Breast cancer affects millions of women worldwide and is the most commonly occurring cancer in women. While there are many different types of breast cancer, roughly 20% of all cases are driven by amplification and overexpression of the growth-promoting protein human epidermal growth factor receptor two (HER2). HER2 positive breast cancers are more aggressive and spread at a faster rate than hormone receptor driven tumors; however, these tumors have the option to be treated with new monoclonal antibody therapies that target the HER2 protein such as Trastuzumab, Pertuzumab; antibody-drug conjugates (ADC) such as Trastuzumab-Emtansine or recently Trastuzumab deruxtecan; and HER2-Kinase inhibitors. Therefore, the accurate selection process for patients whose tumors test positive for the HER2 protein and the precise evaluation of the HER2 level in the tumor is critical to ensure patients safety and the treatment success.

Over the last 20 years, our experts have helped design, develop, and validate novel HER2 biomarker assays and introduce them into routine diagnostics. We are both proud and humbled to be part of this long endeavor to provide breast cancer patients today with better prospects via innovative diagnostics and therapies with real clinical benefits. Standardized biomarker testing in clinical trials and diagnostic routines help select the most eligible patients for treatment while ensuring that they avoid unnecessary side effects. We look forward to the continued support of our pharma partners’ precision oncology programs to advance novel breast cancer therapies that improve survival for patient groups still waiting for adequate treatment.

Dr. Thomas Henkel
Former CEO of Targos and now Discovery’s Executive Vice President Science & Innovation

Biomarker analysis as a key component of HER2 assay design

When analyzing breast cancer tumors for prognostic and predictive biomarkers, estrogen receptor (ER), progesterone receptor (PR), and HER2 positive status are critical for guiding the therapeutic regimen. HER2 is a growth-promoting protein and member of the human epidermal growth factor receptor family. However, while HER2 breast cancers have a higher proliferation rate and are more aggressive in nature, HER2 targeted therapy has greatly improved outcomes in combination drug targeting in patients. Whereas ER and PR receptor status, sensitivity is evaluated by nuclear protein expression via immunohistochemical (IHC) staining, HER2 is assessed by IHC to evaluate protein expression in the cell membrane and/or by in situ hybridization (ISH) methods that evaluate gene amplification.

Exact measurement of predictive biomarkers such as ER, PR or HER2 is essential to decide on the risk of a patient for a relapse after surgery, the appropriate drug regimen, and importantly on the avoidance of unnecessary side effects for the patients. Thus, the biomarker tests and their evaluation has been validated in many clinical studies.

Addressing the challenge

Twenty years ago, the quest was started for a validated, sensitive and predictive biomarker HER2 test for trastuzumab, the first approved anti-HER2 drug. Therefore, Roche needed a standardized selection for patients and commissioned the expertise of Targos Molecular Pathology, acquired by Discovery in 2021, for this challenging task.

Dr. Josef Rüschoff and Dr. Thomas Henkel of former Targos (now Discovery) set out on an international scientific mission to find the predictive biomarker solution. At that time, none of the biomarkers were standardized, which led to many discrepancies. The team tested 12,000 patient samples sent from 1,000 clinical centers where the tumors were HER2 positive to match the standardized protocols and rule out false positives. Surprisingly, even though the incoming samples had been tested locally, the Targos team found that only 66% could be confirmed positive so they could be enrolled in the clinical trial. This false positive rate is not only disappointingly inaccurate, but it leads to many possible consequences, from the patient trying a drug they won’t respond to or even experiencing negative side effects.

Her2 Testing Graphic

Through years of commitment and dedication, Dr. Rüschoff and Dr. Henkel’s team successfully helped to develop, validate, and apply a HER2 companion diagnostic assay for breast cancer into the clinical trial testing for Roche’s Trastuzumab (Herceptin). These standard validated methods for IHC and FISH were used on formalin-fixed paraffin embedded(FFPE) tumor samples to determine eligible patients for Trastuzumab treatment.

As a result of 10 years of biomarker testing in clinical trials, our standardized testing established Trastuzumab, Pertuzumab and the antibody-drug conjugate Trastuzumab-emtansine as an effective treatment for several tumor types with a wide variety of HER2 expression levels. It confirmed that these drugs could significantly improve disease-free survival for patients with HER2-positive breast or gastric cancers. It was an exciting journey and we are thankful to have taken part in this endeavor.

Dr. Thomas Henkel
Former CEO of Targos and now Discovery’s Executive Vice President Science & Innovation

Results and conclusions

As a result of the clinical validation with Targos (now Discovery as of May 2021) together with standardized reagents, automated staining platforms, and data from ring studies and publications, reduced the global HER2 testing discrepancies to a minimum.

Instrumental for this increase in biomarker and treatment standardization, were also the many training courses led by the former Targos team, now Discovery Biomarker Academy, who helped to share the experience with the HER2 clinical trials testing with 2,000 pathologists around the world.

Discovery continues today to develop biomarker assays for clinical trials and if successful, to introduce them into the routine diagnostics. Actual biomarkers trained in the Discovery Biomarker Academy include PD-L1, MSI markers and – still HER2 – but now the analysis of low expressing tumors, targeted by the new drug Trastuzumab-deruxtecan.

To read our HER2 case study click here.