The past decade has seen an explosion of novel agents for breast cancer across subtypes. Although each new advance improves therapeutic options for patients, it also brings forth a challenging question: Who needs what treatment? Not all cancers are created equally, and similarly not all patients need every available therapy to have an excellent outcome. 

One of the past year’s themes in breast oncology has been how to “right size” therapy for each patient with curable disease—to give enough for an excellent outcome, but also to try not to overtreat patients either. This is coupled with the challenge of integrating novel therapies into our armamentarium. 

Guest Editors

Erika Hamilton, MD

Carey Anders, MD

Dr. Hamilton is Director of Breast and Gynecologic Cancer Research at Sarah Cannon Research Institute. In addition to caring for patients with breast and gynecologic cancers in the clinic, she is also an investigator for phase I, II, and III clinical trials. Dr. Anders is Professor of Medicine in the Division of Medical Oncology at Duke Cancer Institute and Medical Director of the Duke Center for Brain and Spine Metastasis. Her clinical practice is focused on the care of patients with breast cancer, particularly those diagnosed at a younger age and those with recurrence in the central nervous system.

Less Is More in Some Patient Subgroups

Several key studies have helped us to explore offering less therapy for certain subgroups of patients in an attempt to avoid overtreatment, including ADAPT for HER2-positive disease, as well as RxPONDER in hormone receptor–positive disease. ADAPT showed us that even without a chemotherapy backbone, dual HER2-targeted therapy of pertuzumab and trastuzumab yields a pathologic complete response in more than one-third of patients.¹ Using this type of de-escalation approach upfront could help us figure out who needs subsequent cytotoxic therapy, and for whom dual HER2-directed antibodies alone could be enough. Building upon TAILORx, which showed many patients with hormone receptor–positive breast cancer could safely omit chemotherapy, RxPONDER took this a step further to explore this approach among patients with node-positive breast cancer. RxPONDER demonstrated that postmenopausal women with hormone receptor–positive/HER2-negative disease with one to three positive nodes and a 21-gene recurrence score ≤ 25 could safely avoid adjuvant chemotherapy (5-year invasive disease–free survival: 91.9% for endocrine therapy plus chemotherapy vs 91.6% for endocrine therapy alone; hazard ratio [HR] = 0.97, P = .82).^2,3 

New Options for High-Risk Patients

Conversely, we also know that despite excellent therapies, cancer will relapse in some patients; thus, identifying populations that are sufficiently at high risk to justify more therapy can help us add additional agents only where they are needed. Long-awaited results from the OlympiA trial demonstrated that for patients with high-risk, early-stage HER2-negative breast cancer with a germline BRCA alteration, the addition of 1 year of adjuvant olaparib reduced the risk of recurrence by 42% (absolute benefit of 8.8%) and distant recurrence by 43% (absolute benefit of 7.1% at 3 years).⁴ 

Another area of exploration is the addition of adjuvant CDK4/6 inhibitors to endocrine therapy for those patients with hormone receptor–positive breast cancer and a very high risk of relapse. Here, despite similar data in the metastatic setting for all three CDK4/6 inhibitors (abemaciclib, palbociclib, and ribociclib), we saw discordant results from PALLAS and monarchE exploring adjuvant palbociclib and abemaciclib, respectively. It is debatable about whether this could be due to differences between the compounds such as preferential CDK4 over CDK6 activity or the continuous dosing schedule of abemaciclib, or whether this was due to differences in study design. MonarchE appeared to have the highest-risk population—with 59% having N2/3 disease (37% in PALLAS) and lower discontinuation rates (16% vs 42% in PALLAS)—and showed a 4.5% difference in 2-year disease-free survival rates in favor of endocrine therapy with abemaciclib.^5,6 We await further follow-up from monarchE later this year. 

Novel Therapies Bring Opportunities and Challenges

In addition to efforts to tailor the “right therapy for the right patient,” the past year has also yielded significant advances in new agents for the treatment of breast cancer. Perhaps one of the greatest areas of growth is that of HER2-positive advanced disease, where there are presently at least eight HER2-targeted agents approved for use in the United States—including monoclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates. 

Although the standard algorithm for treatment of advanced HER2-positive breast cancer has been quite uniform for years with taxane, trastuzumab, and pertuzumab in the first line and ado-trastuzumab emtansine (T-DM1) as second-line therapy, the addition of new agents and new data has posed sequencing challenges. The combination of the brain-permeable tyrosine kinase inhibitor tucatinib plus capecitabine/trastuzumab improved not only response rates, but also progression-free and overall survival compared with capecitabine/trastuzumab in the HER2CLIMB trial. A unique aspect of this study is that nearly half of patients enrolled with brain metastases, where efficacy of the triplet combination persisted.⁷ 

A novel antibody-drug conjugate, fam-trastuzumab deruxtecan-nxki, illustrated unprecedented, single-agent efficacy with a response rate of more than 60% and progression-free survival of more than 16 months in a heavily pretreated population following T-DM1 treatment.⁸ Recently, in a press release, we have learned that trastuzumab deruxtecan outperformed T-DM1 in the second-line setting,⁹ with formal results forthcoming. Finally, the SOPHIA phase III study illustrated a progression-free survival benefit with chemotherapy plus margetuximab-cmkb, the novel anti-HER2–targeting antibody with an Fc portion engineered to increase antibody-dependent cellular cytotoxicity, beyond trastuzumab/chemotherapy but unfortunately did not translate to improved overall survival.^10,11 

So, where do we go from here? Beyond second line, many factors come into consideration including the presence or absence of brain metastases, preference for oral or intravenous therapy, preexisting toxicities, performance status, and individual preferences. Future efforts in this space will undoubtedly be focused on optimal sequencing given the number of tools in our toolkit.

Beyond CDK4/6 Inhibitors in Hormone Receptor–Positive Breast Cancer

Moving onto advances in the hormone receptor–positive space, we are seeing a focus beyond CDK4/6 inhibitors, including a deeper understanding of resistance mechanisms to CDK4/6 inhibitors and emerging targets in this space. Several gene mutations have emerged as targets including PI3K, ESR1, ERBB2, and beyond. Next-generation sequencing to assess for these alterations has become routine and can be performed in both circulating tumor DNA (ctDNA) as well as tumor. SOLAR1 and BYLieve both illustrated the benefit of the PI3Kα-specific inhibitor alpelisib when combined with fulvestrant, the latter in a patient population post CDK4/6 inhibitors.^12,13 Although mutations in the ERBB2 gene in clinically HER2-negative breast cancer are rare, targeting this alteration with neratinib, trastuzumab, and fulvestrant yielded a response rate of nearly 50% and warrants additional investigation.¹⁴ Finally, the acquisition (and clearance) of mutations in the ESR1 gene during treatment for patients with hormone receptor–positive advanced, pretreated breast cancer was shown to be prognostic in the PADA-1 study,¹⁵ and it will be one place where the development of oral selective estrogen receptor degraders will focus. 

Promise of Immunotherapy in Triple-Negative Breast Cancer

Finally, the big story in triple-negative breast cancer over the past year has been immunotherapy based. In the high-risk, early-stage setting, we saw the approval of pembrolizumab in combination with standard chemotherapy in KEYNOTE-522. In addition to improved pathologic complete response rates, pembrolizumab yielded a 6% improvement in event-free survival (84% vs 76%; HR = 0.63, P = .00031). This early-stage approval for pembrolizumab follows the approval in the first-line treatment of patients with PD-L1–positive (Combined Positive Score (CPS) ≥ 10) metastatic triple-negative breast cancer in combination with chemotherapy from KEYNOTE-355.¹⁶ Although atezolizumab had previously received accelerated approval in this space, it was withdrawn based on the current metastatic triple-negative breast cancer treatment landscape and the terms of accelerated approval. Thus, pembrolizumab remains our current immunotherapy option at the current time. 

Beyond immunotherapy in the metastatic triple-negative breast cancer space, we are excited to add the first approved antibody-drug conjugate, sacituzumab govitecan-hziy, to our armamentarium. Sacituzumab govitecan boasted improvements in overall survival compared with traditional chemotherapy (12.1 vs 6.7 months, HR = 0.48, P < .001) for patients with pretreated metastatic triple-negative disease.¹⁷ 

Although the past year has been fraught with many challenges, we have continued to see consistent advances in the treatment of our patients with breast cancer. Collective advances in care have been based on studies that are allowing us to tailor or “right size” our therapies to maximize outcome, while minimizing short- and longer-term side effects, in parallel with continued progress in the development of newer treatment strategies. With continued innovative persistence and collaboration, we will undoubtedly see continued progress in the treatment of breast cancer. 

DISCLOSURE: Dr. Hamilton has served as a consultant or advisor to Arvinas, AstraZeneca, Black Diamond, Boehringer Ingelheim, CytomX Therapeutics, Daiichi Sankyo, Dantari, Deciphera, Eisai, Genentech/Roche, H3 Biomedicine, Lilly, Merck, Mersana, Novartis, Pfizer, Puma Biotechnology, Seattle Genetics, and Silverback Therapeutics; and has received institutional research funding from AbbVie, Acerta Pharma, Akesobio Australia, Amgen, ArQule, Arvinas, AstraZeneca, Black Diamond, Boehringer Ingelheim, Clovis Oncology, Compugen, Curis, CytomX Therapeutics, Daiichi Sankyo, Dana Farber Cancer Hospital, Deciphera, eFFECTOR Therapeutics, EMD Serono, Fochon, Fujifilm, G1 Therapeutics, Genentech/Roche, H3 Biomedicine, Harpoon, Hutchison MediPharma, Immunogen, Immunomedics, Infinity Pharmaceuticals, InventisBio, Karyopharm Therapeutics, Leap Therapeutics, Lilly, Lycera, Macrogenics, MedImmune, Merck, Mersana, Merus, Millennium, Molecular Templates, Novartis, Nucana, Olema Pharmaceuticals, OncoMed, Onconova Therapeutics, Orinove, Pfizer, PharmaMar, Plexxikon, Polyphor, Puma Biotechnology, Radius Health, Regeneron, Rgenix, Seattle Genetics, Sermonix Pharmaceuticals, Shattuck Labs, Silverback, Stem CentRx, Sutro, Syndax, Syros Pharmaceuticals, Taiho Pharmaceutical, Takeda, TapImmune Inc, Tesaro, Torque, Verastem, Zenith Epigenetics, and Zymeworks. Dr. Anders has received honoraria from AstraZeneca, Eisai, Elucida Oncology, Genentech/Roche, Immunomedics, IPSEN, PUMA, and Seattle Genetics; has served as a consultant or advisor to AstraZeneca, Eisai, Elucida Oncology, Genentech/Roche, Immunomedics, Ipsen, Puma Biotechnology, and Seattle Genetics; has received research funding from G1-Therapeutics, Lilly, Merck, Nektar, Novartis Pharmaceuticals UK Ltd, Pfizer, Puma Biotechnology, Seattle Genetics, Tesaro, and Zion; has patents, royalties, or other intellectual property with UptoDate.com and Jones and Bartlett; and has received travel, accommodations, or expenses from Eisai. 

REFERENCES

1. Nitz UA, Gluz O, Christgen M, et al: De-escalation strategies in HER2-positive early breast cancer (EBC): Final analysis of the WSG-ADAPT HER2+/HR- phase II trial: Efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab +/- weekly paclitaxel. Ann Oncol 28:2768-2772, 2017.

2. Kalinsky K, Barlow WE, Meric-Bernstam F, et al: Abstract GS3-00: First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy in patients with 1-3 positive nodes, hormone receptor-positive and HER2-negative breast cancer with recurrence score < 25: SWOG S1007 (RxPONDER). Cancer Res 81(suppl):GS3-00, 2021.

3. Sparano JA, Gray RJ, Makower DF, et al: Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med 379:111-121, 2018.

4. Tutt A, Garber JE, Kaufman B, et al: OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER2-negative early breast cancer. J Clin Oncol 39(suppl 18):LBA1, 2021.

5. Johnston SRD, Harbeck N, Hegg R, et al: Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol 38(suppl 15):3987-3998, 2020.

6. Mayer EL, Dueck AC, Martin M, et al: Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): Interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 22:212-222, 2021.

7. Murthy RK, Loi S, Okines A, et al: Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 382:597-609, 2020.

8. Modi S, Saura C, Yamashita T, et al: Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 382:610-621, 2020.

9. AstraZeneca: Enhertu significantly improved progression-free survival in DESTINY-Breast03 head-to-head trial vs. trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer. Press release, August 9, 2021. Available at https://www.astrazeneca.com/media-centre/press-releases/2021/enhertu-head-to-head-trial-meets-primary-endpoint.html. Accessed September 10, 2021.

10. Rugo HS, Im SA, Cardoso F, et al: Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: A phase 3 randomized clinical trial. JAMA Oncol 7:573-584, 2021.

11. MacroGenics I: MacroGenics announces final overall survival results from SOPHIA study of Margenza in patients with HER2-positive metastatic breast cancer. Press release, September 7, 2021. Available at http://ir.macrogenics.com/news-releases/news-release-details/macrogenics-announces-final-overall-survival-results-sophia. Accessed September 10, 2021.

12. Andre 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.

13. Rugo HS, Lerebours F, Juric D, et al: Abstract PD2-07: Alpelisib + letrozole in patients with PIK3CA-mutated, hormone-receptor positive, human epidermal growth factor receptor-2-negative advanced breast cancer previously treated with a cyclin-dependent kinase 4/6 inhibitor + fulvestrant: BYLieve study results. Cancer Res 81(suppl 4):PD2-07, 2021.

14. Jhaveri K, Saura C, Guerrero-Zotano A, et al: Abstract PD1-05: Latest findings from the breast cancer cohort in SUMMIT: A phase 2 ‘basket’ trial of neratinib + trastuzumab + fulvestrant for  HER2-mutant, hormone receptor-positive, metastatic breast cancer. Cancer Res 81(suppl 4):PD1-05, 2021.

15. Bidard FC, Callens C, Dalenc F, et al: Prognostic impact of ESR1 mutations in ER+ HER2- MBC patients prior treated with first line AI and palbociclib: An exploratory analysis of the PADA-1 trial. J Clin Oncol 38(suppl 15):1010, 2020.

16. Cortes J, Cescon DW, Rugo HS, et al: Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): A randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 396:1817-1828, 2020.

17. Bardia A, Hurvitz SA, Tolaney SM, et al: Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med 384:1529-1541, 2021.