Nick Mulcahy

June 06, 2016

CHICAGO — When breast cancer clinicians return to their jobs from this year's American Society of Clinical Oncology (ASCO) 2016 Annual Meeting, they will likely face inquiries from postmenopausal patients who are or have been receiving adjuvant antiestrogen therapy about the MA.17R study that was featured at the plenary session.

The trial results were published in the New England Journal of Medicine and have been widely covered in mainstream media, such as the New York Times and the BBC.

The 1918-patient trial demonstrated that extending treatment with an aromatase inhibitor (letrozole [Femara, Novartis Pharmaceuticals Company], 2.5 mg daily) to 10 years after an initial 5 years of therapy with an aromatase inhibitor/tamoxifen (multiple brands) improves disease-free survival (but not overall survival).

Specifically, the disease-free survival rate for the additional 5 years was 95% for patients treated with letrozole and 91% for patients receiving placebo — an absolute improvement of 4% for patients on treatment.

This translated into a 34% reduction in the relative risk for disease recurrence/occurrence of a contralateral breast cancer (hazard ratio, 66%; P = .01) for the treatment group.

However, the improvement with the extra 5 years of treatment came at a cost. Most notably, there were more bone fractures in the letrozole group than in the placebo group (14% vs 9%; P = .001) and more cases of new-onset osteoporosis (11% vs 6%; P < .001).

"Bone health remains important to risk/benefit consideration," said the study's lead author, Paul Goss, MD, PhD, of the Massachusetts General Hospital Cancer Center, in Boston, at a meeting press conference.

Median follow-up in the study was 6.3 years; the median age of the patients was 65 years.

Dr Paul Goss

At a postplenary discussion of the results, Dr Goss did not advocate for the use of letrozole for an additional 5 years in postmenopausal women with hormone-positive primary tumors, saying he wanted to leave that to guideline committees and others. Clinicians can do "what they want to" with the data, he said.

To get a sense of what clinicians will tell patients about the study ― and whether or not they will advocate for the extra 5 years of treatment ― Medscape Medical News interviewed a number of oncologists attending the meeting.

Here is what five clinicians will be telling their patients about MA.17R and about taking an aromatase inhibitor for potentially 10 years.

Dr Patricia Ganz

Patricia Ganz, MD, University of California, Los Angeles. "This is a question that comes up frequently in practice. There are many women who are doing well on their AI therapy and have anxiety about discontinuing their medication, and [they wonder] what is going to prevent them from having a recurrence.

This is a question that comes up frequently in practice. Dr Patricia Ganz

"I will pull up the New England Journal article and show them that roughly 1000 women received the drug vs 1000 who received placebo, and if we compare the outcomes, we see 31 fewer recurrences [of any type] in those who took the drug [67 vs 98]. The majority of the [recurrence] benefit was in contralateral breast cancers [13 vs 31]. In terms of distant recurrence, there was a difference of only 11 cases [42 vs 53].

"I will also talk about the increased risk of fractures that occurred [in the active-treatment group] and subtle differences in quality of life. If they discontinue their aromatase inhibitor, they might have a return of some of the benefits of having estrogen in their body — some may appreciate that, some may not.

"I use this high-level evidence [from the study] to have discussion about their values and preferences. They may decide to stick it out longer to see how they do. Two or three years later, they may also decide to quit. And I can support that decision, because the number of events prevented by taking the medication for another 5 years is rather modest. At the same time, everyone taking the drug has the potential to have fractures and other symptoms.

"In terms of additional insights, our hope for this study is [that further analysis may answer the question]: Is there a high-risk profile? The absolute benefit of treatment may be greater for women with large tumors or those with lots of positive nodes. If we had that information, we could tailor who we recommend to have the extra treatment."

Stephen Vogl, MD, private practice, New York City. "I am going to tell my patients: the extra years of treatment didn't do much. They had a 30% reduction in distant metastases, but it is not clear if they are prevented or just delayed; it is not clear how lethal they are. The virulence of breast cancer relates to the time to recurrence [with earlier being more virulent]. These are very late recurrences, and nine of the extra 11 distance metastases were in bone, which are really not virulent.

No, don’t bother. Dr Stephen Vogl

"I have patients who have been waiting for [the results]. I have been telling them: 'I am going to come back and tell you whether you should take some more of it or not.' Some of them have been off for a few years. I'm going to tell them, 'No, don't bother.' "

Harold Burstein, MD, Dana-Farber Cancer Institute, Boston. We have known from other trials that pushing the treatment envelope out to 10 years is a good idea. Ten years of tamoxifen is a little better than 5 years of tamoxifen; 5 years of tamoxifen and then 5 years of an aromatase inhibitor is a little better than 5 years of tamoxifen alone [which was the earlier study, MA- 17].

"The topline result is, yes, longer durations do reduce the risk of recurrence and do help prevent second cancers.

"But I think, for the clinical discussion, it comes down to two things: The first is, what is the patient's risk of recurrence, based on what we already know about the stage of the cancer? And number two, how well has that patient tolerated treatment so far?

For the clinical discussion, it comes down to two things. Dr Harold Burstein

"For women who have had high-risk breast cancer ― typically, stage 2 or 3 cancers, node-positive breast cancers ― their risk moving on in years 5 to 10, 10 to 15 is still reasonably high. And for those women, there is going to be a larger benefit to continuing treatment and pushing the therapy out to a total of 10 years. But in contrast, for the women who had smaller, node-negative cancers, there is probably going to be a lot less in the way of benefit ― their residual risk is a lot smaller.

"The second thing to discuss is how the patient is doing. Women will tell us how they are feeling on these AIs. Some women have symptoms, but it does not get in the way of their lifestyle, or they have very few symptoms at all. Those women will be willing to take longer durations of treatment even for a small benefit.

"Other patients who have a lot of difficulty taking the medications...stopping probably makes sense for them.

"But what I have found is that patients are really good at telling their doctor what the appropriate length of treatment is, because they intuitively understand how risky their cancer is at this juncture, and they understand how they have felt taking the medication."

Barry Kaplan, MD, PhD, Queens Medical Associates, Fresh Meadows, New York. "The benefits are small. There are no data showing improved survival. There are real side effects. It is an expensive treatment. Even though Dr Goss said it was a relatively cheap drug, if you take it for 10 years, it becomes not so cheap. I don't see the point of recommending or using it [for the extra 5 years]. I think the benefits are not proven if you are not getting a survival benefit. These patients have already survived for some time, so these are good patients with hormone-responsive breast cancer. I would not use this treatment after the first 5 years unless the patients really demand it."

Dawn Hershman, MD, Herbert Irving Comprehensive Cancer Center, Columbia University, New York City. "At the end of the day, there needs to be a discussion with each patient about the potential risks and benefits.

"I am more likely to encourage continuing treatment after the first 5 years for patients with high risk of recurrence, patients who still have both breasts and are at risk, and patients who have had minimal or no side effects on AIs.

"Also, for some women, especially those with few side effects, the medication can feel like a 'security blanket.' And discontinuing can cause stress and anxiety.

Discontinuing can cause stress and anxiety. Dr Dawn Hershman

"The bulk of the [disease-free survival] benefit in the study was from a reduction of in-breast recurrences.... For women with minimal side effects, prevention of an in-breast recurrence or new primary may be meaningful, as it results in decreased need for surgery or other adjuvant treatments.

"The reality is that the patients in MA.17R agreed to be on a study of taking the medication for an additional 5 years after being on it for 5. Presumably, if they had severe side effects, they may not have been willing to be randomized on this study. Therefore, these results may not be representative of the whole population of women on aromatase inhibitors.

"The discussions with patients will be more difficult when someone has had severe side effects and makes it through the first 5 years."

The trial was sponsored by the Canadian Cancer Trials Group. The authors have disclosed no relevant financial relationships.

N Engl J Med. Published online June 5, 2016. Full text

American Society of Clinical Oncology (ASCO) 2016 Annual Meeting: Abstract LBA506. Presented June 5, 2016.

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