Assay Offers Molecular Analysis of Breast Cancer Risk Recurrence: Interview With Kenneth J. Bloom, MD

Kenneth J. Bloom, MD Chief Medical Of ficer Clarient, Inc

The options for exploring tumor biology continue to multiply amid technological advances that are making molecular testing options a routine part of oncology treatment, particularly in breast cancer.

Clarient’s InsightDx Mammostrat is a recent addition to the field. The assay examines tissue from patients with early-stage, hormone receptor-positive disease with a panel of 5 biomarkers. The results are then incorporated into an algorithm that generates a risk of recurrence index, with results available within 48 to 72 hours.

Kenneth J. Bloom, MD, chief medical officer of Clarient, Inc, said the assay differs from other analytical breast cancer tests on the market because it goes beyond measuring proliferation and assessing tumor grade.

“The advantage of Mammostrat is that it provides independent information beyond what the treating physicians already know,” Bloom said in a recent interview. “One use could be as a rapid turnaround test following a needle core biopsy that could allow the multidisciplinary breast team to better decide whether neoadjuvant therapy fits in the course of treatment.”

The introduction of Clarient InsightDx Mammostrat to the oncology market is among a series of milestones for the company, which offers more than 350 diagnostic tests for oncology patients.

GE Healthcare acquired the company, which is based in Aliso Viejo, California, in late 2010.

In December, Clarient announced a partnership with ACORN Research, a network of community oncology practices and hospitals, through which tumor-specific biomarker data for each new patient will be collected and analyzed under standardized protocols. The data will be used to personalize treatment for individual patients, as well as to build a databank of information about particular tumor types that can be used in research.

“Having this opportunity where we can marry patient data in the community setting with clinical laboratory testing, both current and future, and being able to integrate all of that information into a biorepository and understand how that relates to outcome is incredibly exciting,” Bloom said.

In this interview, Bloom discussed Mammostrat in further detail.

Slides with tissue samples are prepped for analysis at Clarient Inc’s histology laboratory. The company offers more than 350 cancer diagnostic tests.

OncologyLive: Please describe Mammostrat.

Bloom: Mammostrat is a test that was created to predict the risk of recurrence in women with breast cancer who are estrogen receptor [ER]-positive, lymph node-negative, and are treated with antihormonal therapy. It is an important test because in this class of women, there are significant subsets of patients whose disease will not recur when treated only with antihormonal therapy, and thus they can avoid unnecessary chemotherapy in their care.

How was Mammostrat developed?

Mammostrat was derived out of the Human Genome Project at Stanford University in the late 1990s. They analyzed the expression of all of the genes in a series of breast cancers, leading to the molecular classification of breast cancer into the so-called luminal A, luminal B, HER2-enriched, and basal molecular classes. A sister laboratory looked to translate the genes that were discovered as part of that process into antibodies that could be applied in routine pathology laboratories.

Mammostrat is the culmination of that research. It is the combination of five antibodies that was discovered through that process, that was best able to predict recurrence in ER-positive, lymph nodenegative, tamoxifen-treated breast cancer patients.

How does Mammostrat differ from other assays that give recurrence scores?

The molecular profile tests that are available for predicting recurrence in breast cancer patients are all based on what we already knew about breast cancer—that cell differentiation and the proliferation of tumor cells were absolutely critical to predicting recurrence. The beauty of Mammostrat is that the five antibodies that were discovered don’t include markers of differentiation and proliferation. Instead, they describe the inherent biology of the tumor. Whereas the other molecular assays really just give you more information about what you already know, Mammostrat gives information that is independent of tumor grade and cell differentiation.

What are the genes and related proteins that Mammostrat examines?

Some are known and some were uniquely discovered out of the genome project. The most important gene is known as SLC7A5, which encodes a nutrient transport protein. It seems to be very important in the original Stanford experiments. That protein could separate out luminal A versus luminal B molecular classes.

p53, a gene that’s part of the profile, is recognized for the important role it plays in tumor suppression or growth. The CEACAM5 gene, which encodes an embryonic protein, is a variant of CEA [carcinoembryonic antigen], which is commonly measured in colon cancers, for example.

The other two proteins are slightly different. NDRG1 is a hypoxic-measured protein that several investigators have reported as being important in predicting responsiveness to radiation therapy, for example. And then there’s another antibody known as TRMT2A [formerly known as [HTF9C], which again is independent of proliferation and differentiation.

The Clarient InsightDx Mammostrat

What type of report is generated?

The Mammostrat report will classify the patient into low risk, moderate risk, and high risk. You do get an actual score, but there’s always a caution around absolute scores. That’s because what we wind up sampling for any of these tests, whether it’s a molecular test or an IHC [immunohistochemistry]-based test like Mammostrat, are single sections of a patient’s tumor that generally represent far less than 1% of the patient’s overall tumor. So when you look at the specific score, it can be misleading because if you sampled a different area of the tumor, the absolute score might be different. The category that the patient falls in, whether they have a low risk of recurrence or a high risk of recurrence, tends to stay the same. The category becomes important, and that’s what the oncologists should use as the basis for their decisions.

What is the best use of Mammostrat in clinical settings?

Molecular assays such as Mammostrat should be used in combination with clinical presentation, tumor burden, and all the other factors that the pathologists see under the microscope as part of a multidisciplinary approach to a breast cancer patient that is absolutely critical today.

The question of how to use Mammostrat or any of these molecular assays is related to the level of uncertainty you have regarding the care of your patient. If the clinician and patient are unsure of what therapy choice to pursue after evaluating key variables such as proliferation, grade, stage, and presentation, these assays may help reduce the uncertainty. That I think is the home for these assays.

With that being said, I think the right home for Mammostrat may be following the core biopsy of the patient, a niche that doesn’t exist currently.

Virtually all patients with breast cancer nowadays are first diagnosed on a core biopsy. Following a diagnosis of invasive cancer, most patients in this country first seek surgical intervention, and then following the surgical intervention will see an oncologist.

Mammostrat Biomarkers

Protein Markers

Function

p53

HTF9C

Cell cycle regulation

CEACAM5

Differentiation

NDRG1

Hypoxia

SLC7A5

Nutrient supply

Source: Clarient, Inc, website, www.Clarientinc.com.

Although greatly underutilized in the United States, neoadjuvant therapy might be a better course, especially for those who have higher grade tumors and are definitely going to receive chemotherapy. Mammostrat is a way where up front, at a relatively inexpensive cost, the results could be back in the surgeon’s hands so that he or she could meet with the multidisciplinary breast team and better decide whether neoadjuvant therapy fits in the treatment course of those women.

Molecular tests should be used in concert with other clinical and historical data. Since some decisions are going to be made under uncertainty, gathering more information prior to making a decision is certainly a good thing.

Again, I think the advantage of Mammostrat is that it provides independent information beyond what the pathologist or oncologist already knows.

What are the key clinical trials supporting its use?

Mammostrat has been validated in about 4500 patients to date. Those validations have been published in the Journal of Clinical Oncology, Clinical Cancer Research, and Breast Cancer Research.^1-3 They’ve involved multiple cohorts, including the National Surgical Adjuvant Breast and Bowel Project and the definitive trials that established tamoxifen (B14) and adjuvant chemotherapy (B20) as effective treatments. So it’s been a very well-vetted assay and shows consistent results in virtually every trial where it has been tested.

References

1. Ring BZ, Seitz RS, Beck R, et al. Novel prognostic immunohistochemical biomarker panel for estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24(19):3039-3047.
2. Ross DT, Kim CY, Tang G, et al. Chemosensitivity and stratification by a five monoclonal antibody immunohistochemistry test in the NSABP B14 and B20 trials. Clin Cancer Res. 2008;14(20):6602-6609.
3. Bartlett JM, Thomas J, Ross DT, et al. Mammostrat as a tool to stratify breast cancer patients at risk of recurrence during endocrine therapy. Breast Cancer Res. 2010;12(4):R47. doi:10.1186/bcr2604.