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Considering Metabolic Effects When Making Breast Cancer Treatment Decisions

Considering Metabolic Effects When Making Breast Cancer Treatment Decisions

Each year in the United States, more than 200,000 women are diagnosed with breast cancer, and 40,000 women die of the disease.[1] Approximately two-thirds of breast cancers are hormone receptor–positive, and medications that suppress estrogen are the cornerstone of adjuvant therapy for these tumors. Tamoxifen, a selective estrogen receptor modulator, was the first agent developed for this purpose and is still used widely in premenopausal women. Aromatase inhibitors (AIs), which prevent peripheral conversion of adrenal androgens into estrogen, have largely become the agents of choice for postmenopausal women. Current guidelines recommend that all postmenopausal women with hormone receptor–positive early-stage breast cancer who do not have a contraindication to AIs be treated with one of these agents, either as primary therapy or after 2 to 5 years of tamoxifen treatment as part of a cross-over strategy.[2] These recommendations are based on five large adjuvant trials that demonstrated a 3% to 4% absolute reduction in subsequent breast cancer events in patients who received an AI as part of adjuvant breast cancer treatment compared with patients treated with 5 years of tamoxifen alone.[3-7] However, it is notable that despite the lower rates of recurrence in these trials in the patients who received AIs, most studies have not demonstrated a survival advantage for AIs.

Impact of Adjuvant Therapies on Metabolic Parameters

In their report, Redig and Munshi review the impact of hormone-modifying therapy on metabolic parameters in patients undergoing treatment for breast and other cancers. The authors note that the two categories of drugs used as adjuvant therapy for early-stage breast cancer—tamoxifen and the AIs—have differing effects on metabolic parameters. Tamoxifen has a favorable effect on lipid profiles, and its use has been associated with a lower risk of cardiovascular events—although it is known to increase the risk of venous thrombosis and of liver disease.[8-9] AIs, in contrast, have been shown to adversely affect lipid profiles in some, although not all studies.[10-12] Possibly as a result of these differing effects on lipid profiles, several studies have demonstrated a numerical increase in the number of cardiovascular events in patients treated with AIs as compared with tamoxifen. A recent meta-analysis of 7 studies comparing AIs with tamoxifen in the adjuvant setting demonstrated an increased relative risk (RR) of cardiac events in patients treated with AIs (RR, 1.31; 95% confidence interval, 1.07-1.60; P=0.006).[13] Of note, in the MA.17 study, in which patients who had completed 5 years of adjuvant tamoxifen treatment were randomly assigned to receive either an AI (letrozole) or placebo, rates of cardiac events were similar in the two groups. These results suggest that some of the differences in the number of cardiac events in the other studies could be attributed to a protective effect of tamoxifen rather than to a deleterious effect of AIs.[7]

This information becomes increasingly relevant as rates of long-term breast cancer survival continue to improve. As a result of the widespread use of mammographic screening, 60% of breast cancers are now detected while still localized to the breast, and the 5-year relative survival rate in this setting approaches 98%.[14] Given that every year, more than 400,000 women in the US die of heart disease and 36,000 die of complications of diabetes,[15] many, if not most, women with early-stage breast cancer will die of causes other than their malignancy. In this setting, complications of therapy, especially those that might put women at risk for other diseases, are of increasing importance. To date, the only clear contraindication to the use of AIs has been pre-existing osteoporosis, since these agents are associated with accelerated bone loss and an increased risk of fracture. However, given the adverse impact on lipid profiles and increased risk of cardiovascular events associated with AI use, as described in the review by Redig and Munshi, it may be prudent to consider other comorbidities when selecting adjuvant therapy for breast cancer. Women with cardiac risk factors, such as hypertension and diabetes—especially those with a relatively low risk of breast cancer recurrence—might be better served by a 5-year course of tamoxifen, which would reduce not only their risk of subsequent breast cancer events but also possibly their risk of other diseases.

Metabolic Profiles and Breast Cancer Recurrence

Alterations in metabolic profiles may also be important in women with early-stage breast cancer for other reasons. Goodwin and colleagues demonstrated that women with higher fasting insulin levels at the time of breast cancer diagnosis had twice the risk of distant recurrence and 3.1 times the risk of death seen in women with the lowest insulin levels.[16] Several other investigators have also reported an increased risk of recurrence in women with poor metabolic profiles. Pollak and colleagues demonstrated that women who had high levels of C-peptide, a breakdown product of insulin production, at the time of breast cancer diagnosis had a lower rate of event-free survival than did women with lower levels of C-peptide.[17] Finally, Pasini and colleagues demonstrated that patients with breast cancer who had metabolic syndrome, a condition whose features include elevated fasting glucose levels and increased abdominal adiposity, had a three-fold increase in the risk of cancer recurrence compared with patients who did not have metabolic syndrome.[18] Given the relationship between metabolic parameters and breast cancer recurrence, it is also possible that unfavorable alterations in lipid profiles and other metabolic factors could have an adverse impact on breast cancer–specific survival.

As cancer therapy becomes increasingly personalized in the 21st century, choice of therapy is likely to be influenced not only by the efficacy of a particular agent, but also by its side effects. For many women with early-stage breast cancer, treatment decisions should involve consideration not only of the risk of breast cancer recurrence, but also of competing risks of heart disease and other illness. In addition, as more becomes known about the interactions between metabolic parameters and breast cancer outcomes, adjuvant treatment decisions may become even more complex and individualized.

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References

References

1. American Cancer Society: Cancer facts & figures 2010. Available at http://www.cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf. Accessed July 16, 2010.

2. Winer EP, Hudis C, Burstein HJ, et al: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: Status report. J Clin Oncol 23:619-629, 2005.

3. Howell A, Cuzick J, Baum M, et al: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60-62, 2005.

4. Thurlimann B, Keshaviah A, Coates AS, et al: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747-2757, 2005.

5. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004.

6. Jakesz R, Jonat W, Gnant M, et al: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: Combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366:455-462, 2005.

7. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003.

8. Love RR, Wiebe DA, Newcomb PA, et al: Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Intern Med 115:860-864, 1991.

9. Dewar JA, Horobin JM, Preece PE, et al: Long-term effects of tamoxifen on blood lipid values in breast cancer. BMJ 305:225-226, 1992.

10. Buzdar A, Howell A, Cuzick J, et al: Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: Long-term safety analysis of the ATAC trial. Lancet Oncol 7:633-643, 2006.

11. Coates AS, Keshaviah A, Thurlimann B, et al: Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: Update of study BIG 1-98. J Clin Oncol 25:486-492, 2007.

12. Mouridsen H, Keshaviah A, Coates AS, et al: Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: Safety analysis of BIG 1-98 trial. J Clin Oncol 25:5715-5722, 2007.

13. Cuppone F, Bria E, Verma S, et al: Do adjuvant aromatase inhibitors increase the cardiovascular risk in postmenopausal women with early breast cancer? Meta-analysis of randomized trials. Cancer 112:260-267, 2008.

14. Ries LAG, Eisner MP, Kosary CL, et al (eds): SEER Cancer Statistics Review, 1975-2000. Bethesda, Md; National Cancer Institute; 2003. Available at http://seer.cancer/gov/csr/1975_2000/. Accessed July 20, 2010.

15. Centers for Disease Control and Prevention, National Vital Statistics System: LCWK10: Deaths, Percent of Total Deaths, and Rank Order for 113 Selected Causes of Death, by Race and Sex: United States, 2001-06. Available at http://www.cdc.gov/nchs/nvss/mortality/lcwk10.htm. Accessed July 20, 2010.

16. Goodwin P, Ennis M, Pritchard K, Trudeau M: Fasting insulin and outcome in early-stage breast cancer: Results of a prospective cohort study. J Clin Oncol 20:42-51, 2002.

17. Pollak MN, Chapman JW, Shepherd L, et al: Insulin resistance, estimated by serum C-peptide level, is associated with reduced event-free survival for postmenopausal women in NCIC CTG MA.14 adjuvant breast cancer trial. J Clin Oncol 24(18S):524, 2006.

18. Pasanisi P, Berrino F, De Petris M, et al: Metabolic syndrome as a prognostic factor for breast cancer recurrences. Int J Cancer 119:236-238, 2006.

 
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