RESEARCH

FUNDED PROJECTS

 2021-2023

Experts in Invasive Lobular Carcinoma of the Breast Partner to Bridge Their Findings

University of Colorado Cancer Center, University of Michigan

The Dynami Foundation is supporting a first-of-its-kind collaborative project to learn more about the genomics of invasive lobular carcinoma of the breast (ILC), bringing together scientists at the University of Colorado Cancer Center and the University of Michigan Rogel Cancer Center to study anti-estrogen response and resistance in ILC.

ILC is the most common special histological subtype of breast cancer and will be diagnosed in around 40,000 U.S. women annually. For years, ILC has received limited attention in clinical and basic research, owing in part to the fact that ILC typically presents with tumor biomarkers suggesting ILC are a “low-risk” disease that will respond to anti-estrogen therapies like tamoxifen and aromatase inhibitors. However, recent research shows that patients with ILC face higher risks of disease recurrence, particularly years after the completion of anti-estrogen therapy. New research is needed to understand and address this phenomenon of “late recurrence”.

Work at the CU Anschutz Medical Campus led by Matthew Sikora, PhD, assistant professor of Pathology, has shown that the “estrogen receptor”, which drives cellular response to the hormone estrogen and is targeted by anti-estrogen therapies, in fact, has distinct function in ILC cells. The Sikora Lab found that ER functions central to tumor growth and anti-estrogen resistance may be driven in part through ER interactions with a novel partner protein termed MDC1. ER and MDC1 cooperate specifically in ILC cells, which the lab found was critical for ILC cell growth and anti-estrogen resistance.

Independently, a team at the University of Michigan Rogel Cancer Center led by James Rae, PhD, and funded by the Dynami Foundation, has developed models of treatment response and resistance specifically in advanced or recurrent ILC. These models allow the Rae Lab to dissect how ILC cells develop resistance to both anti-estrogens, the front-line treatment, and newer CDK4/6-inhibitors like Palbociclib, which are the current state-of-the-art for second line therapy for recurrent breast cancer. The Rae Lab has identified potential causes of therapy resistance in these models, but the cellular mechanisms that facilitate the development of resistance remain unclear.

The collaborative project funded by the Dynami Foundation will support a new collaboration between CU and UM to allow the Sikora and Rae Labs to bridge their findings. Their joint project will determine how the genomic activity of ER and MDC1 in ILC cells lead to the development of anti-estrogen resistance, and whether this subsequently mediates CDK4/6 inhibitor resistance. The labs will work together to examine how ER:MDC1 genomic activity can be used to predict treatment response vs resistance in patient tumor samples, and similarly whether this information can treatment decisions in the advanced/recurrent ILC setting.

Tumor-type specific estrogen receptor activity drives therapy resistance and recurrence in invasive lobular carcinoma

University of Colorado Anschutz Medical Campus: Matthew J. Sikora, PhD

University of Michigan: James M. Rae, PhD

Invasive lobular carcinoma (ILC) is uniquely tied to the hormone estrogen. Nearly all ILC contain the estrogen receptor (ER) protein, which is activated by estrogen and drives tumor growth, and ILC is the breast cancer type most strongly linked to estrogen exposure. However, our work shows ER function is distinct in ILC compared to other breast cancers. This manifests in part as resistance to anti-estrogens and increased risk of long-term ILC recurrence years after treatment. We found that ER works with unique “partner” proteins in ILC cells, and that these ILC-specific ER partners drive ILC cell growth and facilitate anti-estrogen resistance. This project will develop a genetic “signature” for the action of ILC-specific ER partners and use this signature to understand how ILC-specific ER activities are associated with clinical treatment responses. We will also examine how ER partner proteins in ILC contribute to the development of treatment resistance and disease progression, toward developing new strategies to target ILC-specific functions of ER.

Mechanism and detection of lobular cancer cell transformation

Jacqueline S. Jeruss and Lonnie D. Shea

Patients with lobular breast cancer can be diagnosed with advanced disease and also develop late onset recurrences from 5-10 years after initial treatment. These characteristics are influenced by the capacity for ILC to remain dormant for an extended time period. The dormant ILC cells are elusive to detection with current diagnostic systems, evade immune surveillance, and are relatively resistant to chemotherapy.

Paget’s description of cancer over 100 years ago described the need for both “seed” and “soil,” with the seed referring to the tumor cells and the soil being the niche in which the cells reside. Niche signals can induce ILC to escape dormancy and resume proliferation with subsequent metastatic outgrowth. Immune cells, in particular, can signal to ILC tumor cells to influence cell responses, and ILC has a relatively high activity for almost all types of immune cells.

We are investigating the signals from immune cells within the niche that influence ILC proliferation and migration – two factors related to tumor cell dormancy. We are also applying a novel device that functions as a synthetic niche, from which we can identify key signals prior to disease progression. This synthetic niche can also serve as a novel tool for monitoring ILC recurrence.

The findings of the 2018 research project (“Molecular Refinement of Invasive Lobular Carcinoma Definition in Tissue and Liquid Biopsies”) were presented as a poster presentation at the prestigious San Antonio Breast Cancer Symposium in 2022. View the full poster

Serial monitoring of circulating tumor cells and circulating tumor DNA in metastatic lobular breast cancer identifies intra-tumor heterogeneity and precision and immuno-oncology biomarkers.

Reconstructive Decision Making in Lobular Breast Cancer

Dr. Paige Myers and Dr. Faisal Al-Mufarrej

The nuances of breast cancer care for women with lobular cancer are often overlooked due to similarities with ductal carcinoma, although the differences in these pathologies may play a greater role in patient decision-making than we realize. Though there are similarities to ductal carcinoma in-situ (DCIS) and infiltrating ductal carcinoma (IDC), there are very distinct features, such as size, laterality, age of presentation, and recurrence rate. There is a paucity of research describing the differences in reconstruction for women with lobular breast cancer compared to ductal. Breast reconstruction is extremely personal and sensitive as optimal treatment depends on individual goals as well as clinical factors specific to the type of cancer. Without dedicated investigation into the reconstructive decision-making process of women with lobular carcinoma, the needs of a significant portion of patients with breast cancer are ignored.

We are investigating patient-centered reconstructive decision-making in women diagnosed with lobular carcinoma in-situ (LCIS) and infiltrating lobular carcinoma (IL) to determine how the unique clinical factors of this pathology impact decision-making compared to DCIS/IDC. We will obtain data on patients from Michigan Medicine and Kormanos Cancer Institute and compare reconstructive treatments. We are studying the largest reconstructive patient data set comparing both clinical and patient reported outcomes between lobular and ductal pathology. Finally, using a validated breast reconstruction survey regarding decision making, we will compare patients who received reconstruction with each type of pathology at these sites.

The impact of this research will be to improve the patient experience and decision-making process considering the differences in individual breast cancer pathology, specifically lobular and ductal cancers. This will result in better patient care as well as patient understanding and satisfaction with their breast reconstruction journey.

Breast cancer risk among Black women with prior history of benign breast disease

Dr. Versha Pleasant

Compared to Whites, Blacks are 40% more likely to die from breast cancer. Black individuals are twice as likely to be diagnosed with triple negative breast cancer, are more likely to be diagnosed with inflammatory breast cancer, and have increased rates of early onset breast cancer. One area that remains understudied in this population is benign breast disease. While most benign breast disease does not increase the future risk of cancer, there is no data specifically demonstrating this in Black women given their higher likelihood of more aggressive breast cancer. Furthermore, while not considered precancerous lesions, high-risk lesions such as atypical hyperplasia and lobular carcinoma in situ (LCIS) carry an increased future risk of breast cancer. There is a paucity of data on the future risk of non-invasive or invasive cancer among Black women with these high-risk lesions versus their White counterparts. Our study aims to examine the risk of breast cancer among Black women with benign breast lesions. We will examine both those with both classically low- and high-risk breast lesions. This study could have implications on our future care of Black women with benign breast disease and could inform preventive care in this population.

2019

The 2019 Uncork For a Cure support has awarded four critical research projects to further understand Invasive Lobular Breast Cancer (ILC), a poorly understood, and understudied subtype of hormone positive breast cancer.

Atypical Invasive Lobular Carcinomas: Pathologic Features, Clinical Outcomes, and Biomarkers of Metastasis

University of Michigan: Celina G. Kleer, M.D.; Lynn Henry, M.D., Ph.D.

University of Pittsburgh/UPMC Hillman Cancer Center: Steffi Oesterreich, Ph.D.

Invasive lobular breast cancer is a subtype of breast cancer that occurs in 5-15% of women with breast cancer. Most invasive lobular breast cancers are driven by hormones and are generally not very aggressive. However, a subset is more aggressive, and tends to be those which do not express estrogen receptors and those that do overexpress the HER2 receptor.  We will perform a pilot study to learn more about these unusual lobular breast cancers. In particular, we are going to describe the characteristics of the atypical lobular cancers that have been diagnosed at the University of Michigan (UM) and the University of Pittsburgh (UPMC), and will investigate which characteristics are present more commonly in patients whose cancers recur. Finally, in order to better understand why some of these cancers are more aggressive, we will look for specific changes in the cancer cells by examining these cancers under the microscope in the laboratories of Drs. Celina Kleer (UM) and Steffi Oesterreich (UPMC). By learning more about these less common but more aggressive lobular breast cancers, we hope to identify new, more effective treatment options, which may lead to a lower likelihood of breast cancer recurrence in the future.

ELUCIDATING THE MECHANISM OF CDK4/6 INHIBITOR-MEDIATED RADIOSENSITIZATION OF ER+ BREAST CANCERS

Despite treatment that includes targeted therapy and radiation (RT), many women with aggressive forms of breast cancer (BC) will experience a recurrence, including women with lobular breast cancer as lobular breast cancer is more likely to metastasize to the surrounding lymph nodes. Our previous work focused on identifying ways in which RT can be more effective for aggressive forms of BC, including in lobular breast cancer. One strategy identified by our group is to use CDK 4/6 inhibitors to help radiation work more effectively. Our group was the first to report the finding that CDK 4/6 inhibition combined with radiation may be an effective radiosensitization strategy. With the funding provided, we are extending these studies to better understand how CDK 4/6 inhibitors and radiation may be used to more effectively treat women with invasive lobular breast cancer. We are determining the mechanism by which CDK 4/6 inhibition confers radiation sensitivity and this will hopefully extend the indication of CDK 4/6 inhibition for women with lobular breast cancer. Based on these studies, we hope to have a rationale to run a clinical trial to determine the safety and efficacy of CDK 4/6 inhibitors with RT in women at high risk for developing BC recurrence, including women with lobular breast cancer.

Conclusions: Our preliminary data suggests that CDK4/6-induced radiosensitization may be effective in ER+ breast cancer models, including models of lobular breast cancer, prior to the development of CDK4/6 inhibitor resistance. The proposed studies provide the preclinical rationale for clinical trials to test combination RT and CDK 4/6 inhibition in women with locally advanced ER+ breast cancer at high risk for locoregional recurrence, including women with lobular breast cancer.

Collaborative Approaches to Improve Understanding of Mixed Invasive Ductal and Lobular carcinoma (mDLC)

University of Pittsburgh/UPMC Hillman Cancer Center:  Steffi Oesterreich, Ph.D.; Adrian Lee, Ph.D.; Peter Lucas M.D., Ph.D.; George Tseng Ph.D.

University of Michigan: Celina G. Kleer, M.D.; Lynn Henry, M.D. Ph.D.

While most breast tumors are classified as IDC or ILC histologies, a subset show both ductal and lobular morphology within the same tumor and are classified as mixed ductal and lobular carcinomas (mDLC). Clinicopathologic comparisons suggest that like ILC, mixed invasive ductal/lobular cancer (mDLC) tend to be mostly estrogen receptor-positive (ER+) and form larger tumor. In contrast, like IDC, mDLC may present with more high grade tumors and are more often treated with chemotherapy or radiotherapy.  Survival studies have reported varying conclusions on mDLC outcome relative to ILC and IDC, and additional studies with larger cohorts are required to be able to draw conclusions. Here we propose to study outcome of patients with mDLC, ILC and IDC seen at UPMC, hoping to integrate data from patients with mDLC treated at UM.

Previous studies suggest the ductal component and lobular component in mDLCs appear histologically similar to IDC and ILC, respectively, however, comprehensive molecular and epigenetic evaluation of mDLC is lacking. There is limited data to understand whether mDLCs are true mixtures of these different histological subtypes or whether in some cases represent unique entities. As part of this Dynami-funded study, we will study the epigenome of mDLC, ie measure DNA methylation in these tumors, and compare to methylation previously described in IDC and ILC. We strongly believe that successful completion of our studies will help to improve understanding of mixed ductal/lobular carcinomas.

Analysis of Dormancy in Invasive Lobular Carcinoma

University of Michigan: Jacqueline S. Jeruss, M.D., Ph.D. and Lonnie D. Shea, Ph.D.

Patients diagnosed with invasive lobular carcinoma (ILC) more often experience longer latency to metastatic recurrence when compared to patients diagnosed with invasive ductal carcinoma (IDC). This difference has been ascribed to the ability of invasive lobular cancer cells to survive and remain dormant over long periods, which can be influenced by a combination of i) intrinsic gene expression patterns in tumor cells, and ii) extrinsic signals at metastatic sites that regulate tumor cell fate. We are committed to investigating the intrinsic and extrinsic factors regulating dormancy in ILC and IDC.

The proposed studies are enabled by a synthetic metastatic niche (MN) to enrich the metastatic subpopulation of invasive ductal and lobular breast cancer cells, and study the intrinsic and extrinsic factors that regulate the entry of ILC and IDC cells into the dormancy state and their eventual reactivation at metastatic sites.

Initial studies will characterize the immune environment and associated cancer cell responses. The immune environment of the primary tumor and metastatic sites will be characterized using multiple cutting-edge technologies. Subsequently, we will investigate the intercellular circuits driving the immune mediated responses to identify the factors that determine the tumor cell responses: dormancy versus oncologic progression. We seek to identify and  then exploit the dominant circuits by which the immune cells influence tumor cell phenotype.

The results of these studies will advance our understanding of the immune cell composition and signaling as it relates to tumor cell responses to initiate dormancy for ILC relative IDC. We anticipate identifying key factors associated with regulation of cellular or immune-mediated dormancy for different subtypes of invasive breast cancer. If successful, these immune mediators or dormancy-associated gene targets can be used to direct drug development to drive the entry of tumor cells into dormancy, or maintain the dormancy state, even in the setting of metastasis, to improve the survival rate of ILC and IDC patients. Additionally, the identification of these factors would allow the use of the synthetic MN as a diagnostic tool for detection of recurrence that avoids biopsy of distant metastatic sites, such as lung or bone, that has associated risks, and can be difficult to access over time.

CHARACTERIZATION OF UNIQUE PHENOTYPE OF LOBULAR BREAST CANCER CTCS

Invasive lobular carcinomas (ILCs), a type of breast cancer, display distinct differences compared to invasive ductal carcinomas (IDCs). They tend to be larger when they are diagnosed, and more often are found to have spread to lymph nodes. When they spread to other areas of the body, this spread is different as well. In the clinic,  ILC is treated the same as IDC, although the response to treatment may be different. Due to these unique features of ILC, there is an urgent need to better understand ILC.One promising way to study tumors is to study circulating tumor cells (CTCs), which are cells that can be found in the blood of cancer patients. Because it is easy to take a blood draw from a patient compared to performing a biopsy, we can test CTCs more readily.The overall goal of our work is to utilize CTC analysis to investigate the biological differences between lobular and ductal carcinomas. The findings from this project will serve as a foundation for further research into these differences, with the ultimate findings leading to a better understanding of and treatments for ILC.

MOLECULAR REFINEMENT OF INVASIVE LOBULAR CARCINOMA DEFINITION IN TISSUE AND LIQUID BIOPSIES

Patients with invasive lobular carcinoma (ILC) account for ~10% of all breast cancer (BrCa) diagnoses. Recently, several studies have demonstrated that patients with ILC have worse prognosis and are less sensitive to endocrine therapies compared to invasive ductal carcinoma (IDC). Therefore, there is a critical need to better define ILC so that more effective therapies can be determined.

Classically, ILC is distinguished from IDC based on tissue morphology. In addition, it has been shown that ILCs have unique molecular characteristics in the tissue.

The objective of this study is to better refine the definition of ILC in tissue biopsies based on molecular and gene expression characteristics using primary cancers and metastatic biopsies collected from patients enrolled in an ongoing study at University of Michigan. In addition, we hypothesize that the use of tumor cells floating in blood so called, “circulating tumor cells”, would help us to better understand patients with this type of BrCa. We will also examine clinically relevant molecular characteristics in the DNA derived from circulating tumor cells to provide insights into heterogeneity of ILC and whether circulating tumor cells molecular characteristics are similar to molecular changes in tissue. Ultimately, having a better comphrehensive definition of ILC could help in the diagnosis and treatment of this special BrCa. It will introduce the possibility of using circulating tumor cells to identify potential targets to direct future treatment.

Updates on the project: Submitted project to the Institutional Review Boards; addressed and reconciled comments from the IRB; Purified single cell CTC previously collected and stored from patients with ILC; extracted DNA from single cell, amplified DNA, and QC to assess the quality of sample before undergoing to genomic analyses.

Planned analysis: We now plan to proceed with sequencing single cells from 10-15 patients with ILC and compare CTC molecular characteristics with those changes in tissue.

The findings of this research project were presented as a poster presentation at the prestigious San Antonio Breast Cancer Symposium in 2022. View the full poster

Serial monitoring of circulating tumor cells and circulating tumor DNA in metastatic lobular breast cancer identifies intra-tumor heterogeneity and precision and immuno-oncology biomarkers.

Cancer biomarkers in a tumor tissue biopsy help doctors determine how best to treat patients with cancer, including lobular breast cancer. However, tissue biopsies have several limitations. They require an invasive procedure of some sort and they only provide information about the specific location in a patient that the biopsy was directed. We now know that cancers that have spread to several parts of the body differ from each other, even though they started from the same organ (like the breast). We call that heterogeneity. Thus, a single tissue biopsy does not provide information from different parts of the tumor. Moreover, as a cancer progresses, it develops more heterogeneity, and it is difficult to perform multiple tissue biopsies to track these changes.

"Liquid biopsies", such as circulating (in the blood) tumor cells (CTCs) and/or circulating cell-free tumor DNA (or ctDNA), can be obtained from a simple blood sample, provide cancer molecular information that represents the entire tumor. Liquid biopsies can be performed much more easily than a true tissue biopsy, and repeated testing with serial blood tests is easy. Although these cells are quite rare, the Hayes lab (and others) have shown that lobular breast cancer is an especially high CTC-producing cancer type. Using a simple blood draw, we have enabled CTC counting, isolation of individual cells, and analysis of their DNA and proteins.

With funding from the Dynami Foundation, we have recently analyzed tumor matched tissue, CTC, and ctDNA from patients with metastatic lobular breast cancer. We have analyzed 126 single CTCs from 15 metastatic lobular breast cancer patients. We have shown that most of these patients harbor DNA defects in their tumor for which targetable, precision treatments exist or are being investigated. Interestingly, a third of them had targetable DNA defects detected in one, but not the other sample types (tissue, ctDNA and CTC). Importantly, 87% of patients had tumors composed of different genetic clones. This was clearly detectable by single-CTC analysis and was either entirely not present, or was ambiguously so in their tissue or ctDNA samples.

Developing an innovative technique, we can detect and track single-cell CTC biomarkers of immunotherapy which also tend to be present more often in lobular vs. ductal breast cancer. Our findings support the continued investigation of CTC in conjunction with tissue and ctDNA enable biomarker-guided, real-time therapy adjustment to extend survival. With additional Dynami funding we will continue to study tumor evolution in metastatic lobular patients by CTC and ctDNA liquid biopsies, which we propose will, in the long run, guide more precise decisions regarding treatment of metastatic lobular carcinoma.

ELUCIDATING THE MECHANISM OF CDK4/6 INHIBITOR-MEDIATED RADIOSENSITIZATION OF ER+ BREAST CANCERS

How to make treatment more effective for the women with aggressive breast cancers, including lobular breast cancer, for whom standard therapies are ineffective; rationally designed treatment intensification.

Despite treatment that includes targeted therapy and radiation (RT), many women with aggressive forms of breast cancer (BC) will experience a recurrence, including women with lobular breast cancer as lobular breast cancer is more likely to metastasize to the surrounding lymph nodes. Our previous work focused on identifying ways in which RT can be more effective for aggressive forms of BC, including in lobular breast cancer. One strategy identified by our group is to use CDK 4/6 inhibitors to help radiation work more effectively. Our group was the first to report the finding that CDK 4/6 inhibition combined with radiation may be an effective radiosensitization strategy. With the funding provided, we are extending these studies to better understand how CDK 4/6 inhibitors and radiation may be used to more effectively treat women with invasive lobular breast cancer. We are determining the mechanism by which CDK 4/6 inhibition confers radiation sensitivity and this will hopefully extend the indication of CDK 4/6 inhibition for women with lobular breast cancer. Based on these studies, we hope to have a rationale to run a clinical trial to determine the safety and efficacy of CDK 4/6 inhibitors with RT in women at high risk for developing BC recurrence, including women with lobular breast cancer.

Conclusions: Our preliminary data suggests that CDK4/6-induced radiosensitization may be effective in ER+ breast cancer models, including models of lobular breast cancer, prior to the development of CDK4/6 inhibitor resistance. The proposed studies provide the preclinical rationale for clinical trials to test combination RT and CDK 4/6 inhibition in women with locally advanced ER+ breast cancer at high risk for locoregional recurrence, including women with lobular breast cancer.

2017

The $170k in proceeds from the 2017 Uncork For a Cure launched The Breast Cancer Survivorship Clinic at the University of Michigan Rogel Cancer Center. The clinic is led by Elanor Sun M.D. and is designed for women who have had breast cancer and to provide patients with strategies to optimize their overall health and wellness—now and in the future.

An overall goal of survivorship is to assist patients in learning more about health issues that may occur following completion of their breast cancer treatment and strategies to address these issues and concerns.

Learn more about The Breast Cancer Survivorship Clinic.