With greater optimism in the fight against breast cancer, 2013 ended with discoveries that lend to a deeper understanding on the pathogenesis and progression of breast cancer. Highlighted here are a few examples of these studies that are likely to shape breast cancer research and ultimately patient care in the future.
HER2 Mutation as a Therapeutic Target in HER2 Non-amplified Breast Cancer
* Bose R et al: Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 2013;3:224-237: Bose et al demonstrated that HER2 somatic mutations in breast cancers that lack HER2 gene amplification are oncogenic and, importantly, are sensitive to treatment with the investigational irreversible HER-kinase inhibitor neratinib in preclinical models.
This study indicated that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer. Although the overall HER2 mutation rate is approximately two percent in primary breast cancers, it reaches over 20 percent in relapsed invasive lobular cancers. This finding led to the ongoing Phase II trial of neratinib in HER2-mutated non-amplified metastatic breast cancer (NCT01670877).
This is one of the first breast cancer trials designed to target genomic alterations identified by whole genome sequencing studies. If successful, it will provide a novel treatment for a subgroup of patients with HER2-negative disease.
ESR1 Mutation as a Resistant Mechanism to Endocrine Therapy in ER+ Breast Cancer
Several groups independently identified the presence of hot spot ligand-binding-domain mutations in ESR1, the gene that encodes the estrogen receptor (ER) α in metastatic ER+ breast cancer that developed acquired resistance to hormonal therapy:
* Li S et al: Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep 2013 4:1116-1130.
* Toy W et al: ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet 2013;45:1439-1445.
* Robinson DR et al: Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet 2013;45:1446-1451.
In the paper by Li et al, eight patient-derived xenograft (PDX) models were established from patients with resistant ER+ breast cancers. Remarkably, 4 PDX models carried genomic variations in the ESR1 gene, including the hotspot ESR1 mutation (n=2), ESR1 gene amplification (n=1), or translocation leading to a fusion protein of ESR1/YAP1 (n=1), all of which were associated with constitutive ER activation and treatment resistance.
In contrast to the situation with primary breast tumors, there was an unexpected high frequency of ESR1 mutation in metastatic endocrine-resistant ER+ breast cancer specimens, six of 11 cases reported by Robinson et al and 14 of 80 cases reported by Toy et al. The hotspot ESR1 mutations in the ligand-binding domain leads to the agonist conformation of the receptor without ligand binding, and therefore promotes estrogen-independent tumor growth and less effective therapy from ER antagonists such as tamoxifen or fulvestrant.
The identification of genetic variations of the ESR1 gene has deep implications in the management of metastatic ER+ breast cancer and calls for the development of ER antagonists effective in the presence of ESR1 mutations. The availability of the PDX models will facilitate the testing of therapeutic interventions.
Estrogen-independent ER Activation by the Major Cholesterol Metabolite 27-Hydroxycholesterol
Two independent groups demonstrated data that links cholesterol metabolism and ER+ breast cancer, implicating another mechanism of treatment resistance to estrogen deprivation therapy:
* Nelson ER et al: 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science 2013;342:1094-1098.
* Wu Q et al: 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast cancer growth. Cell Rep 2013;5:637-645.
Nelson et al provided evidence that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol promotes ER-dependent tumor growth via ER and liver X receptor (LXR), respectively, in mouse models of breast cancer. Statins or inhibitors against the cytochrome P450 oxidase CYP27A1, the enzyme that coverts cholesterol to 27HC, attenuated the enhanced tumor proliferation by cholesterol. The authors further demonstrated that CYP27A1 is expressed in both tumor cells and tumor-infiltrating macrophages and high levels of CYP27A1 expression correlated with high-grade tumors in human breast cancer specimens.
The tumor growth-promoting effect of 27HC was independently demonstrated by Wu et al using xenograft models of various ER+ breast cancer cell lines. In addition, Wu et al demonstrated that local production of 27HC in the normal breast tissue and cancer tissue is significantly increased in cancer patients compared with cancer-free controls. The increased tumor 27HC was correlated with diminished expression of CYP7B1, the enzyme that breaks down 27HC, and reduced expression of CYP7B1 in tumors was associated with poorer patient survival.
These studies provided a rationale for use of agents that reduce the level of CYP27A1 (such as statin) or inhibitors against CYP27A1 as a strategy in the prevention and treatment of ER+ breast cancer. Alternatively, more effective ER targeting by ER downregulators or agents that abrogate the interaction between 27HC and ER may be potential solutions.
APOBEC3B Mutagenesis in Cancer
APOBEC3B, a member of the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) family of cytidine deaminases responsible for C-to-U editing is found to be a probable source of mutations in breast cancer.
* Burns MB et al: APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 2013:494:366-370: Burns et al demonstrated that APOBEC3B messenger RNA is upregulated in most primary breast cancers. Knockdown of APOBEC3B reduced C-to-T transitions, while overexpression of APOBEC3B caused cell cycle deviations, cell death, DNA damage, and C-to-T mutations. In addition to its role in the pathogenesis of breast cancer, subsequent studies implicated APOBEC3B as a source of mutations in five other cancers including cervical, bladder, lung, and head and neck cancers.
These data suggest that APOBEC3B-catalysed deamination could lead to a chronic source of DNA damage and genetic heterogeneity and that APOBEC3B could potentially be a target for cancer prevention.
Access the abstract hyperlinks (shown in grey) for all the studies noted by reading the article on our iPad app, or by reading the pdf on oncology-times.com