differences in cytokine genes may contribute to this preoperative breast pain.