So the good news about this case is that there are a number of therapies. If you assume the patient is relatively asymptomatic, her bone pain has gotten worse but she's still managing her pain with maybe an occasional narcotic at night to sleep, but other than that is doing pretty well, then in my practice I would want to avoid chemotherapy at most costs. Even with multiple liver lesions, patients liver function can still be good. Remember, this is a woman who just 3 years ago got our best chemotherapy, adriamycin cytoxin and paclitaxel. So I'm not really inclined to jump back on the chemotherapy bandwagon at this point.

What has she not had in the endocrine domain? She's not had tamoxifen, she's not had a type 1 aromatase inhibitor which is exemestane, and that's it. What you want to do is think about incorporating anti-estrogen therapy. It always makes me feel a little better if you can layer a targeted agent on top of that.

In this patient my choice would be exemestane everolimus based on the BOLERO2 data. I was quite impressed, at least in the New England Journal of Medicine publication, the independent review showed a 6 month improvement in progression-free survival. The way I would describe my recommendations to the patient is "I really don't want to start you on the chemotherapy pathway at this point, and we have anti-estrogen therapies that you've not had, both pills being exemestane or tamoxifen, and we have a targeted agent known as everolimus that shown to make both of those drugs work better."

Kimberly Blackwell, MD: Choices of Therapy

What considerations underlie these choices?

In 2016, we're lucky that we have a number of choices. Many of them have only been studied in the first- or second-line metastatic setting and many of them have only been studied with a type 2 armoatase inhibitor. For the case of the CDK inhibitors, that's letrozole or fulvestrant, that's our other agent that we can combine with our endocrine agents. We don't really have a lot of data about the use of CDK inhibitors past the second-line, whereas with the use of everolimus, we've studied that in patients who have progressed on a type 2 armoatase inhibitor. That's the eligibility criteria for the BOLERO2 study.

I think in terms of data-driven decision making, we have data in this setting, and also in this very practical thought of "what targeted agent can I get covered in combination with anti-estrogen therapy," I think everolimus is a good choice. If you were really worried about her liver lesions, or she was having bumps in her liver function test, it's also appropriate to consider capecitabine, which is an oral chemotherapy agent, but I don't think there's any harm in trying an 8-week course of a targeted agent and anti-estrogen therapy. I would just keep a close eye on her and, given that she's 3 years out from her initial diagnosis and is still having minimal symptoms, I think it's very appropriate to choose an anti-estrogen strategy.

Kimberly Blackwell, MD: Considerations for Different Therapies

What are the expectations of therapy in this setting?

We know on average that when women have progressed on first-line endocrine therapy, the median progression free survival unforunately remains under 1 year. We really want to think about incorporating a targeted agent with the anti-estrogen therapy, or participation in clinical trials. What I would tell this patient is that if I were to start her on an anti-estrogen agents such as exemestane in combination with everolimus, that at least when it was studied with that combination in the first-line setting, the median progression free survival, and there were different endpoints, was about 10.6 months compared to 4.1 months when the anti-estrogen agent was used alone.

I'd also tell the patient that there are added side effects when you add everolimus, and these include mucositis, anemia, and a very rare form of lung irritation/inflammation known as pneumonitis. With everything we do in cancer, we have to highlight the benefits, which is if we add this pill, it will make your anti-estrogen work better, but also highlight the possible side effects.

Kimberly Blackwell, MD: Expectations of Therapy

Are there any clinical trial data that would inform this choice?

For this patient population, which is really they've had adjuvant endocrine therapy, they've progressed within roughly a year on first-line endocrine therapy, we really don't have a study that helps us with big decision making like is chemotherapy better than anti-estrogen strategies. In my own practice I try to milk out as much as I can out of the anti-estrogen strategies before going back to chemotherapy in incurable metastatic breast cancer. That's more based on minimizing the toxicities and hopefully prolonging the benefits of what I do for patients facing stage IV breast cancer.

We have very little data bout whethr we should switch to anti-estrogen therapy or stay on anti-estrogen therapy, or should we switch to chemotherapy, but my bias, and you would have to see a really quick response, would be to continue using anti-estogren strategies. Likewise, for this particular patient who's had a type 2 armoatase inhibitor and fulvestrant, we don't have a study that says what is best. Is it best to go back to a type 2 AI with a targeted agent, which many people would at least consider in the use of CDK inhibitors, or is it best to switch to a different anti-estrogen therapy, which exemestane is different than anastrozole, which the patient had received previously, and everolimus. We don't have any clinical trial data, nor do we have any molecular markers that say "okay, you have a PI3K kinase inhibitor and you should go on this, and if you have a CDK amplification you should go on this."

With that said, my bias is not to go back to the same anti-estrogen to jazz it up a little bit and use a different non-cross resistant agent. So we do know that exemestane works in patients who have had type 2 armoatase inhibitors, in this case anastrozole. I would also think about tamoxifen. I think people forget a lot about tamoxifen, and we do have very good data of tamoxifen being synergistic with everolimus. Not neccessarily in this line of therapy, but in the neoadjuvant setting, very good data that they work well together.

Kimberly Blackwell, MD: Clinical Trial Data Supporting These Choices

This is a lady who presented with small volume liver metastases, and in her case she was on adjuvant anastrozole when she relapsed. For her bone metastases we gave her denosumab and then changed it to another hormonal therapy fulvestrant. Now she has progression in both bone and liver, but it's minimal  it's not a lot. The real question here is what to do, and we have a lot of options, but in this case I think I would give exemestane and everolimus.

Adam Brufsky, MD, PhD: Choices of Therapy

The idea here is that you want to do something that clearly has a proven benefit, number one, and that there are clinical trial data that support it. Number two, you want to do something that allows somebody to maintain a quality of life for as long as possible and is really less cumbersome to the patient.

Adam Brufsky, MD, PhD: Considerations for Different Therapies

The therapy choice that I would make is exemestane and everolimus, and I think that when compared to the standard of care which existed before everolimus, exemestane alone had about a 4-month progression-free survival. When exemestane and everolimus were given together, that progression free survival went up to about 9 months. In fact, if you look at some of the data from the clinical trials, the independently reviewed data, it's probably about 10 months.

Adam Brufsky, MD, PhD: Expectations of Therapy

The BOLERO-II trial was a trial of about 400 or 500 women who half had received exemestane alone and half had received exemestane and everolimus. All of these women had progression on a non-steroidal aromatase inhibitor. Basically in this trial, the progression free survival was over 8 to 10 months, depending on who analyzed the data  if it was investigators looking at the data or an independent review committee looking at the data.

Clearly it doubled the progression free survival and what it did, which is really important for these sort of trials and for women who have progressive disease, is there is a certain percentage of women who are going to be long-term non-progressors. That is 10%, 15%, 20% at 2 years, and this makes a big difference in your clinic. These women clearly had progressive disease and are wondering what they're going to do, and actually now they come back to your clinic and they're doing well for a fairly, substantially long period of time.

The major side effects that were seen in this trial that were important to note were about 8% to 10% of people had fairly severe stomatitis. That can be fairly painful and can interfere with eating and drinking. There are many ways to deal with this. Some of us use a steroid mouthwash prophylactically, and there are some clinical trials of that that are currently ongoing. Some of us use a reduced dose. We actually hold the dose for a few days, say if someone is on 10 mg per day of everolimus, we'll cut that to 5 mg per day. There are many ways to deal with this.

Also other side effects we need to be concerned about hyperglycemia in a small number of women, and we also need to be concerned about pneumonitis-like syndrome that can actually mimic progressive disease. If someone does become short of breath on these therapies, you have to be careful that it's not from progression in lungs, but potentially from the pneumonitis from the everolimus, which in many cases is reversible.

ER+/HER2-Breast Cancer with Adam Brufsky, MD, PhD and Kimberly Blackwell, MD: Case 1