Updates from the 2017 San Antonio Breast Cancer Symposium

Bisphosphonates

You may have heard of bisphosphonates as medicines that help protect bone health, but in recent years studies found they also protect against breast cancer traveling to your bones. The American Society of Clinical Oncology released guidelines this year that recommend offering bisphosphonates to postmenopausal women who are candidates for other systemic treatments like chemotherapy or hormonal therapy. But these recommendations left some lingering questions, including how long is best for people to take a bisphosphonate to reduce their risk of recurrence.

The phase III SUCCESS A trial took a look at one of the bisphosphonates, zoledronic acid, and compared the outcomes for people who took it for 2 years against those for people who took it for 5 years. The trial found there was no difference between the two groups in how long people lived without breast cancer traveling to other parts of the body and how likely they were to die from any cause at 5 years after chemotherapy. Additionally, people taking zoledronic acid for 5 years had more problems with side effects.

While the study does suggest that 2 years was as good as 5 years with fewer side effects, presenter Wolfgang Janni, MD, PhD, encouraged further study to see if longer treatment provides more protection over the long term after treatment ends. This was backed up later in the day by Julie Gralow, MD, as part of the Alamo Breast Cancer Foundation’s discussion panel for patient advocates. Dr. Gralow noted that the average age in the trial was 53 and that people in the trial also got chemotherapy. Women likely to have breast cancer spread to the bones would be older, postmenopausal, and have a diagnosis that might not require chemotherapy.

Sacituzumab govetican

Results from a phase I/II basket trial of sacituzumab govetican showed positive results for people with metastatic, triple-negative breast cancer who have already been treated with three other kinds of medicine.

Sacituzumab govetican is an antibody drug conjugate, a treatment that pairs a chemotherapy medicine with a targeted therapy. Treatment with sacituzumab govetican got a response from 34 percent of people treated. People in the trial tended to keep receiving it longer than they did previous treatments for metastatic breast cancer, for a median duration of response of 7.6 months. The medicine did come with side effects, including neutropenia, nausea, and diarrhea, but presenter Aditya Bardia, MD, MPH noted that the number of people getting those effects, and how serious they were, were in line with other treatments.

These are early phase trials, and a phase III trial will be needed before sacituzumab govetican gets FDA approval, so one is recruiting in the U.S. currently. The ASCENT III trial is planning to confirm these results in the same population: people with metastatic triple-negative breast cancer who have already had three or more treatments. The responses so far have been enough for a breakthrough therapy designation from the FDA, which will help approval along if results look similar to those seen here.

MONALEESA-7

Ribociclib (Kisqali) was shown to improve results for pre- and perimenopausal women with hormone receptor-positive metastatic breast cancer, when used as first line treatment in the MONALEESA-7 trial. Ribociclib was only approved by the FDA in March when it became the second CDK 4/6 inhibitor to be approved for postmenopausal women with hormone receptor-positive metastatic breast cancer. Now researchers are looking for other ways to use it and other CDK 4/6 inhibitors.

MONALEESA-7 shows that ribociclib can work for women who have not gone through menopause or who may have started going through it and have infrequent periods. In the trial, women were given ribociclib along with the LHRH-agonist goserelin, which stops the function of the ovaries while it is being taken, and hormonal therapy, either tamoxifen or a non-steroidal aromatase inhibitor. This was compared to a control group that also took hormonal therapy and goserelin, but was given a placebo instead of ribociclib. The median progression free survival was 23.8 months for the ribociclib group, which was significantly longer than the 13 months seen in the control group.

In the question-and-answer period, Steven Vogl, MD, rose to say that these results should immediately change practice for women in this group, a sentiment that was shared on Twitter by Julie Gralow, MD. In the evening panel discussion, Maura Dickler, MD, said these were not surprising results but important ones for women who have not been through menopause yet and who do not always get the same level of attention in research.

Other Studies

Not all presented studies lead to a change in treatment right away, but whether they are the basis for future treatments or learning that a study treatment doesn’t work as expected, they contribute to our knowledge of breast cancer and help pave the way forward for treatment. A number of studies presented Tuesday will not have immediate effects, but could shape future treatments.

A meta-analysis of 16 randomized trials – which enrolled a total of 21,000 women – explored ways to shorten the time between cancer treatments. Giving treatments closer together gives tumors less of a chance to grow in the time between doses. While the size of doses is usually backed with strong evidence, this study explored whether treatments could be given closer together, or with treatments that are normally given together being given one at a time over subsequent visits, with short intervals. The study found significant, though modest, gains. In her discussion, Maura Dickler, MD, noted that certain chemotherapy regimens have already shifted toward these kinds of schedules, but many have not. This study could encourage another look at chemotherapy schedules.

The phase III POETIC trial studied the use of peri-operative aromatase inhibitors. Participants were given 2 weeks of treatment with aromatase inhibitors before and after surgery to remove the cancer. The study found this treatment did not improve outcomes, but researchers used the opportunity to look at Ki67 levels as well. The results showed that if Ki67 was high and remained high after treatment with an AI, the person was more likely to have a recurrence – about twice as likely as someone who had high Ki67 levels that then became low levels after treatment. These results may help researchers understand why some breast cancers become resistant to hormonal therapy and find other ways to keep the cancer from growing.

Hormonal Therapy and Ovarian Suppression

Thursday afternoon brought two of the most discussed presentations of the day. Both studied treating hormone receptor-positive breast cancer in women who had not gone through menopause with hormonal therapy and medicine to stop the function of their ovaries, called ovarian suppression.

One presentation looked at the SOFT trial, which compared three treatments:

• tamoxifen alone
• tamoxifen with ovarian suppression
• an aromatase inhibitor with ovarian suppression

The trial’s goal was to see if adding ovarian suppression to treatment with tamoxifen would improve outcomes, but early trial results presented a few years ago did not show an improvement in disease-free survival.

The SOFT researchers returned to San Antonio Thursday to present the long-term follow up of the trial, which included findings on overall survival. These later results, with a median 8 years of follow-up, showed that women who had ovarian suppression and tamoxifen had a 4.2 percent absolute improvement in disease-free survival over women taking tamoxifen alone, and that it led to a small but significant improvement in overall survival.

The second part of the SOFT trial that looked at combining an aromatase inhibitor with ovarian suppression was combined with the TEXT trial and presented separately. When this part of the study findings was presented a few years ago, treatment with the AI exemestane and ovarian suppression did perform better than tamoxifen and ovarian suppression. The 8-year follow-up presented Thursday confirmed those results, showing a 4 percent absolute improvement in disease-free survival compared to tamoxifen with ovarian suppression. But in this treatment group, the study found no significant improvement in overall survival.

The results from these analyses were positive for the use of ovarian suppression alongside hormonal therapy to treat early-stage hormone receptor-positive breast cancer. And they were further supported by an analysis of five studies that had been presented earlier Thursday morning showing that ovarian suppression with a GnRH agonist protected women from loss of fertility due to chemotherapy. But it is not clear precisely how these findings will affect treatment.

Ann Partridge, MD, led a discussion on the afternoon’s sessions and pointed out some complicating factors in using ovarian suppression, specifically the side effects it causes. Ovarian suppression comes with both short-term side effects, like hot flashes, and potentially serious long-term side effects, including bone loss and heart problems. Deciding who will benefit from treatment with ovarian suppression will require looking at a person’s breast cancer subtype, their risk of recurrence, their age, if they are experiencing side effects and how they are coping with them, and hearing what they would prefer. Dr. Partidge stressed the latter on her last slide stating that the “best treatment is one the patient will take.”

Acupuncture

In the same session, Dawn Hershman, MD, presented the SWOG 1200 trial, which looked at the use of acupuncture to relieve joint pain caused by aromatase inhibitors. The trial randomized 226 people in treatment centers around the country to

• get true acupuncture
• get faked acupuncture, which used thinner needles and shallow puncture in spots that aren’t used in acupuncture
• be put on a “wait list” and have no acupuncture or faked acupuncture during the study period

The results found that at 6 weeks people getting true acupuncture reported less pain. The relief was consistent even as sessions happened less often over time. Acupuncture also helped with related problems like joint stiffness.

Having a relief for joint pain that does not require medicine could encourage more people to take aromatase inhibitors for the full recommended period, because joint pain is a common side effect that leads people to stop taking the medicine or to talk with doctors about changing the medicine they are on.

Ann Partridge, MD discussed this study Thursday night and expressed excitement at those possibilities but pointed out that whether people stay on a medicine is a complicated choice and one helpful factor may not show a big change in the population. Additionally, who you go to for acupuncture matters, and there is little oversight in providers, if you happen to have any nearby. And while this was a very large, well-designed trial, Dr. Partridge said further studies should explore what acupuncture looks like in the long-term, how long the benefits last, and how often people have to go to acupuncture sessions.

Duration of Treatment

How long people should take a medicine has been a topic of discussion throughout the SABCS 2017. While there is scientific evidence behind current guidelines, researchers continue to consider if longer periods of treatment could lead to better outcomes – as has been seen with some hormonal therapies in recent years – or if people could see the same benefits from shorter periods of treatment. Shorter periods of treatment could help avoid some side effects, lower medical costs and encourage staying on the medicine for the full course of treatment.

The ABCSG-16 trial took people with hormone receptor-positive breast cancer who had already taken some form of hormonal therapy for 5 years, then randomized them to take the aromatase inhibitor anastrozole either for 2 additional years or 5 additional years, for a total of 7 or 10 years of hormonal therapy.

Researchers found no significant difference between the treatment groups in the time a person went without any signs of breast cancer over 10 years. But they did see that the number of people who continued to take anastrozole as recommended decreased at a steady rate across the 10-year period. About 20 percent stopped taking it by the 2-year mark, and 40 percent stopped by the 5-year mark, the point at which the second arm finished the study treatment. And, people on the longer treatment plan had more bone fractures than on the shorter plan. The study showed no benefit to extending hormonal therapy for more than 2 years with an aromatase inhibitor.

Later Thursday morning, results from the SOLD trial explored giving standard trastuzumab (Herceptin) treatment for 9 weeks, instead of the full year that is currently recommended for people with HER2-positive breast cancer. The 9-week period came from earlier research suggesting tratuzumab and chemotherapy had a greater effect given together. Researchers believed giving trastuzumab longer than this 9 weeks might be unnecessary, but the findings showed giving treatment for 1 full year resulted in a better rate of disease-free survival.

The results were close. The 1-year group had 90.5 percent disease-free survival while the 9-week group had 88 percent, leading some experts to wonder if internationally, offering treatment for 9 weeks might make the treatment available to people who can’t afford a full year of the medicine and still greatly reduce their risk of recurrence more than getting no treatment at all. But for the best results, the researchers concluded that 1 year of treatment should remain the standard.

Predicting Outcomes

Douglas Yee, MD presented an analysis of the I-SPY2 trial that looked at using pathological complete response (pCR) to predict outcomes such as event-free survival and distant recurrence-free survival.

The I-SPY2 trial was used because it is a platform trial, a clinical trial format that allows researchers to test many medicines during the course of the trial, adding or dropping medicines under study as findings show they do or do not work. The analysis found that, across treatments and breast cancer subtypes, when pathological complete response was achieved, the rates of event-free survival and distant recurrence-free survival were very high and consistent – as high as 92 to 95 percent event-free survival at 3 years, depending on the subtype.

Pathological complete response is a measure that can be seen quickly, right after treatment. Using pCR to predict outcomes could eventually let the FDA approve new treatments for clinical use faster. It can also help identify people who are either high risk and need more treatment, or low risk and can avoid some treatments, especially those with long-term side effects.

Talazoparib

Talazoparib became the second PARP inhibitor this year to show positive results for people with advanced breast cancer and an inherited mutation on one of the BRCA genes. The EMBRACA trial, presented late Friday afternoon, showed that talazoparib extended progression-free survival in people with locally advanced or metastatic breast cancer that is HER2-negative.

EMBRACA was a phase III, open label study. A total of 431 patients were randomized, two-to-one, to be treated with either 1 milligram of talazoparib taken daily as a pill, or their doctor’s choice of standard medicine: capecitabine, eribulin, gemcitabine or vinorelbine. They continued on the assigned treatment until the disease grew or side effects became unacceptable.

Researchers were primarily interested in progression-free survival, the length of time until the cancer grows or spreads. In EMBRACA the median length of progression-free survival was

• 8.6 months for people taking talazoparib
• 5.6 months for people taking their doctor’s choice of medicine

Further, the proportion of people who reached one year of progression-free survival was

• 37 percent of people taking talazoparib
• 20 percent of people taking their doctor’s choice of medicine

Treatment with talazoparib worked better than standard therapy in every subgroup studied, and it met the other study outcomes including overall response (62.6 percent with at least partial response compared to 27.2 percent on their doctor’s choice). The overall survival rate also appeared better in the talazoparib group, but there has not been enough follow-up yet to tell if that difference is significant. Researchers will continue to follow-up on that and other measures.

The most common side effects of talazoparib were anemia, fatigue and nausea, and the number of serious side effects was close but slightly higher than in the group taking the doctor’s choice treatment (31.8 percent to 29.4 percent, respectively). But more people on their doctor’s choice of medicine chose to leave the study due to side effects (9.5 percent to 7.7 percent on talazoparib).

The EMBRACA results come about 6 months after the OlympiAD trial was presented at ASCO and showed positive results for olaparib, the first time a PARP inhibitor showed a benefit in a phase III trial for people with breast cancer.

Weight Loss and Breast Cancer Risk

A study of the Women’s Health Initiative, a large study that observed behaviors and health of 93,676 women, found a connection between weight loss and a lower risk of breast cancer. The women in this study had not previously had breast cancer. Women who lost 5 percent of their body mass during the 3 years looked at in this study had a significantly lower chance of bring diagnosed with breast cancer. Researchers also looked at women who gained at least 5 percent more body mass during the three years observed. For most categories, people who gained weight and people who stayed the same weight fared the same, but triple-negative breast cancers occurred significantly more often in the group that gained weight.

Though this study does not have direct applications for people who already have breast cancer, it furthers the case for encouraging people who are not diagnosed to take preventive action. High body mass index (BMI) is linked to many health problems including breast cancer, and this study shows that losing weight can have a direct effect on the chance of diagnosis. The link to triple-negative breast cancer is also one that may attract further study, since that diagnosis has fewer targeted therapies available and is very likely to require chemotherapy.