Optimizing Treatment Benefit in Older Breast Cancer Patients

June 15, 2010

Breast cancer is predominantly a disease of older women. Many of these older patients with breast cancer have low-risk disease owing to low proliferation indices, positive hormone receptors, node-negativity, or p53-negative and HER-2 (human epidermal growth factor 2)-negative tumors.[1,2] They do well without chemotherapy and will receive adjuvant hormonal therapy with tamoxifen or an aromatase inhibitor. Yet there are older women who do not have these favorable tumor characteristics and so are potential candidates for chemotherapy. The review by Muss points out this issue, highlighting benefits of chemotherapy and describing appropriate treatment regimens for these patients.

Breast cancer is predominantly a disease of older women. Many of these older patients with breast cancer have low-risk disease owing to low proliferation indices, positive hormone receptors, node-negativity, or p53-negative and HER-2 (human epidermal growth factor 2)-negative tumors.[1,2] They do well without chemotherapy and will receive adjuvant hormonal therapy with tamoxifen or an aromatase inhibitor. Yet there are older women who do not have these favorable tumor characteristics and so are potential candidates for chemotherapy. The review by Muss points out this issue, highlighting benefits of chemotherapy and describing appropriate treatment regimens for these patients.

The aging of the population, improved life expectancy, and the control of comorbidity will lead to a dramatic increase in the number of older women who will need to be appropriately evaluated. Unfortunately, persisting ageism results in undertreatment and poorer survival.[3] Physicians and patients often underappreciate the potential life expectancy when the diagnosis is made. The top quartile of survival for 70-year-old women is more than 21 years, with a median survival time of 15 years.[4] The risk of recurrence is well within this possible life expectancy, making the issue of adjuvant treatment pertinent to almost all patients.

Keys to Appropriate Evaluation

Clearly, comorbidity is essential to evaluate when making treatment decisions. Mortality in hormone receptor positive, node-negative patients is predominantly from noncancer causes. Approximately 80% of patients with node-negative disease and 60% with node-positive disease will die from causes not related to cancer. The ability to assess the risk-benefit ratio for an elderly cancer patient will rely on appropriate evaluation. Ideally, this will be in the form of a comprehensive geriatric assessment (CGA), particularly for patients with comorbidities. The CGA may also uncover issues not usually appreciated in routine medical evaluation, such as depression; dementia; poor social support; increased vulnerability, which can potentially lead to increased dependence; and increased therapy-related toxicity. A shorter, oncology-specific assessment is being developed. The National Comprehensive Cancer Network (NCCN) guidelines for older adults include the Vulnerable Elders Survey.[5,6]

The article by Muss includes an excellent presentation of patient subgroups that aids in clinical decision-making. Use of the helpful aids Adjuvant! Online and OncotypeDx is discussed. In node-negative, hormone-receptor–positive (HR+) patients, an aromatase inhibitor is often prescribed. There needs to be an emphasis on bone health in these patients, because fracture risk is a significant toxicity.[7,8]

Selecting Therapy

As noted by Muss, there is significant uncertainty about use of chemotherapy in older patients with node-positive, HR+ tumors. Although data are accumulating that indicate older patients in this group may benefit from adjuvant chemotherapy, most of the information is derived from retrospective analyses of studies in which older patients make up a very small percentage of the total study population. This is an area in which a geriatric assessment would be most beneficial. It seems that the most benefit to be derived from chemotherapy would be in patients who have a life expectancy of approximately 10 years-that is, those with minimal comorbidity and no dependency in activities of daily living/instrumental activities of daily living. The risk of recurrence would have to be high even with adjuvant hormonal therapy. This relative risk: benefit is often difficult to assess and is an area that needs further study, to assist clinicians.

While it may be easier to just administer hormonal therapy to HR+ patients, this may result in significant undertreatment. A variety of alternative regimens are available, particularly those not containing an anthracycline. The cyclophosphamide, methotrexate, 5-fluorouracil (CMF) regimen is often given to older patients but is not necessarily better tolerated, particularly by patients who have renal insufficiency. The dose-dense regimens should be included as a possible option, as older patients derive the same benefit from them. This regimen can be given as a single-agent sequential regimen, which may minimize some of the associated anemia.[9-11] Standard intravenous regimens have also been shown to be superior to an oral single agent.[12] In older patients who are HER2-positive, trastuzumab (Herceptin) is beneficial. There have been very few studies, however, evaluating toxicity in older patients. Cardiac evaluation as is usually done for anthracyclines should be performed, and other risk factors such as hypertension should be controlled. Muss’s recommendation that a nonanthracycline regimen should be utilized is appropriate. Triple-negative tumors have a high risk of recurrence, and chemotherapy is clearly indicated except in patients with significant life-limiting comorbidity.

Further Research Is Needed

Dr. Muss provides an excellent overview of the clinical issues in treating older women with breast cancer. While more research needs to be done, breast cancer is one area in which there are some data to inform clinical decisions. Use of hormonal therapy is well studied, with known benefits and toxicities. Although for most malignancies older patients have been underrepresented in clinical trials, Dr. Muss’s studies have provided important data on older patients with breast cancer. He has been a true leader in studying older women, both in retrospective analyses and in the recently published prospective adjuvant study. His work has brought to light most of the critical issues regarding older patients and has helped clinicians to treat older women effectively and safely. Older patients and physicians need to be encouraged to participate in clinical trials in the area of assessment and treatment, to provide additional information for patient and regimen selection. More work needs to be done to help our older, vulnerable patients get their appropriate treatment.

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

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7. Perez EA, Josse RG, Pritchard KI, et al: Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: A companion study to NCIC CTG MA.17. J Clin Oncol 24:3629-3635, 2006

8. Mincey BA, Duh MS, Thomas SK, et al: Risk of cancer treatment-associated bone loss and fractures among women with breast cancer receiving aromatase inhibitors. Clin Breast Cancer 7:127-132, 2006.

9. Muss HB, Biganzoli L, Sargent DJ, et al: Adjuvant therapy in the elderly: Making the right decision. J Clin Oncol 25:1870-1875, 2007.

10. Muss HB, Berry DA, Cirrincione C, et al: Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: The Cancer and Leukemia Group B Experience. J Clin Oncol 25:3699-3704, 2007.

11. Muss HB, Woolf S, Berry D, et al: Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. JAMA 293:1073-1081, 2005.

12. Muss HB, Berry DA, Cirrincione CT, et al: Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 360:2055-2065, 2009.