Breast cancer genomic analysis reveals invasive lobular carcinoma subtypes

The study findings, published in the journal Cell, stemmed from a large, comprehensive, genomic analysis of breast cancers. The study was the latest effort for a single tumor type coming from The Cancer Genome Atlas, a federally-funded, multi-institution effort to map the genetic mutations in cancer. The study involved the analysis of genetic and molecular patterns in more than 800 breast cancer samples -- including 127 samples of invasive lobular carcinoma, a disease that's been studied on a limited basis in previous genomic studies.

"We revealed that invasive lobular carcinomas are genetically distinct, and that there are biologically defined subgroups of the disease that could have important clinical implications," said the study's senior author Charles M. Perou, PhD, a UNC Lineberger member and the May Goldman Shaw Distinguished Professor of Molecular Oncology. "Lobular cancers are not a single homogeneous group, but may represent at least three different diseases that appear to differ in their microenvironmental features, and which also show differences in outcomes."

Invasive lobular breast cancers represent about 10 to 15 percent of invasive breast cancers, and are the second most commonly diagnosed invasive breast histological type behind invasive ductal carcinoma. They develop in the milk-producing glands of the breast, according to the American Cancer Society. This cancer type is harder to detect, and can pose challenges to the surgeon in identifying the extent of the cancer, said Lisa Carey, MD, co-director of the UNC Breast Center, physician-in-chief of the N.C. Cancer Hospital, and the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research.

"We treat them similarly to their more common ductal counterparts, but in part because that is because we have a poor understanding of the biology underlying lobular carcinomas," Carey said. "Gaining insight into the molecular basis for lobular breast cancer may allow us in the future to tailor treatments specifically for them."

Based on gene expression data, TCGA researchers identified three subtypes of the disease. Patients with the "reactive-like" subtype had significantly better overall survival compared with patients with the "proliferative" subtype. And while the researchers did not find significant differences in survival for patients in the third "immune-related" group, they did find that those patients had higher levels of immune system-related functions and high expression of a number of oncology drug targets.

"Now that we have these important new subgroups of invasive lobular carcinoma, we can go in in and try to validate some of the findings about differences in outcome, and see if these new genomic classifications make a difference in terms of patient's responsiveness to drugs," Perou said. "This is how personalized medicine is developed."

The study also reaffirmed a previous finding that loss of the function of a molecule called e-cadherin is the hallmark of invasive lobular carcinoma, and it uncovered new mutations in genes that regulate estrogen receptor signaling in these cancers.

"Estrogen receptor signaling is a driver of breast cancer growth for most breast tumors, including lobular cancers," Perou said."We found that there are known regulators of estrogen receptor signaling that are mutated in these cancers. One of these looks to be mutated in lobular cancers, and that's a gene called FOXA1, and another is mutated in ductal cancers, and that's a gene called GATA3. This could eventually tell us something about the responsiveness of these cancers to hormone therapy."

The researchers also found increased activity of a signaling pathway called the PI3K/Akt pathway in invasive lobular carcinomas. Based on the findings, the researchers believe that investigative drugs that target this pathway may be a particularly attractive for this breast cancer type.

"This work in The Cancer Genome Atlas has been incredibly helpful and enlightening because it's now providing us the genetic blueprint of breast cancers, and more specifically in this case, lobular breast cancers," Perou said. "We now know which genes are mutated, and which genes aren't, which pathways are activated, and which pathways aren't, through this incredibly comprehensive look at these tumors. The whole playing field is illuminated -- we know who the players are -- the challenge is now to translate this into improvements in patient care."

More than 200 authors collaborated on this study, which was supported by funding from The Cancer Genome Atlas project, an NCI Breast SPORE program grant, and the Breast Cancer Research Foundation. Specific authors also received funding support.