Standards for identifying appropriate populations for treatment with HER2-targeted therapies are evolving.
HER2-positive breast cancer is associated with poor clinical outcomes, including lower overall survival and an increased risk of distant metastases, node-positive disease, and recurrence. At the Oncology Nursing Society 37th Annual Congress, Kristine Abueg, RN, MSN, OCN®, Kaiser Permanente, Roseville, California, discussed the evolution of the standards for identifying appropriate populations for treatment with HER2-targeted therapies.
Identifying HER2-positive patients starts with immunohistochemistry (IHC). The IHC process involves staining a breast tumor biopsy and assigning it a HER2 status. Tumors are rated as 0+, 1+, 2+, or 3+.
Scores of IHC 0+ or 1+ categorize the patient as HER2-negative. IHC 3+ indicates the patient is HER2-positive. Specifically, IHC 3+ is defined by ASCO as "uniform intense membrane staining of >30% of invasive tumor cells" (www.goo.gl/eDlsa).
A score of IHC 2+ means the pathologist is uncertain and the testing continues to the next level, in situ hybridization (ISH). ISH testing is done either through the fluorescence in situ hybridization (FISH) test or the chromogenic in situ hybridization (CISH) test, depending on institutional preference.
“With ISH testing, the tumor [sample] is stained again, and the stain will highlight both the HER2-mutated genes, as well as the CEP17, or, ‘normal,’ genes,” according to Abueg. The genes are then counted and HER2-status is determined through the ratio of HER2 to CEP17 genes.
Prior to 2007, a HER2/CEP17 ratio ≤2 meant the patient was HER2-negative. A ratio >2 indicated the patient was HER2-positive and eligible for targeted therapies.
Abueg said, however, that research subsequently demonstrated that there were accuracy issues with the HER2 status tests. Specifically, an analysis compared testing of the same tumor sample in both community pathology labs and “reference” pathology labs, and the data showed that approximately 20% of the biopsies were scored differently in the two settings.
According to Abueg, “The implications were that there were a fairly good number of patients out there who either tested positive for HER2 and really weren’t, or, more importantly, were HER2-positive and we denied them a drug that they might have needed.”
Abueg said the reporting of these scoring discrepancies changed clinical practice. In 2007, ASCO revised its definition of HER2-positive and added retesting requirements to their tumor scoring protocol. The new guideline shifted the ISH score for HER2-negative status from <2 down to <1.8. ISH scores ranging between 1.8 and 2.2 are now considered “equivocal” and required retesting. Patients with ISH scores >2.2 are now categorized as HER2-positive and eligible to receive targeted treatments.
Despite these guideline updates, several clinical trials have shown that patients categorized by current standards as HER2-negative still benefited from the HER2-targeted treatment trastuzumab. Abueg said these results and data from other ongoing studies could, in the next five to ten years, further change the definition of HER2-positive.
Abueg noted that ongoing clinical trials are already examining the safety and efficacy of trastuzumab in patients with an IHC 1+ score, as well as in patients categorized by the FISH test as HER2-negative.