Support Continues for Extending Hormonal Therapy in Early-Stage Hormone Receptor-Positive Breast Cancers
Thursday morning’s presentations at the 2018 San Antonio Breast Cancer Symposium focused on treatments for hormone receptor-positive breast cancers. Three studies looked at how hormonal therapy is given, focusing on how long people with early-stage disease should take hormonal therapy and at what dose. The SOLAR-1 trial looked at a new targeted therapy for people with metastatic breast cancer whose disease has a mutation in the PI3K pathway, which occur in 40 percent of hormone receptor-positive breast cancers.
A meta-analysis isn’t a trial itself, but a look at other studies to get a fuller view of a certain feature or treatment. This meta-analysis, by the Early Breast Cancer Trialists’ Collaborative Group, looked at 22,192 women across 11 randomized trials. All trials tested adding 5 years of hormonal therapy with an aromatase inhibitor to 5 years of hormonal therapy (for a total of 10 years on hormonal therapy) to prevent breast cancer from returning.
The study broke the group into three categories: women who took 5 years of tamoxifen, women who started on tamoxifen and then moved to an aromatase inhibitor, and women who took an aromatase inhibitor from the start.
All groups showed a decrease in the chances of cancer returning, either in the breast or to other parts of the body, in the years after they continued hormonal therapy or stopped. People who took tamoxifen for 5 years had a lower risk of breast cancer returning immediately if they stayed on hormonal therapy compared to people who stopped after 5 years. For people who were on aromatase inhibitors, their risk looked the same in the first 2 years of the study period, whether they stayed on hormonal therapy or not, but starting in the third year women who were still taking an aromatase inhibitor had a lower rate of recurrence than those who had stopped hormonal therapy.
The researchers also broke out the data by other factors, including if and how many lymph nodes were found to contain breast cancer cells. They found a larger difference in risk for recurrence if more lymph nodes were found with cancer. Women who had no nodes with cancer cells had a very similar – and low – risk, whether they stayed on hormonal therapy or not. For women with four or more lymph nodes with cancer cells, the chances of cancer coming back went from 12.2 percent if they continued hormonal therapy to 19.9 percent if they did not.
Researchers continue to consider the question of how long women should take hormonal therapy. This study showed a wide benefit to staying on hormonal therapy, but ongoing research may identify different groups who either benefit from the extended treatment or not. Part of that was captured here, with different treatment histories showing different patterns of recurrence risk and the effect on risk changing with the number of involved lymph nodes.
Still, more information is needed. The study found more side effects with continued treatment, including higher risk of bone fractures, and long-term data were not yet available from some studies included in the analysis. Those findings will be of interest, since many recurrences of hormone receptor-positive breast cancers occur more than 5 years after primary treatment.
The phase III AERAS trial also looked at the question of extending hormonal therapy after 5 years. Women had finished menopause and been treated for 5 years with the aromatase inhibitor anastrozole (Arimidex) or had started tamoxifen and then switched to anastrozole for 2 years. They were then randomized to stop hormonal therapy or continue anastrozole for another 5 years.
At 5 years of follow-up, those on extended therapy were more likely to have gone without cancer returning:
- 91.9 percent of women taking continued anastrozole did not have cancer return.
- 84.4 percent of women assigned to stop hormonal therapy did not have cancer return.
As in the meta-analysis, continuing treatment came with ongoing side effects, including more bone fractures and more reports of joint pain. In the question-and-answer session, some doctors raised concerns that the population of trial participants was too selective, because the women had all been postmenopausal since the start of hormonal therapy and the average body mass index was lower than expected.
AERAS was not able to show an effect on overall survival. But more positive results for extended therapy continue to help define which women may reduce the chance of cancer returning by extending hormonal therapy. Your doctor can help you weigh the risks against the benefits of continuing hormonal therapy beyond 5 years.
One study Thursday looked at giving low doses of tamoxifen to women with Ductal Carcinoma in Situ (DCIS) or Lobular Carcinoma in Situ (LCIS). DCIS and LCIS consist of abnormal cells that have stayed where they first developed. They increase the risk of developing invasive breast cancer later.
After establishing the standard dose for tamoxifen many years ago, the research community has not further studied the smallest dose that can be given to still have an effect. This trial randomized women to a 5 milligram daily dose of tamoxifen or a placebo for 3 years. That dose is significantly less than the standard dose given today of 20 milligrams. The aim was to lower the risk of developing invasive breast cancer while potentially limiting the side effects that can come with the current prescribed dose of tamoxifen.
The study found that the rate of invasive breast cancer incidence for women taking low-dose tamoxifen was half that of people taking the placebo. Because researchers studied a large group of people for a long time, they measured the rates of invasive disease using person years, which include both the number of people in the study and how long each person spends within it. Over 1,000 people years, 11.6 of those taking tamoxifen were diagnosed with invasive breast cancer, versus 23.9 of those taking the placebo.
Researchers said these findings could be put into practice right away, though the prescription would have to be for 10 milligrams every other day because tamoxifen is not made today as a 5 milligram capsule. Finding this protective effect with a smaller dose of tamoxifen could spur on further study as researchers look more for the right level of treatment for different groups. That means giving more treatment to people who need it but giving less treatment to people who don’t get further benefit from it.
Researchers gave results from an analysis of the SOLAR-1 trial, which looked at a new targeted therapy called alpelisib added to fulvestrant (Faslodex). Alpelisib is being studied in people with metastatic hormone receptor-positive breast cancer that tests positive for a mutation in the PIK3CA gene. It is not yet FDA approved, but initial promising results were announced in October at the European Society for Medical Oncology annual congress.
Alpelisib is a PI3K (phosphatidylinositol-3 kinase) inhibitor, meaning it blocks the PI3K pathway through which signals are carried through cancer cells. This pathway is thought to be involved in breast cancers becoming resistant to hormonal therapy. About 40 percent of hormone receptor-positive breast cancers have a mutation on the PIK3CA gene that makes this pathway hyperactive.
The study was open to men or postmenopausal women with hormone receptor-positive, HER2-negative breast cancer. Everyone had their disease grow within a year of finishing treatment for early-stage breast cancer or while taking anti-estrogen therapy for metastatic breast cancer. Participants were split into two arms, those with a mutation in the PIK3CA gene and those without. Those groups were split and randomized to get fulvestrant either with a placebo or with alpelisib.
The primary goal of the trial was to measure median progression free survival – the time a person goes without cancer growing or traveling to another part of the body – in the arm with a PIK3CA mutation, and this was achieved:
- People taking alpelisib went 11 months without cancer growing.
- People taking a placebo went 5.7 months without cancer growing.
A concern with PI3K-inihibitors is high blood sugar or hyperglycemia; the PI3K pathway is involved in the way the body regulates insulin. But researchers said high blood sugar can be easily identified and managed with medicine. Earlier PI3K inhibitors under study had too many side effects, which did not allow them to be further developed.
Overall survival will be watched in future follow-ups, but the positive results today show promise for a potential new treatment option for people with hormone receptor-positive metastatic breast cancer whose cancers have a PIK3CA gene mutation.