Study shows more women with invasive lobular breast cancer should qualify for tailored clinical trials

Lobular breast cancer news 2020

Image: 3D reconstruction of the human breast depicting lobules and ducts. Credit: Patrick Aouad, École Polytechnique Fédérale de Lausanne.

A new study led by scientists at The Institute of Cancer Research, London, has changed our understanding of invasive lobular breast cancer – and could increase the number of patients who access new treatments via lobular breast cancer specific clinical trials.

In the study, researchers showed that the diagnosis criteria for invasive lobular breast cancer – a type accounting for 10-15 per cent of breast cancer cases – should be expanded to include an extra subset of tumours that have not previously been included.

The study, which was published in a special issue of Cancers and funded by Breast Cancer Now, could impact the diagnosis of up to 10 per cent of patients with invasive lobular breast cancer, who currently may miss out on the chance to access clinical trials for new potential treatments.

Diagnosis criteria

Invasive lobular breast cancer, which develops in the lobes of the breast that produce milk, is usually diagnosed by the loss of a protein called E-cadherin. The loss of E-cadherin, which is involved in helping cells stick together, can be seen under a microscope in tumour samples that have been stained with a special dye.

In some patients, however, this protein is only lost in parts of the tumour, while other parts still contain it or show abnormal E-cadherin staining, making a definitive diagnosis of lobular breast cancer difficult.

Comprehensive DNA analysis supports expansion of diagnosis criteria

A team of researchers at the ICR sought to address whether these mixed tumours were similar enough genetically to the E-cadherin deficient tumours to be classed as the same type.

They used whole genome sequencing and methylation analysis – a measure of DNA activation – on two samples of the same tumour from nine individual patients: one from an area completely lacking E-cadherin and one where E-cadherin was still appearing on the surface of, or misplaced inside, cells.

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The researchers revealed that the two samples from each patient were very similar in both their mutations and methylation profiles. Importantly, most ‘heterogenous’, or mixed, tumours also harboured mutations to the E-cadherin gene in both the apparently E-cadherin positive and negative areas.

Taken together, these findings suggest that tumour cells from both locations arose from common ancestor cancer cells in each patient, and both should be classified as invasive lobular breast cancers.

Broadening access to clinical trials

Study co-leader Dr Rachael Natrajan, Team Leader of the Functional Genomics Team in the Breast Cancer Now Toby Robins Research Centre at the ICR, said:

“Our study provides the first comprehensive genome-wide characterisation of invasive lobular breast cancers with varied E-cadherin expression and shows they should be considered as being similar to more classical E-cadherin deficient tumours. An important implication of this work is that women with these atypical tumours could still benefit from new therapies for invasive lobular breast cancer and should be offered the chance to take part in the same clinical trials.”

The phase II ROLo trial, for example, which is based on earlier work by Professor Chris Lord and his team at the ICR and was funded by Breast Cancer Now, excludes women whose tumours show partial or abnormal E-cadherin staining. The work from Dr Natrajan’s team suggests that these women should also be included in such trials.

Study co-leader, Dr Syed Haider, Leader of the Bioinformatics Group in the Breast Cancer Now Toby Robins Research Centre at the ICR, said:

“While whole genome sequencing studies are rapidly becoming more common, there remains an unmet need for detailed characterisation of tumours with specific molecular traits in rare subtypes of breast cancer. Here, we used a cost-effective technology to study the whole genomes of mixed invasive lobular breast cancers, showcasing the remarkable potential of big data in taking us a step closer to delivering precision medicine.”

— Update: 19-03-2023 — found an additional article Diagnostic Challenge of Invasive Lobular Carcinoma of the Breast: What Is the News? Breast Magnetic Resonance Imaging and Emerging Role of Contrast-Enhanced Spectral Mammography from the website for the keyword lobular breast cancer news 2020.

1. Introduction

Breast cancer (BC) affects millions of women worldwide. Invasive lobular carcinoma (ILC) is the second most common type of invasive breast cancer accounting for 5–15% of cases [1,2,3]. The incidence of ILC is highest in white older women [4] and over the last two decades it has increased, also due to the use of hormone replacement therapies [5,6,7,8,9].

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Generally, diagnosis is late at a more advanced tumoral stage than other BC types [10,11,12,13,14]. In fact, ILC tends to be clinically silent and difficult to detect through imaging due to its underhand growth pattern [15].

ILC is well recognized by pathologists and is composed of relatively small, discohesive epithelial cells infiltrating the fibrous stroma in a single-file pattern with minimal stromal reaction. Pathological hallmark features of ILC include lack or loss of cell–cell adhesion molecule E-cadherin (encoded by CDH1 gene) [2,16,17] and positive for both the oestrogen (ER) and progesterone receptors (PgR) and negative for the human epidermal growth factor receptor 2 (HER-2) [2].

Invasive ductal carcinoma (IDC) is generally identified as a mass on clinical and radiological examinations and as it originates from mammary ducts, microcalcifications are also a common sign on mammography [18]. ILC originates in the lobule structures that show individual layers of cells traversing the surrounding tissues similar to the threads of a spider’s web. This infiltrative growth pattern generally does not induce conspicuous desmoplastic reaction and architectural distortion neither forms a mass. The lesion often shows a mammographic density less than or equal to surrounding breast parenchyma, indistinguishable from normal breast tissue [19] and microcalcifications are a rare mammographic finding (variating widely from 0 to 24%) [20].

These widespread growth patterns make diagnosis particularly challenging.

Digital mammography is the first level imaging examination for breast cancer diagnosis with a sensitivity between 63 and 98% [1]. However, its diagnostic performance in ILC detection is more limited ranging between 57–81% [9], especially in dense breast tissue (in extremely dense breast tissue, ILC detection can be as low as 30%) [17].

Digital breast tomosynthesis (DBT) has the potential to explore breast tissues by producing thin slices of the mammographic view. DBT reduces the tissue-masking effect and improves lesion conspicuity with a better evaluation of parenchymal distortion, asymmetries and ill-defined masses, which are common findings in ILC [21,22]. Despite its advantages, DBT is based on differential tissue X-ray attenuation and can remain suboptimal.

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Ultrasound (US) is not used as a screening tool and generally evaluates suspicious findings detected at clinic or at mammographic examinations.

All these imaging diagnostic techniques can help radiologists detect equivocal malignant signs but often a correct diagnosis can be challenging even at later stages when tumors are larger, multifocal, multicentric and metastatic.

Therefore, it is important to improve breast imaging methods to detect and diagnose ILC.

At present, breast magnetic resonance imaging (BMR) is recognized as the most sensitive diagnostic tool to detect and stage ILC. BMR provides information about the morphology of the lesion but also an analysis of tumor neoangiogenesis. BMR is quite useful in patients in whom the diagnosis of ILC is proved and the disease extent is uncertain from physical exam and mammography/ultrasound tests. BMR may detect additional diseases not otherwise appreciated through conventional imaging and may provide more accurate staging information to guide surgical treatment [23,24].

Recently a new emerging digital mammography technology based on contrast enhancement evaluation, contrast-enhanced spectral mammography (CESM), is improving cancer detection and decreasing misdiagnosis rates [25].

CESM combines conventional mammography with the intravenous administration of an iodinated contrast material offering both morphological and functional information of breast tissue [26,27,28].

Several studies have shown that the diagnostic performance of CESM is similar to that of MRI and that CESM may be useful for indications previously reserved for MRI [25,29].

In our breast diagnostic unit, CESM has been used since May 2019 and our experience is showing the new potential in helping diagnosis in different clinical settings.

In this study, we compare the ability of CESM and BMR in the detection and staging of invasive lobular carcinoma to investigate the potential of CESM in the diagnostic work-up of a patient with ILC.


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About the Author: Tung Chi