Pi3k And Mtor Inhibitors
PI3K and mTOR are key components in signaling downstream of HER2 . The m-TOR inhibitor everolimus has been extensively studied in breast cancer, and it is approved for treatment of ER-positive HER2-negative BC on the basis of BOLERO-2 trial . However, it showed less encouraging results in two large phase III trials in HER2-positive MBC . BOLERO-1, which studied addition of everolimus to trastuzumab + taxanes in first line metastatic treatment, reported that everolimus was associated with increased toxicity without any improvement in either PFS or OS . BOLERO-3 tested addition of everolimus to trastuzumab + vinorelbine in second line metastatic treatment for patients previously exposed to trastuzumab and taxanes. The addition of everolimus in the BOLERO-3 led to a statistically significant improvement of PFS . However, numerically the median PFS was prolonged by less than 2 months and there was no improvement in OS . A joint analysis of BOLERO-1 and BOLERO-3 was conducted in search for biomarkers to select patients benefiting most from treatment with everolimus. It showed that somatic mutations in the PI3K pathway could be used to predict response, and that everolimus benefit was mainly limited to ER-negative patients .
Summary Of Treatment Options For Metastatic Breast Cancer
Hormone receptor-positive, HER2-negative breast cancer
Hormonal therapy is considered the standard initial treatment for HER2-negative metastatic breast cancer that is also hormone receptor-positive, and is often given in combination with targeted therapy. However, chemotherapy may also be given. A clinical trial may also be an option for treatment at any stage.
Hormone receptor-negative, HER2-negative breast cancer
In general, chemotherapy or targeted therapy is given for treatment of triple-negative breast cancer. A clinical trial may also be an option for treatment at any stage.
HER2-positive breast cancer that has spread to parts of the body other than the brain
In general, HER2-targeted therapy is regularly added to treatment for HER2-positive breast cancer that has spread. The drugs used depend on the treatments already given and whether the cancer is hormone receptor-positive. The treatment recommendations for first-line, second-line, and third-line or higher treatment are listed below. A clinical trial may also be an option for treatment at any stage.
Second-line treatment is used for people with early-stage breast cancer who had the cancer either spread during initial treatment with trastuzumab or return within 12 months after stopping treatment with trastuzumab. It is also used for people whose cancer worsens while receiving first-line treatment.
The preferred second-line treatment is the drug T-DM1.
Tucatinib Neratinib And Lapatinib
The tyrosine-kinase inhibitors FDA-approved for metastatic breast cancer treatment are:
Tyrosine-kinase inhibitors are a class of drugs that target enzymes important for cell functions . These drugs can block tyrosine-kinase enzymes at many points along the cancer growth pathway.
A tyrosine-kinase inhibitor in combination with trastuzumab and chemotherapy can be used to treat HER2-positive metastatic breast cancer. This combination may give women with HER2-positive metastatic breast cancer more time before the cancer spreads compared to treatment with trastuzumab and chemotherapy alone .
Adding the tyrosine-kinase inhibitor tucatinib to treatment with trastuzumab and chemotherapy may also increase overall survival in women with HER2-positive metastatic breast cancer who were treated with trastuzumab in the past .
Neratinib is also used to treat HER2-positive early breast cancer.
Tucatinib, neratinib and lapatinib are pills.
Learn about neratinib and treatment of early breast cancer.
Tucatinib, neratinib and lapatinib and brain metastases
Many drug therapies cannot pass through the blood to the brain . So, they cant treat breast cancer that has spread to the brain.
However, tucatinib, neratinib and lapatinib can pass through the blood-brain barrier and may be used to treat some metastatic breast cancers that have spread to the brain.
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Immune Checkpoints And Immunotherapy Trials In Hr+ Breast Cancer
Despite the limited number of TILs, low PD-L1 expression and low mutational burden in HR+ breast cancer , there has been an effort to determine if ICB has a role in HR+ disease . While, to date, clinical trials testing ICB in HR+ breast cancer have not yet translated to FDA approval, there is opportunity to learn from both past and ongoing trials to identify the ideal therapeutic sequencing, combination strategies and patient population to extract value in this immunologically cold subtype of breast cancer, as reviewed below.
Table 2 Clinical trials in HR+ breast cancer assessing the safety and efficacy of ICB as monotherapy or in combination with chemotherapy and other treatment modalities.
Cancercares Free Support Services And Programs
It can be very difficult to receive a diagnosis of breast cancer, and adjusting to the necessary changes in your life can be challenging.
CancerCare can help. We are a national nonprofit organization providing free, professional services to anyone affected by cancer. Our licensed oncology social workers can provide support and education, help in navigating the complicated health care system, and provide information on support groups and other resources.
To learn more about how CancerCare helps, call us at 800-813-HOPE or visit www.cancercare.org.
You will likely also build your own personal support network, composed of family and friends. In doing so, its best to take some time to think about the people in your life and how they are best suited to help. Match the task to their strengthsask a family member who loves to shop to pick up something for you at the store ask a friend whos a good listener to come over for a chat.
Treatment recommendations are individualized, taking into consideration the biology of the cancer, its stage and the overall health of the individual.
Treatment for cancer usually includes a combination of surgery, radiation and drug therapy. Surgery and radiation focus on the disease in the breast and lymph nodes, and are referred to as locoregional therapies.
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Tests To Detect Spread
If you notice signs that your HER2-positive breast cancer may have spread, talk to your doctor. This is especially important if your symptoms are new, wonât go away, or you canât tell why they may be happening.
But itâs important not to panic. Keep in mind that symptoms such as bone pain can happen from arthritis, getting older, or even from your breast cancer treatment. Meanwhile, a cough and shortness of breath could just mean you have a cold or the flu. And itâs normal to feel tired and to not be hungry after youâve had cancer treatment.
To figure out if your breast cancer has spread, your doctor might do a variety of tests. These can include:
- Blood tests, some of which may look for tumor âmarkersâ
- Bone scan
Breast Cancer Hormone Receptor Status
Breast cancer cells taken out during a biopsy or surgery will be tested to see if they have certain proteins that are estrogen or progesterone receptors. When the hormones estrogen and progesterone attach to these receptors, they fuel the cancer growth. Cancers are called hormone receptor-positive or hormone receptor-negative based on whether or not they have these receptors . Knowing the hormone receptor status is important in deciding treatment options. Ask your doctor about your hormone receptor status and what it means for you.
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What Are The Side Effects Of Treatment
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.
What Is The Life Expectancy For Each Cancer Stage
Your outlook depends on the stage of your cancer when its discovered. Cancer is staged by number, starting with 0 and going to 4. Stage 0 is the very beginning and stage 4 is the last stage, also called the metastatic stage because its when cancer has spread to other areas in the body.
Each number reflects different characteristics of your breast cancer. These include the size of the tumor and whether cancer has moved into lymph nodes or distant organs, like the lungs, bones, or brain.
The cancer subtype doesnt play a role in staging, only in treatment decisions.
Survival statistics of women with the major subtypes of breast cancer such as ER-positive, HER2-positive, and triple-negative are grouped together. With treatment, most women with very early stage breast cancers of any subtype can expect a normal life span.
Survival rates are based on how many people are still alive years after they were first diagnosed. Five-year and 10-year survival are commonly reported.
According to the American Cancer Society, 5-year survival rates are:
- stage 0 100 percent
- stage 3 72 percent
- stage 4 22 percent
One thing to note is that these statistics also included women with the more aggressive HER2-positive and triple-negative cancers. And it takes five years to get to a five-year statistical survival rate, so newer therapies are not included in these numbers.
Its likely that a woman with ER-positive breast cancer diagnosed today may have a higher chance of survival.
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Progression Of Her2+ Mbc
Sarah Sammons, MD, provides an overview of the progression HER2-positive metastatic breast cancer and common areas for the development of metastases, including in the brain.
Sarah Sammons, MD: HER2 positive breast cancer 20 or 30 years ago had 1 of the highest risks of spreading distantly and developing metastatic disease. Over the last few decades, given the highly effective HER2-targeted therapies that weve had, that has somewhat changed. HER2-positive early stage breast cancer is now 1 of the earliest, most curable breast cancers, given the highly effective therapies that we have.
That certainly does leave a small portion of patients with high-risk, early-stage disease who progress and become metastatic. A large portion of the metastatic HER2-positive population has what we call de novo metastatic disease. Their early stage disease is not caught soon enough, and by the time their disease is diagnosed, they already have metastatic disease, which is disease that has spread beyond the breast and regional lymph nodes.
The Present: Addressing Hormone Resistance Via Molecular Therapies
Since their FDA approval in the latter 20th century, modern hormonal therapies have demonstrated significant PFS for ER+ mBC patients . However, post-diagnosis approximately 30-50% ER+ breast cancer patients on these hormonal therapies acquire resistance, requiring additional or substitutive treatment for the further clinical benefit . Recent research suggests this resistance to occur via the PI3K-AKT-mTOR, CCND1-CDK4/6-RB, BCL2-p53-MDM2, ESR1 and other cell-signaling pathways, demonstrating the potential efficacy of molecular-based therapies in advanced breast cancer.
Despite early successes in molecular targeting of the PI3K-AKT-mTOR pathway, others pursued the molecular targeting of other frequently deregulated pathways in ER+ mBC. The CCND1-CDK4/6-RB pathway, innately vital to cell cycle control, regulates whether a cell advances or arrests at the G1-S phase of the cell cycle. Furthermore, it was estimated that 35% HR+ breast cancers demonstrated amplification in the CCND1, the gene that encodes cyclin-D1, and 16% demonstrated amplification in the gene encoding CDK4, suggesting the theoretical utility of their inhibitors in ER+ mBC therapeutics .
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How Can Hormone Receptors Be Used To Slow Cancer Growth
Blocking the action of estrogen and/or progesterone could possibly stop the cancer from growing. There are a few ways in which this can happen:
- Blocking the hormone receptor with another compound prevents the estrogen or progesterone from being able to attach to the receptor and activate the cell.
- Prevent the body from making the hormone: This can be done with medication to block the production of the hormone, or with surgery to remove the organ that makes it. For example, estrogen production can be significantly decreased by surgically removing the ovaries.
- Eliminate the hormone receptors on cells or change their shape: This makes it impossible for the hormone to attach itself to the cell receptor and to activate it, essentially making the hormone unable to function.
What Is Metastatic Breast Cancer
Metastatic breast cancer is not a specific type of breast cancer. Its the most advanced stage of breast cancer.
Metastatic breast cancer is breast cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body .
Although metastatic breast cancer has spread to another part of the body, its still breast cancer and treated as breast cancer.
For example, breast cancer that has spread to the bones is still breast cancer . Its not the same as cancer that starts in the bone. Breast cancer cells have invaded the bones. So, its treated with breast cancer drugs rather than treatments for cancer that began in the bones.
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What This Means For You
Its important to remember two things about this study:
For both of these reasons, the study results should be interpreted with caution.
If youve been diagnosed with metastatic HER2-positive breast cancer, you and your doctor will consider a number of treatment options, including anti-HER2 targeted therapy medicines and chemotherapy. If surgery is not recommended for you, you may want to bring up this study and talk to your doctor about why surgery isnt in your treatment plan.
Together, you and your doctor will develop the best treatment plan for your unique situation.
For more information on metastatic breast cancer treatments, visit the Breastcancer.org Metastatic Breast Cancer pages.
To talk with others who have been diagnosed with metastatic breast cancer, join the Breastcancer.org Discussion Board forum Stage IV/Metastatic Breast Cancer ONLY.
Reviewed by: Brian Wojciechowski, M.D., medical adviser
Neratinib In Cns Disease
The phase II NEfERT study directly compared neratinib against trastuzumab in combination with paclitaxel in the first-line setting for HER2+ MBC. Although the neratinib arm was not superior to trastuzumab in terms of overall PFS, it did reduce the risk of CNS recurrence by 50%, from 17.3% in the trastuzumab arm to 8.3% in the neratinib arm .74 The risk of CNS progression was also lower in the neratinib arm .74 Neratinibs apparent ability to control CNS disease was consistently observed across patients with and without baseline brain metastases. As previously, the neratinib/paclitaxel arm was associated with a 30% risk of G3-4 toxicities , predominantly G3 diarrhoea.74
Although only patients with treated, stable brain metastases were included in the NALA study, notably fewer patients treated with neratinib required CNS intervention , further confirming its superior CNS activity compared to lapatinib.70
Unfortunately, the adjuvant phase III ExteNET study where a year of adjuvant neratinib following 12 months of trastuzumab was found to significantly prolong IDFS, neratinib did not significantly reduce the incidence of CNS recurrence over 5 years in comparison to placebo, although the number of events was very low in both arms , so it is difficult to draw any meaningful conclusions.76
Inhibitors Of Hsp90 And Angiogenesis
Experimental studies suggested a potential role for HSP90, angiogenesis, and topoisomerase inhibitors in treatment of different types of cancer. However, clinical trials have not yet justified including these drugs into routine clinical practice in HER2-positive MBC.
HSP90 is a chaperon protein, which is required for proper folding and function of hundreds of its client proteins , including HER2 and its key downstream targets . Preclinical studies reported anti-tumor activity of HSP90 inhibitors on a wide range of BC cells, with HER2-positive cell lines being particularly sensitive . In 2011, a phase II clinical trial studied effect of an HSP90 inhibitor tanespimycin on 31 HER2-positive MBC patients who previously progressed on trastuzumab . It reported objective responses to the tanespimycin + trastuzumab combination in 22% of the patients with median PFS of 6 months and median OS of 17 months. While this was a positive result, the efficiency of tanespimycin + trastuzumab looked modest in comparison to trastuzumab-emtansine reported shortly afterward . Another HSP90 inhibitor showed limited efficacy in HER2-positive MBC in a phase II trial reported in 2013 . No further clinical trials of HSP90 inhibitors were reported in HER2-positive MBC since then. However, the overall interest and experimental studies of HSP90 are continuing, with focus on biological complexity of HSP90 functions in cancer .
How Her2 Affects Treatment
Treatment for breast cancer depends in part on the stage and type and is different in each case, but typically involves some combination of surgery, radiation, chemotherapy, or other drug therapies. These other drug therapies depend partly on whether your cancer is HER2-positive. If it is, certain medications can work well, such as:
Antibody-drug conjugates. These drugs target chemotherapy directly to HER2 protein on cancer cells.
Kinase inhibitors. These medications stop proteins like HER2 from sending signals.
How Her2 Affects Staging
Your HER2 status helps determine the pathology of your specific breast cancer. Your HER2 status can also help determine how aggressive the cancer is. Your doctor will use this information to evaluate your treatment options.
As of 2018, the breast cancer staging system that the American Joint Committee on Cancer uses now incorporates HER2 status.
Staging is complex and must take various other factors into account, such as:
- the size of the tumors
- the cancers hormone status
- whether the cancer has spread to nearby lymph nodes
- whether the cancer has spread beyond the breast
- whether the cancer cells look abnormal
For example, these two cancers are both classified as stage 1B: