Late last year, the American Society of Clinical Oncology and College of American Pathologists published a comprehensive update of guidelines for HER2 testing,¹ the first such update since their initial landmark publication in 2007.² This new report, summarized in this issue of The ASCO Post, provides the opportunity to take stock of progress in anti-HER2–directed therapy and testing over the past 6 years.

One might ask what is new and why an update of the guidelines is needed now. Over the past few years, much has been learned about the HER2 signaling pathways in breast cancer, and three additional anti-HER2 drugs—lapatinib (Tykerb), pertuzumab (Perjeta), and ado-trastuzumab emtansine (Kadcyla)—have joined trastuzumab (Herceptin) on the market in the United States. The importance of well-defined predictive markers matched to targeted therapeutics is increasingly understood, and the need to perform and interpret such predictive assays correctly is also clearly recognized.

Numerous Strengths

The strengths of the new guidelines are numerous. First, they strongly recommend that testing be performed on any invasive primary breast cancer derived from a patient for whom systemic therapy is under consideration. Second, they provide very specific guidelines about how such testing should be done and interpreted, focusing on the commonly used immunohistochemistry and in situ hybridization assays to detect protein expression and DNA amplification, respectively.

Third, they clearly tie the use of anti-HER2-targeted agents to knowledge about HER2 status of the tumor—gone are the days of empiric use of a targeted therapy like trastuzumab. Finally, the guidelines highlight the important partnership between oncologist and pathologist in the testing process and correctly place the patient in the center of the discussion.

Of course, these will not be the last words on this subject because of the rapid pace of discovery in this field. Indeed, these guidelines presage areas that we will need to follow. For example, breathtaking progress is being made in the realm of multigene testing through transcriptional profiling. The 2013 HER2 testing guidelines recommended against the use of these assays as a means to select for or against anti-HER2 therapy for now, but it seems likely that RNA-based, multiplex assays will ultimately emerge as part of our testing repertoire.

Even more intriguing is the question of whether next-generation sequencing approaches will soon inform the use of anti-HER2 therapies, given the report of rare mutations in the HER2 (ERBB2) gene.³ The need to develop and validate reproducible and reliable assays that can inform a clinical decision for the patient should not be forgotten in our rush to embrace these new technologies.

Emerging Challenges

These guidelines also foreshadow the emerging need for serial assessment of a predictive marker with their recommendation that biopsy of a metastatic site to reestablish HER2 status be considered in women with stage IV disease.

One of the unexpected discoveries of 2013 was the documentation of mutations in another critical gene in breast cancer, ESR1, which encodes the estrogen receptor–alpha protein (reviewed in Oesterreich and Davidson).⁴ These ESR1 gene mutations appear to be extremely rare in primary breast cancers, but are detected in a subset of metastases that emerge in women who have received adjuvant endocrine therapy. This finding emphasizes the dynamic nature of breast cancer, a disease with the potential for a long natural history and the opportunity for multiple interventions that might alter the tumor.

The substantial challenges of tumor heterogeneity are also highlighted, including intratumor heterogeneity, heterogeneity between metastases, and heterogeneity over time. Little is known at present about how HER2 status evolves over time and under the pressure of serial HER2-targeted agents with variable mechanisms of action; even less is known about how (or even if) we need to evaluate this serially in the individual patient to inform our clinical recommendations.

What else might we hope for in the next version of these guidelines? The search for markers of sensitivity or resistance to anti-HER2 therapies beyond HER2 expression by immunohistochemistry or gene copy number by in situ hybridization has been surprisingly unhelpful thus far. We can hope that such markers will soon become apparent and that suitable assays for their testing and guidelines for their use will be established.

Ongoing Trials

Finally, even though the paradigm of positive HER2 testing driving the selection of anti-HER2 targeted therapy seems well established, we should not forget the provocative finding from the first adjuvant trastuzumab trials that benefit from trastuzumab was observed in a handful of women with tumors with “normal” HER2 expression.⁵ This observation is now being prospectively explored in a randomized trial of trastuzumab vs no trastuzumab in women who would not normally be candidates for anti-HER2 therapy based on conventional testing and current clinical recommendations (NCT01275677).

The results from this trial, along with the many ongoing trials of second-generation anti-HER2–targeted therapies in the adjuvant, neoadjuvant, and metastatic settings, will provide a fertile ground for refinement of our understanding, evaluation, and implementation of HER2 testing and targeting in the future.

Disclosure: Dr. Davidson reported no potential conflicts of interest.

References

1. Wolff AC, Hammond ME, Hicks DG, et al: Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31:3997-4013, 2013.

2. Wolff AC, Hammond ME, Schwartz JN, et al: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118-145, 2007.

3. Bose R, Kavuri SM, Searleman AC, et al: HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 3:224-237, 2013.

4. Oesterreich S, Davidson NE: The search for ESR1 mutations in breast cancer. Nature Genet 45:1415-1416, 2013.

5. Paik S, Kim C, Wolmark N: HER2 status and benefit from adjuvant trastuzumab in breast cancer. N Engl J Med 358:1409-1411, 2008.