A recently updated ASCO guideline offers both new and revised guidance on the treatment of hormone receptor–positive, HER2-negative metastatic breast cancer.1
Harold J. Burstein, MD, PhD, FASCO
“ASCO regularly updates its guidelines to make sure everything is current and valuable for oncologists and patients. About a year ago, there was a new agent approved—alpelisib—for use in combination with estrogen therapy for hormone receptor–positive, HER2-negative breast cancer,” said guideline expert panel chair Harold J. Burstein, MD, PhD, FASCO, of Dana-Farber Cancer Institute. “In addition, there are emerging biomarkers that might guide treatment, like the ESR1 mutation. Those advances created an impetus for updating and refining our guidance.”
The expert panel, comprising clinicians from a variety of specialties as well as a patient advocates, performed a thorough review of evidence published since the parent guideline was released in 2016.2 They paid particularly close attention to findings from the SOLAR-1 trial3 of alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor–positive, HER2-negative metastatic breast cancer as well as to data on biomarkers and the CDK4/6 inhibitors palbociclib,4-11 ribociclib,12-17 and abemaciclib.18-22
Expert panel member Hope S. Rugo, MD, FASCO, of the University of California San Francisco Comprehensive Cancer Center, noted that the panel intentionally zeroed in on evidence related to endocrine therapy instead of chemotherapy because of the improvements these therapeutics have brought patients with hormone-sensitive tumors.
“That approach allowed us to delve into the details of the data and make a comprehensive and evidence-based guideline, compared to guidelines that look overall at the treatment of metastatic disease,” Dr. Rugo said.
Making Informed Treatment Decisions
Although the original guideline for this focused update remains largely intact, the update does offer some important qualifications. Among the guideline’s recommendations are encouraging the use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, which have been shown to improve progression-free survival and, in some cases, overall survival in many women with metastatic breast cancer. CDK4/6 inhibitors are now considered a preferred treatment approach in combination with a nonsteroidal aromatase inhibitor for postmenopausal women and premenopausal women undergoing ovarian-function suppression.
“Now, we can unreservedly recommend that patients receive CDK4/6 inhibitors with first-line endocrine therapy for metastatic disease.”— Hope S. Rugo, MD, FASCO
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“Our first guideline was in 2016, and it’s interesting to go back to it now to see what we understood at that moment, which was that evidence on CDK4/6 inhibitors was still emerging,” Dr. Rugo said. “Now, we can unreservedly recommend that patients receive CDK4/6 inhibitors with first-line endocrine therapy for metastatic disease.”
Another key recommendation emphasizes the use of alpelisib—approved by the U.S. Food and Drug Administration based on results from SOLAR-1—in combination with endocrine therapy for PIK3CA-mutated disease in postmenopausal patients in combination with fulvestrant, a selective estrogen receptor degrader. The guideline also emphasized the importance of proactive safety management with alpelisib.
In addition, the guideline update addressed the use of biomarkers in treatment decision-making, such as using next-generation sequencing to detect PIK3CA mutations for determining the use of alpelisib or offering poly (ADP-ribose) polymerase (PARP) inhibitors to women with BRCA1 or BRCA2 mutations who are nonresponsive to endocrine therapy. The expert panel considered whether evidence supported routine testing for ESR1 mutations, which can indicate relative resistance to aromatase inhibitors, but data on that biomarker are still emerging.
Building a Better Knowledge Base
The literature review process revealed key areas where additional research is needed to further optimize treatment selection as well as treatment sequencing. These areas include exploring novel endocrine therapies, analyzing impending phase III clinical trial data on CDK4/6 combination treatments designed to helped mitigate treatment resistance, and clarifying the extent to which patients with hormone receptor–positive, HER2-negative metastatic breast cancer and rare PALB2 mutations can benefit from PARP inhibitors.
“I think the really critical areas of investigation going forward include oral selective estrogen receptor degraders—so we aren’t relying solely on injectable fulvestrant following aromatase inhibitors—and further evaluation of agents that can potentially overcome resistance mechanisms, including when tumors have ESR1 and fibroblast growth factor mutations,” Dr. Rugo said. “The more oral therapies we can have and the more we can address the resistance that we know develops in these tumors, the more we can offer people better quality of life and longer responses to therapy.”
Dr. Burstein added that ongoing genomic analyses of tumors and more precise characterization of hereditary cancers are additional key areas.
“We continue to see impressive innovations in hormone receptor–positive, HER2-negative metastatic breast cancer, with different classes of drugs showing improvements in overall survival and newer emerging targeted therapies,” he said. “We hope the update offers clear guidance on when and how to use these drugs and tests that help patients with advanced breast cancer do as well as they possibly can.”
1. Burstein HJ, Somerfield MR, Barton DL, et al: Endocrine treatment and targeted therapy for HR-positive, HER2-negative metastatic breast Cancer: ASCO Guideline update. J Clin Oncol. July 29, 2021 (early release online).
2. Rugo HS, Rumble RB, Macrae E, et al: Endocrine therapy for hormone receptor–positive metastatic breast cancer: American Society of Clinical Oncology Guideline. J Clin Oncol 34:3069-3103, 2016.
3. André F, Ciruelos EM, Juric D, et al: Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: Final overall survival results from SOLAR-1. Ann Oncol 32:208-217, 2021.
4. Finn RS, Martin M, Rugo HS, et al: Palbociclib and letrozole in advanced breast cancer. N Engl J Med 375:1925-1936, 2016.
5. Im SA, Mukai H, Park IH, et al: Palbociclib plus letrozole as first-line therapy in postmenopausal asian women with metastatic breast cancer: Results from the phase III, randomized PALOMA-2 study. J Glob Oncol 5:1-19, 2019.
6. Rugo HS, Finn RS, Dieras V, et al: Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat 174:719-729, 2019.
7. Cristofanilli M, Turner NC, Bondarenko I, et al: Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): Final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 17:425-439, 2016.
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11. Verma S, Bartlett CH, Schnell P, et al: Palbociclib in combination with fulvestrant in women with hormone receptor-positive/HER2-negative advanced metastatic breast cancer: Detailed safety analysis from a multicenter, randomized, placebo-controlled, phase III study (PALOMA-3). Oncologist 21:1165-1175, 2016.
12. Im SA, Lu YS, Bardia A, et al: Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med 381:307-316, 2019.
13. Hortobagyi GN, Stemmer SM, Burris HA, et al: Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 375:1738-1748, 2016.
14. Hortobagyi GN, Stemmer SM, Burris HA, et al: Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol 29:1541-1547, 2018.
15. Slamon DJ, Neven P, Chia S, et al: Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med 382:514-524, 2020.
16. Slamon DJ, Neven P, Chia S, et al: Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol 36:2465-2472, 2018.
17. Tripathy D, Im SA, Colleoni M, et al: Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): A randomised phase 3 trial. Lancet Oncol 19:904-915, 2018.
18. Johnston S, Martin M, Di Leo A, et al: MONARCH 3 final PFS: A randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer 5:5, 2019.
19. Kaufman PA, Toi M, Neven P, et al: Health-related quality of life in MONARCH 2: Abemaciclib plus fulvestrant in hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy. Oncologist 25:e243-e251, 2020.
20. Sledge GW Jr, Toi M, Neven P, et al: The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: A randomized clinical trial. JAMA Oncol 6:116-124, 2020.
21. Goetz MP, Toi M, Campone M, et al: MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol 35:3638-3646, 2017.
22. Sledge GW Jr, Toi M, Neven P, et al: MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 35:2875-2884, 2017.
Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, July 30, 2021. All rights reserved.