Kevin Kalinsky, MD, MS

Kevin Kalinsky, MD, MS, associate professor, Department of Hematology and Medical Oncology at Emory University School of Medicine, and the Louisa and Rand Glenn Family chair in Breast Cancer Research, director of the Glenn Family Breast Center, and director of the Breast Medical Oncology at Winship Cancer Institute, discussed selective estrogen receptor downregulators (SERDs) being explored for the treatment of breast cancer.

 Right now in clinical practice, the only approved selective estrogen receptor down regulator or SERD is fulvestrant [Faslodex]. At San Antonio, we saw the results of the first randomized study with an oral SERD. This was the EMERALD study or assessment versus physician choice, hormonal therapy. And we saw there was a statistically significant improvement in outcomes such as progression-free survival, particularly for those who have 

 mutations, which we're seeing [in] about a third of patients with hormone receptor-positive or negative disease, which those tumors have progressed on endocrine therapy.

 But there are a smattering of other SERDs that are coming down the pike. [These are] randomized studies, including studies with amcenestrant.

 So, this field is rapidly moving forward, not just anticipated in the metastatic setting, but also in the early-stage setting. And there are some studies that are ongoing and should be opening for patients in the early setting with oral SERDs as well as other hormonal therapies.

Videos

Kevin Kalinsky, MD, MS,  discussed selective estrogen receptor downregulators being explored for the treatment of breast cancer clinical trials.



SERDs in Development for the Treatment of Breast Cancer

For this particular patient, she would have had surgery first. Commonly, we give chemotherapy next, and then we give radiation, then we give hormonal therapy.

There is no safety concern about giving the hormonal therapy with the radiation, but it’s more if there are toxicities. It’s good to know when it’s due to, as opposed to having 2 things going on at 1 time.

I tend to start the aromatase inhibitor and then add on the abemaciclib after a few months, just demonstrating that they are tolerating it. And that’s again, just because I don’t want there to be a confounding factor.

And monarchE patients had 16 months before they needed to start their abemaciclib. So we don’t need to urgently initiate the abemaciclib.

Which is why I tend to start it just after we know that the patient’s taking the aromatase inhibitor and they’re adherent, and then I start the abemaciclib for 2 years. And then I continue that aromatase inhibitor after that.

There is an important distinction in terms of the timing that we see relapse. So if we see a patient that’s recurring on the abemaciclib and the aromatase inhibitor, this would give some concern, and I would think, the patient’s resistant to those medicines.

And I would think about switching that particular patient to fulvestrant-based therapy. And I’d have some reservations about giving them a CDK4/6 inhibitor, especially if they’re recurring on Verzenio. And that’s a little bit different than somebody who received their abemaciclib, goes on to get an aromatase inhibitor, and then, let’s say, 3 years later recurs.

In that particular situation, I would feel more comfortable about potentially utilizing an aromatase inhibitor and CDK4/6 inhibitor. And this field is moving so quickly that we really don’t have data about sequencing yet, but we’re awaiting some data in the metastatic setting about sequencing from some randomized phase 2 studies. And there’s a phase 3 trial that’s going to be addressing this question.

I do some genomics, and I do think that there’s a role for it, checking for 

 mutations. Commonly, that’s checked with circulating tumor DNA [ctDNA]. We know that patients who are taking aromatase inhibitors are less likely to benefit compared to something like fulvestrant [therapy]—the IM [intramuscular] injection of the SERD [selective estrogen receptor degrader] in the metastatic setting for patients who have 

But there’s an entire class of oral SERDs that are coming down the pike. In San Antonio, in 2020, we saw the results of the EMERALD study with Elacestrant, which demonstrated an improvement in progression-free survival with those who have 

 mutations; comparing that particular oral SERD with the standard of care, physician choice, anti-estrogen therapy.

So that’s not something that’s available in the clinic now, but I think moving forward, and hopefully soon, we’ll see oral SERDs as an option for patients.

I do think that, to me, what’s going to be exciting in the next few years are the oral SERDs. I do think that that’s going to be changing the landscape of how we treat patients in the metastatic setting and potentially in the early-stage setting as well.

I think the other unmet need for patients with early-stage disease is that the biology of this cancer is that we can see a late recurrence. So recurrences 10 to 20 years later.

And hopefully, we’ll identify predictors of late recurrence as well as ways to mitigate that, and the oral SERDs may have a place in that paradigm. I think that there’s a lot of excitement about circulating tumor DNA.

And there are some prospective retrospective studies suggesting their potential utility in the early-stage setting and there are some studies that are opening/open, that are specifically looking at, not just the prognostic implications of having ctDNA positivity, but also the potential predictive utility. Meaning, then you change the therapy, can you delay the risk of recurrence? And I think that that’s really where the field is going.

Case: A 67-Year-Old Woman with ER+/PR+ Breast Cancer

A 67-year-old, postmenopausal woman presents with a newly diagnosed lump in her left breast

She has 2 grown children, no family history of cancer, and underwent menopause at age 48

PMH is significant for hypertension that is well controlled with medication

Imaging demonstrated a 4.4-cm solid mass in the right upper quadrant with no suspicious adenopathy

Core biopsy: positive for invasive ductal carcinoma, ER 100%/PR 40%; 

 IHC 1+; Ki-67 30%; modified Bloom-Richardson grade 3

Lumpectomy and sentinel lymph node biopsy performed

Tumor size is 4.5 cm, and 2/5 LNs are positive for metastatic disease

Patient underwent partial mastectomy with no residual disease

She is started on adjuvant chemotherapy with cyclophosphamide and docetaxel

She is given radiation therapy to intact breast

Followed by aromatase inhibitor + 2 years of abemaciclib

Guidance on how to treat a 67-year-old patient with ER-positive/PR-positive breast cancer, and additional therapies in the pipeline that have the potential to improve treatment. 

HR+ Breast Cancer: Future Treatment Opportunities

So there’s palbociclib [Ibrance], ribociclib [Kisqali], and abemaciclib. All 3 are approved in patients with hormone receptor-positive, HER2-negative disease along with endocrine therapy.

The mechanism of action is similar across the agents. The palbociclib and ribociclib are given 3 weeks on and 1 week off. Abemaciclib is given twice a day continuously. Their safety profile is a little bit different.

Palbociclib and ribociclib causes more neutropenia. The rates of febrile neutropenia are so low, about 1.5%. But we see that the rate of neutropenia is lower with abemaciclib compared to the other 2.

However, abemaciclib has a different toxicity profile, and we see gastrointestinal issues or some diarrhea particularly early on.

The other thing with ribociclib, just to be mindful of, is that at week 1 and week 3, and then also at week 5, it’s important to do EKGs [electrocardiogram] just looking for QT prolongation [when the heart muscle takes a longer time to contract and relax than usual], and there can be some drug-drug interactions just to be mindful of.

The most common adverse event that we see with palbociclib and ribociclib can be neutropenia. So it is important to check that blood count every 2 weeks for the first 2 months.

And then, I generally, because I’m seeing patients in the metastatic setting monthly, continue to check that blood level. For abemaciclib, the main toxicity that we can see can be gastrointestinal issues. And even when you prescribe that medication, it comes with Imodium. So it’s important to have that on hand. If diarrhea develops, you don’t need to take that medication prophylactically. But if it develops, and generally patients tend to tolerate that agent once you get through a month or 2, that’s when we see the highest rate of diarrhea. And of course, we can manage these with dose modifications.

Other potential side effects include things like fatigue, and there is a slightly higher rate for alopecia. And then when you compare utilizing abemaciclib in the early stage versus the metastatic setting, what I would say is that really it’s important for these first few months to stay in close contact with the patient, just is in terms of gastrointestinal issues.

And the early-stage setting, we’re not seeing those patients ultimately as frequently as we do in the metastatic setting. So once a patient’s been on abemaciclib, and they seem to be tolerating the medication, and they’re several months in, we’re seeing these patients a little less frequently than what we do in the metastatic setting.

If new symptoms occur, then of course, we’ll see the patient, but that seems to be the big differential in terms of how we manage early versus metastatic disease.

An overview of CDK4/6 inhibitors available for patients with advanced or metastatic HR-positive breast cancer, and recommendations for managing common adverse events associated with therapy.

CDK4/6 Inhibitors for Advanced HR+ Breast Cancer

We’ve known from metastatic disease that with CDK4/6 inhibitors there can be significant advantage of utilizing them in the metastatic setting.

And we’ve seen across the various studies in the metastatic setting progression-free survival benefit and for some of the agents an overall survival benefit. So there’s been a lot of interest about utilizing these agents in the early-stage setting.

And the data that we’ve seen with palbociclib [Ibrance] did not yield an improvement in invasive disease-free survival. But with monarchE we did see an improvement with invasive disease-free survival.

And how that study was designed, is that these were some higher risk patients and all those patients received endocrine therapy plus or minus 2 years of abemaciclib [Verzenio]. And these data have been updated, and recently published in the 

, demonstrating that those 2 years lead to an improvement in invasive disease-free survival.

The drug was approved based upon these data, meaning abemaciclib was approved in the early-stage setting in patients who are high risk, and by that I mean that they had a Ki67 that was 20% or greater and had 1 to 3 nodes involved. And had other high-risk features like grade 3 tumors or tumors that are greater than 5 centimeters. And the FDA [Food and Drug Administration] approved this particular agent in that setting and that’s what’s included in the label.

ASCO [American Society of Clinical Oncology] since has come out and been a little bit more open in terms of definition of high risk. But for this particular patient, she does meet these criteria of grade 2 tumor, 1 to 3 nodes involved, high Ki67. It would be totally appropriate to think about abemaciclib for this patient.

When doing an analysis looking at Ki67, what was seen, if you look in those different cohorts that had a lower Ki67 or a higher Ki67, the absolute benefit was different between the population.

So the population who had a higher Ki67 had a numeric benefit of invasive disease-free survival after about 3 years or so, of about 7%. And that was lower in the population who had a lower Ki67.

Though the hazard ratio is the same between those 2 populations, the FDA approved the drug in those patients who have a higher Ki67 because those patients have a higher risk.

And that lead towards that population having a higher numeric benefit in terms of the absolute benefit with the abemaciclib.

The rationale for treating patients with early-stage HR-positive breast cancer with abemaciclib and endocrine therapy.

CDK4/6 Inhibition in Early-Stage HR+, HER2- Breast Cancer

For this particular patient, if we find that there’s 1 independent factor for risk, it’s the presence or absence of lymph nodes.

This patient has no positive disease. Ki67 is a marker for tumor proliferation. Anything greater than 14% is considered quote-unquote, high, but clearly, we see Ki67s that are 80% to 90%, and those are more proliferative tumors compared to somebody who’s just 30%. Size is important.

I think also genomics. So, we talked about the 21-gene [recurrence] assay. We have data from the RxPONDER trial that patients who are postmenopausal have a recurrence score that’s less than 26 with 1 to 3 positive nodes don’t benefit from the addition of chemotherapy. So it’s an important prognostic indicator. This particular patient had a recurrence score that was 30, grade 3 tumor, Ki67 30%. All of those factors would lead me to discuss doing chemotherapy with her.

And her tumor was strongly ER-positive, PR-positive as well. So she’ll benefit from doing endocrine therapy and she would be a candidate for 2 years of abemaciclib [Verzenio] as a result of the monarchE study.

Because she had a high recurrence score and some of the other factors that I mentioned that can be concerning like the grade and the Ki67, all those factors lead somebody to think about, maybe this isn’t the kind of tumor that’s just going to be endocrine sensitive.

And they would benefit from doing chemotherapy and our recurrence 30 and would have been entirely appropriate to give this patient chemotherapy. Commonly, we do the chemotherapy first then followed by the endocrine therapy.

There are options like aromatase inhibitors or tamoxifen. For this patient, I would start out with an aromatase inhibitor because we know that the relative and absolute risk for this patient is high enough that there would be a difference in terms of preferential use of an aromatase inhibitor.

We would think about abemaciclib for this patient because she would have been eligible for the monarchE study. The other thing just to mention is that for somebody who’s premenopausal.

So if I saw this patient and she was 40 years old with this recurrent scoring, 2 nodes involved, etc., I would talk with this patient about doing ovarian function suppression.

As we know from data like the SOFT TEXT trial that they seem to benefit even more than a decade out from that sort of approach. So this particular patient was premenopausal.

The other thing I would think about adding would be a GnRH [gonadotropin-releasing hormone] or undergoing some sort of procedure like oophorectomy to induce menopause because she would have an absolute benefit with doing that.

Criteria used by breast oncologists to risk stratify patients who present with HR-positive breast cancer.

HR+ Breast Cancer: Prognostic Indicators

This is a 67-year-old patient who is postmenopausal, and who palpates a new lump in her left breast. She has no family history. Has only hypertension that’s well controlled on medication.

So, as part of her workup, she undergoes breast imaging which identifies a 4.4 centimeter solid tumor in her breast. No suspicious adenopathy.

So she undergoes a core biopsy that is positive for invasive ductal carcinoma that is strongly estrogen receptor-positive at 100% and progesterone receptor is 40%. It’s HER2 negative by protein expression and there’s a Ki67 of 30%. It’s grade 3. So she undergoes a lumpectomy and has a sentinel lymph node biopsy.

It’s a T2, N1 MX lesion. It’s around 4 centimeters, 2 out of 5 lymph nodes are involved. She undergoes testing with the 21-gene recurrence assay, which is 30 and her performance is excellent. So she does not have any residual disease.

She starts her adjuvant chemotherapy with docetaxel [Taxotere] and cyclophosphamide. She completes radiation therapy to the intact breast, and then she goes on to receive an aromatase inhibitor, 2 years of abemaciclib with the plan of continuing the aromatase inhibitor after.

So this is a common occurrence. Hormone receptor-positive, protein-negative breast cancer is the most common type of breast cancer that we see. Patients can either palpate that lesion or they may just undergo screening imaging and it can be detected.

We’re seeing during the pandemic that rates of mammography, screening mammography, has decreased. So it’s not infrequent that we’re seeing more patients come in with palpable breast lesions.

And risk factors can vary but could include long-term exposure to hormone replacement therapy, family history, that’s important. We know that approximately 1 in 8 women can develop breast cancer in their lifetime, but those patients who have a high family risk may be at higher risk.

And we certainly utilize hereditary genetics to determine whether somebody, especially if they have a high family history or other red flags, like they’re premenopausal at the time of diagnosis, may have a familial predisposition for the development of breast cancer.

Kevin Kalinsky, MD, MS, presents a case of ER-positive/PR-positive breast cancer and highlights the prevalence of cases such as this in the United States.

Kevin Kalinsky, MD, MS | Authors

Articles

SERDs in Development for the Treatment of Breast Cancer

HR+ Breast Cancer: Future Treatment Opportunities

CDK4/6 Inhibitors for Advanced HR+ Breast Cancer

CDK4/6 Inhibition in Early-Stage HR+, HER2- Breast Cancer

HR+ Breast Cancer: Prognostic Indicators

Case Impressions: A 67-Year-Old With HR+ Breast Cancer