Kathryn Newlin, RN, MSN, ANP-BC, on Updates in HR-Positive, HER2-Negative Metastatic Breast Cancer

Kathryn Newlin: At JADPRO Live 2024 in Grapevine, Texas, my co-presenter, Sunita Burjik and I, presented on hormone-positive HER2-negative metastatic breast cancer updates. So just real quick, as you know, hormone-positive HER2-negative breast cancer is the most common breast cancer, accounting for about 70% of all breast cancers. Endocrine therapy is the cornerstone treatment for these patients. However, tumors can acquire resistance to endocrine therapy, but many novel treatment approaches have been put into place for offering additional options for these patients. So, as you know, CDK4/6 inhibitors have been the mainstay first-line treatment for metastatic breast cancer hormone-positive patients. Those medications include ribociclib, abemaciclib and palbociclib. All three of these have provided significant responses for those patients in clinical trials. Progression-free survival was found up to two years and beyond, and overall survival has shown greater than four and a half years. So you want to take careful consideration when selecting which CDK4/6 inhibitor is appropriate per patient. There are abemaciclib, which is daily administration, versus cyclic dosing, which is seen with ribociclib and palbociclib. So you want to make sure a patient, are they able to follow a cyclic schematic. You also want to take into consideration comorbidities. Does the patient have a history of hepatic toxicities or cardiac toxicities or abnormal electrolyte imbalances? If so, you would want to avoid ribociclib. In patients with a GI history, you're going to want to take into consideration those patients who have a history of Crohn's disease or IBS that can potentially already cause baseline diarrhea because we know that abemaciclib has the potential to cause more diarrhea or GI toxicity. So some gold nuggets seen in clinical trials. It was found that abemaciclib does cross the blood-brain barrier. Additional things to consider. For patients who have small volume bone-only disease and are largely asymptomatic, you could consider palbociclib. Additionally, palbociclib is generally very well tolerated in an elderly patient and has previously shown to be an effective regimen for geriatric patient population for those who have multiple comorbidities. After progression on a CDK4/6 inhibitor, we have several FDA-approved novel targeted therapy options for patients who harbor a somatic mutation and become resistant to endocrine therapy and CDK4/6 inhibitors. You really want to incorporate comprehensive biomarker testing into daily practice. In August of 2020, the FDA approved Guardant360 and FoundationOne for companion diagnostic testings to be used for such patients. As of May 2024, the FDA has approved treatment options for ESR1 mutation, PIK3CA mutation, AKT1 and p10 alterations, as well as BRCA1 and 2 genetic mutations. So first, we'll talk about ESR1 mutations. These can develop after progression on first-line treatment. The longer exposure to endocrine therapy increases your chances of developing an ESR1 mutation. So you're going to want to check companion diagnostic testing at each line of progressive disease. Elacestrant was approved for an ESR1 mutation based off of the EMERALD trial results. Typically, Elacestrant is usually pretty well tolerated. Next, our PIK3CA mutation. This is seen in about 40% of our patients with hormone-positive HER2-negative metastatic breast cancer. It does carry a worse overall survival, but there are two medications that have been FDA approved to treat patients with PIK3CA mutations. This is albolicib, which was approved based off of the SOLAR-1 trial, and capivasertib, which was approved off of the CAPItello-291 trial. Both of these medications are used in combination with full-vestorant. These medications have similar side effect profiles. You're going to want to watch for hyperglycemia. So somebody who has a history of diabetes or uncontrolled blood sugars, you're going to want to optimize blood sugars, check a fasting glucose prior to treatment, hemoglobin A1C, and utilize ambulatory glucose monitoring and practice. This is the most common cause of discontinuance with these medications is hyperglycemia. Additional side effects to consider, rash or diarrhea. So you're going to want to prescribe your anti-diarrheals upfront and consider a second-line generation antihistamine to use prophylactically daily. There are currently no head-to-head studies for albolicib versus capivasertib, but this could be considered in the future. Next are our germline BRCA mutations. There are two treatment options with PARP inhibitors or someone who harbors a germline BRCA mutation. Those medications are olaparib, which was FDA-approved based off of the Olympiad trial, and talazaparib, which was FDA-approved from the EMBRACA trial. With both of these medications, you're going to watch for hematologic toxicities. It can cause fatigue. So you're going to be wanting to check labs, doing a good physical examination and review of systems. So the Olaparib-expanded phase two clinical trial was presented at ASCO 2024 this year. We know that Olaparib has been approved for journaling BRCA1 and BRCA2 patients. We wanted to see if Olaparib was an effective monotherapy for our germline PALB2 mutations, as well as those somatic mutations for BRCA1 and BRCA2. There were other germlines that were evaluated but were not clinically significant. Overall, both cohort one, the germline PALB2 mutation and cohort two, the somatic BRCA1 and BRCA2 mutation found to have improved progression-free survival, objective response rates, duration of response, clinical benefit rate, all within 10 to 12 weeks. A big question in the world of CDK4/6 inhibition is are you able to switch from a first line to a second line CDK4/6 inhibitor? There is much anticipation of the role it could play in the future to give us additional treatment options. I'd love to go into great detail, but on the basis of time, I will just mention the primary four clinical trials that did research switching from a first line to a second line CDK4/6 inhibitor. That is the MAINTAIN, postMONARCH, PALMIRA and PACE trials. In the absence of a somatic mutation, both the postMONARCH and the MAINTAIN trial support switching from a CDK4/6 inhibitor to another CDK4/6 inhibitor. The evolution of HER2 staining has opened the door for additional treatment options for our hormone-positive HER2-negative metastatic breast cancer patient. Patients who were previously diagnosed as HER2-negative, who harbor a one-plus or two-plus expression, also known as HER2-low, now have treatment options. Studies that were done under the DESTINY-Breast clinical trial umbrella revolutionized the antibody drug conjugants for metastatic breast cancer patients. Ongoing research has opened another category known as HER2-ultralow, and has shown promising data in Destiny-Breast06. This was also presented at ASCO 2024 this year. HER2-ultralow was a result of patients who had incomplete or faint staining seen on less than 10% of HER2 cells on IHC. It showed that they may benefit from an HER2. This accounts for about 20% to 25% of patients who previously had no options for anti-HER2 treatment. We need to consider new assays to be able to distinguish between HER2-negative and an ultra-low with faint staining. Additionally, we have another antibody drug conjugate, sacituzumab govitecan, that we not only can use in the triple-negative metastatic breast cancer patient population, but also with our hormone-positive HER2-negative breast cancer patients, and this was based off of our TROPiCS2 clinical trial. An Avalesa was recently approved for endocrine-resistant PIK3CA mutation, hormone-positive, HER2-negative metastatic breast cancer patients. These patients had to have relapsed during or within 12 months of adjuvant endocrine therapy completion. This was seen in the INAVO120 phase three clinical trial. It is given in combination with palbociclib and fulvesterant. There are so many emerging generations of estrogen receptor therapies on the horizon. We hope to see these outperform standard-of-care agents that are currently in practice. These emerging generation estrogen receptor therapies range from Oral SERDs, novel SERMs, SERCAs, PROTACs and CERANs. Thank you so much for listening to our recap from JADPRO Live 2024.