Aditya Bardia, MD, MPH, FASCO, is a professor in the Department of Medicine, Division of Hematology/Oncology and director of Translational Research Integration at UCLA Health Jonsson Comprehensive Cancer Center.

 Let us discuss the use of CDK4/6 inhibitors a little further; is there any patient where you wouldn’t use a CDK4/6 inhibitor, Mark? Have you found a patient?

 Maybe if they’re allergic to it, but I was so struck by the subset analysis in PALOMA-2 [NCT01740427] where they looked at all the variables: bone-only disease, age, even very advanced age, they looked at on the forest plot. They looked at some very long disease-free intervals and there was still a significant benefit by adding the CDK4/6 inhibitor in that data set; it’s just astonishing. You can’t really—based on clinical demographic or pathologic features—you can’t identify a subset of patients who doesn’t statistically benefit from the addition of CDK4/6. I don’t find any good reason not to use it. In this country, looking at some postmarketing research data, the penetration in the first line for use of CDK4/6 inhibitors is not 100%, it’s not even close. There’s a stubborn 20% or so right now that are getting chemotherapy first, which is not appropriate in as much as CDK4/6 inhibitors are arguably even more efficacious and less toxic; that probably has to do with cost. These drugs are very expensive, and the co-pays are very high, consequently there may be a subset of patients for whom it may be difficult to get the drug. Now, for patients who don’t have any resources, all the manufacturers for all 3 of these have very fine programs where you can get drug access, no problem. But it’s everyone in the middle who has a real job, a career, a family, is a retiree: those are the patients where it may be tough to make those co-pays. I suspect that’s why in market research data it hasn’t caught up to where we think it should be as academics.

 Medicare share of cost, depending on the Part D plan that a patient has, can be quite daunting for some. Does anybody else have a different opinion on who you wouldn’t give a CDK4/6 inhibitor to?

 I think somebody who had a toxicity issue. Very rarely that can happen, despite multiple dose reductions they did not have tolerance and still have the neutropenia. They couldn’t take it, or diarrhea was an issue with abemaciclib and they just couldn’t take that on, especially in somebody who has a very endocrine-sensitive disease and an extremely long disease-free interval from their adjuvant therapy; maybe a few bone metastases only. A very elderly patient population potentially one could consider that as an option, as well. Short of that, I would agree that “Why not use a CDK4/6?” is a very appropriate question rather than thinking about why we should not give it to them.

 I think somebody mentioned previously that someone perhaps who’s very elderly with multiple medical comorbidities, competing causes of mortality, or the breast cancer is probably not going to be the problem in the end; certainly some of those patients could be treated well without a CDK4/6 inhibitor, but just about everybody else with a reasonable performance status, I think CDK4/6 inhibition is the best.

 Except for if you get ILD [interstitial lung disease], which I currently have one patient; ILD on abemaciclib got better, ILD on ribociclib, OK, I give up. It’s the only patient I’ve ever seen with symptomatic ILD. It’s very rare.

 It is very rare. I think I have one patient in clinic as well that just had it, so it’s only one that I had.

 We don’t know the risk factors for interstitial lung disease other than being from Japan and probably overall some subset of Asian descent, other than that, we don’t know. My patient was Russian, so didn’t fit into that group. The other decisions that we make about treatment, we talked about menopausal status; it’s not very common, but if a patient comes in with brain [metastases] or with hormone receptive positive diseases, does that change your decision about the CDK4/6 inhibitor partner?

 It does. The data that we have currently for the CDK4/6 inhibitors, it does appear that abemaciclib might be more active in the brain, so certainly that would be one scenario where I would favor abemaciclib over the other CDK4/6 inhibitors and choose that for that particular patient. I’ve done that in clinic for a few handfuls of patients who did present with brain metastases at the time of the diagnosis. That doesn’t happen very commonly in HR-positive disease, but in the handful of patients that it has, I have chosen abemaciclib as my first choice.

Videos

Comprehensive insight on the barriers to CDK4/6 inhibition in HR+/HER2- breast cancer, from both medical and accessibility perspectives.

HR+/HER2- Breast Cancer: Identifying Barriers to Use of CDK4/6 Inhibition 

Aditya Bardia, MD, MPH, assistant professor of medicine, Harvard Medical School, attending physician, Medical Oncology, Massachusetts General Hospital, discusses the use of endocrine therapy in estrogen receptor (ER)–positive breast cancer.

Better endocrine options remain an unmet need for patients with ER-positive breast cancer, particularly in the later settings, says Bardia. The treatment for both ER-positive breast cancer and ER-positive, metastatic breast cancer utilizes endocrine therapy, Bardia adds. The addition of a CDK4/6 inhibitor to endocrine therapy remains the recommended first-line treatment for this patient population, though patients eventually experience disease progression, Bardia explains.

Though endocrine therapy is recommended in the second- and third-line settings, response rates remain low with this treatment, Bardia continues. Fulvestrant (Faslodex) is the only selective estrogen receptor degrader (SERD) currently approved by the FDA, Bardia explains. However, since fulvestrant is administered as an intramuscular shot, researchers are interested in developing oral SERDs to create better endocrine therapy options for patients, Bardia concludes.

Aditya Bardia, MD, MPH, discusses the use of endocrine therapy in estrogen receptor–positive breast cancer.


Dr. Bardia on the Rationale of Utilizing Endocrine Therapy in ER+ Breast Cancer

 In terms of what's exciting related to ctDNA (circulating tumor DNA), there are the upcoming planned studies with interventions. The idea being that if you detect ctDNA and then intervene, you can improve outcomes. That's exciting. The other thing that's exciting in the ctDNA space are these newer technologies that bring in methylation or other strategies—not just focusing on tumor DNA, but other strategies to increase the detection rate. At the end of the day, in the MRD (minimal residual disease) space, it's about the sensitivity of the assay, so you can detect the first instance where something is going to be a problem that needs to be intervened upon. Thus, the sensitivity of the assay is a critical piece. We look forward to newer assays that are even more sensitive than the existing ones.

 I think when we look at the ctDNA data that we have right now we're clearly at the beginning of the process. I encourage my surgery and medical oncology colleagues to recognize that we want to enroll our patients in registry trials, because really, every patient is a test case. This gives us dynamic information as we treat the patient and follow them. We can actually gain a great deal of insight just with an N-of-1 trial following that patient. And what's going to happen is the more studies that we do, the more collective knowledge that we get, the more meaningful this information will become. Hence, I really do believe that this is a dynamic test that is going to move us to even more precision management of our patients. And when you recognize that we have so very little to offer our breast cancer patients when it comes to systemic surveillance, I think that makes that even a higher priority.

 Regarding the role of ctDNA and the management of breast cancer, I think ctDNA assays should be viewed as a liquid biopsy. It gives you information, not just about the presence of disease, but also the molecular type, which can be helpful for therapy selection in the metastatic setting. Thus, if you're thinking of tumor genotyping, plasma-based genotyping can be very valuable. And that essentially is what ctDNA assays are.

Closing out their discussion on circulating tumor DNA in breast cancer management, experts share closing advice on practical strategies to use testing in clinic.

Practical Advice on the Use of ctDNA Testing in Breast Cancer 

 Detection of ctDNA (circulating tumor DNA) in the adjuvant setting is an exciting area of research. There are a number of ongoing studies in this space—both studies to look at the frequency of detection, impact, and outcomes, but also intervention studies. For example, in hormone receptor-positive breast cancer, there are ongoing trials looking at the efficacy of a CDK4/6 inhibitor in patients who have detectable ctDNA. In the US, the study wings leader and there are similar studies in the UK as well. For patients with triple-negative breast cancer, there was a study presented by Nick Turner, MD, PhD, and his team in the San Antonio Breast Cancer Symposium. They looked at the efficacy of an immunotherapy agent pembrolizumab in patients who had detectable ctDNA. The number of patients with detectable ctDNA was small. Then the study had to close early because of the COVID-19 pandemic and other reasons. But the study provided proof of principle that you can detect ctDNA. What was interesting from the study was that a number of patients who had ctDNA detected also had radiological evidence of metastatic disease. For subsequent studies, it provides an important proof of principle point, which is that if you are designing a study with ctDNA and a patient has detectable ctDNA, it's important to do radiological scans to confirm that the patient does not have radiological evidence of metastatic disease. The other thing that was interesting from that study was that use of single-agent immunotherapies are unlikely to be very effective in this setting. There was only 1 patient who had declined a ctDNA test. Others did not, with the use of adjuvant immunotherapy as a single agent. Thus, we likely need other interventions in this space. And there are ongoing plan studies to look at novel agents in this MRD [minimal residual disease] space. Which will be exciting, because if effective, that would delay the evidence of metastatic disease and put potentially even cure, additional patients’ cell, which is what we look for with our adjuvant therapies - is to increase the cure rate.

 An interesting study that was just presented at the San Antonio Breast Cancer Symposium incorporated a follow-up of the I-SPY 2 trial (NCT01042379), which was first published last year with respect to doing circulating tumor DNA testing before initiating neoadjuvant chemotherapy, during neoadjuvant chemotherapy, and following chemotherapy. Now expanding that to following after surgery, Dr Priyanka Sharma and her colleagues at The University of Kansas presented the I-SPY 2 data at San Antonio, and what we found is that looking at pathologic response after surgery, we know that our goal is to find a PCR, a pathologic complete response. But what we found from the I-SPY 2 data looking at ctDNA is there's a subset of patients who don't have a PCR who still have a prognosis every bit as good as patients who did have a PCR; in other words, those patients who have an elevated ctDNA prior to treatment and quickly go to 0 after initiation of treatment have a prognosis every bit as good as patients with a PCR. Thus, there's a subset of patients who still have residual cancer after surgery who may not need further chemotherapy, and this is actually very complementary to what we do now postoperatively, looking at RCB or residual cancer burden scores. Perhaps incorporating the ctDNA results with the RCB scores will be very complementary and make this an even more powerful test for making treatment decisions after surgery in our neoadjuvant patients.

Shared insight on how clinical trial data behind circulating tumor DNA in breast cancer may affect future treatment strategies.

Other Clinical Studies on ctDNA Use in Breast Cancer 

Kevin Kalinsky, MD, MS, is a professor and director of the Division of Medical Oncology in the Department of Hematology and Medical Oncology at Emory University School of Medicine; and the Louisa and Rand Glenn Family Chair in Breast Cancer Research and director of the Glenn Family Breast Center at Winship Cancer Institute of Emory University in Atlanta, Georgia.

Data from the following clinical trials are discussed:

GS2-05 oral presentation: Randomized comparision of adjuvant aromatase inhibitor exemestane + ovarian function suppression (OFS) vs tamoxifen + OFS in premenopausal women with hormone receptor-positive early breast cancer: update of the TEXT and SOFT trials

GS3-00: First results from a phase 3 randomized clinical trail of standard adjuvant endocrine therapy +/- chemotherapy in patients with 1-3 positive nodes, hormone receptor-positive and HER2-negative breast cancer with recurrence score < 25: SWOG S1007 (RxPONDER)

GS1-08: CCTGMA.32, a phase 3 randomized double-blind placebo-controlled adjuvant trial of metformin vs placebo in early breast cancer: Results of the primary efficacy analysis (NCT0110143)

GS1-05: Datopotamab deruxtecan in advanced/metastatic HER2 breast cancer: Results from the phase 1 TROPION-PanTumor01 study

Patrick Neven MD, PhD; Sara A. Hurvitz, MD; Kevin Kalinsky, MD, MS; and Aditya Bardia, MD, MPH, share insight on updates in key clinical trials and novel therapies in breast cancer presented at SABCS 2021.

SABCS 2021 Updates in Key Clinical Trials for Breast Cancer

ctDNA [circulating tumor DNA] testing really falls into a much larger category of liquid biopsies, whether looking for circulating tumor DNA, or looking for circulating cancer cells or exomes. There are a number of tests that have been available for really over 2 decades looking at this. When you look at circulating tumor DNA, my medical oncology colleagues have been using this for a decade for targeting therapies, so that by identifying certain somatic mutations that are present in microscopic levels, they may actually target therapy. That has been around and has proven to be effective for a small subset of patients. What’s new about the circulating tumor DNA testing, especially as it pertains to the Signatera test, is that that’s a personalized test designed using the patient’s tissue from their breast cancer, where we could then design a unique test, which has a much higher sensitivity and specificity. That test, I think will be very effective as we’re looking at a systemic surveillance.

Another area for circulating tumor DNA testing is in the screening realm, and I think this is a very exciting area right now, looking at far more cancers than just breast cancer. We’re fortunate that we do have a relatively good screening tests for breast cancer; mammograms and supplemental tests, such as ultrasound and MRI, will find many cancers. But there are many cancers where we don’t have screening tests, and perhaps circulating tumor DNA will bridge that gap and allow us to do more effective screening for other cancers. Now, as it pertains to breast cancer, while I think our screening methods are good, we know that we miss cancers. We know that women with dense breasts, for example, if a woman has a screening mammogram and has dense breast tissue, there’s a 25% to 50% chance we won’t see their cancer by mammography. Now, perhaps ctDNA…and it’s wonderfully complementary to imaging, so by combining the 2, I would anticipate that the ability to screen for breast cancer should definitely improve. Likewise, for personalized screening for younger women for whom we know mammograms aren’t as effective, perhaps by incorporating ctDNA screening, this will give us a better chance of really looking at the highest-risk population and trying to do more precision prevention and early detection.

A brief synopsis on the use of circulating tumor DNA for cancer detection versus treatment selection in breast cancer management.

ctDNA in Breast Cancer: Cancer Detection Vs Therapy Selection 

Surgery has traditionally been the primary treatment for breast cancer, and other than the exceptional situations for the patient who presents with metastatic disease, surgery is usually the first line of therapy. Whether we do it in a neoadjuvant setting or an adjuvant setting, we know that there’s a subset of patients that will relapse despite surgical treatment, whether supplemented with radiation therapy and/or systemic treatment, whether chemotherapy and/or endocrine therapy. The value of doing ctDNA [circulating tumor DNA] testing is that we may have the opportunity to identify that relapse maybe 12 to 18 months earlier, than through traditional systemic surveillance. If we find those patients earlier, then the goal is that by finding this earlier, we can perhaps identify better ways to treat them, and maybe improve their survival.

Now, there’s also a subset of patients who after chemotherapy and surgery, whether the surgery precedes the chemotherapy, or whether the chemotherapy precedes the surgery, after they’ve completed standard treatment, what we’ve learned from ctDNA testing is that there is a subset of patients who don’t get to zero after completion of their treatment, who have molecular residual disease, MRD. What we’re learning, unfortunately, is patients who don’t get to zero after traditional therapy, their risk of relapse approaches 100%, so we know that if we have patients who we can’t get to zero, we need to find an alternative way of treatment. And one of the wonderful things about systemic treatment now is there’s really a laundry list of different agents that are potentially available. And if we try standard therapy, and we can’t get to zero, I think that’s the exact circumstance where we want to know that by intervening with alternative regimens, that we might ultimately have a better impact on those patients, because without changing it, we know they’re not going to do well.

 At the San Antonio Breast Cancer Symposium, we saw another ctDNA study by Nick Turner, [MD, PhD,] and his team. They looked at patients in the adjuvant setting, who had plasma that was analyzed for ctDNA based on the Signatera assay. As a reminder, the Signatera assay first profiles the tumor to identify tumor-specific mutations, and then detect those in the plasma. It’s like a personalized test. The team found that patients who had detectable ctDNA after surgery, there were 14 out of 48 patients. Those were the ones who were at higher risk of relapse, compared to those who did not have ctDNA detected, with a hazard ratio of 3.7. Thus, it provides proof of principle that detection of ctDNA in the post-surgical time point is associated with worse metastasis-free survival. And in this setting, an intervention that could clear ctDNA might be able to prevent or delay metastases. It’s not ready for prime time yet, but is something that is being investigated in clinical trials, to see if you can A, detect ctDNA, and B, intervene in patients who have detectable ctDNA, in order to improve outcomes.

Aditya Bardia, MD, MPH, and Barry Rosen, MD, discuss the role of circulating tumor DNA in the adjuvant setting of breast cancer.

Role of ctDNA in the Adjuvant Setting of Breast Cancer 

P1-18-16: First-line aromatase inhibitor + palbociclib with randomized switch to fulvestrant [Faslodex] + palbociclib upon detection of circulating 

 mutation in HR+/HER2 metastatic breast cancer patients: Global safety results of PADA-1, a UCBG-GINECO phase 3 trial

PD2-05: Genomic profiling of PAM50-based intrinsic subtypes in HR+/HER2 advanced breast cancer across the MONALEESA studies

PD13-03: Ribociclib [Kisqali], everolimus, exemestane [Aromasin] triplet therapy in HR+/HER2 advanced breast cancer after progression on a CDK4/6 inhibitor: Final efficacy, safety, and biomarker results from TRINITI-1

PD02-04: Molecular plasticity of luminal A breast cancer and response to CDK4/6 inhibition: The biomarker program of the PENELOPE-B trial investigating post-neoadjuvant palbociclib

Sara A. Hurvitz, MD; Aditya Bardia, MD, MPH; Patrick Neven, MD, PhD; and Kevin Kalinsky MD, MS, discuss SABCS 2021 updates on the use of CDK4/6 inhibitors in HR+/HER2 breast cancer.

SABCS 2021 Updates in CDK4/6 Inhibitors in Breast Cancer

P1-17-11: Updated data from AMEERA-1: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor degrader (SERD), combined with palbociclib [Ibrance] in postmenopausal women with ER+/HER2 advanced breast cancer

GS2 -02: Elacestrant, an oral selective estrogen receptor degrader (SERD) vs investigator's choice of endocrine monotherapy for ER+/HER2 advanced/metastatic breast cancer following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial

PD13-08: First-in-human safety and activity of ARV-471, a novel PROTAC estrogen receptor degrader, in ER+/HER2 locally advanced or metastatic breast cancer

Experts in the management of breast cancer review recent data on SERDs (selective estrogen receptor degraders) in ER+/HER2 advanced breast cancer presented at SABCS [San Antonio Breast Cancer Symposium] 2021.

Aditya Bardia, MD, MPH, FASCO

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