ASCO Guideline Update Supports New Second- and Third-Line Treatments for HER2-Positive Breast Cancer

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ASCO has issued a new practice guideline update on the use of systemic therapy for HER2-positive breast cancer, just 4 years after the previous practice guideline update was released in 2018.1,2 This latest update reviews results from multiple clinical trials published between 2016 and 2021 that could inform new therapeutic algorithms and potentially alter the standard of care in systemic therapy for this patient population, especially in the second- and third-line settings.

Nancy E. Davidson, MD

Nancy E. Davidson, MD

“The field of HER2-targeted therapy for advanced breast cancer is moving forward very quickly, so there are a number of new agents and combinations of testing approaches that have emerged over the last few years,” said Nancy E. Davidson, MD, of Fred Hutchinson Cancer Research Center, and Expert Panel Co-Chair. “As a consequence, we felt it was a good time to look at the evidence base to help practitioners and patients decide the appropriate sequence of treatment for them.”

Weighing a Wealth of New Data

Systemic therapy has the potential to help reduce cancer-related symptoms, prolong the time until tumor progression, and improve overall survival for patients with advanced breast cancer. However, systemic therapy for advanced disease may also produce unwanted side effects that can negatively impact a patient’s quality of life. Thus, treatment selection and sequencing are critical factors that allow oncologists to use these therapies appropriately.

To ensure clinicians are up to date on the evidence that supports systemic therapies in patients with HER2-positive disease, an expert panel conducted a targeted, systematic literature review and identified 14 phase II and III clinical trials from 2016 to 2021 that contributed substantially to the field’s understanding of systemic treatment for HER2-positive disease, including studies that enhance the field’s understanding of HER2 signaling pathways. These 14 trials served as the foundation of the panel’s recommendations. 

Sharon H. Giordano, MD, MPH, FASCO

Sharon H. Giordano, MD, MPH, FASCO

Although the panel’s support for combination trastuzumab, pertuzumab, and taxane as first-line treatment is unchanged from the previous guideline update, recommendations for treatment approaches in the second- and third-line settings have been updated. “One of the most important changes to the guideline is the recommendation for [fam-trastuzumab deruxtecan-nxki] as second-line treatment,” said Sharon H. Giordano, MD, MPH, FASCO, of The University of Texas MD Anderson Cancer Center, and Expert Panel Co-Chair. 

The change was based on the results of the DESTINY-Breast03 trial, which showed a statistically significant and highly clinically meaningful reduction in progression-free survival (hazard ratio = 0.28) for patients treated with trastuzumab deruxtecan when compared with ado-trastuzumab emtansine.3

Drs. Giordano and Davidson both noted that because this drug is new and has some known pulmonary toxicity, it will need to be studied further and deployed in the field with care. 

“The panel recommended trastuzumab deruxtecan as a new standard of care for second-line therapy. This new option represents an important advancement in treating metastatic HER2-positive breast cancer, given the magnitude of the benefit of trastuzumab deruxtecan,” Dr. Giordano added. “However, clinicians should be aware of the risk of interstitial lung disease and pneumonitis with this regimen, which occurred in about 10% of treated patients—although only 1% had grade 3 or higher pulmonary toxicity.”

The guideline also recommended the option of tucatinib with trastuzumab and capecitabine in the third-line setting, based on the overall survival benefit seen in the HER2CLIMB trial and the efficacy of this regimen against brain metastases.4,5 

Preparing for Practice Change 

The Panel hopes that the exciting developments in the management of disease in patients with HER2-positive disease will lead to better patient outcomes, but they could add to the complexity of the treatment landscape. Currently, there is little concern that these complexities will hinder practice change. 

“I am not worried about uptake. I think oncologists will adopt these changes pretty quickly, as the results of the trials comparing to second-line trastuzumab emtansine have shown improvements in progression-free survival and are quite compelling,” Dr. Davidson said. “Of course, I also anticipate that these agents will now be tested in clinical trials in even earlier situations, so that helps set the agenda for practice guidelines in the future.”

Drs. Davidson and Giordano said that additional studies of these new agents and algorithms will be needed to optimize patient outcomes. For instance, the use of tucatinib with capecitabine and trastuzumab in the second-line setting for patients with brain metastases will need to be explored. Other studies will be needed to determine whether and when in earlier stages of HER2-positive breast cancer these new agents can be used, which biomarkers are most useful for sensitivity and resistance, which patients will or will not benefit from therapy, and how to partner these treatments appropriately with other agents.

“For me, as a clinician, it is exciting to think about these changes and that we needed to update a very comprehensive practice guideline review so soon after the last update,” Dr. Davidson said. “It is wonderful to see we have made that much progress.” 


1. Giordano SH, Franzoi MAB, Temin S, et al: Systemic therapy for advanced human epidermal growth factor receptor 2–positive breast cancer: ASCO guideline update. J Clin Oncol. May 31, 2022 (early release online).

2. Giordano SH, Temin S, Chandarlapaty S, et al: Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: ASCO clinical practice guideline update. J Clin Oncol 36:2736-2740, 2018.

3. Cortés J, Kim SB, Chung WP, et al; DESTINY-Breast03 trial investigators: Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med 386:1143-1154, 2022. 

4. 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. 

5. Ramakrishna N, Anders CK, Lin NU, et al: Management of advanced human epidermal growth factor receptor 2–positive breast cancer and brain Metastases: ASCO Guideline Update. J Clin Oncol. May 31, 2022 (early release online).

Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, June 2, 2022. All rights reserved.