Κυριακή, 3 Απριλίου 2016

GENETICS OF BREAST LOBULAR CARCINOMA

Invasive lobular carcinoma (ILC) accounts for up to 15% of all invasive breast cancers and has long been recognized as being different from infiltrating ductal carcinoma (IDC). Now, a genomic characterization details the differences and shows that ILC is a unique biologic subset of breast cancer, a finding that may lead to distinct therapeutic initiatives in the future.
The genomic landscape of ILC has changed significantly in recent months, and is now better understood, says Lisa A. Carey, MD, Distinguished Professor of Breast Cancer Research, University of North Carolina at Chapel Hill, and physician-in-chief, North Carolina Cancer Hospital.
She and Michael L. Gatza, MD, of Rutgers University, in New Brunswick, New Jersey, wrote an editorial published onlineMarch 28 in the Journal of Clinical Oncology.
The editorial was prompted by a report on the genomic profiling of the largest dataset of primary ILCs, published online February 29 in J Clin Oncol, as well as two other reports, one from the Cancer Genome Atlas (TCGA) project, and the other from a European cohort.
These three reports, all published within the past few months, have produced "remarkably consistent results that identify at least three significantly altered and therapeutically relevant pathways," the editorialists write. They show that in ILC, changes are seen in genes associated with the phosphatidylinositol 3-kinase (PI3K) pathway, in genes regulating hormone receptor (HR) signaling, and, significantly, in human epidermal receptor (HER) genes.
"It is now clear that ILC and IDC are distinct molecular diseases, a fact that should be considered in future experimental and therapeutic initiatives," the editorialists comment. The new findings could lead to new approaches to the management of ILC, tailored with targeted, hormonal, or immune therapies.
"However, clinical practice in the management of ILCs is not poised for change just yet," Dr Carey told Medscape Medical News. The new approaches to treating ILC, using both new and older drugs, will have to be tested in clinical trials. But the findings from these studies, showing the unique alterations in ILC, will now allow that to happen.
"ILCs pose diagnostic challenges in determining the extent of disease both on imaging and during a physical examination," Dr Carey told Medscape Medical News. "They also have unusual patterns of metastatic spread that can make them harder to treat," she said.
"Although they [ILCs] behave differently with respect to their recurrence and pattern of spread, they are treated as HR-positive, HER2-negative breast carcinoma," Dr Carey said.
"That's why this study, along with a few other datasets, are important, as they allow us to define ILCs from a biologic standpoint," Dr Carey said.
The ILC Genomic Landscape
For the study published in J Clin Oncol, the researchers analyzed tumors with lobular histology obtained from four institutional biobanks ― two in Brussels, Belgium; one in Milan, Italy; and one in Marseilles, France.
The samples were analyzed for mutations (n = 413) and for copy number aberrations (n = 170)
The most frequently altered mutations were in CDH1, seen in 65% of tumors. The editorialists comment that this hallmark feature of alterations in CDH1 may be associated with an increased risk for invasion and metastases, as occurs in other cancers. Metastatic ILC has unusual patterns of spread to sites such as the ovaries, the lining of the gastrointestinal tract, and the peritoneum, they note.
Another common finding was loss of heterozygosity or deletion, seen in 94% of patients. In addition, more than half the tumors examined had mutations in one of three genes associated with the PI3K pathway — PIK3CAPTEN, and AKT1.
ILCs also showed alterations in transcriptional regulators, such as TBX3FOXA1KMT2CGATA3, and ARID1A, with high prevalence. Focal copy number gain in ESR1, which is associated with increased expression, was seen in 25% of lobular tumors.
"The occurrence of ESR1 copy number changes may help better understand the potential to treat patients with ILC with endocrine therapy," commented lead author Christine Desmedt, PhD, of the Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Brussels.
In addition, the HER genes HER2 and HER3 were mutated or amplified in approximately 14% of all ILC tumors. "These data suggest that ILC has the highest incidence of HER2-mutated, nonamplified tumors among all breast cancer subsets," the editorialists write.
"Our paper is the first to clearly point out in a large cohort of ILCs that the prevalence of HER2 and HER3mutations is significantly higher than in primary invasive ductal carcinoma," Dr Desmedt said.
Clinical Implications
"Our results need to be investigated in the context of clinical trials," Dr Desmedt told Medscape Medical News.
"It will be important to identify if the genomic alterations we identified in ILC may help individualize treatment," she added.
According to the editorialists, "[T]he increased incidence of PI3K/Akt pathway mutations from both the current study and the TCGA suggest that the ILC tumor environment provides a favorable cellular context for altered Akt signaling and that the targeting of the PI3K/Akt pathway may be particularly relevant in ILC."
Dr Desmedt suggested that since AKT1 mutations are more frequently seen in ILC and are associated with short-term risk for relapse, lobular histology may be used as inclusion criteria for agents targeting AKT1.
The editorialists indicate that the data on HER mutations corroborate those reported in the TCGA cohort. "Together, these studies suggest that the ERBB family signaling may significantly contribute to ILC biology," they write, but they indicate that the clinical relevance of these alterations needs to be further investigated.
Dr Desmedt and colleagues point out that HER2 mutations in ILC are associated with a short-term risk for relapse. Ongoing trials (NCT01670877 and NCT01953926) using HER2-directed therapies are underway. "[These trials] will shed more light on the clinical relevance of such genetic alterations," the authors state in their discussion.
Dr Desmedt explained that clinical trials targeting HER2 mutations in unselected patients may only benefit a small patient population. Considering that ILC represents a minority of unselected patients, it may be cost-effective to consider HER2 mutations for inclusion criteria when evaluating these agents, she said.
Again, given the rare occurrence of HER3 mutations in ductal carcinomas, dual blockade of HER2/HER3with pertuzumab (Perjeta, Genentech, Inc) and trastuzumab (Herceptin, Genentech, Inc) is a potential treatment approach for patients with ILC that harbor HER3 mutations, Dr Desmedt told Medscape Medical News.
ILCs are hormone-receptor positive, suggesting that endocrine therapy could be beneficial. FOXA1mutations occur at a higher incidence in ILC, whereas GATA3 mutations occur more often in IDC. Mutations in both of these genes are associated with the modulation of ER activity. "This would suggest that the response to endocrine therapy may be different for patients with lobular than ductal carcinomas," Dr Carey told Medscape Medical News.
"[We] can expect these alterations to play a role in modulating response to hormone treatment. However, this will need to be investigated in the context of a clinical trial," the authors opine.
The editorial highlights observations unique to ILC that have been reported in the TCGA and European cohorts — an immune-related subset with an apparently high expression of lymphocyte signaling pathway components. "This finding may have consequences for the use of immune checkpoint inhibitors or other immune-based approaches in ILC," they write.
Several study authors reported having consulting or advisory roles with one or more pharmaceutical companies. Dr Carey has received research funding from GlaxoSmithKline and Genentech.
J Clin Oncol. Published online March 28, 2016.

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