Systemic Therapy for Older Women With Breast Cancer

Introduction

Cancer is a common and more frequent problem in older persons.[1,2] Currently, about 50% of breast cancer cases occur in women aged 65 years and older. Illnesses that were disabling and often fatal in the past are now treated effectively, and people are living longer. Treatments for cancer are also evolving, and prolonging the lives of cancer patients is now possible for many malignancies, including breast cancer.

The incidence of breast cancer in the United States has begun to decrease.[3] Mortality rates have also been decreasing in recent years,[4] and with increased use of mammographic screening, breast cancers are being detected at earlier, more curable stages. Moreover, adjuvant therapies have become more successful, and new drugs (such as the taxanes) have improved response rates and tolerability of therapy for patients with metastatic disease.

Regardless of age, the treatment of breast cancer involves complex decisions about risks vs benefits for each patient. As age increases, the number of comorbidities increases,[2] making the potential risks of systemic therapy greater and the potential benefits smaller. Preventing breast cancer and its recurrence and/or progression, however, becomes more important as we are able to help people with many diseases live longer.

This article will discuss the use of hormonal therapy and chemotherapy in older women. There is no unanimously accepted definition of "older," but most clinicians consider patients aged 65 years and over to be in this category.

Decreasing the Incidence of Breast Cancer

The incidence of breast cancer increases with age.[5] Potential strategies to decrease the risk of breast cancer in the geriatric population include changes in life-style such as increasing exercise, dietary modifications such as following a low-fat diet, and drug therapy with selective estrogen-receptor modulators. The data suggesting that life-style and dietary changes may lower breast cancer risk are controversial and far from compelling. Since most women with breast cancer are likely to die of other causes, exercise and dietary modification are prudent recommendations for most patients, irrespective of breast cancer risk.

At present, the use of selective estrogen-receptor modulators is the most exciting option for breast cancer prevention. These agents include tamoxifen(Drug information on tamoxifen) (Nolvadex), raloxifene(Drug information on raloxifene) (Evista), and toremifene(Drug information on toremifene) (Fareston).[6] Only tamoxifen has been approved by the Food and Drug Administration (FDA) to decrease the incidence of breast cancer. Raloxifene has been approved for the treatment of osteoporosis, and preliminary data suggest that it may also significantly decrease the incidence of breast cancer.[7,8]

Trials of Tamoxifen

Three published trials have evaluated the potential preventive benefit of tamoxifen: the National Surgical Adjuvant Breast and Bowel Project Prevention trial (NSABP P-1),[9] the Royal Marsden Hospital chemoprevention trial,[10] and an Italian randomized trial in women who had undergone a hysterectomy (Table 1).[11] The major differences between these trials have been discussed in detail elsewhere.[12] The NSABP P-1 trial was the only one of the three with a large cohort of older women. It showed a 50% reduction in the incidence of invasive and noninvasive breast cancer among women who took tamoxifen.

NSABP P-1 Trial: In NSABP P-1, 30% of participants were 60 years of age and older and 6% were over the age of 70 years.[9] Women with a 1.67% risk of developing breast cancer within 5 years were eligible for the trial. All women aged 60 years or older in the United States meet these criteria, irrespective of other risk factors. Tamoxifen lowered the incidence of both in situ and invasive lesions. There was a 55% reduction in the incidence of invasive breast cancer associated with tamoxifen use in older women; the 5-year probability of invasive breast cancer developing in women 60 years of age and older decreased from almost 4% to about 2%.

This effect was limited to estrogen-receptor (ER)-positive invasive tumors; ER-negative tumors were found with similar frequency in the tamoxifen and placebo-treated groups. Risks associated with the use of tamoxifen in older women included a significantly higher incidence of endometrial cancer and thromboembolic events. In addition, tamoxifen use increased the frequency of vasomotor and gynecologic symptoms and problems with sexual function.[13]

Royal Marsden Hospital Trial: The Royal Marsden Hospital chemoprevention trial included women at increased risk of breast cancer based on family history.[10] As such, the majority of women in this trial (61%) were younger than age 50 years; women over age 70 years were ineligible. At a median follow-up of 70 months, the use of tamoxifen did not decrease the incidence of breast cancer.

Italian Trial: The Italian randomized trial included any woman who had undergone a hysterectomy.[11] Approximately one-third of women in the Italian trial were over age 55 years, and only 11.7% were age 60 or older; women over age 70 were ineligible. No decrease in the incidence of breast cancer was associated with the use of tamoxifen, but women in this trial were at lower risk for breast cancer compared to women in the other two reported trials.

Both the Royal Marsden Hospital chemoprevention trial and the Italian randomized trial allowed women who were taking hormone replacement therapy to participate. In the Italian trial, the rate of breast cancer was lower among women taking hormone replacement therapy plus tamoxifen than in the cohort taking replacement therapy alone (log rank P = .0216). This is not currently accepted practice in the United States.

Trials of Raloxifene

Raloxifene is another selective estrogen-receptor modulator with a toxicity profile similar to tamoxifen that allegedly causes fewer endometrial changes.[14] In the Multiple Outcomes of Raloxifene (MORE) trial, 7,705 women with osteoporosis were randomly assigned to receive one of two different doses of raloxifene or placebo for 3 years.[8] Participants were primarily white (95%) and over age 62 years (82%). At 40 months of follow-up, women taking raloxifene had 43% fewer vertebral fractures and a 76% lower incidence of invasive breast cancer.

The rate of breast cancer for all arms of this trial was low (10.5 per 1,000 women given placebo and 2.5 per 1,000 women given raloxifene), but the difference was still statistically significant (response rate [RR] = 0.24; 95% confidence interval [CI] = 0.13-0.44). Hormone-receptor-positive tumors were preferentially prevented, and thrombotic events were more prevalent in women receiving raloxifene in this trial as well, but no increase in endometrial cancer was seen.

A second prevention trial (NSABP P-2) comparing tamoxifen with raloxifene, the STAR trial, is underway. Targeted accrual is approximately 22,000 postmenopausal women.

Calculating Breast Cancer Risk

All women over age 60 years were eligible for NSABP P-1 based on their calculated risk of breast cancer. Breast cancer risk assessment is becoming a routine part of general medical care, and many women are reviewing the risks and benefits of "preventive" tamoxifen with their doctors. The risk of developing breast cancer can be easily calculated using the Gail model. An updated version of this risk assessment tool is available on the Internet at http://cancertrials.nci.nih.gov.

Moreover, Gail and his colleagues have recently provided detailed clinical data on how to calculate the potential benefits and risks of tamoxifen therapy, factoring in available epidemiologic data on the risks of thromboembolic complications and endometrial cancer (Table 2).[15] For example, in a 65-year-old white woman with an intact uterus and a thromboembolic risk similar to that of patients in the NSABP P-1 trial, the 5-year risk of invasive breast cancer needs to exceed 7.0% in order for the benefits of tamoxifen therapy to outweigh the risks. The benefits of tamoxifen would outweigh the risks in the same woman who had a hysterectomy and whose risk was 3.5%.

In older women, the preventive benefits of tamoxifen may outweigh the risks, but these women should be counseled about the risks and benefits of preventive tamoxifen. They should also be encouraged to participate in the STAR trial.