The emergence of HER2-low therapies has revolutionized patient care. The identification of drugs that can target breast cancers with low levels of HER2 expression (1+ or 2+ by immunohistochemistry and FISH non amplified) provides new treatment opportunities for a subset of patients.
“When one considers that roughly 50 percent of all breast carcinomas may fall under this definition of HER2-low, there is a large potential for impact,” says Erinn Downs, DO, FASCP, breast pathologist at Mayo Clinic, in Scottsdale, AZ.
Dr. Downs, along with Ali Brown, MD, FASCP, ASCP Chief Officer, Quality, and Aysegul Sahin, MD, FASCP, an internationally recognized breast pathologist at MD Anderson Cancer Center, have created educational content for one of ASCP’s CME/CMLE-accredited
online courses designed to help pathologists, laboratory professionals, and other members of the cancer care team apply the latest scientific evidence when evaluating HER2 status and be comfortable having an open dialogue surrounding challenging HER2 cases and how treatment is informed by HER2 status.
The results of the DESTINY-Breast04 trial led to the approval by the Food and Drug Administration (FDA) for the antibody-drug conjugate (ADC), Enhertu (fam-trastuzumab-deruxtecan-nxki, which includes the HER2 targeting monoclonal antibody trastuzumab, a cleavable linker and deruxtecan which is a topoisomerase I inhibitor). The indication is for the treatment of patients with unresectable or metastatic breast carcinoma that is HER2-low. (This includes both hormone receptor positive cancers as well as some triple negative breast cancers.) The trial was a randomized, multicenter study that included 557 patients with either unresectable or metastatic HER2-low breast cancer, including both hormone receptor positive (HR+) and hormone receptor negative (HR-) patients that have already received prior chemotherapy treatment. The participants were randomly assigned to either receive the ADC or the physician’s choice of chemotherapy.
The median progression-free survival in the HR+ cohort that received the ADC was 10.1 months versus 5.4 months in the physician’s choice cohort while the median overall survival in the HR+ cohort was 23.9 months for those that received the ADC versus 17.5 months in the physician’s choice cohort. For the HR-group, median progression free survival was 8.5 months in the ADC receiving cohort and 2.9 months in the physician’s choice cohort; median overall survival was 18.2 months in the ADC cohort and 8.3 months in the physician’s choice cohort. These are significant results in a patient population that was previously heavily treated.
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“There are now ongoing clinical trials evaluating HER2-low targeting therapies in the neoadjuvant and adjuvant setting,” Dr. Downs says, adding, “It will be interesting to see these data.”
Meanwhile, the laboratory team had to make changes as HER2-low therapies were emerging. Dr. Downs explained how the laboratory team has implemented these changes.
“It is really about communication with the oncologists and ensuring that our reports give them the information that they need,” she says.
Scoring and reporting by the ASCO/CAP HER2 guidelines ensures a level of standardization. This drug indication still relies on the current ASCO/CAP definitions of HER2 immunohistochemistry (where 1+ is faint, partial staining of the membrane in greater than 10 percent of cancer cells or 2+ with weak to moderate complete staining of the membrane in greater than 10 percent of cancer cells with reflex testing showing that HER2 FISH is nonamplified).
“One change to reporting that our group has considered is including a notation that breast carcinomas that are HER2 1+ or HER2 2+ and FISH nonamplified are currently considered ‘HER2-low.’ In the correct clinical setting, these patients may be eligible for targeted therapy,” Dr. Downs says.
New breast primaries, recurrences and sites of metastatic disease are routinely tested for estrogen and progesterone receptors as well as HER2 and that information is used by the oncologists to identify patients that may be eligible based on these assays as well as additional clinical information.
Communication with the multidisciplinary cancer care team is critical to ensure patients with HER2-low breast cancer are easily identified, tracked/reported, and treated. Consistent scoring and reporting based on the ASCO/CAP guidelines allows for the identification of patients that may benefit from targeted therapy based on what is currently understood.
“We do know this is an evolving field, and we will need to be ready to adapt to changes as more data become available regarding this patient population,” Dr. Downs-Kelly says. “It is anticipated that the next iteration of the ASCO/CAP HER2 breast cancer guidelines will address HER2-low, and it is possible that other assays or methods of detection will be more efficacious in identifying those patients most likely to respond. Until then, we have had a low threshold for sharing HER2 immunohistochemistry cases among our breast pathology group, especially those cases with faint, partial membrane staining near the threshold of 10 percent.”
ASCP has comprehensive education on HER2-low breast cancer offered in a variety of formats based on how ASCP members want to learn. The different formats allow providers to get a general overview of the topic, along with the pertinent issues and case-based discussions. This allows for individualized learning in a format that is best suited to the learner.
Learn more about ASCP’s comprehensive education on HER2-low breast cancer
here.
Resources
1. Narayan P, Dilawari A, Osgood C, Feng Z, Bloomquist E, Pierce WF, Jafri S, Kalavar S, Kondratovich M, Jha P, Ghosh S, Tang S, Pazdur R, Beaver JA, Amiri-Kordestani L. US Food and Drug Administration Approval Summary: Fam-Trastuzumab Deruxtecan-nxki for Human Epidermal Growth Factor Receptor 2-Low Unresectable or Metastatic Breast Cancer.
Journal of Clinical Oncology. 2023 Feb 13:JCO2202447. doi: 10.1200/JCO.22.02447. Epub ahead of print. PMID: 36780610.
2. Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.
New England Journal of Medicine. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690. Epub 2022 Jun 5. PMID: 35665782.
