Growing Use of Molecular Pathology May Help Avoid Overtreatment of Early Breast Cancer

A Conversation With Laura J. van’t Veer, PhD


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Laura J. van’t Veer, PhD

Laura J. van’t Veer, PhD

The emerging field of molecular pathology focuses on the study and diagnosis of disease through the examination of genes and gene activity within organs and tissues. This information has transformed our thinking about the biologic diversity of breast cancers and has enhanced our treatment decisions. To shed light on current progress in molecular pathology in the breast cancer setting, The ASCO Post spoke with internationally renowned molecular biologist Laura J. van’t Veer, PhD. Dr. van’t Veer is Professor of Laboratory Medicine, Program Leader of the Breast Oncology Program, and Director of Applied Genomics at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. She is also the inventor of the 70-gene signature test MammaPrint and cofounder and part-time employee of Agendia, the company that manufactures the test.

Professional Background

Please tell the readers a bit about your background and your current position and work. 

By training, I am a molecular biologist, but I have been working in the hospital setting since 1993. I’ve always been interested in applying new scientific findings in the clinic, so that’s why I set up a molecular pathology department in the hospital. I conducted my own research that focused on breast cancer tumor diagnostics as well as genetic hereditary risk and counseling. Over the years, I’ve also been involved in protocol development and regulatory issues. 

Added Accuracy

We think of classic pathology as studying a specimen on a slide under a microscope. What is different about molecular pathology?

In molecular pathology, we sort of “look under the cell’s hood” and detect the status of gene mutations or other genetic activities that drive the biology of the tumor. A more accurate diagnosis is possible when it is based on both morphologic changes in tissue and molecular testing. 

Growing Trend

Is hospital-based molecular pathology a growing trend?

Yes. In the early 1990s, I was one of the first molecular pathologists to start a hospital-based department, which was at the Netherlands Cancer Institute. The Institute was at the forefront in understanding the clinical value of molecular pathology in the diagnostics of cancer, which is now more common practice.

“In molecular pathology, we sort of ‘look under the cell’s hood’ and detect the status of gene mutations or other genetic activities that drive the biology of the tumor. A more accurate diagnosis is possible when it is based on both morphologic changes in tissue and molecular testing.”
— Laura J. van’t Veer, PhD

MammaPrint Research

You’ve been involved in a clinical trial looking at the clinical utility of your genomic assay called MammaPrint. Please describe this work.

MammaPrint is a prognostic and predictive diagnostic test for patients with early-stage breast cancer, which examines gene activity of the tumor. In 2000, we took a series of tumor samples from breast cancer patients for whom we knew their disease course. We selected a subset of patients who had an early recurrence of disease and compared their gene activity with another group of breast cancer patients who never had a disease recurrence and for whom we had 8-year follow-up data. 

Microarrays allowed us to compare all the gene activity expressed in a tumor cell, which encompasses about 25,000 genes. We used informatics analysis to recognize the pattern of expression in the subset of genes that would allow us to identify a tumor headed for an early recurrence vs no recurrence. It was based on a pattern of expression from 70 genes, which was marked “on” in the aggressive tumors and “off” in the slow-growing tumors. 

This 70-gene prognostic signature study was published 15 years ago,1 and we had an initial validation series from a patient diagnosed at the Netherlands Cancer Institute.2 We decided to found a company called Agendia, where we developed the 70-gene signature test into a diagnostic microarray called MammaPrint. 

MINDACT Trial

Does your microarray have clinical benefits that have been verified by a randomized trial?

Yes. From the time of our first publication onward, we were interested in the utility of MammaPrint in identifying those at low risk for breast cancer recurrence and reducing overtreatment with chemotherapy. Over the years, there has been a 50% increase in the prescription of chemotherapy in breast cancer. However, only about 25% of women diagnosed with early-stage disease will have a recurrence. So, in short, if you treat 80% of these women with chemotherapy, there’s a lot of unnecessary treatment. 

The European Organisation for Research and Treatment of Cancer (EORTC) Breast Cancer Group tested our hypothesis with a trial called MINDACT, in which we enrolled 6,693 patients with early-stage breast cancer who would undergo risk assessment for recurrence based on common clinicopathologic factors and the genomic microarray test.3 We analyzed four groups of women. Two were concordant, so they were at “low-low” or “high-high” risk by both modalities. The others were discordant, so they were “low-high” or “high-low.” 

We were particularly interested in the group of patients who were clinically assessed as high risk and would be candidates for chemotherapy but who were genomically found to be at low risk by MammaPrint. The aim of the study was to show whether it was safe for those patients to forgo chemotherapy. Patients in that discordant group categorized as clinically high risk and genomically low risk were randomized to use either their clinical or genomic assessment for the decision to receive or not receive chemotherapy. The MINDACT trial is unique in that it tested the clinical utility of a genomic test in the context of the current clinical high-risk setting and prospectively assessed whether it was safe to forgo chemotherapy.

The primary aim was to ascertain whether the rate of 5-year survival without distant metastasis would be 92% or higher in patients with high-risk clinical factors and a low-risk genomic profile who did not receive chemotherapy. At 5 years, the rate of survival without distant metastases in this group was 94.7%, which achieved our primary aim. 

Practical Application

What are the clinical implications of these findings?

We showed that women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, having no chemotherapy based on the MammaPrint signature, had an excellent 5-year survival rate without distant metastases of about 95%. This was increased by a nonsignificant 1.5% in those receiving chemotherapy, a small benefit not thought to be worth the toxicity of chemotherapy by most patients. This suggests that about 46% of women with breast cancer who are at high clinical risk might not need chemotherapy, which is a huge cost and burden of unnecessary treatments that have considerable side effects. 

Disclosure: Dr. van’t Veer is cofounder, part-time employee, stockholder, and on the management board of Agendia, the manufacturer of MammaPrint.

References

1. van't Veer LJ, Dai H, van de Vijver MJ, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530-536, 2002.

2. van de Vijver MJ, He YD, van't Veer LJ, et al: A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999-2009, 2002.

3. Cardoso F, van't Veer LJ, Bogaerts J, et al: 70-gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med 375:717-729, 2016.



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