Building a System of Focused Care for Lobular Breast Cancer

 

How Dana-Farber investigators are pioneering new approaches to help understand, diagnose, and treat this distinct form of breast cancer

In the 1940s, two pioneering pathologists published the first detailed accounts of an unusual form of breast cancer. Using the most advanced tools of the day — a microscope and a trained human eye — they scrutinized cancer cells in a surprising region of the breast. While tumors were well known to arise in the ducts, which carry milk from its production hubs to the nipple, these cancerous cells appeared within the lobules, where milk is produced. The unique subtype had other curious features. The tumor cells appeared loose, less cohesive, and grew in a hallmark single-file pattern.

A half-century would pass before the biological underpinnings of this unusual pathology became clear, namely: the loss of a key protein (called E-cadherin) that helps cells adhere to each other — a finding that helped explain the striking linear features the pathologists observed. And another 20 years would pass before a large-scale analysis, harnessing the power of genomic technologies, shed light on the molecular landscape of this breast cancer subtype — known as invasive lobular carcinoma (ILC) — and helped cement it as a distinct biological entity.  

"Within the past decade, it's become increasingly clear that lobular breast cancer is a unique disease that is biologically distinct from other forms of breast cancer," said Rinath Jeselsohn, MD, a breast medical oncologist and director of the new Invasive Lobular Breast Cancer Program at Dana-Farber. "Because of this, it requires its own attention and investigation, both from a preclinical and clinical standpoint."

 

 

ILC accounts for roughly 10 to 15% of all breast cancers, and an estimated 33,600 women are diagnosed with the disease each year, according to a 2025 report by the American Cancer Society. The report also underscores a concerning trend: the incidence of ILC has increased more steeply each year since 2012 (2.8%) than that of all other forms of breast cancer combined (0.8%).

These developments, along with the momentum in both the laboratory and clinic to understand ILC as a distinct subtype, helped propel the launch of Dana-Farber's Invasive Lobular Breast Cancer Program in 2024 — one of the only programs of its kind in the U.S. It brings together advanced clinical expertise with world-leading research capabilities to improve the care of patients with ILC. "The program includes several key initiatives, including a dedicated patient registry as well as clinical trials focused on ILC, which are currently under development," said Jeselsohn. "This will enable us to study ILC as a distinct form of breast cancer and create opportunities tailored to our patients with ILC."

 

Detecting Lobular Cancer

A defining feature of ILC is the loss of the cell adhesion protein, E-cadherin — a discovery that emerged in the 1990s. This biology has implications not only for how tumor cells behave, but also for their structure and, importantly, for how the disease is detected.

"One of the big frustrations for patients with ILC right now is screening," said Kristina Fanucci, MD, MHS, a breast medical oncologist at Dana-Farber who specializes in ILC. "Because these tumors tend to emerge more in sheets or spidery infiltrations, they don't usually form a discrete mass, which makes them harder to pick up on a screening mammogram."

These detection challenges mean that ILC tumors are more often identified at a more advanced stage compared to ductal tumors (now known as "no special type").  

"So ILC patients often feel that these screening measures have failed them because their tumors are at a bigger size when they are found," said Fanucci. "I think there's also a lot of concern that the treatments we have for ILC are not going to be effective because they haven't been developed specifically for patients with that subtype. While there are specific treatments that were shown to be less effective in ILC in certain settings, there is evidence that many of the medicines we have are very helpful for ILC."

Treatment Targets

Fanucci, Jeselsohn, and their colleagues are working to gain a deeper understanding of the molecular vulnerabilities of ILC tumors. These insights can drive new ideas about which existing drugs might target these vulnerabilities, and in turn, help clinicians determine which patients' tumors are likely to respond well to which treatments.

For example, at the San Antonio Breast Cancer Symposium (SABCS) in 2025, Jeselsohn and her colleagues presented two studies of patients with metastatic forms of ILC. Using a variety of analytic methods, including genomic, transcriptomic, and immune profiling, the researchers identified molecular signatures in ILC that help illuminate its unique biology and suggest potential therapies that could target this breast cancer subtype.

Compared with tumors of no special type, the researchers found that metastatic ILC tumors have higher rates of mutation in several genes, including PI3K (also called phosphatidylinositol 3-kinase), which is involved in cell growth; FOXA1, which plays a role in estrogen receptor function; and ERBB2, the gene that encodes the HER2 protein.

The team is now working to apply these insights toward designing a new slate of clinical trials that will test potential therapies targeting these vulnerabilities specifically in patients with ILC.

"There are many open questions in the field right now," said Jeselsohn. "We need to better understand the biology of ILC and develop tools to determine which ILC patients are most likely to benefit from specific treatments."

Biology of ILC

Despite the relatively recent recognition of ILC as a distinct subtype, Dana-Farber investigators have been forging a path toward ILC-focused insights for their patients for several years. Ten years ago, Otto Metzger, MD, and his colleagues launched an investigator-initiated trial called PELOPS (Palbociclib and Endocrine therapy for Lobular breast cancer Preoperative Study). This phase 2, randomized study enrolled more than 180 patients, about half with ILC. In the first “window” phase, patients received either tamoxifen (a selective estrogen receptor modulator, or SERM, that blocks the effects of estrogen) or letrozole (an aromatase inhibitor that interferes with estrogen production), both forms of so-called endocrine therapy. Then, they were re-randomized to receive either endocrine therapy alone or endocrine therapy combined with palbociclib (a CDK4/6 inhibitor). The initial data from the trial were presented at SABCS in 2024 and are now being prepared for publication.

"This trial is noteworthy for a few reasons, but perhaps most significantly, it is the first prospective clinical trial of endocrine-based therapies focused on ILC," said Metzger.  

Metzger, Jeselsohn, and their colleagues found that while there was molecular evidence to suggest that an aromatase inhibitor works better than tamoxifen in patients with ILC, there were no meaningful clinical differences when compared to no special type (NST) breast cancer. However, when they looked more comprehensively at patient tumor samples using transcriptomic technologies, they noted differences between ILC and NST tumors across the two treatment groups.

"The results are not practice-changing, but they are telling us that the estrogen receptor axis in ILC is different from NST breast cancer, which is confirming our preclinical data as well," said Jeselsohn.

In separate laboratory research, she and her colleagues conducted extensive molecular analyses on ILC cells and found that the suite of genes activated by the estrogen receptor is distinct in ILC compared with NST. Together, the studies provide mounting evidence that the estrogen receptor axis — the collection of molecules and signals that kick into gear once estrogen binds to its receptor — is unusual in ILC tumors compared to NST. "It's not clear yet what this means clinically, but it is an active area of ongoing work for us," Jeselsohn said.

One possibility is that the activity of novel endocrine therapies — some are now FDA-approved, others are in clinical trials — may differ in ILC compared with NST breast cancer.

Imaging and Theranostics

Another area of interest in ILC is theranostics, which involves the use of a radioactive medicine to both diagnose and treat a tumor. This type of medicine, also known as a radioligand, has two key parts: a targeting portion that binds to a specific target on cancer cells, and a radioactive portion, which releases energy that either helps create images (for diagnosis) or destroys the tumor (for treatment). This is a rapidly growing area in oncology, driven by the remarkable success of a handful of theranostic agents in both prostate cancer and neuroendocrine tumors. As a result, researchers are now investigating a variety of new molecular targets.

"That's really promising because these targets may also be present in lobular breast cancer as well as other types of breast cancer," said Heather Jacene, MD, clinical director of nuclear medicine at Dana-Farber. Researchers at Dana-Farber are launching several clinical trials to test different theranostic agents in breast cancer, including ILC.

The excitement in this area — for ILC and for other cancer types — is not simply because of the prospect of new molecular targets being added to the armamentarium of anticancer drugs.

"For a lot of cancer treatments right now, you do a single biopsy of a tumor to look for a target, but that gives you a view of the tumor in just that one location," explained Jacene. "With theranostics, you get images that allow you to look across the entirety of the tumor, which allows you to see how much of a target is present throughout and then to predict whether the patient may or may not respond to a drug against that target."

In addition, the diagnostic side of theranostics has yielded an important advance. A new radioactive tracer, fluoroestradiol (FES), which was approved by the U.S. Food and Drug Administration in 2020, is allowing clinicians to visualize lobular tumors. These tumors can be challenging to detect with standard imaging tests, including PET-CT scans.

"This imaging modality, known as FES-PET, can enable the detection of metastatic lesions in ILC that might otherwise go undetected with standard imaging," said Jeselsohn. As of last year, NCCN guidelines, the recognized standard for cancer care, now recommend FES-PET for patients with recurrent or metastatic ILC. Jeselsohn is also leading a newly opened clinical trial, called FES Track, to investigate how the new imaging method is changing treatment decisions in breast cancer, including ILC.

"Even though theranostics and the principles of nuclear medicine have been around for over 85 years, they’ve had a fairly small footprint," said Jacene. "But now, this area is growing rapidly. And it's incredibly exciting to bring more effective tools and therapies to patients — including those with ILC."

By Nicole Davis, PhD