INVITED COMMENTARY

Thinking beyond the tumor to better understand chronicsymptoms in breast cancer survivors

N. Lynn Henry • Daniel J. Clauw

Received: 7 September 2011 / Accepted: 26 September 2011 / Published online: 11 October 2011

� Springer Science+Business Media, LLC. 2011

Over 200,000 women are diagnosed with breast cancer

each year in the United States, and more than 80% are alive

10 years after diagnosis [1]. Treatment generally includes

surgery, radiation therapy, chemotherapy, and/or targeted

therapies. Choice of treatment is determined by assessing

the likely benefit of each therapy for an individual patient,

taking into consideration tumor characteristics and likeli-

hood of disease recurrence. Additional personalization of

the treatment regimen is generally based on pre-existing

patient comorbid conditions, such as heart failure or

peripheral neuropathy, which can increase the potential

risks of therapy.

Most long-term breast cancer survivors recover fully

from treatment. However, a substantial proportion experi-

ence chronic symptoms, including pain and fatigue, which

negatively impact quality of life [2]. The etiology of these

symptoms in patients that otherwise remain free from

disease recurrence is unclear, especially since all patients

typically undergo similar procedures or therapy regimens.

Importantly, clinicians are currently unable to accurately

predict which patients will experience significant or even

disabling long-term toxicity. Identification of patients

likely to develop chronic treatment-related toxicities before

initiation of therapy would permit a more informed dis-

cussion about the risks and benefits of therapy and could

guide treatment-decision making.

Underlying patient characteristics unrelated to the

treatments administered for breast cancer may play a role

in the development of chronic pain. For example, an

individual’s pain processing systems are responsible for

influencing whether or not she perceives pain as well as the

level of pain she feels. Some women experience hyperal-

gesia (increased pain in response to a painful stimulus) or

allodynia (pain in response to a normally non-painful

stimulus) as has been demonstrated by both patient self-

report and functional neuroimaging [3, 4]. Both hyperal-

gesia and allodynia can be triggered by a peripheral injury

or an inflammatory process, both of which can be present in

patients with breast cancer.

Moreover, different individuals in the population have

markedly different baseline pain and sensory sensitivities,

and it appears as though the ones that are the the most

sensitive are at the highest likelihood of going on to

develop chronic pain following acute pain. Thus, increased

pain and sensory sensitivity has characteristics of both a

trait that is partly genetically determined (by genes such as

catechol-O-methyltransferase, COMT) and a state that can

be induced or worsened when there is acute peripheral

nociceptive input. Many of our treatments for breast cancer

(surgery, radiation, chemotherapy regimens that lead to

nerve damage, or endocrine therapies that cause musculo-

skeletal pain) do induce acute peripheral nociceptive input.

Could our treatments for breast cancer, not unlike

deployment to war, be a setting where individuals are

commonly exposed to a number of painful physical,

emotional, and immune stressors? Most will recover

following treatment for breast cancer, but some will be left

with unresolved pain, fatigue, memory problems and sleep

This is an invited commentary to article

doi: 10.1007/s10549-011-1757-y

N. L. Henry (&)

Division of Hematology/Oncology, Department of Internal

Medicine, University of Michigan Medical School,

1500 East Medical Center Drive, Med Inn Building C450,

Ann Arbor, MI 48109-5843, USA

e-mail: norahh@med.umich.edu

D. J. Clauw

Department of Anesthesiology, University of Michigan Medical

School, Ann Arbor, USA

123

Breast Cancer Res Treat (2012) 133:413–416

DOI 10.1007/s10549-011-1804-8

disturbances, not because of the tumor or even directly

because of any treatment, but rather because these all are

potent triggers of ‘‘centralization’’ and ‘‘chronification’’ of

pain and other symptoms [5–7].

There is considerable variability in acute and chronic

pain sensitivity among humans, in part related to inherited

genetic variants in specific genes related to pain [8].

Studies of multiple chronic pain states, including fibro-

myalgia, temporomandibular joint disorder (TMJD), and

knee osteoarthritis, have revealed associations between

chronic pain and variants in genes that encode for a number

of enzymes, including COMT. Both a specific single

nucleotide polymorphism (SNP) in COMT (Val158Met),

as well as a haplotype based on four different SNPs in

COMT, have identified patients with increased pain sen-

sitivity or who are more likely to develop chronic pain

disorders, such as TMJD [9, 10]. Since the recognition of

COMT, many other genes, most thought to be acting to set

the gain on neural function in either the central or

peripheral nervous system, have also been identified that

likely play a similar role to COMT [11–13]. To date, most

of the focus on pain genes in cancer has been on those

controlling opioid metabolism or activity [14, 15], and

investigators have not generally suspected that genetic

factors may also be playing a broader role in triggering

other common symptoms in central pain states, such as

fatigue, memory problems, and sleep disturbances [16].

Because of this association between inherited COMT

variants and predisposition to chronic pain, as well as data

linking the Val158Met COMT polymorphism with cogni-

tive dysfunction in women with breast cancer, Fernandez-

de-las-Penas and colleagues investigated the impact of an

inherited genetic variant in the COMT gene on cancer pain

and fatigue in 128 breast cancer survivors, as reported in

this issue of Breast Cancer Research and Treatment [17].

They showed that women homozygous for the Met allele

had greater fatigue, neck pain, and sensitivity to pain,

compared with women who carried at least one Val allele,

which is consistent with previously published data of

associations between COMT and pain in other chronic pain

conditions [9, 10, 18]. As mentioned by the authors, a

limitation of this study is the focus on a single SNP, since

reports in the literature suggest that the COMT haplotype

may be more predictive of pain sensitivity [9]. SNPs

associated with pain have also been identified in other

genes [11–13]. In addition, the impact of concurrent

medications, including both endocrine therapy for breast

cancer and supportive care therapies for symptom man-

agement, was not accounted for in the analysis. Finally, it

is unclear whether the association between the COMT SNP

and fatigue is direct, or whether the fatigue is related to the

chronic pain, which is in turn associated with the genetic

variant.

Overall, these findings strongly suggest that some

women may be predisposed to chronic pain following

treatment for breast cancer because of individual factors

present before diagnosis of their disease. Mechanisms

underlying development of chronic pain differ from those

for acute pain. Although the inflammation and/or

mechanical damage from breast cancer surgery plays an

important role in development of acute pain, breast cancer

survivors who develop chronic pain potentially have an

underlying diathesis that makes them more sensitive to

acute and chronic pain based on a higher central nervous

system (CNS) ‘‘volume control’’ setting rather than the fact

that they have more peripheral nociceptive input. This

subset of individuals with prominent hyperalgesia or allo-

dynia in the general population is more likely to go on to

experience chronic pain after acute pain, such as trauma or

surgical procedures [19, 20]. In addition, this ‘‘centrally

driven’’ pain state is commonly associated with other

CNS-mediated co-morbidities, including fatigue, sleep

disturbance, and mood disorders.

Many of these CNS-mediated symptoms, including

pain, fatigue, sleep disturbances, cognitive difficulties, and

mood disturbances, are commonly found in breast cancer

patients, and can substantially negatively impact QOL [21].

Frequently, each symptom is individually targeted by cli-

nicians, such as by prescribing analgesics for pain man-

agement, antidepressants for depression, and sedatives for

insomnia. However, it is increasingly recognized that these

symptoms tend to co-occur rather than exist in isolation.

For example, common clusters of symptoms that have been

identified include (1) fatigue and pain, (2) fatigue, pain,

and depression, and (3) fatigue, pain, and insomnia [22].

Therefore, treatment approaches that target multiple CNS-

mediated symptoms, rather than each individual symptom

in isolation, may more effectively improve the QOL of

breast cancer survivors.

In addition, since this chronic pain may be due to central

rather than peripheral factors, this has substantial impli-

cations for the treatment of breast cancer survivors. Studies

in other chronic pain disorders, including fibromyalgia and

knee osteoarthritis, have demonstrated more benefit from

treatment approaches that are centrally acting, including

serotonin norepinephrine reuptake inhibitors (SNRI) such

as duloxetine and milnacipran [23–25], and cognitive

behavioral therapy [26], compared to standard analgesics

(e.g. NSAIDs, opioids).

A few studies of treatment-related pain in breast cancer

have evaluated these management approaches. One common

treatment-emergent symptom is the aromatase inhibitor

musculoskeletal syndrome (AIMSS), which affects about

half of treated women and can lead to premature treatment

discontinuation or poor adherence to therapy [27]. Despite its

prevalence, however, the etiology remains unclear and

414 Breast Cancer Res Treat (2012) 133:413–416

123

treatment has been challenging. Many standard analgesics

are ineffective. However, less conventional treatments have

been shown to be promising. For example, a randomized,

placebo-controlled study of acupuncture for AIMSS dem-

onstrated decreased patient-reported pain levels in patients

treated with 6 weeks of acupuncture compared to those who

received sham acupuncture [28]. A separate pilot study of

patients with AIMSS demonstrated potential benefit from

duloxetine, including an average decrease in pain of 60%

with 8 weeks of therapy as well as improvements in func-

tional status and decreases in depression scores [29]. Based

on these promising findings, a randomized phase III trial of

duloxetine is in progress. Approaches such as these may be

useful for management of breast cancer survivors, since they

may more effectively treat the chronic pain, and also

improve other associated symptoms such as fatigue,

insomnia, and mood disturbances. Ultimately, the aim is to

improve the QOL of breast cancer survivors, as well as

adherence and persistence with adjuvant therapies.

Personalization of therapy takes into account charac-

teristics of both the tumor and the individual, although the

features of individuals that have been most frequently

focused on are the pre-existing medical conditions and

inter-patient differences in drug metabolism and activity.

However, it is becoming clear that other aspects of the

individual need to be considered, including genetic pre-

disposition to chronic treatment-related toxicity, such as

pain, as these could have implications for treatment deci-

sion-making. We have only begun to understand which

patients are predisposed to these conditions, and how best

to manage their symptoms. Trials to identify effective

treatment approaches are urgently needed.

Acknowledgments NLH is the Damon Runyon-Lilly Clinical

Investigator supported (in part) by the Damon Runyon Cancer

Research Foundation (CI-53-10).

Disclosures NLH receives research funding from Eli Lilly, Astra-

Zeneca, and Sanofi Aventis. DJC receives research funding from

Forest Laboratories and Merck and is a consultant for Cypress Bio-

sciences, Eli Lilly, Forest Laboratories, Jazz Pharmaceuticals, Merck,

Pierre Fabre Pharmaceuticals USA, Pfizer, and UCB.

References

1. American Cancer Society: Breast Cancer Facts & Figures 2009–2010.

http://www.cancer.org/research/cancerfactsfigures/breastcancer

factsfigures/breast-cancer-facts–figures-2009-2010. Accessed 25 Aug

2011

2. Bower JE (2008) Behavioral symptoms in patients with breast

cancer and survivors. J Clin Oncol 26:768–777

3. Giesecke T, Gracely RH, Grant MA, Nachemson A, Petzke F,

Williams DA, Clauw DJ (2004) Evidence of augmented central

pain processing in idiopathic chronic low back pain. Arthritis

Rheum 50:613–623

4. Gracely RH, Petzke F, Wolf JM, Clauw DJ (2002) Functional

magnetic resonance imaging evidence of augmented pain pro-

cessing in fibromyalgia. Arthritis Rheum 46:1333–1343

5. Clauw D (2003) The health consequences of the first gulf war. Br

Med J 327:1357–1358

6. Clauw DJ, Engel CC Jr, Aronowitz R, Jones E, Kipen HM,

Kroenke K, Ratzan S, Sharpe M, Wessely S (2003) Unexplained

symptoms after terrorism and war: an expert consensus statement.

J Occup Environ Med 45:1040–1048

7. Hassett AL, Clauw DJ (2010) The role of stress in rheumatic

diseases. Arthritis Res Ther 12:123

8. Mogil JS, Yu L, Basbaum AI (2000) Pain genes?: natural vari-

ation and transgenic mutants. Annu Rev Neurosci 23:777–811

9. Diatchenko L, Slade GD, Nackley AG et al (2005) Genetic basis

for individual variations in pain perception and the development

of a chronic pain condition. Hum Mol Genet 14:135–143

10. Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y,

Koeppe RA, Stohler CS, Goldman D (2003) COMT Val158Met

genotype affects mu-opioid neurotransmitter responses to a pain

stressor. Science 299:1240–1243

11. Costigan M, Belfer I, Griffin RS et al (2010) Multiple chronic

pain states are associated with a common amino acid-changing

allele in KCNS1. Brain 133:2519–2527

12. Tegeder I, Costigan M, Griffin RS et al (2006) GTP cyclohy-

drolase and tetrahydrobiopterin regulate pain sensitivity and

persistence. Nat Med 12:1269–1277

13. Valdes AM, De Wilde G, Doherty SA et al (2011) The Ile585Val

TRPV1 variant is involved in risk of painful knee osteoarthritis.

Ann Rheum Dis 70:1556–1561

14. Galvan A, Fladvad T, Skorpen F, Gao X, Klepstad P, Kaasa S,

Dragani TA (2011) Genetic clustering of European cancer

patients indicates that opioid-mediated pain relief is independent

of ancestry. Pharmacogenomics J. doi:10.1038/tpj.2011.27

15. Droney J, Riley J, Ross JR (2011) Evolving knowledge of opioid

genetics in cancer pain. Clin Oncol 23:418–428

16. Williams DA, Clauw DJ (2009) Understanding fibromyalgia: les-

sons from the broader pain research community. J Pain 10:777–791

17. Fernandez-de-Las-Penas C, Fernandez-Lao C, Cantarero-Vi-

llanueva I, Ambite-Quesada S, Rivas-Martinez I, del Moral-Avila

R, Arroyo-Morales M (2011) Catechol-o-methyltransferase

genotype (Val158Mmet) modulates cancer-related fatigue and

pain sensitivity in breast cancer survivors. Breast Cancer Res

Treat (in press)

18. van Meurs JB, Uitterlinden AG, Stolk L, Kerkhof HJ, Hofman A,

Pols HA, Bierma-Zeinstra SM (2009) A functional polymorphism

in the catechol-o-methyltransferase gene is associated with

osteoarthritis-related pain. Arthritis Rheum 60:628–629

19. McLean SA, Diatchenko L, Lee YM et al (2011) Catechol

o-methyltransferase haplotype predicts immediate musculoskel-

etal neck pain and psychological symptoms after motor vehicle

collision. J Pain 12:101–107

20. Yarnitsky D, Crispel Y, Eisenberg E, Granovsky Y, Ben-Nun A,

Sprecher E, Best LA, Granot M (2008) Prediction of chronic

post-operative pain: pre-operative DNIC testing identifies

patients at risk. Pain 138:22–28

21. Dodd MJ, Cho MH, Cooper BA, Miaskowski C (2010) The effect

of symptom clusters on functional status and quality of life in

women with breast cancer. Eur J Oncol Nurs 14:101–110

22. Aktas A, Walsh D, Rybicki L (2010) Symptom clusters: myth or

reality? Palliat Med 24:373–385

23. Arnold LM, Rosen A, Pritchett YL, D’Souza DN, Goldstein DJ,

Iyengar S, Wernicke JF (2005) A randomized, double-blind,

placebo-controlled trial of duloxetine in the treatment of women

with fibromyalgia with or without major depressive disorder. Pain

119:5–15

Breast Cancer Res Treat (2012) 133:413–416 415

123

24. Chappell AS, Ossanna MJ, Liu-Seifert H, Iyengar S, Skljarevski

V, Li LC, Bennett RM, Collins H (2009) Duloxetine, a centrally

acting analgesic, in the treatment of patients with osteoarthritis

knee pain: a 13-week, randomized, placebo-controlled trial. Pain

146:253–260

25. Mease PJ, Clauw DJ, Gendreau RM, Rao SG, Kranzler J, Chen

W, Palmer RH (2009) The efficacy and safety of milnacipran for

treatment of fibromyalgia. A randomized, double-blind, placebo-

controlled trial. J Rheumatol 36:398–409

26. Thieme K, Gracely RH (2009) Are psychological treatments

effective for fibromyalgia pain? Curr Rheumatol Rep 11:443–450

27. Henry NL, Giles JT, Stearns V (2008) Aromatase inhibitor-

associated musculoskeletal symptoms: etiology and strategies for

management. Oncology (Williston Park) 22:1401–1408

28. Crew KD, Capodice JL, Greenlee H, Brafman L, Fuentes D,

Awad D, Yann Tsai W, Hershman DL (2010) Randomized,

blinded, sham-controlled trial of acupuncture for the management

of aromatase inhibitor-associated joint symptoms in women with

early-stage breast cancer. J Clin Oncol 28:1154–1160

29. Henry NL, Banerjee M, Wicha M, Van Poznak C, Smerage JB,

Schott AF, Griggs JJ, Hayes DF (2011) Pilot study of duloxetine

for treatment of aromatase inhibitor-associated musculoskeletal

symptoms. Cancer. doi:10.1002/cncr.26230

416 Breast Cancer Res Treat (2012) 133:413–416

123