Lobular research from the International ILC Symposium 2024

Imagine going through years of clear mammograms only to discover you’ve been diagnosed with a late-stage breast cancer you’ve never heard of — a breast cancer that doesn’t necessarily make lumps or show up on the most common type of breast cancer screening available. 

For the Lobular patients, advocates and medical professionals attending the 2024 International Invasive Lobular Carcinoma (ILC) Symposium, held September 22-25 in Leuven, Belgium, that scenario is all too real.

Sponsored by the Breast Cancer Research Foundation, the Lobular Breast Cancer Alliance (LBCA), Exact Sciences, Dynami Foundation, Lilly, Agendia and others, the fifth ILC Symposium drew more than 150 researchers, clinicians and Lobular patients from Europe, the US, UK, Australia and around the world to learn and share, hear about hopeful discoveries and hash out the pain points and research priorities of long overlooked ILC.

With its imaging issues, lack of Lobular-specific treatments, dearth of clinical trials and data and absence of standardized criteria for diagnoses, all agreed,  Lobular Breast Cancer has problems.

But the scientists, surgeons, providers and even newly diagnosed patients who came together at Irish College in Leuven weren’t there to complain about ILC’s issues. To borrow a phrase from LBCA founder Leigh Pate, they were there to “do something about them.”

The LBCA was Leigh Pate’s brainchild, created to shine a light on ILC’s research and treatment gaps. Since its founding, the organisation has gone on to become the bright beacon of knowledge, community and hope she envisioned; it’s also had a profound influence on the National Cancer Institute and other scientific entities. Lobular is finally on the research radar.

Today, LBCA, European Lobular Breast Cancer Advocates, Lobular Breast Cancer UK, Lobular Ireland, Lobular Breast Cancer Australia and other groups in Norway, Germany, the Netherlands, etc., act as conduits for reliable information, research studies and other collaborations between advocates, researchers and clinicians.

Partnering with science

“One feature that makes this meeting unique is that we actively embrace the participation of patient advocates,” said Dr. Christine Desmedt, head of the Laboratory for Translational Breast Cancer Research at KU Leuven, co-chair of European Lobular Breast Cancer Consortium (ELBCC) and one of the Symposium’s organizers.

“We’ve seen this grow over the years and we want to continue to work together to advance research and care.”

The ILC Symposium draws an even mix of advocates, researchers and clinicians, so patient voices, stories and concerns are shared right alongside the science. Panel discussions, breakout sessions and lectures featured patients and pathologists, surgeons and clinicians, all working to identify obstacles and brainstorm workarounds.

Patient advocates presented posters and acted as research partners on many featured studies. Some continued to contribute even after death through rapid autopsy programs like UPTIDER, housed in Belgium, and Hope for OTHERS, in Pittsburgh.

Lobular Breast Cancer UK funded scholarships for seven Lobular advocates to attend this year’s Symposium and LBCA provided travel scholarships to ten more. LBCA also funded work by KU Leuven clinical researcher Dr. Karen Van Baelen, who urged the scientific and advocate communities to continue to raise their voices to lobby for change. A recent review of breast cancer clinical trials by Van Baelen and the ELBCC found ILC patients “often overlooked” and if they were included, the “documentation was poor.”

“We need objective data on Lobular Breast Cancer in clinical trials,” Desmedt reiterated in her opening remarks. “We need to hammer on the door of the companies running clinical trials to make sure we do better in future years.”

Progress in standardising pathology

Dr. Patrick Derksen, professor of experimental and preclinical oncology at the University Medical Center in Utrecht, The Netherlands, and co-chair of the ELBCC, also stressed the importance of research funding and ILC-specific clinical trials in his Dynami Foundation Leigh Pate Memorial Lecture.

Although ILC has been featured at ESMO, ASCO, SABCS and other major cancer conferences in the last few years, Derksen said there’s a still need for more money and “much more research.”

“We need investigations into therapeutic approaches for preventing recurrence,” he said. “We need way more investigations into what dormancy is, what the cues are that awaken dormant cells.”

There’s also a great need for harmonised diagnosis and treatment of ILC and standardised diagnostic criteria, which the ELBCC and colleagues around the world are working to achieve.

ELBCC’s analysis of breast cancer clinical trials showed that the few trials that included ILC patients lacked specific sub-analyses and didn’t “confirm histological subtype by central pathology.” This and other data led the organization to develop a step-by-step procedure for ILC’s histopathological assessment, published in Modern Pathology. They’re now working to fold it into the World Health Organisation’s Blue Books, used to classify tumors.

A breakout session delved further into the need for standardisation of pathological diagnosis “and how advocates might contribute to moving the research world towards consensus on ILC pathology methods,” said LBCA Executive Director Laurie Hutcheson.

“There was also great promise held out for the use of AI in pathology and in combination with imaging for more accurate ILC diagnoses,” she said. “And that was just on day one.”

Researchers from the ELBCC identified these top clinical challenges and proposed solutions in a poster:

• ILC-subtypes and their clinical impact need to be defined;
• both established and novel breast cancer treatments need to be investigated in lobular populations;
• targeted approaches for ILC’s unique biology need to be identified;
• new standards need to be created to define clinical response for ILC patients with “non-measurable disease”;
• ensure clinical trial designs incorporate analyses of treatments for ILC;
• the utility of liquid biopsy in early disease detection needs to be defined.

“Patient attendees expressed a lot of interest in liquid biopsies,” said Hutcheson, who appeared on several panels. “They’re being promoted now by the pharmaceutical companies producing them, but most of the available tests have not been assessed for utility in detecting recurrence of lobular breast cancer.”

In other words, it’s not yet known what detecting circulating tumor DNA actually means for patients with recurrence.

“What do we do if the test comes back positive?” one oncologist asked during a session on imaging and post-treatment surveillance. “That’s the question.”

Identifying new targets and treatments

Unfortunately, when it comes to clinical and preclinical research, ILC still lags behind other cancers, mainly due to a lack of models and cell lines.

“We don’t have the wide variety of cellular models or patient-derived xenografts or organoids that we have in other cancer histotypes,” said Dr. Chris Lord from the Institute of Cancer Research, London. “Although there has been a great effort to generate model systems. It’s clearly very important.”

University of Pittsburgh researcher Dr. Jagmohan Hooda gave an update on the endowed BCRF biobank Leigh Pate created before her death which is developing new models for ILC research. Overseen by LBCA Scientific Advisory Board founder Dr. Steffi Oesterreich and Institute for Precision Medicine Director Dr. Adrian Lee, also from U-Pitt, and former LBCA SAB member pathologist Dr. Jorge Reis-Filho, now vice-president of cancer biomarker development at AstraZeneca, the repository houses lobular tumor organoids, images, and data that researchers across the globe can tap for studies and trials.

Hooda said the biobank now boasts nine established ILC organoids currently undergoing genomic characterisation. Eventually they’ll be used to “better understand ILC and create effective treatments.”

Other scientists shared their projects designed to identify and test new targets, including:

• research out of the Institute of Cancer Research in London that’s exploring E-cadherin’s various roles and vulnerabilities, and has identified a selective Aurora-A kinase inhibitors as a potential target for metastatic ILC therapy;
• a joint UK and France collaboration investigating the immune landscape of pleomorphic ILC with an eye toward exploiting its vulnerabilities with new immunotherapies;
• a Scottish study delving into the signaling pathways that lead to endocrine therapy resistance,identifying one — Interleuken-6/STAT3 — as a potential driver of endocrine therapy resistance and a target for future treatment;
• a newly launched neoadjuvant trial in the U.S. for early-stage ILC patients with HER2+ mutations combining the kinase inhibitor neratinib with endocrine therapy.

Patient efforts to increase awareness, improve care

In addition to sharing stories of missed symptoms, dismissive doctors, denied scans and other lived experiences, patient advocates highlighted their efforts to raise awareness, improve clinical care and drive more lobular-specific research.

LBCA’s Hutcheson shared progress made by advocates and scientific allies in a poster outlining the organisation’s establishment of October 15 as Global Lobular Breast Cancer Awareness Day, an effort which resulted in government proclamations, press conferences and news stories and a number of events around the world, including LBCA members ringing the opening bell at the Toronto Stock Market and the launch of new Lobular Breast Cancer research and treatment programs at three major cancer centers.

“This year, we informally declared the day,” Hutcheson said. “Next year we’ll strive for even more events worldwide and formal congressional recognition in the US declaring October 15 as Lobular Breast Cancer Awareness Day henceforth, and for as long as it is needed until more study yields better methods of detection, biomarkers, specific treatments and ultimately, a cure.”

And Lobular Breast Cancer UK (LBCUK) co-founder and Chair Claire Turner, part of the Symposium Planning Committe, worked with researchers from University of Aberdeen and De Montfort University in Leicester on a qualitative and quantitative survey that found significant geographical and imaging variations in the clinical care and post-treatment surveillance of lobular patients.

These variations, they wrote, “highlight a clear area for change in guideline recommendations and clinical pathways” and the charity is currently using the data to push for new breast cancer treatment guidelines from NICE (National Institute for Health and Care Excellence) and SIGN (Scottish Intercollegiate Network which set the standards for patient care in the UK.

“Clinical change is a key priority for Lobular patients,” Turner said, “and concerns about imaging, particularly ongoing monitoring and surveillance, is one area that impacts on patients for many years post diagnosis in both primary and secondary [or stage 4] cases.”

Patient advocates also raised awareness through the launch of a digital postcard campaign designed to provide relevant information and improve patient-clinician interactions.

LBCUK advocates and researchers from De Montfort surveyed ILC patients about their treatment experiences and found “health professionals had low awareness of ILC” and that “ILC was not referred to during diagnosis, treatment or ongoing monitoring decisions.”

They created a set of four “postcards” that patients could take with them to their appointments to help bridge this gap, each featuring key facts and questions about ILC diagnosis, treatment, post-surgery treatment and recurrence.

Turner said patients are already downloading the cards from the LBCUK website.

“We’re working to empower patients to be able to get the information they require to make the right decisions about their treatment and the confidence to ask questions about Lobular should they need additional data,” she said.

Advocacy groups have also created educational videos and podcasts, leaflets and flyers in multiple languages, scientific blogs and digital brochures, patient story videos, and Lobular metastasis infographics.

Action plans and next steps

After three days of lectures, bidirectional learning, tasty lunches and lovely walks through historic Leuven, attendees shared key take-home points and identified ambitious next steps for both the research and patient community.

In the realm of pathology, research allies are working to standardize — officially — the criteria for diagnoses of ILC and its subtypes; boost awareness of ILC variants and mixed ILC-Non Specfic Type/Ductal tumors as well as the clinical significance of each; create training programs for pathologists in the use of AI and create AI-driven prediction models for response to therapy and patient outcomes.

In imaging, the list was equally long. All agreed that better modalities for screening and surveillance are desperately needed, but opinions differed as to what was best.

MRIs capture the most breast cancers, but also have the highest false positive rate. They are still considered too pricey and impractical for general screening (except for those at high risk) and are not always an option for surveillance, due to shortages of both machines and radiologists. The gadolinium contrast used in administering MRIs also remains a concern. Some experts recommended abbreviated breast MRI for screening dense breasts, though access is an issue plus the lack of insurance coding in the US means patients are billed for a full MRI. Others promoted new but not yet widely available technologies like contrast-enhanced mammography and whole-body diffusion-weighted MRI.

While mammograms aren’t ideal for capturing lobular tumors, clinicians reminded attendees that mammograms still detect many Lobular Breast Cancers. 

“If you’re not able to access MRIs, screening with a mammogram is still a better strategy than no screening at all,” Hutcheson said.

Risk-adapted, or tailored, screening was also presented as a way to prioritise preventive screening for those with dense breasts and other risk factors.

Fortunately, emerging technologies seem poised to improve the imaging landscape for lobular patients. New tracers for PET scans are in development (some, like FES-PET are already here), which will eventually help with metastatic detection and response to disease. The same for liquid biopsies — not just blood but other biofluids like pleural effusion and abdominal fluid (or ascites) — once their utility is established.

The PLUMB study, led by UCSF surgeon Dr Rita Muktar and currently recruiting, aims to evaluate liquid biopsies’ efficacy in detecting ILC in circulating tumor DNA in a cohort of metastatic ILC patients. And artificial intelligence is also starting to play a role in the detection of both early-stage breast cancer and metastatic ILC.

Tumor dormancy was identified as another gaping hole in ILC research, especially considering Lobular’s “long tail” — the disease can recur as metastatic 20 or 30 years after initial treatment either due to ILC’s slow growth pattern or the reawakening of dormant cells.

Experts want to understand why dormant cells awaken and what might help keep them dormant and said future investigations will look at the role of exercise, BMI/obesity, ethnicity and individual patient biology in maintaining dormancy. Tumor microenvironments also need further study, experts agreed.

Another priority — not just for researchers but for patients — is creating more personalised approaches to prescribing endocrine therapy since “one size does not fit all.” Many unanswered questions remain. Why do some patients develop harsher side effects from endocrine therapy than others? And why and how in some patients does Lobular develop resistance to this type of therapy (and others)?

The list of ILC research priorities — and yes, daunting problems — went on and on. But few in attendance seemed discouraged.

Instead, patients, clinicians and researchers were inspired by the progress made over the years, fully embracing Leigh Pate’s life philosophy of not just sitting around complaining about problems but doing something to resolve them.  

At the symposium’s close, Dr. Christine Desmedt thanked all for their hard work and announced that the next ILC Symposium will be in San Francisco in 2026, noting “that will give us more time to focus on the science.”

See you there.