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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

breast cancer indicates that the disease has spread to several lymph nodes and/or to tissue around the breast or breast bone. However, locally advanced disease is not metastatic disease and has not spread to distant parts of the body. Locally advanced disease is typically stage III disease and is often managed in a way similar to early-stage disease. (See the previous Medical Journeys installment for more on early-stage disease.)

The stage IV designation, however, indicates that the cancer has to distant parts of the body -- most often the bones, lungs, or liver. cancer can be diagnosed initially, or can develop as a recurrence after treatment for an earlier stage of breast cancer.

The is key to the management of metastatic disease and usually includes medical, surgical, and radiation oncologists, and radiologists and pathologists. Genetic counselors, dietitians, financial advisors, and other supportive care providers may also be part of the team.

Genetic Testing

Genetic testing can help guide treatment options, advise on surveillance for other cancers, and help family members determine their own cancer risks. National Comprehensive Cancer Network guidelines that all patients with metastatic disease, including breast cancer, undergo such testing as the information may change the treatment plan. In early stage (stage I-III) hormone receptor positive breast cancer, molecular testing is often done to see if a patient will benefit from chemotherapy. Options for molecular testing are Oncotype DX, MammaPrint, and Prosigna.

A single mutation test evaluates for a mutation in a specific area of one gene, while a single-gene test analyzes an entire gene to determine if there are any mutations, and a panel test looks for mutations in multiple genes.

Single mutation and single-gene tests most often focus on , such as BRCA1, BRCA2, and PALB2. Panel tests will look for those mutations and other inherited genetic mutations tied to breast cancer, such as ATM, BRIP1, CDH1, CHEK2, MRE11A, MSH6, NBN, p53, PALB2, PTEN, RAD50, RAD51C, STK11, and TP53. While single gene testing was done more often in the past, panel testing is now the most common way to do genetic testing.

Stages III and IV disease are most often treated with systemic therapy -- i.e., one or more of the treatment modalities below. Treatment for stage III disease usually begins with neoadjuvant systemic therapy, followed by surgery and then adjuvant treatment including radiation and additional systemic therapy. In stage IV disease, surgery is not routinely performed as the disease has already spread outside of the breast and axilla. Radiation therapy is sometimes done to manage symptoms or complications from the cancer.

Chemotherapy

Chemotherapy is often used in combination with other treatments, such as immunotherapy or anti-HER2 therapies, depending on the breast cancer type, to treat locally advanced breast cancer.

The most commonly used in breast cancer include taxanes, anthracyclines, cyclophosphamide, platinum-based agents, capecitabine, vinorelbine, gemcitabine, eribulin, and nab-paclitaxel. The decision to use specific drugs and regimens depends on the stage of the disease; estrogen receptor (ER), progesterone receptor (PR), and HER2 status; and in metastatic disease, the prior treatments received also play a role in treatment regimen decisions.

Adverse events can vary depending on the chemotherapy drug used, the patient's overall health, and the duration of treatment.

Common with chemotherapy include but are not limited to nausea and vomiting, fatigue, hair loss, mouth sores and dry mouth, anemia, neutropenia, thrombocytopenia, diarrhea, constipation, peripheral neuropathy, skin and nail changes, taste and appetite changes, and cognitive issues with memory and concentration.

Endocrine Therapy

Cancers are designated as hormone receptor-positive or hormone receptor-negative. A patient's tumor tissue is tested for . If it is positive for estrogen receptor (ER+) and/or progesterone receptor (PR+), the patient may be a candidate for endocrine therapy, also known as hormone therapy.

for metastatic breast cancer includes:

• Selective estrogen receptor modulators that block estrogen from binding to its receptors (i.e., tamoxifen).

• Aromatase inhibitors that reduce the production of estrogen in postmenopausal women by inhibiting aromatase enzyme activity.

• Gonadotropin-releasing hormone agonists that suppress ovarian function in premenopausal women (these are combined with tamoxifen or aromatase inhibitors).

• Selective estrogen receptor degraders (SERDs) that block and degrade estrogen receptors.

• CDK 4/6 inhibitors are a class of medications combined with endocrine therapy in both early stage and metastatic hormone receptor positive breast cancer. These medications induce cell cycle arrest, resulting in a blockade of cancer cell proliferation.

Common adverse events with endocrine therapy can include hot flashes, night sweats, mood changes, joint and/or muscle pain, and vaginal dryness. Each of the endocrine therapies has its own specific side effects as well.

Targeted Therapy

pinpoints specific cancer genes, proteins, or the tissue environment that fosters cancer growth.

Hormone receptor positive metastatic breast cancer can become resistant to first-line endocrine therapy and there are many other targeted therapies that can be utilized. Other therapeutic agents available include PI3K inhibitors and mTOR inhibitors, which target the PI3K/AKT/mTOR pathway that is associated with cell growth, survival, and proliferation and elacestrant, a novel SERD that targets ESR1-mutated ER+, HER2-negative metastatic breast cancer.

CDK 4/6 inhibitors are often used in the first-line setting with endocrine therapy but can be used in later lines of treatment as well. Novel estrogen-receptor targeted therapies are in development as well.

Poly (ADP-ribose) polymerase (PARP) is an enzyme involved in DNA repair. PARP inhibitors prevent PARP enzymes from repairing tumor DNA. PARP inhibitors are effective in people with HER2-negative high-risk early-stage or metastatic breast cancer who have a pathogenic variant (mutation) in the BRCA1 or BRCA2 genes.

are used for breast cancers that overexpress the HER2 protein -- in about 20% of breast cancers. For example, trastuzumab is a monoclonal antibody that targets the HER2 molecule, and is often used in combination with pertuzumab and chemotherapy.

There are other anti-HER2 treatments available as well, such as the antibody-drug conjugates, trastuzumab deruxtecan, and ado-trastuzumab emtansine. The combination of trastuzumab, capecitabine, and tucatinib is a regimen used in metastatic HER2-positive breast cancer.

Tumor-agnostic, or tissue-agnostic drugs are agents used for any tumor that has a specific mutation, no matter where the tumor started. Patients with metastatic breast cancer with rare high microsatellite instability tumors can receive pembrolizumab, while patients with certain NTRK gene mutations (about 2% of breast cancers) may be candidates for larotrectinib or entrectinib.

Pembrolizumab is an immune checkpoint inhibitor and is used in stage II-III triple-negative breast cancer (TNBC) and metastatic breast cancer.

Adverse events of targeted therapy , and vary from person to person. A common toxicity of anti-HER2 therapies is cardiotoxicity and patients need regular cardiac monitoring with echocardiograms.

Future Directions

There are many ongoing clinical trials with novel investigational agents aiming to improve outcomes in all breast cancer subtypes. Novel antibody-drug conjugates and estrogen-receptor targeted agents are being evaluated in clinical trials.

Adoptive cell therapies, such as chimeric antigen receptor T-cell therapy -- where a patient's T cells are extracted, genetically modified or trained to recognize cancer cells, and then reintroduced into the patient to target and attack the cancer -- are being investigated in metastatic TNBC, but these treatments are not available in the clinic yet. In addition, tumor-infiltrating lymphocyte adoptive cell therapy is being studied in metastatic disease.

Tumor microenvironment are drugs designed to alter the tumor microenvironment in order to make it more favorable for an immune response. Agents that target regulatory T cells (Tregs) or myeloid-derived suppressor cells are being investigated for treating HER2-positive and HER2-negative cancers.

A HER2 peptide-based vaccine known as nelipepimut-S () has demonstrated immune activity for both HER2-amplified and non-amplified breast cancer, which is currently being studied as a combination therapy with other therapeutic agents, such as trastuzumab.

Read previous installments in this series:

Part 1: Breast Cancer -- The Basics of Diagnosis, Staging, and Treatment

Part 2: Breast Cancer: Making the Diagnosis With Breast Biopsy

Part 3: What to Know About Management of Early-Stage Breast Cancer