Treatment of Older Patients With HER2-Positive Tumors
Overexpression of HER2 is associated with a higher risk of recurrence and a phenotype that provides a target for trastuzumab(Drug information on trastuzumab) therapy. Addition of trastuzumab to chemotherapy in patients with HER2-positive tumors causes a further 50% proportional reduction in the risk of recurrence and breast cancer death compared with chemotherapy alone.[33,34] Older women with HER2-positive breast cancer should be considered for both trastuzumab and chemotherapy, which is likely to be beneficial in most patients except those with small, HR+, node-negative tumors and life expectancies less than 5 years. Hormone receptor status is important in defining prognosis and those with both HR+ and HER2-positive tumors have a better prognosis than those with HR-/HER2-positive cancers (this latter group having the highest risk of recurrence of any breast cancer phenotype when trastuzumab is not used). Trastuzumab is usually well tolerated but is associated with an age-related risk of cardiac toxicity. Prior to administration of trastuzumab in elders, hypertension should be controlled if present and optimal management of any pre-existing cardiac disease should be instituted. To minimize the risk of cardiac toxicity, non–anthracycline-containing regimens such as docetaxel (Taxotere) plus carboplatin(Drug information on carboplatin) should be considered. This regimen has demonstrated similar efficacy to anthracycline-containing regimens but with minimal risk of cardiac toxicity. Cardiac monitoring is similar for younger and older patients; patients’ left ventricular ejection fraction should be measured every 3 months while they are being treated with trastuzumab.
Treatment of Older Patients With ER-, PR- and HER2-Negative (Triple-Negative) Tumors
About 15% of older patients have triple-negative tumors, a phenotype that confers a major increase in risk of recurrence within 5 years of diagnosis. Except for those with limited life expectancy and very small tumors, older women with triple-negative breast cancer should be offered chemotherapy.
There is no role for endocrine therapy in this setting. The EBCTCG analysis of chemotherapy or not in women with ER-poor tumors showed a 10-year reduction in breast cancer mortality of 6% in women aged 50 to 69 years with older chemotherapy regimens such as CMF. In addition, an analysis of randomized trials of more intensive anthracycline- and taxane-containing chemotherapy regimens in patients with node-positive tumors showed that these more intensive regimens provided the greatest reductions in recurrence in women with HR− tumors.
Another large retrospective review showed that current anthracycline- and taxane-containing regimens provided similar reductions in recurrence and death from breast cancer in both older and younger patients. A recently published trial in those patients aged ≥ 65 years of age that compared capecitabine(Drug information on capecitabine) with standard chemotherapy (either CMF or doxorubicin(Drug information on doxorubicin) and cyclophosphamide(Drug information on cyclophosphamide)) showed superiority for standard treatment in improving both relapse-free and overall survival. Of note, an unplanned subset analysis showed that the major benefit for chemotherapy was in patients with HR− tumors. Older patients with triple-negative tumors and cardiac disease should be considered for nonanthracycline regimens in this setting such as docetaxel(Drug information on docetaxel) and cyclophosphamide or CMF.[41,42] Recommendations for systemic adjuvant therapy for each of the groups summarized previously are presented in Figure 2.
Follow-up and Survivorship
Follow-up of older women with breast cancer should be the same as for younger patients and should follow the ASCO (American Society of Clinical Oncology) or NCCN (National Comprehensive Cancer Network) guidelines. Older patients, however, require close monitoring of toxicity during chemotherapy treatment, as even low-grade toxicity (for example grade 1–2 neuropathy) can have major effects on function. The vast majority of cancer survivors in the US are older patients, with breast cancer patients being the largest group. Most of these women are likely to die of non–breast cancer causes. For many of these women, however, the oncologist remains the major caregiver. Oncologists should work closely with primary care physicians to make sure that other significant comorbid illness is optimally managed. Older patients should be offered support groups and be included in survivorship programs when available.
Older patients are less likely to be enrolled in clinical trials,[44,45] especially adjuvant breast cancer trials. Recent studies indicate that about 30% of accruals to all phase II and III Cancer Cooperative Group trials are patients 65 years and older.[46,47] Increasing age is an independent variable associated with a lower probability for offering breast cancer trials to older patients, yet when offered participation, older patients are as likely to partake as younger patients (about 50% for both age groups. The barriers to trial participation for older patients are numerous and include age bias and concerns about toxicity.[48,49] Another major factor is eligibility criteria; it is estimated that older patients could account for up to 60% of clinical trial participants if organ and physical function exclusion criteria were relaxed. Healthy older women with estimated survivals exceeding 5 years and in generally good health should be offered participation in state-of-the-art phase II and III trials. In addition, trials designed specifically for older but more vulnerable older patients are needed. Further, efforts to predict which older patients are most likely to experience treatment-related toxicity need to be expanded. Incorporation of a brief, primarily self-administered CGA is currently being tested in the Cooperative Group clinical trial setting and may provide a better means for defining loss of function and predicting which older patients are likely to experience major side effects (see CALGB 340401; www.cancer.gov; CHNMC-06170).
The decision to use adjuvant chemotherapy in older patients and which regimen to use is frequently challenging. Healthy elders with 5 to 10 more years of life expectancy should be managed like younger postmenopausal patients and should be considered for state-of-the-art treatment programs, including clinical trials. Recently developed nonanthracycline regimens are safer than older anthracycline regimens and appropriate for lower-risk older patients for whom chemotherapy is indicated, or in combination with trastuzumab in patients with HER2-positive tumors. For higher-risk patients in good health, newer, more intensive regimens containing both anthracyclines and taxanes are still the treatments of choice. CGA may be of great help in estimating the potential for functional loss in patients with and without recognized comorbidities. Newer, shorter, and mostly self-administered CGAs are likely to help select patients most likely to experience major toxicity. The major barrier to consideration of adjuvant chemotherapy in older breast cancer patients is physician bias. Greater efforts are needed to educate both physicians and patients about life-expectancy issues, as well as efforts aimed at identification of factors other than age that may better predict treatment-related toxicities.
Financial Disclosure: Dr. Muss is a consultant for Wyeth/Pfizer, Amgen, Roche, Bristol-Myers Squibb, Boehringer- Ingelheim, Sandoz, and Abraxis.