Moving Beyond Binary: Redefining HER2 Breast Cancer Classification and Treatment

The classification of HER2 breast cancer has evolved beyond the traditional binary system of positive or negative. Breast cancers that were previously classified as HER2-negative but exhibited some immunohistochemical (IHC) expression are now reclassified as HER2-low. This emergence of the HER2-low designation has prompted extensive research to investigate the effectiveness of HER2-targeted therapies in patients with HER2-low cancers, where the expression of HER2 is minimal. Hope S. Rugo, MD, FASCO, is a professor of medicine in the Division of Hematology and Oncology at the University of California San Francisco (UCSF) and director of Breast Oncology and Clinical Trials Education at the UCSF Helen Diller Family Comprehensive Cancer Center. Dr Rugo joined the Breast Care Center in 1999 following a decade of experience at UCSF specializing in malignant hematology and bone marrow transplantation for various diseases, including breast cancer. Her motivation to venture into the field of breast cancer was driven by the desire to integrate innovative therapies based on a comprehensive understanding of cancer biology into the treatment of women with breast cancer. In this article, Dr Rugo discusses treatment using ADCs for metastatic HER2-low breast cancer as well as the limitations of diagnostic testing methodologies for classifying HER2 expression.

Can you provide insight into the impact of moving away from the binary perception of HER2 breast cancer as either positive or negative?

We are now in a new era of HER2 breast cancer, particularly in the unresected, metastatic setting, that is no longer considered binary as positive or negative. What we were initially looking at in terms of defining HER2 positivity was based on gene amplification and protein overexpression, and that correlated with response to HER2-targeted therapies. The whole idea behind testing and the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines was how to define the patient population whose tumors are likely to respond to HER2-targeted therapy.¹ We were challenged in that endeavor because protein expression, by IHC, could be done with different antibodies. We discovered that if you have a lot of protein and the tumor looked positive by even IHC staining, you generally had gene amplification of the HER2 gene, also known as ERBB2. However, we uncovered a group of patients who had some evidence of protein expression but could or could not have gene amplification.
 
These previously defined HER2-negative breast cancers that exhibited some degree of IHC expression subsequently were designated as “HER2-low.” HER2-low is currently defined as IHC 1+ or IHC 2+ with a negative fluorescent in-situ hybridization (FISH) score.² These observations and new designation of HER2-low led to researchers examining whether HER2-targeted therapies worked in patients who have HER2-low cancer with only a little HER2 expression. A phase 3 trial of 3270 women with HER2-low breast cancer treated in the adjuvant setting with trastuzumab plus chemotherapy vs chemotherapy alone failed to prove any beneficial effect of trastuzumab. We recognized that some patients who were not HER2-positive by central testing (only by local testing) and that breast cancer cells with lower levels of HER2 expression still benefited from HER2-targeted therapy.³

How has the availability of this ADC changed the treatment landscape for metastatic HER2-low breast cancer?

We now have a new generation of approved ADCs that have a higher DAR and the ability to deliver the toxin in a more efficient and effective manner for advanced unresectable, metastatic breast cancer. There are some drugs that have lower DARs and still work in this setting. Evidence emerged suggesting that you may see some efficacy in HER2-low metastatic breast cancer, a disease that is not HER2-positive by ASCO/CAP guidelines, but with some HER2 on the cell surface.¹ This led to the US Food and Drug Administration (FDA) approval of T-DXd in 2022, the first targeted therapy for unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer.⁴
 
This approval was based on findings from the phase 3 DESTINY-Breast04 trial (ClinicalTrials.gov identifier: NCT03734029), which found that the median progression-free survival (PFS) in those treated with T-DXd vs standard-of-care chemotherapy was 10.1 months vs 5.4 months, respectively (hazard ratio for disease progression or death, 0.51; 95% CI, 0.40-0.64; P<.001), with median overall survival (OS) increasing to 23.9 months vs 17.5 months, respectively (hazard ratio for death, 0.64; 95% CI, 0.48-0.86; P=.003). Among all patients treated regardless of HR status, T-DXd demonstrated a median PFS of 9.9 months vs 5.1 months for chemotherapy (hazard ratio for disease progression or death, 0.50; 95% CI, 0.40-0.63; P<.001), with a median OS of 23.4 months for T-DXd compared with 16.8 months for the control arm (hazard ratio for death, 0.64; 95% CI, 0.49-0.84; P=.001).⁵
 
For DESTINY-Breast04, the PFS and OS for the primary endpoint—HR-positive, centrally determined, HER2-low disease—was impressive. That is huge because now these patients are getting T-DXd. We are also finding patients who do not respond because they would not have been trial candidates. However, this is our new standard of care for this population of patients. It is exciting that we have been able to now translate HER2-targeted therapy to a broader group of patients with HER2-low-expressing breast cancer. It has been a huge advancement to have additional treatment options for these patients, and seeing an improvement in survival that is a little more than 5 to 6 months is huge in this setting. Some of them were HER2-positive by central testing, so you must be careful about testing for HER2 because we want to know who is HER2-positive. Regardless of whether you use the primary sample or a metastatic sample, or even an older sample, the research has predicted benefit from T-DXd, so that is really encouraging for clinical practice. Nevertheless, while the outcome in HR-positive disease was the primary endpoint and this represented a large cohort, the study was not powered to assess outcomes in the HR-negative subgroup, which was relatively small.⁵ Consequently, we need to define the optimal treatment sequencing for the 2 subgroups.
 
More patients in the T-DXd arm experienced adverse events that led to treatment discontinuation compared with the control arm (16.2% vs 8.1%, respectively). In terms of toxicities, alopecia, nausea, vomiting, constipation, diarrhea, anemia, and thrombocytopenia were more frequent in the T-DXd arm, while neutropenia was more frequent in the chemotherapy arm. Drug-related interstitial lung disease (ILD) or pneumonitis occurred in 45 (12.1%) of the patients who received T-DXd.⁵
 
Something we have learned, and are still learning, is how to monitor for and treat patients who have early ILD/pneumonitis. In patients with asymptomatic ILD, you have to hold the drug and consider low-dose steroids. Then 3 weeks later, we repeat the noncontrast CT scan. I have been able to successfully restart the drug in almost all patients. For symptomatic ILD, you must permanently discontinue the drug and immediately begin steroids, and then start the workup. We need to learn how to re-treat these patients in the safest way so that we do not stop a very effective therapy. That includes the significant nausea from this drug. Overall, this is a drug that can be given fairly easily with reasonable control of toxicity in the majority of patients. We still need to understand what to do and how well it works in patients who have less HER2 expression.

How do you incorporate recommendations from the 2023 NCCN guidelines⁶ for T-DXd as preferred second-line therapy for HER2-low for patients with recurrent unresectable or metastatic breast cancer?

Results of the phase 3 DESTINY-Breast04 trial led to T-DXd becoming a new standard of care for patients with pretreated HER2-low metastatic breast cancer. The NCCN guidelines for the use of T-DXd reflect the clinical trial eligibility for DESTINY-Breast04. It also allows us to use other ADCs approved for HR-positive and triple negative disease, irrespective of HER2 status.
 
Data from the FDA-approved ADCs, including sacituzumab govitecan, suggest substantial efficacy for the HER2-low tumors and the future for this class.^7,8 There is a lot of interest in novel ADCs in development, including trastuzumab duocarmazine, disitamab vedotin, and datopotamab deruxtecan.^9,10 As I noted earlier, more potent cytotoxic payload and higher DAR may explain activity in HER2-low breast cancers. We expect to see those data in the not-too-distant future. That is going to create another situation of health care professionals trying to decide what drugs should be given first, second, third, and so on.

What are the limitations of current diagnostic testing methodologies for classifying HER2 expression?

The current tests (IHC and FISH) were designed to identify patients with HER2-positive disease that responded to trastuzumab. The tests were not validated for detecting the difference between 1+ or 2+ or 0 within the framework of HER2-low. And for the purposes of T-DXd, what are the differences between 0 and not 0? HER2-low can be like a moving target—positive, negative, then positive again. You need the best testing mechanisms. However, the reliability of IHC results is influenced by preanalytical, analytical, and postanalytical factors. FISH may be a more robust technique than IHC, but the high cost of reagents and the need for expensive laboratory equipment used in evaluating fluorescent signals that fade over time demonstrate significant limitations of this technique.¹¹ Accurate and reproducible testing strategies and techniques are the key aspects to identifying patients who may benefit from ADCs.
 
There is a lot of interest now in whether better mechanisms of protein expression might help, whether between 0 and 1+ is good enough. This remains to be defined, including specialized testing to quantify the protein. A subset of the DESTINY-Breast06 trial (ClinicalTrials.gov identifier: NCT04494425) will look at 150 of 850 total patients who have more than 0 but less than 1+ to determine if T-DXd has the same response in that group of patients with HER2-ultralow. How can we know for sure that if a patient is 0 in every testing, they will not have any response to the T-DXd? It is important to highlight that in this trial, HER2-low and an IHC score more than 0, less than 1+ will be confirmed by a central lab prior to inclusion in order to ensure that patients enrolled in the trial have a tumor that will be categorized according to the eligibility criteria of the study. But certainly, if a test is more precise, it is likely to be at least as predictive or maybe more predictive than the tests that we are currently using. Tests to identify that these HER2-low tumors and the tumors with an IHC score of more than 0, less than 1+ have been using a traditional IHC assay and scoring system. New technologies may help to better identify these patients with this subtype of tumor.

What are the clinical implications of evaluating the efficacy of T-DXd in HER2-ultralow, HR-positive metastatic breast cancer?

The DESTINY-Breast06 trial will evaluate the efficacy, safety, and tolerability of T-DXd compared with investigator’s choice chemotherapy in patients with HER2-low, HR-positive metastatic breast cancer whose disease has progressed on endocrine therapy. This subgroup in the DESTINY-Breast06 trial includes patients with HER2 IHC 0 but minimal expression (IHC score >0 but <1+). The recently presented data of the DAISY trial (ClinicalTrials.gov identifier: NCT04132960) suggested meaningful activity of T-DXd even in patients with HER2-0 metastatic breast cancer (best overall response rate was 30.6%; median PFS was 4.2 months).¹² T-DXd may be an effective option in patients who have very low expression of HER2. We all believe that it will be a positive trial, and hopefully we will see data by the end of the year. It is also being used for HER2-positive disease in the neoadjuvant and post-neoadjuvant settings.

What impact do results from the DESTINY-Breast04 trial have for treating patients with other types of cancer that would also be considered HER2-low, including subsets of those with colorectal, lung, and gastric cancer?

We know gastric cancer and some other cancers express HER2 and respond to HER2-targeted therapies.¹³ That has become a very interesting area to study for T-DXd because if you have positivity, you also are going to have tumors that have low expression. These are really exciting areas for study, and I expect that we will see a lot of advocacy.

This Q&A was edited for clarity and length.

Disclosures

Hope S. Rugo, MD, reported affiliation with Daiichi Sankyo Company, Limited; Eisai, Inc; Genentech, Inc; Eli Lilly and Company; MacroGenics, Inc; Merck & Co, Inc; Mylan N.V.; Novartis Pharmaceuticals Corporation; OBI Pharma, Inc; Odonate; Pfizer, Inc; Puma Biotechnology, Inc; and Seagen, Inc.

References

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8. Schmid P, Cortes J, Marmé F, et al. Sacituzumab govitecan (SG) efficacy in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) metastatic breast cancer (MBC) by HER2 immunohistochemistry (IHC) status in the phase 3 TROPiCS-02 study. Ann Oncol. 2022;33(suppl 7):S88-S121. doi:10.1016/annonc/annonc1040
 
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10. Meric-Bernstam F, Krop IE, Juric D, et al. Phase 1 TROPION-PanTumor01 study evaluating datopotamab deruxtecan (Dato-DXd) in unresectable or metastatic hormone receptor–positive/HER2–negative breast cancer (BC). Cancer Res. 2023;83(suppl 5):PD13-08. doi:10.1158/1538-7445.SABCS22-PD13-08
 
11. Furrer D, Sanschagrin F, Jacob S, Diorio C. Advantages and disadvantages of technologies for HER2 testing in breast cancer specimens. Am J Clin Pathol. 2015;144:686-703. doi:10.1309/AJCPT41TCBUEVDQC
 
12. Diéras V, Deluche E, Lusque A, et al. Trastuzumab deruxtecan (T-DXd) for advanced breast cancer patients (ABC), regardless HER2 status: a phase II study with biomarkers analysis (DAISY). Cancer Res. 2022;82 (suppl 4):PD8-02. doi:10.1158/1538-7445.SABCS21-PD8-02
 
13. Mitani S, Kawakami H. Emerging targeted therapies for HER2 positive gastric cancer that can overcome trastuzumab resistance. Cancers (Basel). 2020;12(2):400. doi:10.3390/cancers12020400

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