Tamoxifen was the first targeted therapy for breast cancer. In women with ER+ breast cancer, with tamoxifen given for 5 years as adjuvant treatment, the odds of recurrences decreased by 39%, and death decreased by 30% in both pre- and postmenopausal women.8 Then the ATLAS data came, which randomly allocated patients to continue another 5 years of tamoxifen vs placebo, for a total of 10 years of treatment with tamoxifen. With a mean of 7.6 years of further follow-up after entry at year 5 in this trial showed that recurrence and breast cancer mortality during the second decade after diagnosis are reduced more effectively by 10 years of adjuvant tamoxifen than by 5 years.9 The current recommendation for pre- and postmenopausal is 10 years of tamoxifen.
In addition we have 3 aromatase inhibitors (AIs), anastrozole, letrozole, and exemestane, which block the production of estrogen in postmenopausal females. Anastrozole and letrozole are nonsteroidal, and exemestane is steroidal. There are countless big randomized trials using all of these drug in different combinations. In most of these trials, AIs are shown to be equal to tamoxifen when they are compared with each other, but their AE profile is different.
The recommendation by the American Society of Clinical Oncology and NCCN guidelines is to use only AIs for 5 years. There are different combinations: You can give tamoxifen for 2 to 3 years, followed by 5 years of an AI, or 5 years of tamoxifen and 5 years of an AI. Some patients wants to stop because of AEs, but others want to continue. Patients can develop osteoporosis and arthritis from an AI and hot flashes from tamoxifen.
Mr. Crawford, How would you manage of these AEs from these treatments?
Mr. Crawford. Because this woman is young, age 32, and premenopausal, tamoxifen would be the recommended endocrine therapy for her being ER+/PR+. But the role of the leuprolide acetate is to induce a chemical oophorectomy. We are putting her into ovarian ablation by using the leuprolide acetate.
The tamoxifen is relatively well tolerated, but as an ER blocker, it has a different AE profile than does an estrogen production decreaser. With tamoxifen patients tend to complain about hot flashes, edema, fluid retention, altered menses, spotting vaginal discharge, vaginal bleeding, and dryness. These medications also increase the risk of venous thromboembolism (VTE), and there is some concern about increased risk of developing endometrial cancers with these medications. We can give it either once or twice daily. There’s nothing that really says 10 mg twice daily vs 20 mg once daily is any different. So we may play with dosing to see if patients tolerate it better one way or the other.
There are medications that we can offer to help manage the hot flashes. These medications don’t necessarily make the hot flashes go away, but they can decrease the hot flash intensity or and/or frequency. Many medications have been evaluated for hot flashes. The best data are for venlafaxine, which is usually given once a day at bedtime (dosage 37.5-75.0 mg). There has been success with gabapentin titrated up to a dose of about 300 mg 3 times daily. They are fairly similar for decreasing hot flash scores and intensities, but the patient preferences were more favorable toward the venlafaxine than for the gabapentin.
The AIs, on the other hand, have a different AE profile. With tamoxifen we see vaginal discharges, bleeding, endometrial cancer risk, and VTE risk, but these are not significant problems with any of the AIs. The AE profiles for AIs include hot flashes, but more often it is complaints of bone pain, arthralgias, and myalgias. Probably the top reason why most patients discontinue taking AIs is arthralgia and myalgia.
Because we have shut off estrogen production with the AIs, and estrogen is an important component of maintaining good bone health and bone homeostasis, patients are at an increased risked of losing or declining bone mineral density (BMD). It is recommended that these patients get placed on routine calcium and vitamin D supplementation with routine dual-energy X-ray absorptiometry scans, so we know whether we will need to initiate osteoporosis treatment, whether with oral bisphosphonates, intravenous bisphosphonates, or subcutaneous rank ligand inhibitors.
With bisphosphonates there may be a slight increase in fracture rates. But we have to balance that with the BMD concerns. If the patient progresses into the metastatic setting and we know that there’s a fair chance that there’s going to be some skeletal involvement, those people are also at an increased risk of fracture. While there is a slight concern about the increased risk of fractures with bisphosphonates, I tend to believe that the benefits outweigh the risks.
Go to www.fedprac.com/AVAHO for a discussion of the next steps in the treatment for the patient after she returned 2 years later with nausea, vomiting, acute onset headache, and 2 brain lesions that were about 2 cm.
