Efficacy of Trastuzumab Deruxtecan Highlights the Need for Consistent HER2 Testing Practices in Metastatic Breast Cancer

Michelle Shiller, DO, AP/CP, MGP

According to findings from the phase 3 DESTINY-Breast02 (NCT03523585) and DESTINY-Breast03 (NCT03529110) trials presented during the 2022 San Antonio Breast Cancer Symposium, the HER2-directed antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu) has shown promising efficacy among patients with HER2-positive metastatic breast cancer, according to Michelle Shiller, DO, AP/CP, MGP.

Additionally, results from the phase 3 DESTINY-Breast04 trial (NCT03734029) have underscored the importance of accurately and consistently determining the level of HER2 expression for patients with breast cancer.^1-3

In DESTINY-Breast02, patients with HER2-positive metastatic breast cancer who had previously been treated with ado-trastuzumab emtansine (T-DM1; Kadcyla) were randomly assigned to receive either trastuzumab deruxtecan (n = 406) or treatment of physician’s choice (n = 202). Treatment with the ADC led to significant improvements in terms of progression-free survival (PFS; HR, 0.36; 95% CI, 0.28-0.45; P < .000001) and overall survival (OS; HR, 0.66; 95% CI, 0.50-0.86; P = .0021) compared with physician’s choice of treatment. Most patients in the experimental arm (80.3%) as well as the comparator arm (78.7%) had a HER2 status of 3+ by immunohistochemistry (IHC).¹

DESTINY-Breast03 enrolled patients with HER2-positive unresectable or metastatic breast cancer following treatment with at least 1 prior anti-HER2 regimen and randomly assigned them to receive trastuzumab deruxtecan (n = 261) or T-DM1 (n = 263). Treatment with trastuzumab deruxtecan was found to reduce the risk of death by 36% compared with T-DM1 (HR, 0.64; 95% CI, 0.47-0.87; P = .0037). Again, most patients on both arms of the trial were found to be HER2 3+ by IHC (89.7% vs 88.2%, respectively).²

However, findings from DESTINY-Breast04 showed that there are some discrepancies between different methods of determining HER2 expression. According to an analysis of the patient population of the trial, samples with historical and central HER2 results (N = 1108) were centrally scored as HER2-low at a rate of 77%. Among the samples that were not centrally scored as HER2-low, HER2 IHC 0 was scored at a rate of 88%.³

In an interview with OncologyLive®, Shiller, medical director of Cancer Genetics with Baylor Sammons Cancer Center in Dallas, Texas and medical director of Genomics and Molecular Pathology Services with Pathgroup in Nashville, Tennessee, discussed the evolving role of HER2 as a biomarker for the treatment of patients with breast cancer and the impact of findings from the DESTINY-Breast02, DESTINY-Breast03, and DESTINY-Breast04 trials on the HER2 testing landscape.

OncLive^®: How have the data from DESTINY-Breast02 and DESTINY-Breast03 trials illustrated the importance of HER2 as a biomarker?

Shiller: HER2 has been an important biomarker in breast cancer for many years. As we continue to learn more about HER2 as a biomarker in breast cancer, and as new therapies come to the marketplace, it is important to continue to reevaluate this biomarker.

The data from the DESTINY-Breast02 and DESTINY-Breast03 trialsshow us that these patients who historically had great responses to the traditional trastuzumab [Herceptin] therapeutic, have even better responses to the ADC trastuzumab deruxtecan. It seems to be related to those patients who have high expression of HER2, as evaluated in accordance with the ASCO/CAP 2018 guidelines. These would be those patients that are overexpressed by HER2 IHC 3+ in greater than 10% of tumor cells or those who have HER2 amplification assessed by FISH, again in accordance with the ASCO/CAP 2018 guidelines.

How have the data from DESTINY-Breast04 disrupted HER2 testing algorithms?

That’s where we’ve seen more of an impact with respect to HER2 testing in breast cancer. There is a bit of a collision, if you will, between what our standard guidelines are for interpreting HER2 as a biomarker and the data from the DESTINY-Breast04. This new data is very important because it gives therapeutic opportunities to a lot of patients who may have otherwise exhausted their options, particularly in those hormone receptor–positive patient populations.

Previously we would render our interpretation 0, 1+, 2+. Per the ASCO/CAP 2018 guidelines, 2+ routed the patient next into needing FISH testing to then ultimately determine what is happening specifically with the ERBB2/HER2 signal by determining the actual gene copy number in a numeric fashion. This vital step in the assessment of HER2 has not changed. But, when patients with a finding of a 1+ or 2+ IHC are identified, their cases are now starting to walk down the road of considering therapies aligned HER2-low expression according to the DESTINY-Breast04 data.

More specifically, if the interpretation is HER2 1+ by IHC, this meets the definition of HER2-low per the DESTINY-Breast04 trial and allows the patient to be considered in the metastatic setting for the ADC therapy. However, with the ASCO/CAP 2018 guidelines, the terminology utilized for a 1+ interpretation is negative.

This can be very confusing for providers, and it’s something that we as pathologists need to have some nimbleness with during this time where we are essentially working with 2 interpretive outputs. We still must use the 2018 guidelines, and I am confident that an update to the 2018 guidelines will come soon. The 2018 guideline says that 1+ interpretation is negative. However, what is helpful to do is next to mention, ‘As per the DESTINY-Breast04 trial, HER2 1+ is consistent with an interpretation of HER2-low, consideration for the ADC for HER2 may be available in the appropriate metastatic setting.’

If the interpretation 2+ IHC is rendered, the case should still go to FISH in keeping with the 2018 guidelines, which is also the criteria that was used in the DESTINY-Breast04 trial. When the FISH interpretation is negative, then ultimately using a combined interpretation of HER2-negative according to the ASCO/CAP 2018 Guidelines, and HER2 low according to DESTINY-Breast04 will be important to drive therapeutic consideration.

This is where it’s been a little bit confusing, especially in the absence of one harmonized guideline to help communicate what it is that we're seeing underneath the microscope and how that gets translated into clinical care.

How have the data from DESTINY-Breast04 affected the importance of standardizing definitions around HER2 expression levels?

When we get a guideline update, that will really help to put context around things. Perhaps we will move to a combined and integrated interpretation where we communicate the expression, because we do need to know the level of expression, together with how the expression matches criteria for the ADC therapy. Knowing the specific extent of expression is helpful to all members of the team as the patient’s response to therapy is monitored.

I can see where we will have an integrated interpretation of: a) IHC report only: HER2 IHC 1+ negative; HER2-low, b) IHC report first: HER2 IHC 2+ needs further workup [reflex to FISH]; then a FISH report stating: HER2 IHC 2+, needs further workup; HER2-non-amplified; HER2 low [when FISH is non-amplified]. Specifically, the final HER2 status will be integrated and rendered in the FISH report.

Have similar repercussions been seen with other ADCs in breast cancer?

Not yet.

Have we seen improved efficiencies or processes for tissue evaluation?

At our institution, whenever a diagnosis of invasive breast cancer is made, we automatically reflexively order hormone receptor and HER2 testing, including when the diagnosis is made on breast biopsies, resections, and metastatic lesions. As such, the only impact the DESTINY-Breast 04 data had on our process was considering our interpretive templates and a re-assessment within the department with respect to consistency with HER2 reporting. With respect to partnering with our clinical colleagues and oncologists, we shared a version of the new interpretive template prior to release for their feedback to ensure it was sufficient for their needs.

Is there anything else you’d like to emphasize around pathological assessment in breast cancer?

Since the data from DESTINY-Breast04 creates new treatment opportunities for patients with breast cancer, standardization within reporting and interpretation is now more important than ever. Active participation in the CAP proficiency program is vital. I also think conducting internal assessments, as well as participating in other performance enrichment programs will increase the diagnostic finesse and prowess to further minimize the concerns with interobserver reliability in order to ensure that no eligible patient is left behind.

References

1. Krop I, Park YH, Kim SB, et al. Trastuzumab deruxtecan vs physician’s choice in patients with HER2+ unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine: primary results of the randomized, phase 3 study DESTINY-Breast02.Presented at 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS2-01.
2. Hurvitz S, Hegg R, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: Updated survival results of the randomized, phase 3 study DESTINY-Breast03.Presented at 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS2-02.
3. Prat A, Modi S, Tsurutani J, et al. Determination of HER2-low status in tumors of patients with unresectable and/or metastatic breast cancer in DESTINY-Breast04. Presented at 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract HER2-18.