Lat1 Expression In Breast Cancer Brain Metastasis Patient Samples
After obtaining Institutional Review Board approval, the Stanford STRIDE database was queried for patients with brain metastases from primary breast cancer, seen at Stanford Hospitals and Clinics between 2008 and 2018. Patient charts were individually reviewed to confirm radiographic evidence of brain metastasis , as well as molecular subtype . Formalin-fixed paraffin-embedded tissue samples for corresponding patients were obtained from Stanford Pathology. De-identified patient FFPE blocks that contained adjacent normal brain, together with brain metastasis, tissues were included in IHC analysis. We confirm that written informed consent was obtained from the patients, and that the studies were conducted in accordance with the Declaration of Helsinki ethical guidelines.
Crosstalk Between Tumor And Brain Microenvironment
Breast cancer cells also adapt to the local microenvironment in the brain and co-opt neurons, astrocytes and microglial cells to proliferate and establish metastases.
Metastatic breast cells have been shown to develop neuronal characteristics, expressing the GABAA receptor, GABA transporter, GABA transaminase, parvalbumin, and reelin, allowing them to take up GABA, shunt it to nicotinamide adenine dinucleotide phosphate production and facilitate proliferation of the tumor cells in the brain microenvironment . Kim et al. showed that murine astrocytes co-cultured in direct cell-to-cell contact with human breast cancer cells caused up-regulation of survival genes in the tumor cells, thus protecting them from the toxic effects of chemotherapy.
Zhang et al. demonstrated that microRNAs from astrocytes cause human and mouse tumor cells with normal expression of PTEN, to downregulate PTEN expression in the brain environment. The loss of this tumor suppressor gene expression allows proliferation of brain metastases. Subsequent blockade of astrocyte secretion restored PTEN and suppressed brain metastasis in vivo. Loss of PTEN is associated TNBC subtype and portends a shorter survival time. Hohensee et al. showed that upregulation of PTEN in a TNBC cell line led to reduced migration and invasion to the brain. Autocrine and paracrine activation of GM-CSF/CSF2RA and AKT/PTEN pathway on both astrocytes and tumor cells mediated this crosstalk.
Mutational Somatic Copy Number Alteration And Subclonal Analyses Of Primary Tnbc Tumors And Brain Metastases
First, we analyzed the tumor mutational burden of primary tumors relative to BrM using WES. On average, BrM harbored a greater mutational load than primary tumors . Upon analysis of matched primary-BrM WES pairs , however, there was no significant difference between tumor location and TMB . An analysis of shared mutations within matched pairs revealed varying degrees of mutational conservation between anatomical locations . The degree of variant sharing between matched pairs was generally greater than the degree of mutations shared between primaries and BrM globally , highlighting interpatient tumor heterogeneity and mutational divergence. We assessed whether a survival benefit was conferred by increasing TMB, as TMB has been considered a proxy for neoantigen burden . There was no significant association between TMB and survival from the time of primary TNBC diagnosis in the context of a model that included standard clinicopathological features . Next, we examined the mutational spectrum of genes with known associations to breast cancer development . We found that these genes were altered in 70% of combined primary and BrM samples, with TP53 being the most commonly mutated gene , in accordance with its known relevance to TNBC . The next most frequently altered genes were MAP3K13 and PIK3CA, which were mutated in 13% and 10% of samples, respectively all other genes were mutated less frequently, occurring in 7% or less of samples .
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Should You Get Genetic Testing
Breast cancers arenât typically passed down through families. But thereâs a strong association between TNBC and the BRCA1 gene mutation. This link âis significantly higher compared to other kinds of breast cancer,â Greenup says.
Thereâs evidence that 20% to 35% of Black women with TNBC may test positive for the BRCA1 gene mutation. And thereâs a 50/50 chance youâll have one of these mutations if your mother or father has one.
Most of what we currently know about familial breast cancer is based on the genes of white people. Thereâs ongoing research to pinpoint TNBC-related variants that may show up more often in other races and ethnicities.
So far, besides the BRCA1 gene, the following genetic mutations raise your odds of TNBC:
Experts may suggest multigene tests down the road. But the current national guidelines suggest genetic testing only for BRCA1 or BRCA2 genes if:
- You have a family history of breast or ovarian cancer
- You or a close family member is diagnosed with TNBC at age 60 or younger
- Youâre diagnosed with any breast cancer at age 50 or younger.
Still not sure if genetic testing is right for you? Ask your primary care doctor or gynecologist to review your cancer history.
âThey can determine whether or not you need a referral to a high-risk breast cancer clinic or genetic counseling,â Lee says.
âThatâs why the evaluation is so important,â Lee says. âYou do have to document your risk.â
Fast Relief With Fewer Side Effects
About half of the women were experiencing a visceral crisis at the time they joined the study. The others had metastatic tumors that were causing substantial symptoms, though not yet at the level of a crisis, or rapidly advancing disease.
The team randomly assigned the participants to receive either ribociclib plus hormone therapyconsisting of goserelin , which blocks the production of hormones by the ovaries, and either letrozole or anastrozole , drugs called aromatase inhibitorsor combination chemotherapy.
The chemotherapy combinations could include docetaxel plus capecitabine , paclitaxel plus gemcitabine, or capecitabine plus vinorelbine, depending on the drugs normally used at the hospitals where the participants were treated.
Women in both groups could continue treatment as long as tumor growth was kept at bay and the side effects were tolerable.
At the San Antonio meeting, Dr. Lu presented the study results that had been collected through April 2022. At that point, women who received the ribociclib combination had a median progression-free survival of 2 years, versus just over 1 year for those in the chemotherapy group.
This result is significant and clinically meaningful, said Dr. Lu.
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Healio: Are There Any Drugs Coming In The Pipeline That Youre Excited For
Anders: One of the key classes of drugs that were very curious about in the setting of breast cancer brain metastasis is immunotherapy. Weve seen substantial advances in the setting of non-small cell lung cancer and melanoma brain metastases with intracranial responses to immunotherapy agents. We have a lot to learn in breast cancer and would hope that we would see responses in our patients with triple-negative disease. Based on the comment I made earlier, targets within triple-negative breast cancer are a lot harder to identify, so leveraging the immune system would be a very attractive way to treat triple-negative breast cancer brain metastasis.
The other class of drug that we are interested in for brain metastasis are PI3K inhibitors. Studies have shown that activation of the PI3 kinase pathway and its associated oncogenic signaling pathways are higher in brain metastasis compared with primary tumors. There are ongoing studies looking at brain permeable PI3K/mammalian target of rapamycin inhibitors in the setting of breast cancer brain metastasis.
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What Is The Treatment For Her2
Treatment for HER2-positive breast cancer can include one or more of the following:
- Hormone therapy
The combination of treatments, as well as the kinds of targeted therapies youre given, will depend on how advanced the cancer is and whether its hormone-sensitive or recurrent.
If your cancer is stage 1, you may have surgery and then be given chemotherapy plus HER2-targeted therapy afterward. The therapy will usually be trastuzumab, with or without pertuzumab, for up to a year.
If your cancer is stage 2 or stage 3, you will likely be given chemotherapy and HER2-targeted therapy before surgery to shrink the tumor, with another round of targeted therapy after surgery, for up to a year.
If your cancer is hormone-sensitive, you may be given hormone therapy along with the targeted therapy. Hormone therapy is administered in pill form, and is given for 5 to 10 years.
In some cases, cancers that are both HER2 and HR positive may not need chemotherapy.
The targeted therapies mentioned above are designed to target the HER2 proteins on cancer cells in order to keep the cancer from growing. Like chemotherapy, theyre given intravenously .
Targeted therapies for HER2-positive cancer include:
Cell Culture And Drug Treatment
MDA-MB-231-BR3 cells were a kind gift from Dr. J.E. Price and were authenticated and Mycoplasma negative at passages 4 and 14. Cells were authenticated by STR profiling and proved to be Mycoplasma negative by real-time qPCR Mycoplasma contamination detection test . MDA-MB-231-BR3 is a derivative of the MDA-MB-231 cells selected for their ability to metastasize into the brain. To monitor brain metastases in situ by in vivo bioluminescence imaging , the MDA-MB-231-BR3 cells were transduced with a lentivirus containing synthetic firefly luciferase gene. Cells were cultured in DMEM supplemented with 10% FBS and maintained in a humidified incubator with 5% CO2 at 37°C. QBS10072S was synthesized and provided by Quadriga BioSciences, Inc. For in vitro studies, QBS10072S was dissolved in tissue culture-grade dimethyl sulfoxide and diluted into PBS. For in vivo studies, a lyophilized mixture of QBS10072S and Captisol was reconstituted in 0.9% saline prior to use. Detailed QBS10072S information is provided in the Supplementary Materials and Supplementary Tables S1S5.
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Development Of Brain Metastases In Patients With Mtnbc
29% of the patients developed BM, among whom about a quarter presented BM at initial diagnosis of mTNBC. About half of patients in the first recurrent BM group had synchronous extracranial metastases. The most common involved sites were lymph nodes , lung , bone , and liver . The cumulative incidence of BM at 1 and 2 years was 17% and 25%, respectively. The median time from the diagnosis of extracranial metastases to BM was 10 months .
Seventy-six patients had symptomatic brain metastasis. The most common symptoms of BM were headache , vomiting , motor impairment , and vertigo .
Sixty-nine patients had three or fewer brain lesions, and 58 had more than three lesions. Intracranial metastases were located in the supratentorial region in 65 patients , in the infratentorial region in 12 patients , in both supra-and infratentorial regions in 30 , in the brainstem in 6 patients , and 14 patients had meninges involvement. Sixty-nine patients had limited intracranial metastases .
Potential Therapeutic Targets For Tnbcbm Treatment
TNBCBM patients are still followed by the current medical community, and continuous exploration of valuable potential therapeutic targets is the priority of the future research. The ultimate goal is to reduce the incidence of BM and prolong the survival period of these patients. We review the emerging therapeutic targets with the aim of laying the foundation for the treatment of TNBCBM.
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Family History And Metastatic Triple
All breast cancers are tough to get rid of once theyâve spread to other parts of your body. But mTNBC presents more of a challenge because there are no hormones to target. But the number of therapies available is growing. And while your family history doesnât directly affect treatment, your genes and the genes in your tumor may change the kind of anti-cancer drugs your doctor uses.
For example, you may benefit from standard treatment along with newer drugs like immunotherapy, drug-antibody conjugates, or PARP inhibitors.
âThe mainstay of treating triple-negative breast cancer is chemotherapyâ Lee says. âBut thereâs a lot of work going on to try to find new agents and new combinations of agents to improve treatment.â
T And B Cell Repertoire Analysis
We used RNA-Seq data from primary TNBC tumors and BrM to perform T cell and B cell repertoire profiling. Relative to primary TNBC, TNBC BrM had lower read counts of T cell receptor alpha and beta , with BCR heavy chain and light chain abundance showing trending but non-significant differences . This result is in accordance with RNA-seq data that showed less T cell and B cell abundance in the primary samples relative to BrM . Repertoire diversity was indexed as modeled Shannon entropy , which is a diversity index that accounts for both the richness of the sample and relative species abundance . Thus, a large Shannon entropy score reflects a more diverse distribution of TCR/BCR sequences. The modeled Shannon entropy was lower for BrM compared to primary tumors . A comparison of matched BrM and primary TNBC pairs only, however, did not show a reduction of TCR/BCR read counts and modeled Shannon entropy .
Figure 4 T cell and B cell repertoire analysis revealed adaptive immune cell deficit in BrM relative to primary triple-negative breast cancer. The distribution of read counts and modeled Shannon entropy for all samples is displayed in , respectively. The same information is displayed, respectively, in for matched pairs . Wilcoxon rank-sum test was performed on log10-transformed or raw values to determine the statistical significance. Significance codes: p< 0.1 *p< 0.05 **p< 0.01 ***p< 0.001.
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Differential Gene Expression And Pathway Analysis Support An Immune Cell Deficit In Tnbc Brm Relative To Primary Tnbc Tumors
Gene expression was evaluated by utilizing RNA-Seq data between the primary tumor and BrM tissues. In total, there were 1,669 differentially expressed genes between these 2 groups, with 935 genes upregulated and 734 genes downregulated in the BrM tissues compared to primary tumors . Gene ontology analysis of DEGs revealed a significant enrichment of immune-related terms in the primary TNBC tumors compared to the BrM , whereas GO terms associated with the nervous system were significantly higher in the BrM relative to the primary TNBC tumors . Canonical pathway analysis of DEGs in primary tumors versus BrM illustrated a similar preponderance of immune signaling-related pathways as well as nervous system-related pathways associated with DEGs in BrM relative to primary tumors . Upstream regulator analysis further demonstrated an association of immune-related signaling activity with DEGs in primary tumors relative to BrM and an association of potential oncogenic drivers with regulation of BrM DEGs .
Lat1 Is Overexpressed In Tnbc Brain Metastases
LAT1 is overexpressed in primary TNBC , but LAT1 expression in brain metastasis from TNBC has not been investigated in detail. The studies of brain metastasis from other primary cancers suggest that LAT1 overexpression is common for brain metastasis . Consistent with this, gene expression analysis of primary breast cancers and matched brain metastases suggests that LAT1 expression is equally high in brain metastases and primary breast tumors . IHC analysis of patient samples revealed high LAT1 expression in TNBC brain metastases . Importantly, LAT1 levels in the brain metastases were higher than in adjacent non-malignant brain, where most LAT1 signal was associated with blood vessels . Among breast cancer subtypes, LAT1 expression in brain metastases mirrored reported LAT1 expression in primary breast tumors , with TNBC having the highest LAT1 and luminal A cancers having notably low LAT1 levels. Thus, QBS10072S has the potential to serve as a selective therapy for TNBC brain metastasis.
Incidence Of Female Breast Cancer
Breast cancer is the most common cancer in the United States , with estimated 284,200 new cases expected in 2021, accounting for 14.8% of newly diagnosed cancer cases in the US There will be 43,600 deaths attributable to breast cancer, accounting for 7.2% of all cancer-related deaths.1 Triple-Negative Breast Cancer accounts for about 15% to 20% of breast cancers diagnosed worldwide. They are most commonly seen in younger women and older African American women.25 When diagnosed, they are more likely to have lymph node involvement and are aggressive tumors with a higher relapse rate and a poor prognosis. A study by Lin et al reported the greatest risk of death in the first 2 years after initial diagnosis.6 The overall 5-year survival rate of TNBC is around 74.577%.710
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Healio: How Can Oncologists Manage Breast Cancer Brain Metastases And What Are The Fda
Anders: One of the first things for optimal management of patients with brain metastasis is to have a multidisciplinary team that includes the medical oncologist, but also includes local therapy partners largely radiation oncologists, as well as neurosurgeons, if resection is required. We at Duke, at our Center for Brain and Spine Metastasis, also have incorporated palliative care into our multidisciplinary team and thats been very effective.
Much of systemic therapy choices revolve around the subtype of breast cancer that the patient is presenting with be it HER2-positive disease, triple-negative disease or hormone-receptor-positive disease.
In the setting of hormone-receptor-positive disease, we follow our typical algorithm of endocrine therapy with biologic agents. Abemaciclib has been a very nice option because, of the CDK 4/6 inhibitors, it is the most brain permeable and we have the most data for abemaciclib in brain metastasis compared to the other CDK 4/6 inhibitors.