New Treatment Paradigm Required for Breast Cancer in Young Women

Ruth O'Regan, MD

Younger women with breast cancer, which make up around 20% of patients, present with unique disease characteristics that warrant careful consideration of potentials treatments, particularly given the potential for long-term side effects, according to Ruth O’Regan, MD, at the 2017 Lynn Sage Breast Cancer Symposium.

Evidence has emerged that premenopausal women with breast cancer could benefit from different lengths of treatment of the addition of ovarian suppression in the adjuvant setting. However, it is still unclear who should receive 5 years of tamoxifen versus 10 years and findings from the Suppression of Ovarian Function (SOFT) and Tamoxifen and Exemestane Trial (TEXT) looking at the addition of ovarian suppression to either tamoxifen or an aromatase inhibitor were unclear. These trials showed that the regimens were similar in effectiveness among women who had not had chemotherapy, but they differed significantly in the number of side effects.

“Going forward, finding the molecular profiling biomarker to tell us which patients need this approach is going to be important,” said O’Regan, a professor of Medicine that University of Wisconsin School of Medicine and Carbone Cancer Center. “The other problem with SOFT and TEXT is that they compared it to 5 years of tamoxifen and we now very often give 10 years of tamoxifen or 5 years of an aromatase inhibitor after tamoxifen.”

In an interview withTargeted Oncology,O’Regan, discussed the different types of cancer seen in younger patients, and adjuvant considerations. Additionally, she explored the utility of using risk assessment assays for premenopausal women with breast cancer.

Targeted Oncology:Can you please provide an overview of your presentation?

O’Regan:I was asked to talk about the adjuvant management of breast cancer in premenopausal women. What we initially did was reviewed what breast cancer is like in premenopausal women. Overall, only about 20% of breast cancers we see occur in women that are still having regular periods. Less than 10% occur in women of the age of 40 and less then 2% in women under the age of 35.

If one looks biologically, what is found is that they are more likely to get triple-negative breast cancer (TNBC) and less likely to get Luminal A cancer. There is data demonstrating that as the age increases the rate of TNBC goes down whereas the rate of Luminal A goes up.

However, if you look at the molecular profiling assays that we use to make decisions, such as the 21-gene recurrence score or the 70-gene signature, there was about a third of premenopausal patients under the age of 50. Some of those patients had low-recurrent score cancers and there was no reason to believe that they didn't do fine without chemotherapy. Even though they biologically get more aggressive cancers, I still think the assays that we use are applicable to these younger women.

When you look at adjuvant therapy, we treat pre- and postmenopausal women the same when it comes to chemotherapy, whether they have TNBC, HER2-positive cancers, or even estrogen receptor (ER)-positive cancers. The big difference is how we manage them from an endocrine therapy perspective. For decades, using tamoxifen for 5 years was the standard, but more recently we’ve used it for 10 years. The SOFT and TEXT trials looked at either adding an ovarian suppression with either tamoxifen or an aromatase inhibitor in women who were undergoing ovarian suppression. This showed a modest difference in favor of adding ovarian suppression.

One of the key things we don't know is which patients need this approach and it is more toxic. We don't know the long-term toxicities of these approaches. One of the things that we used to make decisions are women of younger age, because there was a benefit for women under the age of 35. We reviewed some data showing that if you have cancers that have low progesterone receptor and high Ki-67 and have received chemotherapy, they appear to benefit from either the addition of ovarian suppression or an aromatase inhibitor.

Can you discuss any ongoing biomarker research?

We use molecular assays to make a lot of decisions in ER-positive breast cancer. It would be interesting to use one of the existing assays such as 21-gene recurrence score, 70-gene signature, or the Breast Cancer Index, to determine which patients really need this more intensive endocrine therapy approach. The good news is that they have samples in about 80% of the patients that entered SOFT and TEXT. At this point, no RNA has been extracted but I think that is something that we will see. It's just a question of will one of these trials pan out as something that will make sense as a biomarker for these patients.

Are there any ongoing trials for these patients that could be particularly exciting?

As far as trials, there is nothing specific trying to validate anything that we've done before, and that is probably not going to be done because these are large trials. However, premenopausal patients are eligible for some of the adjuvant trials that are ongoing right now, such as PALLAS, which is investigating adding palbociclib with endocrine therapy in patients with higher-risk ER-positive breast cancer. The SWOG study is looking at adding everolimus to endocrine therapy, which may produce some signals. The other CDK inhibitors are also going to be going into adjuvant trials soon.

That's an important question because it is not clear how beneficial chemotherapy is in Luminal B cancers and since they may be somewhat resistant to endocrine therapy, using one of these targeted agents to enhance the endocrine therapy makes sense. I would encourage premenopausal patients to ask their oncologists about these trials.

What are the specific challenges that premenopausal patients face?

One of the big challenges for premenopausal patients is typically the younger patients trying to maintain fertility. We have fairly good data suggesting that if you give ovarian suppression during the duration of chemotherapy, they are not as likely to develop permanent ovarian failure and are more likely to get pregnant.

One trial that recruited patients with ER-positive breast cancer showed an improved disease-free survival if you gave ovarian suppression through chemotherapy. That is one of the things that they struggle with. A lot of times, I'll see patients who are told that they can never get pregnant, which is not true. I have had a lot of patients that got pregnant after a diagnosis of breast cancer. We usually want them to wait at least 2 years, if not longer. If they are taking tamoxifen, they can stop it and then restart it later.

The other issue to keep in mind is that these women are undergoing these therapies when they're quite young so we are not sure what is going to happen to their bones or in terms of coronary heart disease. The SOFT and TEXT studies did show that there was an increased rate in hypertension and glucose intolerance in patients who got ovarian suppression, which is slightly worrying. We don’t know the long-term side effects of this ovarian suppression on these women and that is important to investigate.