The 2020 San Antonio Breast Cancer Symposium (SABCS) saw more posters than ever focused on lobular breast cancer. One goal of the Lobular Breast Cancer Alliance (LBCA) is to raise awareness and educate about ILC. With the support of those researchers and the help of multiple research advocates we are pleased to present lay summaries of the majority of those posters below. To see the poster, click on the title. Posters are published on this website with permission of the authors.
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a common technique for mapping of vascular (i.e., blood vessel) function in a patient. It measures blood perfusion (the passage of blood), fractional blood volume, and vascular permeability (i.e., how well the vascular system allows the necessary bidirectional passage of small molecules, gases and plasma proteins), while performing an MRI of the breast. Using this technique, the authors were able to measure the longest tumor diameter, functional tumor volume and peak signal enhancement ratio (SER1); a reflection of the tumor vascularity by comparing contrast washing in and out of the tumor. The authors compared these features of the MRI on patients who were imaged before and after neoadjuvant therapy (treatment given before surgery) correlating these findings with recurrence free survival.
In this retrospective study, they reviewed MRIs of patients who received either chemotherapy (n=42) or endocrine receptor targeted (n=34) neoadjuvant therapy. The 2 groups of patients differed in the average age, proportion of early-stage disease, and the number of patients with HER2+ receptors on their tumors. The mean follow -up time for both groups was 4.9 years. Pretreatment longest tumor diameter and functional tumor volume were higher in the neoadjuvant chemotherapy group. Those receiving neoadjuvant chemotherapy had a significantly greater reduction in post treatment functional tumor volume than those treated with targeted estrogen receptor therapy, however other post treatment parameters did not differ between the two groups. Higher pre-treatment SER was associated with a higher risk of recurrence in patients regardless of whether they received chemotherapy or targeted hormone receptor treatment prior to surgery.
The conclusion drawn was that pre-treatment SER measurements in DCE-MRI imaging may be an independent prognostic indicator for lobular cancer, if validated by larger studies.
1 Signal enhancement ratio (SER) is a quantitative method for characterizing neoangiogenesis (i.e., the mechanism in cancer that permits the creation of new blood vessels to supply cancerous tumors and ensure their growth) in breast cancer.
Lay summary by Janice Axelrod and reviewed by study author
The histology (i.e., the microscopic structure of the tissue) and pattern of spread in metastatic lobular breast cancer tumors have presented challenges in imaging. These characteristics are often hard to see with current technology such as traditional CT and PET scans. It should also be noted that the majority of lobular tumors are Estrogen Receptor Positive (ER+).
FES (Fluoroestradiol F-18) is a novel imaging tracer which measures estrogen expression in tumors. The authors compared FES and FDG (Flourodeoxyglucose) PET imaging. FDG-PET is the tracer currently used and measures glucose activity in tumors, but can also pick-up inflammation or infection.
The authors retrospectively reviewed both FES and FDG PET scans in 38 metastatic lobular breast cancer patients with up to 10 lesions per patient (total of 192 lesions) in various metastatic sites. The samples were derived from studies at The University of Washington Medical Center from 1995-2015. This study demonstrated that the FES estrogen tracer did just as well as the FDG glucose tracer in detecting metastatic lesions. Both had value in detecting ILC, however, at a higher SUV (standardized uptake value – higher values indicate malignancy), specifically seen in bone lesions (N=150), there was an indication that FES-PET can provide additional information.
FES may provide a surrogate way to measure Estrogen Receptor Expression and help in predicting responses to Anti-Estrogen therapies. The investigators of this study have also explored the role of FES-PET in lobular metastatic breast cancer patients with bone involvement. (https://cancerres.aacrjournals.org/content/80/4_Supplement/P1-01-07)
FES-PET has been approved by the FDA but remains to be seen how available it will be and if insurers will provide coverage. More studies are needed to define the clinical utility of FES-PET in metastatic lobular breast cancer.
Lay summary by Julia Levine and reviewed by study author
This poster examines the landscape of 1900 metastatic invasive lobular carcinomas (ILC) profiled for genomic mutations in >300 genes using the Foundation Medicine test. The authors wanted to understand if there were differences in clinically actionable biomarkers and therapy resistance mutations across ILC, biopsied from different metastatic sites. The group examined biomarkers associated with response to immune checkpoint inhibitors (ICPI), a class of drugs that activates the immune system to fight the tumor. High TMB and PD-L1 staining have been associated with response to these agents. The authors found elevated rates of high TMB in ILC when compared to IDC, with the highest rates in GI and skin metastases. While PD-L1 staining was lower in ILC metastases overall, high rates were observed in GI and skin metastases. These findings suggest that ILC GI and skin metastases may be potential candidates for ICPI therapy.
PIK3CA alterations were observed in a large number of ILC metastases (58%). This may predict sensitivity to PI3K pathway inhibitors. Prevalence was similar across sites, meaning that women with ILC may benefit from PI3K-targeting agents regardless of where their tumor has metastasized. The authors also found a high prevalence of mutations associated with resistance to ER-targeted agents (e.g., mutations in ESR1, NF1, and ERBB2). Significant differences were observed in the types of resistance mutations across sites (for example, ERBB2 mutations were common in liver metastases (21%) but were rare in GI and female reproductive metastases (3%).
This work has potential implications for post-progression treatment options and overall, these findings confirm that ILC is a unique genomic disease relative to IDC. The study further identifies unique vulnerabilities of ILC based on the site of metastasis.
Lay Summary by Ethan Sokol
Leptomeningeal metastasis, where cancer spreads to the membrane lining the brain and spine, is a devastating development. Due to the blood -brain barrier, most cancer treatments cannot get to this site, and there is poor survival of just a few months. This project aimed to understand whether unique molecular changes may account for this spread, through the sampling of cerebrospinal fluid (CSF) from patients with leptomeningeal involvement. Invasive Lobular Breast Cancer (ILC) has been shown to have a higher propensity to metastasize to the leptomeninges (LM) than invasive ductal cancer (IDC).
In this study, CSF was collected from 21 patients, and over half were of lobular histology. Of these samples; 10 (48%) were ILC, 8 (38%) were IDC and 3 (14%) were of mixed ILC/IDC. In addition, Whole Exome Sequencing (WES) showed CDH1 loss-of-function mutations (10 out of 21), which is in keeping with the larger number of lobular cases, however it was also discovered in the CSF of two cases with E-cadherin positive IDC.
Studying the cell-free DNA from CSF allowed an insight into the genomic changes in the tumor that has spread to the leptomeninges, and this was compared to the cell-free DNA in the plasma, which circulates through the rest of the body. This showed that the majority of changes in CSF were unique, and not found in the plasma. Therefore, leptomeningeal spread may possess unique molecular changes which drive its spread to that site. The researchers also developed patient-derived mini-tumors (organoids) and animal models, and are using these to study the mechanisms of leptomeningeal metastatic spread, and importantly, to test out novel therapies for its treatment.
Treatment options beyond intrathecal methotrexate are urgently needed and, in the future might be molecularly tailored based on alterations discovered by CSF cfDNA sequencing.
Lay summary by Amanda Fitzpatrick
Invasive lobular carcinoma (ILC) is the second most common type of breast cancer. Many prior studies have shown that they have their unique features when compared to other subtypes. They are usually hormone receptor-positive with a lower tumor grade. Oncotype Dx (ODX) is a molecular test used to predict breast cancer recurrence in early-stage, hormone-receptor-positive breast cancers. It also guides the physician’s decision about whether chemotherapy should be recommended. This study aimed to assess whether ODX-recurrence scores (ODX-RS) can be predicted for ILC and compare other features to invasive ductal carcinoma (IDC) and invasive carcinoma with mixed ductal and lobular features (IMC).
We found that ILC had the lowest percentage of grade 3 tumors, tumors with low progesterone expression, and patients with high-risk ODX-RS. The rate of recurrences was similar between ILC and IDC and IMC had the lowest rate of recurrences. All patients with low-risk recurrences scores by ODX were free of recurrences. There were no significant differences between the variants of ILC and ODX-RS, although patients with the classic variant had the best disease-free survival. Disease-free survival was best in patients with IMC compared to IDC and ILC. Disease-free survival was best in patients with IMC compared to IDC and ILC.
Lay summary by Akisha Glasgow
This study used real world data to assess the effect of the 21-gene recurrence score (RS) assay testing on treatment decision making in patients with Invasive Lobular Carcinoma (ILC) and the economic impact on the Irish healthcare system of testing in this subgroup.
Data consisted of electronic patient records collected between 2011-2019. All patients were HR+, HER-2 negative, lymph node negative, ESBC patients with ILC who had RS testing in Ireland. It was presumed that, without RS testing, chemotherapy (CT) would be recommended to patients with histological grade (G) 2 and 3 tumours and not those with G1 tumours. A total of 166 patients with ILC were identified. Overall, 153 patients (92.2%) had a low RS (525), 12 (7.2%) had high RS (>25), and 1(0.6%) was unknown. Post RS testing 124 patients (74.5%) had a change in CT recommendation; from CT to hormone therapy. In total, only 35 patients (21%) received chemotherapy.
In conclusion, RS testing achieved a 78% reduction in chemotherapy use, which resulted in a net savings of approximately €400,000 in treatment costs. While there is limited evidence into the benefits of RS in ILC, these results demonstrate a considerable decrease in chemotherapy use, as well as a substantial cost savings to the Irish Healthcare System.
Lay summary by Gitte Joergensen and reviewed by study author
PS6-11: Targetable ERBB2 mutation status is an independent marker of adverse prognosis in estrogen receptor positive, ERBB2 non-amplified primary lobular breast carcinoma: validation using a novel gene signature of HER2 activation
We recently showed that mutations in HER2 (ERBB2) are more commonly found in early lobular breast tumors compared to other breast cancer subtypes. These mutations may provide an opportunity to treat early stage ILC with HER2-targeting drugs, even though lobular tumors are very rarely “HER2 positive” by standard clinical tests.
We now present further evidence using gene expression (a measure of gene activity) data from public datasets. We compared the expression of genes in tumors with and without HER-2 mutations. We took the genes that are more active in the mutants and cross-referenced these with the genes that are active in classic “HER2 positive” disease. There were 20 genes that the mutants had in common with HER2 positive disease. We called this our “signature” of HER-2 activity.
To test our gene signature, we used data from another public database to give a “weight” to each of the 20 genes. This was done according to the gene’s ability to predict response to a HER2 targeting drug, Neratinib. Using this weighting, we gave a score to cases of lobular and ductal breast cancer in the METABRIC dataset. This confirmed that patients with lobular disease and high HER2 activity score had a worse prognosis compared to those with lower scores. In contrast, there was no such relationship in ductal tumors.
As well as providing further evidence to support our original findings, we speculate that our HER2 activity score could be used to indicate whether HER2 targeted drugs might be beneficial to individual patients with early lobular breast cancer.”
Read the full published study and clinical commentary here.
Lay Summary by Simon Johnston
Mixed invasive ductal lobular carcinoma (mDLC) is a type of breast cancer that is unique in that it contains components of the two most common histology (i.e., determined by the microscopic tissue structure) types of breast cancer, which are invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). While the different histology types of breast cancer (for example IDC and ILC) are largely managed the same in the clinic depending on their hormone receptor and HER2 status, we are starting to see that the different histology types actually behave differently in many ways. For example, we know that ILC tumors are less responsive to neoadjuvant chemotherapy than IDC, and they are also more likely to be hormone receptor positive.
We evaluated a cohort of mDLC from UPMC and compared their clinical characteristics to IDC and ILC cohorts to see if these unique tumors behaved more or less like one of the main tumor types. Using sophisticated statistical models, we found that mDLC is more similar to ILC than IDC. In cases where breast conserving surgery was attempted, we found (similar to prior reports) that cases with IDC were more successful than ILC with regard to no further need for a subsequent total mastectomy. Interestingly, success rates of mDLC breast conserving surgery fell somewhere in between. Lastly, we performed a meta-analysis of key clinical parameters, which included data from 23 other studies reported on mDLC and notably found that mDLC and ILC are found to have similar rates of hormone receptor positivity across these studies.
Lay summary by Azeda Nazradani
There are very few large cohort analyses comparing clinical and pathological features of ILC. In order to tackle this problem, Investigators from UPMC Hillman Cancer Center, James Cancer Hospital/OSU, and Cleveland Clinic Taussig Cancer Institute/CWRU formed the Great Lakes Breast Cancer consortium. The Institutions worked with their respective cancer registries to collect comprehensive data on patients with IDC and ILC seen at their institutions between 1990 and 2017. A total of N=38,175 records (N=15,792 from UPMC, N=13,040 for CCF, and N=9,343 for OSU) were included in the study. ILC comprised roughly 10% of all samples which corresponds with other established research (IDC N=30,100, and ILC N=3,618).
Comprehensive statistical analyses were performed to compare clinicopathological features, treatments, metastatic sites and co-morbidities. Some significant findings included: differences in age; patients with ILC were older compared to those with IDC (61.2 vs 57.5), patients with ILC were more frequently stage III and IV than IDC, and the tumors were larger. In patients with ILC, the lymph nodes contained more tumor cells compared to those in patients with IDC. Preliminary analyses confirm prior studies showing a worse overall survival in patients with ER+ ILC compared to ER+ IDC, and thus the authors concluded that lobular histology carries distinct prognostic implications.
This study of one of the largest cohort of patients with ILC to date highlights the need for more ILC research and clinical trials for patients with invasive lobular breast cancer.
Lay summary by Steffi Oesterreich and Julia Levine
This study looked at the relationship between body mass index (BMI), metabolic syndrome (e.g., high blood pressure/blood sugar/cholesterol, obesity, diabetes), and tumor subtype, comparing 147 pre-menopausal and 334 post-menopausal patients diagnosed with invasive lobular carcinoma (ILC) between 1996-2000.
The authors showed that post-menopausal women had significantly more ER+/PR- ILC than premenopausal women (25.3% vs 9.9%); %); as opposed to ER+/PR-+ ILC. They were also more likely to have a BMI in the overweight/obese category (53.6% vs 40.1%); and were more likely to have metabolic syndrome (21.9% vs 6.8%). Interestingly, for the post-menopausal group, overweight/obesity status was associated with lower Oncotype Dx Recurrence Scores (RS) while those with normal weight had a greater proportion of high RS tumors. In contrast, there was no association between BMI and RS in the pre-menopausal group. For both groups, there was no association between metabolic syndrome and tumor subtype.
As obesity has previously been associated with poorer outcomes for breast cancer these findings are unexpected and consequently raise the possibility that hormonal factors and estrogenic drive behind ILC differs in pre- vs post-menopausal women.
Lay summary by Gitte Joergensen and reviewed by study author
The observed decreased response of Invasive lobular cancer (ILC) to neoadjuvant chemotherapy and increased acquired resistance to endocrine therapy has promoted researchers to look for alternative treatments, such as immunotherapy to improve overall survival. A response to immunotherapy relies to a large extent on tumor immunogenicity of which varies with histological subtype. Markers of immunogenicity can help predict the likelihood of a cancer responding to immunotherapy.
These markers include PD-L1 expression and Tumor Mutational Burden (TMB). PD-L1 may contribute to immune evasion and is indicative that the tumor may be responsive to immune checkpoint inhibitors. PD-L1 expression is highly variable across all cancers and has shown modest correlation with response in triple negative breast cancers but has yet to be studied thoroughly in ILC. The authors also analyzed the differences in immune cell profiles in the Tumor microenvironment (TME) as well as the differences in subtypes and genomic alterations associated with immunogenicity between ILC and Invasive ductal cancer (IDC)
In this retrospective study there were 868 tumor samples of which 714 were IDC (Invasive Ductal Cancer) and 154 were ILC. Of the ILC tumors, 98% were HR+ and 2% were HER2 + Expression of PD-L1 was lower in the immune and tumor cells in ILC in both subtypes when compared to IDC. TMB on the other hand, was increased in ILC vs IDC. Additionally, ILCs that had a high TMB were associated with low AR (Androgen Receptor) expression, and increased frequency of mutations in ATM, KM2D, RB1 and TP53 genes. These mutations could therefore be potential biomarkers in predicting response to immune therapy.
Immune cell profiling showed a less immunogenic TME for ILC, suggesting that ILC may be less responsive to immunotherapy than IDC. A composite immune biomarker may be better able to characterize the immunogenicity of ILC given that each of these individual biomarkers do not point toward similar conclusions.
Lay summary by Janice Axelrod/Julia Levine and reviewed by study author
The Cancer Genomic Atlas (TCGA) has demonstrated that Lobular Breast Cancer has distinct genomic features, analyzing these features by looking at the number of DNA copies of genes and whole exome sequencing the DNA (observing the sequence or order of all of the chromosomal DNA as well as DNA contained in the mitochondria ( i.e., in the structures within the cell).
This study analyzed 8756 invasive breast cancers of which 1109 were lobular breast cancers. The authors correlated clinical features and genetic abnormalities such as single DNA mutations, small additions or deletions from the DNA, change in copy number of DNA in individual genes, and fusion of genes. There was an average of 2 mutations in each specimen tested. Lobular cancer had an average of 14% of their genomes altered unlike the ductal cancers that had 22% of their genomes altered. Genes of lobular cancers were frequently mutated in 7 specific genes or amplified (overexpressed by a gene by making more copies of a normal gene) in one particular gene, had deep deletions of 2 specific genes in lobular cancers. These gene alterations were different from those seen in the ductal carcinomas.
It is hoped that our knowledge of gene alterations in lobular cancers may help our choice of new targets for future treatments.
Lay summary by Janice Axelrod and reviewed by study author
Invasive lobular carcinoma (ILC) is the second most common histological (i.e., microscopic structure of the tissue) subtype of breast cancer, after the more common invasive ductal carcinoma (IDC). Like ER+ IDC, ILC metastasizes to common sites of ER+ breast cancer, such as bone, but it is also three times more likely to spread to the ovaries, peritoneum, and gastrointestinal tracts compared to IDC, and these unique aspects of metastases remain poorly understood. This study starts to address these unique metastatic features, starting with comprehensive analysis of clinical specimens.
We collected ovarian cancer metastases and sequenced them. This led to identification of a number of potential candidates, including the Calcium-Sensing Receptor (CaSR) that were studied. Our data presented here provide insight on the potential mechanism in which the upregulation of the CaSR supports ILC ovarian metastasis.
We hope that these studies will not only deepen our understanding of ILC ovarian metastasis but will eventually lead to the development of more effective therapies and improve the outcome of patients with this understudied type of breast cancer.
Lay Summary by Steffi Oesterreich