To determine how to most effectively treat a cancer subtype, researchers and clinicians must come to understand all characteristics associated with that particular type of cancer. Despite being the second most common histological subtype of invasive breast cancer in the U.S., invasive lobular carcinoma (ILC) is known to have worse outcomes than invasive ductal carcinoma (IDC) or no special type.
Contributing to these outcomes, the American Cancer Society reports that ILC may be harder to detect on physical exams and imaging like mammograms, than invasive ductal carcinoma, while it accounts for about 1 in 10 invasive breast cancers. Hoping to shed light on this understudied breast cancer type, a multi-center analysis of patients with ILC was recently conducted using records from three large cancer centers.
Studying more than 33,000 patient records from 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), the research published in the Journal of the National Cancer Institute highlighted several important differences between ILC and IDC (2022; https://doi.org/10.1093/jnci/djac159). Specifically, their analysis demonstrated that ILC and IDC are biologically distinct, leading to the need for specific detection and treatment options for the lobular subtype.
Representing OSUCCC - James, Nicole O Williams, MD, a medical oncologist who specializes in managing the treatment of patients with breast cancer, shared that her team became involved in this study because Ohio State has a number of patients with ILC. Williams' team wanted to assess ILC patients' diagnosis, stage of diagnosis, and treatment outcomes as compared to IDC patients. She recalled discovering at the Great Lakes Breast Cancer Symposium that each involved institution was essentially looking to answer the same question.
"We combined our data because we knew we would have a larger number of patients and could derive more meaningful conclusions from the data," Williams explained. "We looked at data diagnosis, stage, grade, ER, PR, HER2 status, type of surgery, radiation treatments, chemotherapy, endocrine therapy, and recurrences as well. We developed the same data collection for all three institutions so that the data could be easily combined together."
Representing UPMC Hillman, Steffi Oesterreich, PhD, co-leader of the Cancer Biology Program at the cancer center and Professor at the University of Pittsburgh School of Medicine's Department of Pharmacology & Chemical Biology, added that her team had been working on ILC for almost a decade prior to this study. They similarly wanted to understand more about the cancer subtype's unique clinicopathological features.
Then, one day Oesterreich was listening to a recording from a meeting of the Lobular Breast Cancer Alliance, which at the time was directed by a patient advocate, the late Leigh Pate. This ultimately led to her team's direct involvement in this study. Susan MacDonald, a patient advocate at the Cleveland Clinic, had mentioned to her that investigators at her facility were starting to do an ILC study, and Oesterreich immediately reached out to them (and then OSU) to collaborate, increasing data numbers.
"Merging the data, having all the necessary paperwork in place to share data, and organizing meetings and phone calls for the different collaborators undoubtedly made the study more challenging and added time-but I think it was the right thing to do," Oesterreich said. "Collaborations are hard but make science so much better!"
Oesterreich said this team effort was especially important to the field as the research community has historically neglected lobular breast cancer for many reasons. First, she explained that this type of cancer "only" accounts for 10-15 percent of all breast cancers, and thus it may have been tempting for researchers to exclude those cases in order to have a homogenous group "necessary for statistical power, which then allows conclusions."
"Second, we had fewer models and thus weren't able to study the disease," Oesterreich explained. "Finally, there was (and still is) the general thought that ILC is just another estrogen receptor-positive breast cancer which is not any different to estrogen receptor-positive IDC."
Wanting to make use of large data within the UPMC system, Oesterreich recognized the opportunity for collaboration with two other centers and was excited as larger data numbers are better if data can be combined. She said the majority of the data came from the institutions' cancer registries, and thus are national data standards, according to the North American Association of Central Cancer Registries.
When extracting data from cancer registry records, her team assessed different clinical features of the tumor (and also the patient) at the time of diagnosis, different treatments, and different outcomes. Also, since the data in use was collected over a long time frame, they were able to look at changes across time.
During their research, Oesterreich recalled that, at the time of diagnosis, the ILC tumors were larger and the tumor cells had more frequently invaded the lymph node, a sign of increased metastatic potential. The grades of ILC tumors were lower, likely due to slower growth of the lobular cells, which is a factor when determining grade.
"Rates of mastectomies were higher for ILC, while we did not detect different use of chemotherapies despite the general thought that chemotherapy has less efficacy in ILC," Oesterreich said. "Long-term outcome in patients with ILC was worse compared to IDC, despite fewer ILC tumors being characterized as aggressive when using molecular tests."
"We found in our study that invasive lobular breast cancers were diagnosed at a later stage, so we saw twice as many Stage III and Stage IV patients. We saw that the diagnosis of ILC was associated with larger tumors, older age, lower grade, and then ER, PR positivity and low HER2 positivity," added Williams. "We also saw that patients with lobular cancer were more likely to have nodal involvements than patients with invasive ductal cancer, and so we classify that as N2 or N3."
Williams shared that they also looked at estrogen-positive cancers and saw that patients with ILC tended to have their disease return. Patients also had a decreased overall survival rate as compared to patients with ER-positive breast cancer.
"I think this is because women who have breast cancer don't always have cancer present itself as a mass. One of the hallmarks of breast cancer is that it loses its anchoring protein, so the cancer cells don't bond with the surrounding cells and tend to grow more in lines," Williams explained. "So oftentimes, these cancers are diagnosed at a later stage, and we're also seeing in surgery that they're found to be larger and have more lymph nodes involved than what we saw on the initial imaging."
From this study, Williams emphasized that a major takeaway was that invasive lobular breast cancer is a different subtype or disease entity than invasive ductal cancer. Although they are treated similarly with surgery and chemotherapy, and if they're deemed to be high-risk enough [for] endocrine therapy, there's a definite need for individualized therapies for patients with ILC. Better tools are needed to identify which patients may benefit from chemotherapy.
While Oesterreich confirmed that treatment options for ILC and IDC do not differ, she said there might be some changes in the management of patients, in that physicians start to consider the increase in late recurrences, unique sites of metastases, and challenges with imaging in their decision-making. She explained that more research in ILC imaging and biomarker development is needed to come to any additional conclusions.
"Increased research efforts and increased patient advocacy for ILC over the last 5-10 years have resulted in more research in ILC," Oesterreich said. "Things are definitely moving in the right direction. But we need to do more as the goal is to have personalized treatment for the different histological subtypes, and we need to identify treatments targeted at the unique behavior of the tumors."
"We need to do more molecular characterization of the tumors because we know that ILC cancers have a specific genomic profile compared to invasive ductal cancers. We can use that information to tailor clinical trials," Williams said.
Additionally, Williams shared that from a treatment standpoint, she believes researchers need to start designing trials looking at invasive ductal cancer and ILC. She also believes there exists a need to develop better screening tools for women with ILC.
According to Oesterreich, questions still need answering. What could be causing them to hibernate somewhere in the body until they are reawakened? Why are more tumors coming back later for patients with ILC?
Lindsey Nolen is a contributing writer.