Hormone receptor positive breast cancer is the most common subtype of breast cancer and was the theme of Wednesday morning here at the San Antonio Breast Cancer Symposium (SABCS), the largest breast cancer conference in the world. For the first time, this year’s SABCS—the 39th—kicked off with a plenary lecture before the standard General Session 1. Dr. Stephen Johnston comes from the Royal Marsden Hospital in London and in the opening plenary lecture he spoke about “Management of metastatic ER+ breast cancer”. And a subsequent paper looked at adding everolimus to fulvestrant. This was then followed by three papers in the General Session which evaluated the duration of hormone therapy in reducing recurrence.
Around two-thirds of breast cancer patients have hormone receptor positive breast cancer. This subtype is generally viewed as treatable and hormone therapy generally cuts the risk of recurrence by half, and risk of death by around one-third. However, the risk of recurrence for hormone positive breast cancer continues even after 20 years, and for this reason many argue that hormone positive breast cancers are never cured. On the other hand the risk of recurrence for triple negative breast cancer is very high initially, but it tapers over time.
Because hormone positive breast cancer shows significant long-term risk of relapse, many researchers feel that extending hormone therapy is a compelling concept. In 2012, the ATLAS study showed that doubling the length of time women take tamoxifen slightly reduces the risk of recurrence (by less than 4%) and of death (by less than 3%). Despite this fairly small benefit and lots of side effect when extending the use of tamoxifen, on average aromatase inhibitors outperform tamoxifen and there has been extensive interest in how the ATLAS findings translate to aromatase inhibitors, which are used to treat post-menopausal women with hormone receptor positive breast cancer.
Dr. Tjan-Heijen presented the first results from the Dutch DATA study [S1-03], which looked at the possible benefit to postmenopausal women with early stage hormone positive breast cancer of using anastrazole for either three or six years, after an initial two to three years of tamoxifen. Around 2,000 women were randomized to receive either three or six years of anastrozole. Although the researchers suggested that for some patients—those with both ER and PR+, HER2-, large tumor and prior chemotherapy—there may be some benefit to extending treatment with an aromatase inhibitor, the study does not support extended use of an aromatase inhibitor after five years. Furthermore, it should be noted that while 80% of patients in the 3-year treatment arm were able to complete treatment, just 60% of patients in the 6-year treatment arm were able to do so.
Dr. Blok presented results of another Dutch trial, the phase III IDEAL trial [S1-04]—which is an acronym for Investigation on the Duration of Extended Adjuvant Letrozole treatment. IDEAL evaluated extending letrozole treatment after five years of hormone therapy and enrolled 1,824 patients between 2007 and 2011. Ten years after diagnosis, there was no observable difference in disease free survival between 2.5 and 5 years of treatment with letrozole. However, there was a slight difference in prevention of a second primary breast cancer. And as with the DATA trial, fewer women were able to complete the longer hormone therapy; 74% in the 2.5 year arm versus 57% in the 5-year arm. The conclusion is there is no benefit of extending AI therapy longer than 2.5 years.
Finally, Dr. Mamounas presented the results of NSARP B-42 [S1-05] which evaluated the possible benefit of extending the aromatase inhibitor letrozole for an additional five years after five years of initial hormone therapy treatment for early stage breast cancer. The study included nearly 4,000 women who took either letrozole or a placebo for an average of about two years after an initial five years of aromatase inhibitor therapy. There was no statistically significant benefit of extending letrozole, either in terms of disease free survival or overall survival, although there was a (non-statistically significant) trend toward improved disease-free survival with longer use of letrozole. The limited benefit was primarily for those with more aggressive breast cancers. And extending treatment comes with side effects, including a slight but serious cardiovascular risk (arterial thrombosis) after 2.5 years.
Indeed, Dr. Gnant, who was the discussant reviewing these papers, said bluntly: “Everyone knows that side effects of AI use are frequent and compliance is likely to be even poorer outside clinical trials.” His concluding comment will surprise no patient who has dealt with hormone therapy: “Some patients actually count down the days until they can stop!”
We must always evaluate benefit and harms with any treatment. And in the case of extended hormone therapy, the small benefits are weighed against significant quality of life side effects. Overall, there appears to be a near consensus that only the highest risk patients who are able to tolerate the treatments should consider extending hormone therapy. For most women on an aromatase inhibitor, none of these findings are practice-changing and the current standard of care is enough.
Genomic tests or biomarkers are often seen as the missing piece of the puzzle to predict risk of recurrence and death. However, both the plenary speaker (Dr. Jonhston) and the discussant (Dr. Gnant) noted that clinical features like tumor size and traditional characteristics of tumor biology are in fact still meaningful in predicting risk.
One study looked at the subject of treating hormone positive metastatic breast cancer. Dr. Noah Kornblum presented PrECOG 0102 [S1-02], a phase II trial which showed some benefit by adding everolimus to fulvestrant. Because it is common for tumors to become resistant to treatment with aromatase inhibitors over time, the researchers are looking for ways to overcome aromatase inhibitor resistance. They hypothesized that fulvestrant plus everolimus would be a better block to tumor growth and indeed the addition of everolimus to the aromatase inhibitor extended progression free survival (the window before the tumor begins growing again) from 5.1 months to 10.4 months. However there was no difference in overall survival shown.
In the opening plenary, Dr. Jonhston argued there has been “tremendous progress” in treating hormone positive metastatic breast cancer, and he cited the ability to delay tumor growth by 14-16 months with single agent hormone therapy, and up to 24 months with combination therapy. I would say this hardly qualifies as “tremendous” for most women living with and dying from metastatic breast cancer; more like incremental progress.