Breast cancer: The body of knowledge grows

May 28, 2016

Scientists’ understanding of the genetics/genomics of breast cancer continues to grow; a revolution is underway both in terms of categorizing breast cancers and targeting treatment that will be effective in individual cases. New perspectives are being offered on the interpretation of biopsies, too. Here is a round-up of some very recent studies.

Genetic variants alter cells’ response to estrogen

An international study of almost 120,000 women has newly identified five genetic variants affecting risk of breast cancer, all of which are believed to influence how breast cells respond to the female sex hormone estrogen.

Estrogen acts as a trigger, binding to a molecule known as an estrogen receptor in most breast cells and triggering a cascade of signals that cause the cell to behave normally. However, the estrogen receptor is switched off in some cells and these do not respond to the hormone.

An international collaboration, led by researchers at the University of Cambridge and the QIMR Berghofer Medical Research Institute, examined the DNA surrounding the gene for the estrogen receptor—known as ESR1—in women with different types of breast cancer against those of healthy controls to identify genetic variants responsible for an increased risk of breast cancer. The results were published in the journal Nature Genetics.

Among their findings, the researchers discovered five cancer-risk variants based within or around the ESR1 gene. This gene has long been known to be related to the risk and progress of breast cancer, but little is understood of how it works and why it should affect breast cancer.

Of the five variants discovered by the team, four were more strongly associated with tumors where the ESR1 gene is switched off, so the tumor cells have no estrogen receptors. These represent around one-fifth of breast cancers.

One of these four variants was of particular interest as it was associated with a rarer type of breast tumor that contain active receptors for the protein known as human epidermal growth factor 2′ (HER2). Such tumors can be treated by the drug trastuzumab (marketed as Herceptin). This is believed to be the first time a specific genetic risk factor for HER2 positive breast tumors has been found.

Researchers had been searching for gene regulatory elements around the ESR1 gene, which act like the volume controls on a radio or TV, turning the activity of the nearby genes up or down. There are two major types of gene regulators: “enhancers,” which increase activity of the genes expressed so that they make more protein, and “silencers,” which have the opposite effect.

When the two teams compared notes, they spotted that four of the breast cancer risk variants coincided with “volume-up” enhancers. These particular regulators did not just affect the ESR1 gene but also other nearby genes. The variants that increased risk of breast cancer directly reduced the effectiveness of each enhancer, hence turning down the volume of ESR1 and the other nearby genes. This reduced the amount of estrogen receptor produced by breast cells. The researchers say that their results suggest the ESR1 gene works with other nearby genes to affect breast cancer development.

The fifth genetic variant was found to be more strongly associated with tumors where the estrogen receptor is switched on. This variant coincides with and alters the effectiveness of the “volume-down” silencer, which means that it increases the amount of estrogen receptor protein produced by breast cells.

Pathologists often disagree on breast biopsy results

A study applying B-Path (Breast Pathology) Study results to patient populations found that pathologists disagree with one another about eight percent of the time when diagnosing a single breast biopsy slide. Discordance was more likely in cases of ductal carcinoma in situ (DCIS) or atypia, with a tendency toward over-diagnosing disease. The findings were published in Annals of Internal Medicine.

Results of the B-Path Study, an evaluation of diagnostic agreement among pathologists interpreting breast biopsy specimens, raised concerns about the accuracy of breast cancer diagnoses in general clinical practice. However, the study was not intended to reflect population impact. To provide a more clinically relevant assessment of accuracy than previously reported, researchers analyzed the B-Path Study data using U.S. population-adjusted estimates. The researchers estimated the probability that a pathologist’s interpretation of a single breast biopsy slide would be confirmed by a consensus-based reference standard derived from three expert breast pathologists interpreting the same slide. For example, if a single slide from a woman’s biopsy was interpreted as DCIS, how likely is it that her slide would get the same diagnosis from a panel of three expert pathologists?

The researchers found that pathologists were likely to agree on invasive breast cancer diagnoses, but agreement was substantially lower for interpretations of DCIS and atypia. For example, one in five women with an initial diagnosis of DCIS would have her biopsy specimen interpreted as atypia or benign by the reference consensus panel, and half of the women with atypia would have their diagnosis downgraded to benign without atypia.

According to the authors, noninvasive but potentially high-risk breast lesions represent a gray area in medicine; there is not always a “right” or “wrong” diagnosis. They suggest that women with borderline findings may benefit from revised guidelines for clinical treatment and management.

New gene identified as cause, early indicator

When mutated, a gene known for its ability to repair DNA appears to instead cause breast cancer, scientists report.

The gene GT198, whether mutated by genetics and/or environmental factors, has strong potential as both as a way to diagnose breast cancer early and as a new treatment target, said Dr. Lan Ko, cancer biologist in the Department of Pathology at the Medical College of Georgia at Augusta University and at the Georgia Cancer Center at AU.

Mutations of the gene are known to be present in both early onset breast and ovarian cancer. Now scientists have shown that the stem, or progenitor cells, which should ultimately make healthy breast tissue, can also have GT198 mutations that prompt them to instead make a perfect bed for breast cancer. Their studies, published in the American Journal of Pathology, were done on an international sampling from 254 cases of breast cancer in pre- and postmenopausal women.

GT198, which is also a coactivator of receptors for steroid hormones such as estrogen, is normally regulated by estrogen. But once mutated, GT198 can enable tumor production without estrogen. “Regardless of how much hormone you have, it’s out-of-control growth,” Ko said of the resulting classic, rapid growth of cancer.

In a cancerous breast, scientists have seen problems with the various components of breast tissue but could not fully explain why they happened. The tissue, called the stroma, includes fat cells, or adipocytes, that provide padding; fibroblasts, which make the framework for tissue; pericytes in blood vessels, which are contractile cells that help regulate blood pressure; as well as myoepithelial cells comprising the outer layer of the ductal system through which milk flows. The new study shows that mutated GT198 directly affects stem cells found on blood vessels that make these various components of breast tissue.

Next steps include pursuing therapies, including antibodies and herb-derived treatments, that target the misguided progenitor cells, instead of only targeting the cancerous breast tissue they produce, Ko said. “We think the way to treat breast cancer is to target the progenitor cells. We want to kill these cells that are feeding the tumor rather than just killing the tumor cells, which is less effective.”

Ko first cloned the human GT198 gene while a postdoctoral fellow at Harvard Medical School, and subsequent studies by her and others have shown it has multiple roles that also include regulating stem cells, cell suicide and turning other genes off and on.

New staging system emphasizes tumor biology as prognostic indicator

A new breast cancer staging system developed by researchers at The University of Texas MD Anderson Cancer Center finds that tumor biology is a critical prognostic indicator for women who undergo neoadjuvant, or pre-surgical, therapy for breast cancer.

The Neo-Bioscore staging system, published in JAMA Oncology, incorporates HER2 status, thereby allowing for more precise prognostic stratification of all breast cancer subtypes. Understanding a patient’s individual response to therapy could inform clinicians of which patients would benefit from additional therapy.

The new system builds on MD Anderson’s earlier development of a breast cancer staging system, CPS+EG, which incorporates preclinical stage (CS), estrogen receptor status (E), grade (G), and post-treatment pathologic stage (PS).

“Neo-Bioscore, which adds HER2 status, is another piece of the puzzle showing that the biology of breast cancer, with respect to prognosis, is critically important,” says Kelly Hunt, MD, a corresponding author on the retrospective study.

For the study, researchers evaluated 2,377 breast cancer patients from a prospectively maintained database; all were non-metastatic invasive breast cancer patients treated with neoadjuvant chemotherapy. None of the evaluated patients were included in the development or validation of the CPS+EG staging system.

A CPS+EG score was determined for each patient, with HER-2 status added to the model. The novel staging system was constructed by adding a point to the CPS+EG score for HER2-negative tumors.

The researchers determined that the cohort validated previous findings: CPS+EG score improved prognostication of patients. They also discovered that when the Neo-Bioscore was applied, there was a shift from the previous CPS+EG scoring, therefore, more refined stratification in 1,786 (or 75 percent) of patients. This shift reflects the number of HER2-negative tumors in the study. Also, when adding HER2, the improvement was highly significant.