Multicenter analysis sheds light on invasive lobular carcinoma
A multicenter analysis of patients with invasive lobular carcinoma, or ILC-; the second most common histological subtype of invasive breast cancer in the United States; showed that, despite its prevalence, ILC is detected later and has worse outcomes than the predominant subtype of invasive breast cancer, known as invasive ductal carcinoma (IDC), or no particular type.
Published today in the Journal of the National Cancer Institute, the study of more than 33,000 patient records from three major cancer centers -; UPMC Hillman Cancer Center, Cleveland Clinic Cancer Center and The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) -; shows that ILC and IDC are biologically distinct, highlighting the important differences between the two diseases and the need for specific detection and treatment options for the lobular subtype.
“Lobular breast cancer accounts for about 10-15% of breast cancer cases, but it has always been overlooked by the research community, so we don’t know much about it,” the co said. -author Steffi Oesterreich, Ph.D., Co-Lead of the Cancer Biology Program at UPMC Hillman and Professor in the Department of Pharmacology and Chemical Biology at the University of Pittsburgh School of Medicine. “There has been a growing awareness that ILC and IDC are distinct, but this large, multicenter study provides compelling evidence that they are two different diseases that require different management.”
Co-lead authors Megan Kruse, MD, a medical breast oncologist at the Cleveland Clinic, and Nicole Williams, MD, a breast medical oncologist at OSUCCC-James, worked with Oesterreich to analyze the records of patients treated in the three cancer centers for ILC or IDC between 1990 and 2017.
These results probably indicate that the detection of lobular breast cancer is delayed. When these tumors are finally detected, they are larger and have already moved to the lymph nodes, indicating that the cancer is spreading. We need to put more effort into improving the early detection of ILC by developing new imaging technologies or other methodologies.”
Megan Kruse, MD, Medical Breast Oncology Specialist, Cleveland Clinic
The idea for the study came about one evening while Oesterreich was washing the dishes and listening to a recording of a Lobular Breast Cancer Alliance conference call she had missed. When Susan MacDonald, a lobular breast cancer advocate from Cleveland, mentioned that Cleveland Clinic researchers were beginning a project to analyze the center’s breast cancer registry, Oesterreich’s ears perked up.
“I thought, ‘Wow, we did the exact same thing at UPMC. It would make sense to collaborate and work together,'” Oesterreich said.
The main feature of ILC is the loss of a gene called E-cadherin that helps cells stick together. As a result, lobular cancer cells grow in rows, producing tumors that look more like cobwebs than the familiar round masses of IDC, Oesterreich explained. These web-like tendrils make ILC difficult to spot on mammograms until the cancer has grown and often advanced.
The analysis revealed that the ILC cells were of lower quality than the IDC cells, meaning they looked more like normal cells. However, ILC tumors were diagnosed twice as often as stage III or IV-; advanced stages in which cancer cells have spread beyond the breast tissue to the lymph nodes or metastasized to other parts of the body. Lobular tumors were also larger in size than their ductal counterparts.
The researchers limited the next part of their analysis to patients with tumors that carry estrogen receptors and lack the HER2 receptor. They found that patients with lobular cancer had worse disease-free survival and overall survival. ILC patients also had more disease recurrences than those with IDC, and recurrences tended to occur later.
“In other words, more tumors come back, and they come back later for patients with ILC,” explained Oesterreich, who also holds the Shear Family Endowed Chair in Breast Cancer Research and is co-director of the Women’s Cancer Research Center. , a partnership between UPMC Hillman and the Magee-Womens Research Institute. “This suggests that tumor cells hibernate somewhere in the body until they wake up. We need to find where these cells hang out and why they wake up.”
A commercially available advanced genomic test called Oncotype DX has been used to predict risk of recurrence and response to chemotherapy in patients with early-stage, estrogen receptor-positive, HER2-negative breast cancer.
The analysis revealed that there was a significant association between the Oncotype DX score and cancer recurrence in patients with IDC. Very few cases of ILC have been classified as high risk, despite having later recurrences, highlighting the need for specific molecular tests that improve predictions of lobular breast cancer.
“Lobular breast cancer and ductal breast cancer are two distinct diseases. Our study shows that lobular breast cancers are diagnosed at a more advanced stage and have an increased risk of recurrence. However, invasive lobular cancer was less likely to be classified as high risk by a commonly used genomic test,” Williams said. “Despite their differences, these cancers are often treated in the same way. We hope these findings will spark research aimed at developing new diagnostic tools and new drugs to improve outcomes for patients with lobular breast cancer.”
Other researchers who contributed to the study were co-first authors Azadeh Nasrazadani, MD, Ph.D., and Jian Zou, MS, both of Pitt or UPMC; Neil Carleton, BS, Yujia Li, BS, Kathryn Demanelis, Ph.D., George Tseng, Ph.D., Adrian V. Lee, Ph.D., all of Pitt or UPMC; Tiffany Onger, MD, and Matthew D. Wright, MD, both of the Cleveland Clinic; and Bhuvaneswari Ramaswamy, MD, of Ohio State University Wexner Medical Center.
This work was supported by the Breast Cancer Research Foundation, the National Cancer Institute of the National Institutes of Health (P30CA047904, P30CA016058 and 1F30CA264963-01), Susan G. Komen, The Henry L. Hillman Foundation, via The Hillman Fellows for Innovative Cancer Research, Gianna Bonadonna Breast Cancer Research Fellowship 2019 awarded by Conquer Cancer, The MacDonald Fund at Cleveland Clinic, and the Anderson Breast Cancer Fund at OSUCCC.
ExactSciences/Mdxhealth, the maker of Oncotype DX, reviewed the manuscript but had no input on study design or analysis.