Current Approaches in Optimizing Targeted Agents and Sequencing Decisions for HR+ Breast Cancer

Kate M. O'Rourke


January 05, 2023

Medscape recently asked breast cancer experts how they sequence targeted agents for HR+, HER2/neu-negative (also known as ErbB-2) metastatic breast cancer. Joining us today are Lisa Carey, MD, Richard and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research and Deputy Director of Clinical Sciences at the University of North Carolina at Chapel Hill; Adam Brufsky, MD, co-director of the Comprehensive Breast Cancer Center at the University of Pittsburgh School of Medicine; Virginia Kaklamani, MD, professor of medicine and leader of the Breast Oncology Program at the University of Texas Health Sciences Center in San Antonio; Michael Gnant, MD, professor of Surgery at the Medical University of Vienna, Austria; and Joyce O'Shaughnessy, MD, Celebrating Women Chair in Breast Cancer Research, Baylor University Medical Center, and Director, Breast Cancer Research Program, Texas Oncology, US Oncology.

Lisa Carey, MD

Lisa Carey, MD: I typically use endocrine therapy plus a cyclin-dependent kinase (CDK) 4/6 inhibitor first because of the progression-free survival (PFS) and overall survival advantage. Then endocrine therapy plus phosphoinositide 3 kinase (PI3K) inhibitor if the patient has PIK3CA mutation, or poly (ADP-ribose) polymerase (PARP) inhibitor if the patient is germline positive. If neither, then I just prescribe endocrine therapy or endocrine therapy plus a mammalian target of rapamycin (mTOR) inhibitor. I have been using the HER2 inhibitor trastuzumab deruxtecan (T-DXd) after first-line chemotherapy — typically capecitabine because it is oral and doesn't make your hair fall out.

Endocrine therapy as first-line treatment is either fulvestrant (if patient has relapse on an aromatase inhibitor [AI]) or an AI. CDK4/6 inhibitors are ribociclib, abemaciclib, and palbociclib. There are survival data in favor of ribociclib, but the cross-trial comparisons are problematic. A wonderful trial, HARMONIA, will test endocrine therapy and ribociclib vs endocrine therapy and palbociclib in the HER2-enriched subtype, which has the poorest prognosis with endocrine therapy alone and where CDK4/6 inhibition is even more important.

Endocrine therapy as second-line treatment is generally fulvestrant although you can use a different AI, tamoxifen (selective estrogen receptor modulator), etc. Alpelisib is a PI3K inhibitor. PARP inhibition is either olaparib or talazoparib; both improve PFS but neither improves overall survival. An mTOR inhibitor is everolimus, which can be combined with multiple endocrine therapy backbones.

Adam Brufsky, MD

Adam Brufsky, MD: As standard first-line therapy, everybody gets hormonal therapy and a CDK4/6 inhibitor. If a patient comes in and hasn't been on anything or it's been more than 1 year off all therapy, they'll probably receive an AI and a CDK4/6 inhibitor. If she is on an AI as adjuvant therapy, she'll receive fulvestrant and a CDK4/6 inhibitor.

As second-line therapy, if the patient has not had a CDK4/6 inhibitor, then she will get fulvestrant and a CDK4/6 inhibitor. If she has had a CDK4/6 inhibitor, then we will test her tumor DNA to see if she has a mutation in PI3KCA. If she has a PI3KCA mutation, then she will get alpelisib and fulvestrant. If she does not have a mutation in PI3KCA, then she will receive everolimus and fulvestrant.

For third-line therapy, if there is still hormonal responses and the patient has not had everolimus, they will get exemestane and everolimus. And then finally after that, they will receive chemotherapy, most probably capecitabine.

If someone progresses on chemotherapy, then at that point, if they are HER2 1+ or HER2 2+, they will get T-DXd.

Virginia Kaklamani, MD

Virginia Kaklamani, MD: Based on survival data, I give a CDK4/6 inhibitor as first-line treatment and for second-line treatment, I give either alpelisib if a patient has PIK3CA mutation or everolimus if not. I typically give ribociclib, but it's not clear to me that the three CDK4/6 inhibitors are different. Third-line treatment is pretty tricky because in most cases, the tumor is endocrine resistant, and I switch to chemotherapy. But if the patient is still endocrine sensitive, I would give tamoxifen or whatever endocrine agent they have not received so far. Also, data with elacestrant and potential approval of the drug may change the above soon.

Michael Gnant, MD

Michael Gnant, MD: We always start with endocrine treatment plus a CDK4/6 inhibitor as first-line treatment. In case of PIK3CA mutation, second-line treatment is alpelisib. For wild type and subsequent lines, there is the option of switching the endocrine therapy, eg, from an AI to fulvestrant while keeping the CDK4/6 (MAINTAIN trial). Chemotherapy is postponed as far back as possible.

Joyce O'Shaughnessy, MD

Joyce O'Shaughnessy, MD: I always start with CDK4/6 inhibitor plus endocrine therapy then follow that with inhibition of PI3K pathway with alpelisib plus fulvestrant for patients with PIK3CA mutant cancers, and with everolimus plus exemestane for endocrine therapy–sensitive patients who don't have liver metastasis. (I have not had good success with everolimus post-CDK inhibitor in patients with liver metastasis). I do this because escape through the PI3K pathway is a major mechanism of escape to CDK4/6 inhibition in preclinical models and because of the BYLieve trial data. Outside of clinical trials, I will consider second anti-CDK4/6 plus endocrine therapy regimen after inhibition of the PI3K pathway. Generally, then I transition patients to capecitabine followed by T-DXd for HER2-low patients or to sacituzumab for HER2-negative patients. I would consider use of sacituzumab in patients who had had T-DXd, generally after one or two intervening regimens, to avoid giving two topoisomerase I inhibitors back to back, until we have trial data looking at this sequence.

I check circulating tumor DNA (ctDNA) periodically, at progression, for HER2 mutations and would consider fulvestrant, neratinib, trastuzumab triplet therapy in these patients per the SUMMIT trial. Once elacestrant is approved, I will want to offer this to patients with ESR1 mutation on ctDNA, alone or in combination with a later-line CDK4/6 inhibitor or everolimus or alpelisib. (Safety data are being generated for elacestrant plus these other targeted agents, so this therapy is not yet available).

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