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Breast Cancer and LM

Breast cancer is a type of cancer that begins in different parts of the breast. Breast cancer usually occurs in women but can affect men as well. The type of breast cancer is based on where the cancer cells start to grow. The most two common types of breast cancer are:

  • Ductal cancer (in the ducts that carry milk from lobules to nipples)
    • Ductal carcinoma in situ (DCIS) – non-invasive or pre-invasive cancer that has not spread outside the ducts.
    • Invasive ductal carcinoma (IDC) – Cancer that starts in the ducts and has spread into surrounding tissue. IDC makes up 70-80% of all breast cancers.
  • Lobular cancer (in the lobules of the glands that make breast milk)
    • Lobular carcinoma in situ (LCIS) – non-invasive cancer that has not spread outside the lobules. LCIS is actually considered a benign breast condition and not cancer.
    • Invasive lobular carcinoma (ILC) – Cancer that starts in the lobules and has spread into surrounding tissue. ILC is the second most common type of breast cancer, making up about 10% of all invasive cases.

Less common types of breast cancer include Paget disease of the breast (in the nipple itself); Phyllodes tumor (in the fat and connective tissue around the ducts and lobules); medullary carcinoma, tubular carcinoma and angiosarcoma (in the lining of the blood vessels and lymph vessels in each breast).

Heather Curley getting breast cancer treatment through an Ommaya port
Common Mutations in Breast Cancer

Cancer is caused by mutations in our DNA that allow cells to grow uncontrollably – and eventually invade surrounding tissue. 

The most known mutations in breast cancer are BRCA1 and BRCA2 (pronounced brack-a one and brack-a two). BRCA stands for BReast CAncer gene). However, there are many others, including:

  • PALB2 (Partner and Localizer of BRCA2)
  • CHEK2 (Checkpoint Kinase 2)
  • CDH1 (CaDHerin 1)
  • PTEN (Phosphatase and TENsin homolog)
  • STK11 (Serine/Threonine Kinase 11)
  • TP53 (Tumor Protein p53)


A person with breast cancer may have none of these mutations or one of these mutations (but not more than one) and the mutations vary by what type of breast cancer you have.

Hormone receptors are another important factor to know when you have breast cancer as they can help determine what treatment will work best. Breast cancer cells may have certain proteins or receptors that can attach to certain substances. For example, some breast cancer cells have receptors that attach to the hormone estrogen (estrogen receptors) or to the hormone progesterone (progesterone receptors). Breast cancer cells may have one, both or none of these receptors:

  • ER-positive (ER+): breast cancers that have estrogen receptors
  • PR-positive (PR+): breast cancers that have progesterone receptors


Cancers may be called hormone-positive (HR+) if they have one or both estrogen or progesterone receptors.

Cancers may be called hormone-negative (HR-) if they do not have either the estrogen or progesterone receptors.

Another important protein that helps breast cancer cells grow quickly is HER2. When breast cancer cells have higher levels of HER2 than normal, the cancer is called HER2+ (pronounced ‘her-2-positive). About 15 to 20 percent of breast cancers are HER2+. If the HER2 levels are normal, the cancer is considered HER2- (her-2-negative).

  • Triple negative: breast cancers that are ER-, PR- and HER2-
  • Triple positive: breast cancers that are ER+, PR+ and HER2+


Breast cancer also can be HER2-low or HER2-ultralow, meaning they have low or very low levels of HER2, but they are not HER2 negative. These cancers do not respond to most HER2-targeted therapies.

Metastatic breast cancer is also known as advanced breast cancer or stage 4 cancer. Metastatic breast cancer is when the cancer spreads to other areas of the body, such as lung, liver, bone and brain.

As many as 10-15% of patients overall with metastatic breast cancer develop brain metastases. Some subtypes have greater risk:

  • 12-15% of patients with HR+/HER2- metastatic breast cancer
  • 30-50% of patients with HER2+ metastatic breast cancer
  • 30-50% of patients with triple negative metastatic breast cancer

Leptomeningeal metastasis (also known as LM, leptomeningeal disease, LMD, or leptomeningeal cancer) differs slightly from brain metastases, as it means that the cancer is growing on the lining of the brain and spinal cord, called the leptomeninges. Most commonly this occurs along with brain metastases.

As many as 5% to 20% of people with breast cancer will develop LM, with HER2+ having the highest risk.

  • About 20% of HER2+ breast cancer patients develop LM

*For up-to-date guidelines for breast cancer treatment, visit the NCCN patient guidelines

Surgery: 

  • Surgery is often a treatment option for breast cancer when the tumor has been found early and hast not spread to other areas.
  • Surgery can be used to remove the tumor, breast tissue and lymph nodes in people with metastatic breast cancer to reduce symptoms. However, it will not treat metastatic disease.
  • Surgery cannot be performed to remove the entire leptomeninges, and it is usually reserved for patients with symptomatic brain metastases in the parenchyma (the functional, active area) of the brain.
  • The role of surgery in leptomeningeal metastases is usually for placement of one of two devices:
    • A reservoir, commonly called an “Ommaya,” is placed under the scalp to ease the collection of cerebrospinal fluid (CSF) and administration of medications into the cerebrospinal fluid (CSF)
    • A ventriculoperitoneal shunt or VPS is inserted in your head to reduce pressure inside the brain by draining extra CSF into the abdomen

 

Hormone Therapy, Targeted Therapy and Chemotherapy

 There are currently no specific FDA-approved therapies for leptomeningeal spread from breast cancer. However, even though many drugs do not cross the normal blood brain barrier, some still can work in the brain or in the leptomeninges.

  • Hormone therapies are used for patients with hormone receptor-positive cancers, such as ER+ or PR+. Most hormone therapies work by lowering estrogen levels in the body or by stopping estrogen from helping tumor cells grow. Hormone therapies can be given on their own or with targeted therapies. They are not typically used for brain metastases or leptomeningeal spread.

  • Targeted therapies are used to target proteins on breast cancer cells or certain mutations in breast cancer cells. These drugs can be used along with other medications, such as hormone therapies for HR positive cancers or chemotherapy. Targeted drugs have demonstrated activity throughout the body and may also work in the central nervous system. Examples include:
    • Monoclonal antibodies
      • Trastuzumab (Herceptin)
      • Pertuzumab (Perjeta)
    • Antibody-drug conjugates
      • Fam-trastuzumab deruxtecan (Enhertu)
      • Sacituzumab govitecan (Trodelvy)
      • Datopotamab deruxtecan (Datroway)
    • Kinase inhibitors
      • Neratinib (Nerlynx)
      • Tucatinib (Tukysa)

 

  • Chemotherapy may be used as the main form of treatment for metastatic breast cancer, or it may be used in combination with other treatments. Chemotherapy may be given before surgery to shrink the tumor or after surgery to kill any remaining cancer cells. It may be given along with radiation therapy or other therapies, depending on the type of breast cancer and how advanced it is.


Many systemic chemotherapies have limited activity in the leptomeningeal space, though they can be used creatively alone or in combination with other therapies. Chemotherapies for metastatic breast cancer include:

  • Eribulin (Halaven)
  • Platinum agents (Carboplatin)

Combination treatments

For patients with HER2+ Breast Cancer and leptomeningeal spread, current treatments include:

  • Trastuzumab deruxtecan (Enhertu)
  • Tucatinib + trastuzumab + capecitabine
  • Intrathecal trastuzumab
  • Neratinib + capecitabine

Sample of interesting drugs in clinical trials:

  • Brain penetrant HER2 TKIs (oral pills): ZN1041, IAM1363, CGT4255
  • Other HER2 targeted antibody drug conjugates (ADCs)

 

For patients with ER+ Breast Cancer and leptomeningeal spread, current treatments include:

  • Chemotherapy: capecitabine, Doxil, Carboplatin +/- gemcitabine, eribulin
  • Trastuzumab deruxtecan (Enhertu)
  • Sacituzumab govitecan (Trodelvy)
  • Hormonal therapy (with partners such as abemaciclib or others)
  • Neratinib combinations (if you have an ERBB2 mutation)
  • PARP inhibitor (if you have BRCA1/2 or PALB2 mutations)
  • Bevacizumab (Avastin) + chemo combos
  • Pembrolizumab (if your tumor has a high tumor mutational burden)

 

Sample of Interesting drugs in clinical trials:

  • Dato-DXD, elacestrant + abemaciclib, brain-penetrant PARP inhibitors, etc.

 

For patients with triple negative breast cancer and leptomeningeal spread, current treatments include:

  • Chemotherapy: capecitabine, Doxil, Carboplatin +/- gemcitabine, eribulin
  • Trastuzumab deruxtecan (Enhertu)
  • Sacituzumab govitecan (Trodelvy)
  • Neratinib combinations (if you have an ERBB2 mutation)
  • PARP inhibitor (if you have BRCA1/2 or PALB2 mutations)
  • Bevacizumab (Avastin) + chemo combos
  • Pembrolizumab (if your tumor has a high tumor mutational burden)

 

Sample of Interesting drugs in clinical trials:

  • Dato-DXD, brain-penetrant PARP inhibitors, bispecific antibodies

For metastatic breast cancer and leptomeningeal spread, some patients may benefit from receiving treatment intrathecally (directly into the spinal fluid) and depending on what is used, along with intravenous (into the bloodstream) treatment.

Intrathecal treatment can be given through a lumbar puncture or an Ommaya port.

  • Intrathecal (IT) therapy for breast cancer and LM includes the use of trastuzumab.
  • These treatments are usually given at a center that takes care of many patients with LM and has experience caring for patients who develop potential side effects.

Radiation Therapy: Radiation therapy might be used before surgery to shrink your tumor or after surgery to kill off any remaining lung cancer cells. Sometimes it’s used as the main form of treatment if you’re not healthy enough for surgery or if the cancer has already spread to other parts of your body. It can also be used to improve your quality of life by treating certain symptoms of breast cancer like pain.

For leptomeningeal cancer, radiation therapy to the whole brain and spine (called craniospinal irradiation or CSI) can be considered but should be approached with care. Side effects of CSI can limit the use of chemotherapy or other therapy and comes with risks of cognitive and functional impairment over time. Recent data suggest that proton radiation therapy may reduce the risk of systemic side effects (although it does not reduce the risk of nervous system side effects).

For more detailed information about breast cancer, please visit: