Comorbidities and Breast Cancer Survival: Lessons from the ATAC Trial

Abstract & Commentary

By Jerome W. Yates, MD, Hematology/Immunology Unit, National Institute on Aging, NIH. Dr. Yates reports no financial relationships relevant to this field of study.

Synopsis: In an analysis of a subset of breast cancer patients enrolled in the ATAC trial, it was apparent that age influences the risk of recurrence, and age and comorbidities significantly influence the risk of death without recurrence. The authors suggest assessment of comorbidities should be incorporated into decisions regarding adjuvant therapies.

Source: Ring A, et al. Influence of comorbidities and age on risk of death without recurrence: A retrospective analysis of the arimidex, tamoxifen alone or in combination trial. J Clin Oncol 2011;29:4266-4272.

It is commonly understood that comorbidities complicate treatment for patients with cancer and negatively influence response rates and survival. Of course, some of these existing comorbidities could, in themselves, be life-threatening. By retrospectively analyzing results from the ATAC (Arimidex, Tamoxifen Alone or in Combination) study, Ring and colleagues examined the effects of comorbidities and age on treatment received, breast cancer-related mortality, and competing causes of mortality. ATAC was a double-blind randomized trial in which postmenopausal women with early-stage breast cancer were assigned to receive anastrozole, tamoxifen, or the combination.

This analysis examined 10-year median follow-up data in the two monotherapy arms (anastrozole, n = 3092; tamoxifen, n = 3094) of the ATAC study. Included in the protocol was an assessment of baseline comorbidities and comparison was made between women age < 70 years and women age > 70 years. The cumulative incidence of breast cancer-related and non-breast cancer-related mortality was assessed according to age and comorbidities.

At enrollment, 1662 (27%) were age > 70 years. This group of older women was more likely to undergo mastectomy and less likely to receive radiotherapy or chemotherapy. Women aged > 70 years had an increased risk of recurrence compared with women aged < 70 years and a substantially increased risk of death without recurrence. The risk of death without recurrence increased with each increment in comorbidity score as determined by the Satariano comorbidity scale. The 10-year estimates for deaths without recurrence were 8.4%, 20.0%, and 30.4% for Satariano scores 0, 1, and 2, respectively (P < 0.001).

Commentary

By examining the influence of comorbidities and age on the risk of death without recurrence in a population of older breast cancer patients enrolled in the ATAC study, it is apparent that for those older than 70 years, the risk of recurrence is greater, the risk of death without recurrence increases, and the risk of death also increases with comorbid conditions.1 The authors conclude "formal assessment of comorbidities should be incorporated into decisions regarding adjuvant therapies." The risk of recurrence in those 70 years or older is not surprising because tumors were larger than in younger patients, fewer had lymph nodes examined, and they received less radiation therapy and chemotherapy. The authors recognize that these factors may contribute to the increased recurrence rate for the older population and add that there may be age-related differential compliance in the older population. Because these women were entered into a clinical trial, their state of health likely was superior at a comparable age to that of the general population of breast cancer patients.

Does this report provide new information that will alter the approach to managing the elderly patient with breast cancer? The major strength of this analysis is a population with a consistent treatment intervention. Unfortunately, the information available to the authors is too shallow to dissect most of the factors and this limits their conclusions. Age is the most reliable dynamic considered in this analysis.

Retrospective reviews of comorbid conditions are likely to be incomplete and the commonly used systems rely primarily only on the number of reported comorbid conditions.1 The reliability of reports of comorbidity depend first on their recognition and second on their documentation in the medical record. Most studies depend on extraction from medical records, while a prospective protocol-driven collection of comorbid conditions would be the ideal. The use of administrative datasets for the reconstruction of comorbidities usually results in under-reporting of some: e.g., alcoholism or mental disease. An earlier report of 1800 postmenopausal breast cancer patients diagnosed in 1992 with stage information demonstrated a higher mortality rate from breast cancer (51.3%).2 This was likely the result of less of a consensus-driven standard of care for the older group. Comorbid conditions requiring active treatment deserve greater attention when assessing elderly breast cancer patients for treatment.

An earlier report of the ATAC trial noted that vasomotor and joint symptoms occurring in the first 3 months of therapy heralded a better endocrine response and fewer recurrences of breast cancer when compared with a group of women without these symptoms.3 The authors conclude that this should be used to reassure the patients with symptoms of the importance of long-term adherence to the treatment regimen. They recognized the problem of continued compliance with a patient-managed oral treatment program. The decrease in recurrences may be a reflection of better patient compliance resulting in more symptoms of the treatment.

The efficacy of long-term adjuvant tamoxifen and aromatase inhibitors in breast cancer is reliant on patients conforming to recommendations of their physicians. A review of the published literature has shown that approximately one out of four patients prematurely discontinued therapy.4 In breast cancer prevention trials, 20-46% of patients prematurely discontinued tamoxifen, and similar estimates have been made for compliance among patients treated in the private practice setting. Others have shown that even among those women with insurance, particularly the elderly, interruptions in adjuvant hormonal therapy in the first year of therapy were common and often continued in subsequent years of therapy.5 It is possible, or even likely, that decreased adherence to the treatment regimen for those age 70 years or older may explain their increased recurrence rate when compared with the younger study participants.

The author's conclusion that "formal assessment of comorbidities should be incorporated into decisions regarding adjuvant therapies" is credible and deserves attention. The assessment should also have some measure of severity and the need for treatment, because all comorbid conditions are not equal.1

References

1. Yates JW. Comorbidity consideration in geriatric oncology research. CA Cancer J Clin 2001;51:329-336.

2. Yancik R, et al. Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA2001;285:885-892.

3. Cuzick J, et al. Treatment-emergent endocrine symptoms and the risk of breast cancer recurrence: A retrospective analysis of the ATAC trial. Lancet Oncology 2008;9:1143-1148.

4. Chlebowski RT, Geller ML. Adherence to endocrine therapy for breast cancer. Oncology2006;71:1-9.

5. Nekhlyudov L, et al. Five-year patterns of adjuvant hormonal therapy use, persistence, and adherence among insured women with early-stage breast cancer. Breast Cancer Res Treat 2011;130:681-689.