Breast Cancer Conference Addresses HER2-Low Therapeutic Subset

Joyce O’Shaughnessy, MD

Celebrating Women Chair in Breast Cancer Research

Baylor University Medical Center

Director, Breast Cancer Research Program

Texas Oncology

US Oncology

Dallas, TX

Keeping up with new developments in breast cancer management is a daunting task. Advancements that refine treatment strategies, improvement in survivorship, and the identification of patient subgroups have a significant impact on the field.

“As new data are presented around the world, there has to be a way to pull it together through appropriate vetting, discussing, debating, and ultimately incorporating it into practice,” Joyce O’Shaughnessy, MD, chair of the 22nd Annual International Congress on the Future of Breast Cancer® East, said in an interview with Targeted Therapies in Oncology. “It also benefits me to hear about new data multiple times, in context, as it is vetted by experts.” O’Shaughnessy is the Celebrating Women Chair in Breast Cancer Research at Baylor University Medical Center and director of the Breast Cancer Research Program at Texas Oncology, both in Dallas.

For attendees of the conference, O’Shaughnessy said the pearls of wisdom that experts provide are action items that can be taken back to the clinic. “We’ve all had those aha moments when we listen to our expert colleagues to see what they’re doing and how they’re practicing and [realize] there might be a different perspective to treatment to explore.”

O’Shaughnessy explained that managing breast cancer requires a multidisciplinary approach, which is outlined in the conference. “Initially, optimal care requires a focus on the local regional area, on the breast itself, and the surrounding lymph node beds,” O’Shaughnessy said. That care is followed by reconstruction, and although it isn’t always required, “it’s very important to the patient’s health and overall well-being.” Finally, there is systemic management so that disease does not recur or metastasize elsewhere in the body.

An Evolving Congress

As the congress has evolved over the years, discussions about novel diagnostics, liquid biopsies, and next-generation sequencing have emerged. “It’s a challenge to stay on top of local and regional data and literature,” O’Shaughnessy said.

For example, this year’s congress emphasizes the emergence of HER2-low breast cancer, described by O’Shaughnessy as “a therapeutic subset of opportunity.” Patients usually undergo HER2 immunohistochemistry (IHC) testing, so developing a new diagnostic tool wasn’t necessary. “Making the diagnosis relevant requires a therapeutic agent, and we have the antibody-drug conjugates ado-trastuzumab emtansine [T-DM1; Kadcyla] and fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu] for patients with HER2-positive breast cancer and most recently HER2-low breast cancer,” O’Shaughnessy said.

In August 2022, the FDA approved T-DXd for adult patients with unresectable or metastatic HER2-low breast cancer (IHC score of 1+ or 2+ and a negative fluorescence in situ hybridization [FISH] test result) who have received prior chemotherapy in the metastatic setting or experienced disease recurrence during or within 6 months of completing adjuvant chemotherapy.¹ Efficacy was established based on findings from the DESTINYBreast04 trial (NCT03734029), a randomized, multicenter trial that enrolled 557 patients with unresectable or metastatic HER2-low breast cancer. The trial included 2 cohorts: 494 patients with hormone receptor–positive disease and 63 patients with hormone receptor–negative disease.²

Patients were randomly assigned 2:1 to receive either T-DXd 5.4 mg/kg (n = 373) by intravenous infusion every 3 weeks or physician’s chemotherapy choice (n = 184), including eribulin, capecitabine, gemcitabine, nab-paclitaxel, or paclitaxel. Median progression-free survival (PFS) in the hormone receptor–positive cohort was 10.1 months (95% CI, 9.5-11.5) in the T-DXd arm and 5.4 months (95% CI, 4.4-7.1) in the chemotherapy arm (HR, 0.51; 95% CI, 0.40-0.64; P < .0001). Median PFS in the overall population was 9.9 months (95% CI, 9.0-11.3) in the T-DXd arm and 5.1 months (95% CI, 4.2-6.8) for those receiving chemotherapy (HR, 0.50; 95% CI, 0.40-0.63; P < .0001).²

In the hormone receptor–positive cohort, median overall survival (OS) was 23.9 months (95% CI, 20.8-24.8) and 17.5 months (95% CI, 15.2-22.4) in the T-DXd and chemotherapy arms, respectively (HR, 0.64; 95% CI, 0.48- 0.86; P = .0028). In the overall population, median OS was 23.4 months (95% CI, 20.0- 24.8) in the T-DXd arm vs 16.8 months (95% CI, 14.5-20.0) in the chemotherapy arm (HR, 0.64; 95% CI, 0.49-0.84; P = .001).²

HER2-Zero and HER2- Low Breast Cancer

During the conference, Paolo Tarantino, MD, clinical research fellow at the Dana-Farber Cancer Institute in Boston, Massachusetts, will be presenting “Are HER2-Zero and HER2-Low New Breast Cancer Subtypes? Clinical Implications.” O’Shaughnessy said investigators are waiting on results of the DESTINY-Breast06 trial (NCT04494425), which compares T-DXd with standard-of-care chemotherapy in patients with HER2-low, hormone receptor–positive breast cancer whose disease has progressed on endocrine therapy in the metastatic setting. “Patients with hormone receptor–positive breast cancer still need to get optimal endocrine therapy, and unfortunately, cancer develops resistance to endocrine approaches,” O’Shaughnessy said.

To be eligible for the trial, patients need to have experienced disease progression after at least 2 previous lines of endocrine therapy for metastatic disease or experienced disease progression within 6 months of starting frontline treatment.

The primary end point is PFS, and secondary end points include OS and objective response rate.

The questions that DESTINY-Breast06 will try to answer are whether T-DXd is effective in this ultralow HER2-expression subpopulation and whether the antibody-drug conjugate is effective in patients who have not had prior chemotherapy. “I suspect that both answers will be positive,” O’Shaughnessy said.

Monitoring for Minimal Residual Disease

During the conference, O’Shaughnessy will be presenting “Is Monitoring for Minimal Residual Disease in Breast Cancer of Clinical Utility?” Liquid biopsies that measure circulating tumor DNA are an emerging approach that can help guide clinical decision-making with implications for prevention, diagnosis, and treatment. The use of liquid biopsies has been explored, but challenges remain to grow its clinical use for optimizing cancer care.

REFERENCES:

1. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. FDA. August 5, 2022. Accessed March 29, 2023. http://bit.ly/3FXu9e8

2. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690