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When breast cancer is , it means that the disease has spread to lymph nodes and/or tissue around the breast or breast bone. Stage III disease is also sometimes referred to as locally advanced breast cancer. However, stage III is not metastatic disease and is often managed in a way similar to that for early-stage disease. (See the previous Medical Journeys installment for more on early-stage disease.)

Stage IV means that the cancer has metastasized and spread to distant parts of the body, most often the bones, lungs, or liver. cancer can be diagnosed initially, or it can develop as a recurrence after treatment for an earlier stage of breast cancer.

A is important for managing metastatic disease. Your team will usually include medical oncologists, surgical oncologists, radiation oncologists, 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. The National Comprehensive Cancer Network provides guidelines for which patients are eligible for testing.

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. Genomic testing is often utilized to guide therapy in metastatic disease and is performed using samples from the tumor, a patient's blood or both.

Mutations are that occur during cell division, or when your cells make copies of themselves. Some look for a single mutation in a specific area of one gene. A single-gene test analyzes an entire gene to determine if there are any mutations. A panel test looks for mutations in multiple genes.

Single mutation and single-gene tests most often focus on common gene mutations, 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, using one of the following treatment approaches. Stage III treatment usually starts with presurgical (also known as neoadjuvant) chemotherapy followed by surgery, and then adjuvant treatment, which includes radiation and often additional systemic therapy. In certain situations, surgery is done first in stage III disease.

In , 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 and stage. The most commonly used chemotherapy drugs are taxanes, anthracyclines, platinum-based agents, cyclophosphamide, 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.

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

Common side effects with chemotherapy include but are not limited to nausea and vomiting, fatigue, hair loss, mouth sores and dry mouth, anemia, neutropenia, thrombocytopenia, digestive problems, 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 depending on whether or not they express the . Tumor tissue is tested for hormone receptor status. 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 breast cancer includes selective estrogen receptor modulators (SERMs such as tamoxifen), aromatase inhibitors (AIs), gonadotropin-releasing hormone (GnRH) agonists, and selective estrogen receptor degraders (SERDs).

• SERMs block estrogen from binding to the ER.
• AIs reduce the production of estrogen in postmenopausal women by inhibiting aromatase enzyme activity.
• GnRH agonists suppress ovarian function in premenopausal women (these are combined with tamoxifen or AIs).
• SERDs block and degrade ERs.
• 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.

The choice of endocrine therapy depends on the tumor characteristics and stage.

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

Targeted therapy pinpoints or proteins or the tissue environment that encourage the cancer to grow.

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, AKT inhibitors, and mTOR inhibitors, which target the PI3K/AKT/mTOR pathway that is associated with cell growth, survival, and proliferation.

Elacestrant is 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 ER 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.

HER2-targeted therapies are used for breast cancers that overexpress the HER2 protein, which can make breast cancer cells grow faster. Approximately 20% of breast cancers are HER2-positive. 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. For example, the immunotherapy drug pembrolizumab is approved for patients who have microsatellite instability-high (MSI-high) or mismatch repair deficient (dMMR) unresectable or metastatic solid tumors and have developed disease progression on other treatment options. Pembrolizumab is also used in stage II-III triple-negative breast cancer and metastatic triple-negative breast cancer.

The side effects of targeted therapy depend on the drug and dose, and vary from person to person. A common toxicity of anti-HER2 therapies is cardiotoxicity and patients need regular cardiac monitoring with echocardiograms.

Personalized Therapy

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 (CAR) 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 triple-negative breast cancer, 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 modulators are designed to make the tumor microenvironment more favorable for an immune response, and these are being investigated for treating HER2-positive and HER2-negative cancers.

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

Follow-Up and Self-Care

Your oncologist will schedule regular follow-up appointments. These visits are a crucial part of managing your health, monitoring potential disease progression, and detecting any changes as early as possible. Engaging in regular physical activity, eating a balanced diet, and limiting alcohol use are lifestyle factors that can be helpful in side effect management, and improving quality of life and perhaps breast cancer outcomes.

Read previous installments in this series:

Part 1: For Your Patients: Breast Cancer Basics

Part 2: For Your Patients: The Crucial Role of the Biopsy in Breast Cancer

Part 3: For Your Patients: Understanding Early-Stage Breast Cancer

"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.