Biological and clinical perspectives on lobular breast cancer
Prof Christine Desmedt and Dr Karen Van Baelen from the Laboratory for Translational Breast Cancer Research at KU Leuven discuss the challenges in diagnosing ILC, a subtype constituting 15% of breast cancer cases.
The diagnostic approach to ILC differs clinically and biologically from the more common subtype, formerly known as IDC or NST. Pathological diagnosis discrepancies led to the World Pathology Working Group addressing the need for standardization, uncovering heterogeneity in diagnostic tools. Incorporating immunohistochemistry improved concordance among pathologists, prompting the formulation of new guidelines for standardized ILC diagnosis.
The distinctive growth pattern of ILC poses challenges for accurate diagnosis using conventional imaging modalities like mammography and ultrasound. Despite the heightened sensitivity of MRI, research indicates an underestimation of ICL lesions. The diverse spectrum of lesion types in ILC leads to treatment disparities, with reduced efficacy of neo-adjuvant chemotherapy in early stages and lower PCR compared to other subtypes, even when compared to those with hormone-sensitive HER2- disease. Data from BIG 1-98 suggest that aromatase inhibitors outperform tamoxifen in ILC. However, the lack of distinction between ILC and NST patients in discussions about novel treatments hampers knowledge regarding optimal therapeutic strategies for ILC patients.
Biological distinctions in ILC encompass, amongst others, notable differences in genomic variations and tumour microenvironment disparities. Genomically, ILC exhibits divergent gene mutation prevalence from NST, evident in histological samples and ctDNA analysis. Especially E-cadherin, the CDH1 gene, serves as a hallmark of ILC. This feature is currently the basis for clinical trials utilizing the concept of synthetic lethality. The higher frequencies of HER2 mutations in ILC compared to NST provide a therapeutic advantage with HER2-targeted interventions like neratinib. Recently, FOXA1 mutations, more prevalent in ILC, have been linked to aromatase inhibitor resistance and accelerated disease progression. Additionally, lobular tumours exhibit an elevated tumour mutational burden, particularly in metastatic settings, though the implications for immunotherapy require further investigation.
At the microenvironmental level, ILC displays notable differences, including a significant reduction in sTILs compared to NST, even within the ER+/HER2- subgroup. The immune microenvironment of ILC is marked by an increased presence of macrophages, specifically M2 macrophages. The substantial remodelling of the extracellular matrix in ILC is seen as a potential source for identifying new therapeutic vulnerabilities.
The procedural risks of accessing individual metastases during a patient’s lifetime create a knowledge gap. This is addressed by programs involving rapid autopsy or post-mortem tissue donation like the UPTIDER program, in which a dedicated substudy focuses on patients with ILC. Analysis reveals numerous metastases overlooked by conventional methods, impacting organs like the liver, heart, and pericardium. Collaboration with research institutes is essential to develop in vivo visualization methods for these metastases, enhancing diagnostic capabilities. Notably, comparing primary histopathological features with metastatic cells highlights the persistence of ER positivity in 80% of metastatic lesions, albeit at a reduced frequency. Conversely, PR positivity is sustained in only 40% of metastatic tumour cells compared to primary counterparts, and sTILs expression is low.
Despite the numerous clinical challenges associated with ILC, the recognized biological distinctions provide opportunities for improving treatment options. The prevalent activation of the PI3K/AKT pathway in most ILC tumours has implications for emerging drugs like capivasertib, recently FDA-approved, with these biological differences moving towards initial steps in clinical validation.
Collaboration with patients and advocates, both in Europe and globally, is of paramount importance. Engaging with the breast cancer community helps prioritize research questions, disseminate findings, and secure funding. This collaborative approach is undertaken with dedication and gratitude for the invaluable contributions made by patients and advocates.
Reference:
Desmedt C, Biological peculiarities of ILC. SABCS #ED02
