Invasive lobular carcinoma is a cancer that starts in the lobules, an area of the breast where milk is produced. It is normally very sensitive to estrogen-targeting therapies because of high expression of the estrogen receptor protein, but rarely shows high expression of the HER2 protein. Pleomorphic invasive lobular carcinoma is a unique subset of lobular breast cancer that has abnormally aggressive tumor cells and results in poorer outcomes than the classic lobular breast cancer. Recently, alterations were found in the ERBB2 gene in lobular breast cancers that recur after initial treatment. The ERBB2 gene directs the cancer cell to make the HER2 protein which is routinely tested for using standard pathologic techniques.
As part of the precision medicine initiative at the Cancer Institute of New Jersey, investigators — which include colleagues from Rutgers Robert Wood Johnson Medical School and RUCDR Infinite Biologics, the world’s largest university-based biorepository, located within the Human Genetics Institute of New Jersey — wanted to define the relationship of ERBB2 alterations in the pleomorphic form of the disease.
“Figuring out specific differences that are not visible under the microscope allows us to intervene with more appropriate and potentially life-saving therapy. With genomic sequencing detecting ERBB2 alterations in this form of cancer, we have an opportunity to identify anti-cancer therapies that would specifically target that abnormality and that would otherwise not be given to those patients who could benefit. These genomic abnormalities would be overlooked with current, standard of care laboratory testing for breast cancer,” says lead author Kim M. Hirshfield, MD, PhD, breast medical oncologist at the Cancer Institute and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School.
Utilizing the invasive breast cancer data set of 962 cases in The Cancer Genome Atlas, all breast cancers with alterations in the CDH1 gene (that gives instructions to make a protein that causes cancer cells to stick to one another and defines lobular breast cancers) were identified. Tumors were evaluated by a pathologist at the microscopic level to classify them as either classic or pleomorphic lobular breast cancer. Independent identification of ERBB2 gene alterations was completed and frequency of that alteration, as well as others in the PTEN, PIK3CA and TP53 genes, were determined. An additional 16 cases from the Cancer Institute were evaluated using an advanced form of tumor DNA sequencing at RUCDR.
Of 116 eligible breast cancers from The Cancer Genome Atlas, 86 were invasive lobular breast cancer. Of that number, 21 cases were found to be the pleomorphic type. Nine ERBB2 mutations (42.9 percent) and three amplifications (14.3 percent) were found in the pleomorphic type and none were found in the classic type. There were no significant differences in the frequency of the other gene alterations examined between the two types of cancer. With that, investigators say the alterations in the ERBB2 gene strongly associate with pleomorphic lobular breast cancer but not the classic form of the disease. Data from the additional 16 cases from the Cancer Institute validate the findings observed on breast cancers from The Cancer Genome Atlas.
“In identifying a specific abnormality in a patient’s cancer instead of the overall organ where it first presented, the opportunity exists to provide tailored therapies for patients,” notes Lorna Rodriguez, MD, PhD, director of the precision medicine initiative at the Cancer Institute and professor of obstetrics, gynecology and reproductive sciences at Robert Wood Johnson Medical School. “Advances in genomic sequencing are helping clinicians go beyond a ‘one size fits all’ approach for treatment.”
“Along with helping to guide the use of existing treatments, such findings can also aid in developing the next generation of therapies through clinical trials. It is our aim at Rutgers Cancer Institute of New Jersey to build upon this work,” notes senior author of the work, Shridar Ganesan, MD, PhD, associate director for translational science at the Cancer Institute and associate professor of medicine and pharmacology at Robert Wood Johnson Medical School.