MASSIMO CRISTOFANILLI, MD, is Director of the Jefferson Breast Care Center at the Kimmel Cancer Center and Thomas Jefferson University and Hospitals.
In recent years we have seen substantial research into the role of the HER2 gene and development of HER2-targeted therapies to treat breast cancer. The HER2 story has become one of the shining examples of progress toward personalized medicine for our patients.
In October, the American Society of Clinical Oncology and the College of American Pathologists issued a new guideline (J Clin Oncol doi: 10.1200/JCO.2013.50.9984 and Arch Pathol Lab Med doi: 10.5858/arpa.2013-0953-SA) on the use of standard laboratory HER2 testing with immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH). IHC identifies the relative amount of protein expression of the HER2 gene while FISH reveals the presence and abundance of the gene itself. These tests are recommended because they are considered to be the most evidence-based. The new guideline is expected to reduce some of the confusion when physicians are faced with equivocal IHC and FISH results.
In recent years, we have also learned through genomics that breast cancer is a highly heterogeneous disease. IHC and FISH cannot identify molecular subtypes of breast cancer and the numerous pathways that cancers hijack to promote their growth and metastasis. It was disappointing to read the statement from the guideline committee that “there is insufficient evidence to support use of mRNA or DNA microarray assays to determine HER2 status in unselected patients.”
This is a missed opportunity. Hopefully we will not have to wait another five years to consider genomic profiling of breast cancer as a standard of practice. I believe most oncologists and pathologists will agree that the current guideline and the new update represent the minimum standard pathology assessment required for selection of patient candidates for HER2-targeted therapies and these guidelines are usually developed on the bases of data and outcomes collected in a retrospective fashion.
Without the use in clinical practice of mRNA or DNA microarray assays, tumor heterogeneity remains a major challenge for clinicians. Tumor complexity will never be completely captured by single gene testing. Tumor heterogeneity associated with the availability of multiple targeted agents requires that we continue to investigate and apply more modern molecular biology and diagnostic technologies to our patients.
At our institution and in my practice, I routinely employ molecular subtyping with breast cancer patients, because it provides more information and better guidance than IHC/FISH alone. The newer molecular tests excluded from the guideline have great promise to complement and possibly replace standard diagnostics. While it is true that we lack confirmatory data from prospective, comparative clinical trials, substantial evidence from recently published and emerging new studies is available for consideration by practicing physicians.
These new studies show that molecular subtyping of breast cancer more accurately classifies breast cancer into one of four molecular subtypes—Luminal A, Luminal B, HER2-type, and Basal-type—while also providing better guidance about neoadjuvant and adjuvant treatment and risk recurrence. One can argue that genomics is still coming of age, but it is maturing rapidly. There are several studies worth noting that were not discussed in the new guideline:
Molecular subtyping of early-stage breast cancer identifies a group of patients who do not benefit from neoadjuvant chemotherapy—and who should not have to endure its side effects and potential longer-term complications. A study published in July 2013 in Breast Cancer Research and Treatment analyzed data from four clinical trials and 437 patients using genomic testing (MammaPrint and BluePrint). The researchers found a group of 90 women (21%) who showed little if any benefit from chemotherapy and who had good outcomes five years after surgery. That group could not be identified using IHC or FISH. They had a five-year metastases-free survival rate of 93 percent—the best of any group in the study.
Another effort, the MINDACT trial, is a multicenter, prospective, Phase III randomized study comparing MammaPrint with a common clinical-pathological prognostic tool (Adjuvant! Online) in selecting patients with negative or one to three positive nodes for adjuvant chemotherapy in breast cancer. Recruitment has finished with 6,700 breast cancer patients enrolled from 119 participating institutions in nine European Countries. It is anticipated that the results will further validate this genomic test as an important prognostic and predictive tool in cancer treatment.
The primary objectives of MINDACT are to confirm that breast cancer patients with a “low risk” molecular prognosis by MammaPrint and “high risk” clinical prognosis can be safely spared chemotherapy without affecting distant metastasis-free survival (DMFS), and to compare different chemotherapy regimens and hormonal therapy.
The I-SPY II Breast Cancer Clinical Trial is a model for integrating biomarkers, adaptive trial designs, and bioinformatics to quickly, inexpensively, and simultaneously test multiple drug candidates. The goal is to help accelerate the development and commercialization of compounds for locally advanced breast cancer.
Finally, the Neoadjuvant Breast Registry—Symphony Trial (NBRST) (pronounced “N-breast”)—is a prospective neoadjuvant registry trial linking four commercially available tests (MammaPrint, BluePrint, TargetPrint, and TheraPrint) and possible additional gene-expression profiles of interest to treatment response, recurrence-free survival (RFS), and DMFS.
For this project, approximately 20 to 30 institutions in the U.S. are contributing clinical patient data from enrolled patients after genomic testing has been successfully performed and the patient has started neoadjuvant therapy. New results were presented at the recent San Antonio Breast Cancer Symposium (SABCS).
Research by myself and others at numerous leading institutions—some of it also presented at SABCS—indicates that in a significant number of cases, molecular subtyping results in the reclassification of HER2 and other breast cancers types (as identified by IHC/FISH) into different subtypes. Molecular subtyping provides more information about both recurrence risk and treatment choices.
Targeted therapies cannot be effective unless they reach patients with the right cancer. Gene-expression profiling more accurately reflects tumor biology by evaluating not only a single gene, but also dependent and related pathways.
The question for oncologists is should they simply follow this new guideline, or along with this guideline, should they consider more recent scientific publications and presentations about the greater accuracy and utility of molecular subtyping? I believe the latter is a better course.
Recommendation of the New ASCO/CAP Report
The ASCO/CAP Guideline for HER2 Testing recommendation is as follows: “The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to >10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing.” (J Clin Oncol doi: 10.1200/JCO.2013.50.9984 and Arch Pathol Lab Med doi: 10.5858/arpa.2013-0953-SA).