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What Is Hr+ Breast Cancer

Stage 0 Vs Stage 1 Breast Cancer

Dr. Denduluri on Treatment Approaches in Early-Stage HR /HER2- Breast Cancer

In stage 1 breast cancer, the cancer is invasive, though its small and contained to breast tissue , or a small amount of cancer cells are found in your nearest lymph nodes .

As we explore stage 0 breast cancer, were talking about DCIS, not stage 1 invasive breast cancer or lobular carcinoma in situ .

Genomic And Transcriptomic Profiling

CIBERSORT is a computational method that quantifies the proportion of 22 functional immune subsets within bulk tissue gene expression profiles. Ali and colleagues used CIBERSORT to analyze bulk gene expression profiles of 10,988 breast tumors from 56 publicly available datasets . Specifically, this study aimed to determine the relationship between TME composition and molecular subtype, survival and response to chemotherapy. In HR+ tumors, the presence of M0 macrophages and regulatory T cells were associated with poor prognosis , which was later confirmed by another group studying the prognostic significance of tumor-infiltrating immune cells in breast cancer . Notably, the HR+ tumors lacking immune infiltration were associated with intermediate or similar survival outcomes compared to HR+ tumors with high or low immune infiltrates. Thus, in this large cohort, the presence of immune cells was not prognostic of outcome in HR+ breast tumors .

Relative Survival Rates For Breast Cancer

The National Cancer Institute gives 5-year relative survival rates for breast cancer based on how far the disease had spread before a doctor found it.

  • Localized : 99%
  • Regional : 86%
  • Distant : 28%
  • Unknown stage: 55%
  • All stages: 90%

While these numbers can give you a general idea, they are an average for women with any type of breast cancer. They arent specific to the HER2+ type. They also come from data that researchers collected from 2010 to 2016, so they dont reflect more recent treatment advances.

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The Pentose Phosphate Pathway

Glucose is converted to glucose-6-phosphate by the hexokinase enzyme during the first stages of glycolysis and is then shunted into the pentose phosphate pathway which is essential for nucleotide synthesis . During the first phase of PPP, G6P is converted to 6-phosphogluconolactone by glucose 6-phosphate dehydrogenase which results in the production of NADPH. 6-Phosphogluconolactone is hydrolyzed by 6-phosphogluconolactonase to produce 6-phosphogluconate resulting in the generation of the nucleic acid synthesis precursor ribulose 5-phosphate and the production of additional NADPH molecules by 6-phosphogluconate dehydrogenase in the last, and irreversible step of the oxidative phase of the PPP . The final, non-oxidative reversible phase in this pathway generates ribose 5-phosphate by the action of ribose 5-phosphate isomerase or xylulose 5-phosphate by ribulose 5-phosphate epimerase . With the action of the enzymes transketolase and transaldolases, PPP is capable of recycling the resulting products back to the PPP oxidative phase where it utilizes G6P and glycolysis .

What Is Metastatic Breast Cancer

HR+/HER2

Metastatic breast cancer, also called stage 4 or advanced breast cancer, is breast cancer that has spread beyond the breasts and nearby lymph nodes to other parts of the body. Metastases often occur in the bones, the lungs, the liver, or the brain.Metastatic breast cancer is treatable but not curable, so a diagnosis means that youll have to take medication for the rest of your life. The course of metastasis varies from person to person, so youll stay on a treatment for as long as its working to slow the progress of the disease.

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Icb In Combination With Chemotherapy For Hr+ Breast Cancer

Given the promising results using chemotherapy with ICB in TNBC, there has been an effort to replicate similar strategies in HR+ breast cancer. Like the early monotherapy trials, the initial chemotherapy plus ICB combination trials focused on heavily pretreated patients in the metastatic setting. The first of these trials used eribulin as a combination agent. Eribulin is a microtubule inhibitor that, in addition to antimitotic activity, has been shown to reverse epithelial-mesenchymal-transition and decreased numbers of FOXP3 and PD-L1 expression as measured through IHC . In the phase II trial, eribulin with or without pembrolizumab was evaluated in 88 patients with HR+/HER2- metastatic breast cancer . In this cohort, the patients had received at least two prior lines of endocrine therapy and up to two lines of chemotherapy. The addition of pembrolizumab to eribulin did not add any benefit to median PFS . In addition, PD-L1 status, TILs and TMB were not associated with median PFS. Importantly, 54.6% of patients who received E+P experienced grade 3-4 adverse events, including 2 treatment related deaths.

Antigen Presentation In Hr+ Breast Cancer

Prior to presentation of antigen complexed with an HLA molecule, that antigen must undergo processing. Components of the antigen-processing machinery have also been evaluated in breast cancer. Liu and colleagues found differential expression of antigen-processing molecules between primary breast tumors with and without associated brain metastases . In particular, primary breast lesions in patients who later developed brain metastases showed lower beta 2 microglobulin expression as well as other APM components, such as transporter associated with antigen processing 1 and 2 , and calnexin, which are essential components for antigen processing and loading on HLA. In addition, CD8 T cell infiltration was significantly higher in primary breast lesions without an associated brain metastasis and was correlated with TAP1 expression. Preclinical data further support these findings. Murine tumor cells stably transfected with silencing hairpin RNA for TAP1 demonstrated a decreased susceptibility to cytotoxic T lymphocytes in vitro and an increased frequency of spontaneous brain metastasis in vivo . These data suggest that a deficiency in antigen-processing machinery may increase the likelihood of metastasis through deficient immune surveillance.

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Blood Tests For Tumor Markers

In some cases, blood tests for tumor markers may be used to help monitor metastatic breast cancer.

For example, you may have blood tests every few months for cancer antigen 15-3 or cancer antigen 27.29 . These tests are similar. Health care providers usually check one, but not both of these blood tests.

Whether the tumor marker test score rises or falls over time may give some information on tumor response to a drug or tumor spread.

Tumor marker tests are not helpful in every case. Some people with rising tumor marker levels dont have tumor growth, and some people with tumor growth have normal or unchanged tumor marker levels.

Health care providers dont make treatment decisions based on serum tumor marker testing alone. They may combine findings from a tumor marker test with information on symptoms and findings from imaging tests . This combined information can help your health care providers understand if a treatment is working well for your cancer.

Talk with your health care provider about whether tumor marker testing is right for you.

Tils In Breast Tumors Before And After Neoadjuvant Systemic Therapy

Heterogeneity of Metastatic HR+ Breast Cancer

Unconventional approaches to measure lymphocyte infiltration have also revealed interesting results from analysis of baseline tumors. In a cohort of TNBC patients, stromal TILs and TILs measured by tumor infiltrating lymphocyte volume were significantly correlated with pCR . In that study TILV were calculated using the formula TILV = % stroma in tumor x % stromal TILs where stromal TILs were assessed according to the standardization and guidelines of the international TILs working group . In an analysis of the ARTemis trial using computational pathology, lymphocyte density was significantly associated with pCR in multivariate analysis but there was no association between pre-treatment lymphocyte density and survival in either HR+ or HR- patients treated with NAC . Subset analyses of lymphocyte infiltrates have been described in breast cancer where TILs are largely composed of CD4+ and CD8+ T cells . In a retrospective study, CD8+ TILs in pre-chemotherapeutic biopsy specimens were found to be independent predictors for pCR irrespective of breast cancer subtype . Conversely, in another study, CD20+ lymphocytes scored by quantitative immunofluorescence positively predicted pCR in response to NAC irrespective of HR and HER2 status, whereas CD3+ and CD8+ lymphocytes did not .

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Ethics Approval And Consent To Participate

Patient consent is not required for observational studies. In addition, patients included in the registry are informed during their treatment that their data can be used for research purposes and they can then refuse to have all or part of their data used. As a cancer registry, the Côte dOr Breast and Gynaecological Cancer Registry has obtained the approval of the French national data protection authority for data recording, and this study was approved by the French national data protection authority

Icb In Combination With Other Treatment Modalities For Hr+ Breast Cancer

ICB in combination with chemotherapy for the treatment of HR+ breast cancer has shown some success, particularly in the neoadjuvant setting however, it remains unclear if chemotherapy is sufficient to reverse these immunologically cold tumors. Importantly, there is a wide variety of treatment options for patients with HR+ breast cancer including targeted molecules and radiation. Thus, there has been an interest in the synergistic potential of these other treatment modalities.

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How Are Breast Tumors Tested For Her2

Women newly diagnosed with invasive breast cancers should be tested for HER2.

A biopsy or surgery sample of the cancer is usually tested with either immunohistochemical stains or Fluorescent in situ hybridization .

See Testing Biopsy and Cytology Specimens for Cancer and Understanding Your Pathology Report: Breast Cancerto get more details about these tests.

Hormone Receptor Positive Breast Cancer

HR+/HER2

Your breast cancer may be hormone receptor-positive or HR+. Some breast cancers have receptors on them that attach to the hormones, estrogen, and progesterone, as they circulate in your body. These hormones feed the cell and help it grow.

  • If your tumor has hormone receptors, it is called hormone receptor-positive or HR+. If your tumor is HR+, the tumor needs estrogen and/or progesterone to grow.
  • About 80% of breast cancers are HR+.
  • If your tumor does not have hormone receptors, it is hormone receptor-negative or HR-.

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Serine Amino Acid Cycle And The Mitochondrial One

Over the past 10 years, significant progress has been made in our understanding of how cancer cells use one-carbon metabolism to synthesize anabolic precursors for nucleotide synthesis and for the production of methyl groups used for RNA, DNA and protein methylation, which collectively contribute to tumor growth . Several studies have demonstrated that amino acid metabolic pathways, including serine and glycine, are connected to the folate cycle which provides the universal 1C acceptor tetrahydrofolate . This intermediate metabolite can accept or donate the one-carbon units necessary to facilitate nucleotide synthesis and to provide methyl groups. In addition to THF, serine hydroxymethyltransferase 1 and SHMT2, which are localized to the cytoplasm and mitochondria, respectively, are essential for catabolizing serine to glycine and 1C units . Alternatively, methylenetetrahydrofolate dehydrogenase which exists in both cytosolic and mitochondrial forms is required to convert methylene-THF to formyl-THF which is essential for purine biosynthesis and NADH/NADPH production .

When Can Metastatic Breast Cancer Occur

Some people have metastatic breast cancer when they are first diagnosed with breast cancer . This is called de novo metastatic breast cancer.

Most often, metastatic breast cancer arises years after a person has completed treatment for early or locally advanced breast cancer. This may be called a distant recurrence.

A diagnosis of metastatic breast cancer is not your fault. You did nothing to cause the cancer to spread.

Metastatic breast cancers come from breast cancer cells that remained in the body after treatment for early breast cancer. The breast cancer cells were always there but were dormant and could not be detected. For some unknown reason, the cancer cells began to grow again. This process is not well-understood.

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S For Interrogating The Tme To Reveal Novel Icb Targets

Recent advances in molecular and genomic profiling, as well as multi-plex tissue analysis have allowed a deep understanding of the TME and have revealed novel mechanisms and opportunities to overcome immune suppression in HR+ breast cancer, as reviewed here. Further strategies aimed at more deeply characterizing the TME of HR+ breast cancer and contrasting it to immune rich, ICB-responsive tumors may greatly facilitate development of novel strategies for the use of ICB in HR+ breast cancer. In this section we aim to review current technologies used to explore the TME and include both advantages and disadvantages to each strategy.

What Are The Side Effects Of Treatment

Neoadjuvant Therapy for HR+ Breast Cancer

Generally, the side effects of hormonal therapies tend to be mild and fairly well tolerated, says Brufsky. The most common side effects are menopausal symptoms , achiness in the joints and bones, and fatigue. AIs can cause some bone loss , but that can typically be well controlled with bone-modifying medications, Brufsky notes. CDK4/6 inhibitors may cause low white blood cell counts as well as some nausea and diarrhea.

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What To Look For In Your Pathology Report

When you have a biopsy for a breast tumor, the pathology report tells you a lot more than whether its cancerous or not. It provides crucial information about the makeup of your tumor.

This is important because some types of breast cancer are more aggressive than others, meaning they grow and spread faster. Targeted treatments are available for some types, but not for all.

Each type of breast cancer requires its own approach to treatment. The information in your pathology report will help guide your treatment goals and options.

Two important items on the report will be your HR status and your HER2 status.

Continue reading to learn more about how HR and HER2 status in breast cancer affects your treatment and your outlook.

What Is Her2 And What Does It Mean

HER2 is a growth-promoting protein on the outside of all breast cells. Breast cancer cells with higher than normal levels of HER2 are called HER2-positive. These cancers tend to grow and spread faster than other breast cancers, but are much more likely to respond to treatment with drugs that target the HER2 protein.

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De Novo Metastatic Breast Cancer

The relationship between de novo mBC and OS , PFS , and BCSS was evaluated, with a significant association reported in 100% , 67% , and 0% of studies, respectively.30,33,39,57,62,91 Four studies demonstrated longer OS in patients with mBC at diagnosis compared with recurrent breast cancer 30,39,57,91 while one study reported shorter OS in patients with de novo mBC.62 Similarly, one study showed longer PFS associated with patients with de novo mBC,30 while another study showed a reverse relationship.33

The association of de novo mBC with OS and PFS was consistent with respect to evidence. The directionality of association was consistent with OS but not with PFS. The effect size of the association between de novo mBC and survival endpoints ranged between weak to moderate.

Alpelisib And Hormone Therapy

HR+/HER2

Alpelisib is a PI3 kinase inhibitor.

PI3 kinase is an enzyme important in cell growth. The PIK3CA gene helps control PI3 kinase enzyme activity. Some breast cancers have a PIK3CA gene mutation. This gene mutation is in the genes of breast cancer, not the person.

PI3 kinase inhibitors are a class of drugs designed to interrupt PI3 kinase signals and stop the growth of breast cancer cells with PIK3CA gene mutations.

Alpelisib in combination with the hormone therapy fulvestrant is FDA-approved to treat hormone receptor-positive, HER2-negative metastatic breast cancers with a PIK3CA gene mutation that have been treated with hormone therapy in the past.

The combination of alpelisib and fulvestrant can give more time before the cancer spreads compared to fulvestrant alone .

If alpelisib is being considered for your treatment plan, your tumor will be checked to see if it has a PIK3CA gene mutation. This can be done by testing tumor tissue or testing for tumor DNA in your blood .

Alpelisib is a pill.

Side Effects

Alpelisib

Some possible side effects include high blood sugar, diarrhea, nausea, decreased appetite, rash, vomiting, fatigue and hair loss.

Blood sugar levels are monitored while taking alpelisib because nearly everyone who takes it gets high blood sugar levels.

Its recommended you take an antihistamine, such as cetirizine , to lower the risk of rash.

Adapted from select sources .

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What Do The Hormone Receptor Test Results Mean

A test called an immunohistochemistry is used most often to find out if cancer cells have estrogen and progesterone receptors. The test results will help guide you and your cancer care team in making the best treatment decisions.

Test results will give you your hormone receptor status. It will say a tumor is hormone receptor-positive if at least 1% of the cells tested have estrogen and/or progesterone receptors. Otherwise the test will say the tumor is hormone receptor-negative.

Hormone receptor-positive breast cancer cells have either estrogen or progesterone receptors or both. These breast cancers can be treated with hormone therapy drugs that lower estrogen levels or block estrogen receptors. Hormone receptor-positive cancers tend to grow more slowly than those that are hormone receptor-negative. Women with hormone receptor-positive cancers tend to have a better outlook in the short-term, but these cancers can sometimes come back many years after treatment.

Hormone receptor-negative breast cancers have neither estrogen nor progesterone receptors. Treatment with hormone therapy drugs is not helpful for these cancers. These cancers tend to grow faster than hormone receptor-positive cancers. If they come back after treatment, its often in the first few years. Hormone receptor-negative cancers are more common in women who have not yet gone through menopause.

Expand The Important Safety Information

Important Facts About Verzenio® . It is also known as abemaciclib.Verzenio is a prescription medicine used to treat a type of breast cancer. It is a medicine you can take if:

  • You have a type of breast cancer called HR+/HER2 and the cancer has spread to other parts of the body
  • Verzenio is given along with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women, along with fulvestrant in women whose disease has progressed after hormonal therapy, or by itself in adults whose disease has progressed after hormone therapy and prior chemotherapy

It is not known if Verzenio is safe and effective in children.

Warnings

Verzenio may cause serious side effects, including:Diarrhea is common with Verzenio, may be severe and may cause dehydration or infection. The most common time to develop diarrhea is during the first month of Verzenio treatment. Your doctor may stop your treatment, lower your dose, or tell you to wait to begin your treatment cycle if you have diarrhea.

At the first sign of loose stools, tell your doctor. You may be advised to start taking an antidiarrheal medicine and drink more fluids.

Low white blood cell counts are common with Verzenio and may cause serious infections that can lead to death. Your doctor should check your white blood cell counts before and during treatment. Tell your doctor right away if you have fever or chills.

  • Trouble breathing or shortness of breath
  • Cough with or without mucus
  • Chest pain

How to take

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