Medically reviewed by Dr. C.H. Weaver M.D. 9/2022
When breast cancer spreads away from the breast to the bones, lungs, liver, brain, skin, or other organs it is said to be metastatic. The treatment goals for metastatic breast cancer are to prolong the duration and quality of life. Treatment for metastatic breast cancer depends on prior treatment, hormonal and menopausal status, location of the recurrence, and whether a precision medicine can be used.
Researchers continue to make great strides in treating breast cancer and in making cancer treatment more tolerable, both physically and emotionally. The greatest recent advances and focus of ongoing research are in Precision Cancer Medicines and Immunotherapy Standard chemotherapy typically destroys both normal and cancerous rapidly dividing cells in a wide range of tissues, often causing side effects by damaging normal cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
Breast cancers that are confined to the breast or area immediately surrounding the breast, called local-regional recurrences, are typically treated with surgery with or without radiation therapy. Most patients who experience a recurrence of breast cancer however have disease that has metastasized or spread to other locations in the body. These patients require systemic treatment that can reach the cancer anywhere in the body. Systemic therapy may consist of chemotherapy, hormonal therapy, or precision cancer medicines or immunotherapy used alone or in combination.1,2 In general treatment for breast cancer is determined by the following:
- Hormone Receptor Positive Cancers
- HER2 Positive Cancers and Other "Targetable Mutations"
- Triple Negative Breast Cancer
- Bone Metastases
- Treatment of Locally Recurrent Breast Cancer
Treatment of Hormone Receptor Positive Cancer
Endocrine or “hormone” therapy is usually the first treatment for hormone receptor positive metastatic breast cancer and chemotherapy is reserved for the treatment of hormone receptor positive cancers that no longer respond to endocrine therapy, hormone receptor negative cancers or individuals requiring immediate shrinkage of the cancer.
Estrogen is an essential female hormone that is produced by the ovaries and adrenal glands. It serves many critical functions in the body, including developing the female sex organs in puberty, preparing the breasts and uterus for pregnancy in adulthood, and maintaining cardiovascular and bone health. Without estrogen, the female body is unable to sustain pregnancy and is susceptible to heart disease and osteoporosis.
Estrogen can also cause some cancers to grow. The breasts, uterus, and other female organs are composed of cells that contain estrogen receptors and estrogen circulating in the blood binds to these receptors and stimulates growth-related activities in the cell. When cells that have estrogen receptors become cancerous, exposure to estrogen increases the cancer’s growth. Cancer cells that have estrogen receptors are referred to as estrogen receptor-positive (ER-positive) cancers. The growth of some breast cancer cells can be prevented or slowed by reducing the exposure to estrogen. This is the goal of endocrine therapy.
Removal of the ovaries, the organ chiefly responsible for producing estrogen in premenopausal women, is one effective approach to eliminating estrogen production and is commonly used in many countries. Another approach is to utilize drugs that can accomplish a similar effect without removing the ovaries. These drugs include tamoxifen, aromatase inhibitors, and most recently cyclin-dependent kinase inhibitors (CDK).
Endocrine Therapy for Hormone Receptor Positive Breast Cancer
Recommendations set forth by a convening Expert Panel specifically for women with HR-positive, metastatic breast cancer included the following.10 A combination of a CDK4/6 inhibitor and endocrine therapy is currently the first choice because the addition of CDK 4/6 inhibitors to endocrine therapy is associated with improved survival and maintained or improved quality of life compared to other endocrine therapies.3-9
- Patients whose cancer cells express any level of HR-positivity should be offered endocrine therapy as initial therapy.
- Sequential endocrine therapy (using one endocrine agent until the patient’s cancer progresses, then switching to a different endocrine agent until the cancer progresses again, etc.) is the preferred treatment of choice.
- Among postmenopausal women, aromatase inhibitors (AIs) are the initial treatment of choice, with or without the addition of the CDK inhibitor.11-14 For example a CDK inhibitor combined with an AI demonstrated a greater than 28-month median progression-free survival as initial endocrine-based therapy for metastatic disease compared to 14.8 months for treatment with an AI alone.
- If the cancer starts to progress on AIs, Faslodex® (fulvestrant) or combination therapy with a CDK inhibitor and an AI can further prolong survival. The CDK inhibitor Ibrance (palbociclib) when combined with Faslodex nearly doubles the duration of survival when compared to an AI alone.12
- Among premenopausal women, ovarian suppression or ablation should be included in the treatment strategy. The CDK inhibitor Kisqali in combination with tamoxifen or an AI plus goserelin improve time of survival without cancer progression to 23.8 months compared to 13 months for tamoxifen or an AI plus goserelin.15
Precision Cancer Medicines
Not all breast cancer cells are alike. They may differ from one another based on what genes have mutations. Precision cancer medicine utilize molecular diagnostic testing, including DNA sequencing, to identify cancer-driving mutations in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells.
HER2 Positive Cancers - Twenty to thirty percent of breast cancers over express (make too much of) a protein known as HER2. Over expression of this protein leads to increased growth of cancer cells. There are several precision medicines that specifically target HER2-positive cells, and regimens using these drugs have significantly improved outcomes among women with HER2-positive breast cancers. Doctors sequence these treatments to obtain optimal results.
- Herceptin® (trastuzumab) recognizes and binds to HER2-positive cells and was the first precision medicine developed for the treatment of breast cancer. Among women with HER2-positive breast cancer, Herceptin used alone or in combination with chemotherapy has been shown to increase response rates and prolong survival. Tykerb (lapatinib) also targets HER2 as well as a related protein known as the epidermal growth factor receptor (EGFR).16-20
- Tukysa (tucatinib) is a highly selective oral tyrosine kinase inhibitor (TKI) that targets HER2. The HER2CLIMB clinical trial compared Tukysa in combination with Herceptin and Xeloda to treatment with Herceptin and Xeloda alone in patients with locally advanced or metastatic HER2-positive breast cancer who were previously treated with Herceptin, Perjeta, and T-DM1. . The addition of Tukysa reduced the risk of disease progression and improved survival, even in women with brain metastases and 33% of Tukysa treated patients survived one year without cancer progression compared to only 12% for Herceptin + Xeloda.26-28
Enhertu (trastuzumab deruxtecan) (DS-8201) is approved for the treatment of patients with HER2-positive metastatic breast including patients with minimal or "low" HER2 expression that historically were not offered HER2 directed therapy. Enhertu is a HER2-targeting antibody drug conjugate (ADC) comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor (DXd) payload by a tetrapeptide linker. It is designed to deliver enhanced cell destruction upon release inside the cell and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered. Enhertu is an effective treatment but is associated with significant lung toxicity in 16% of patients.48,49
- Kadcyla (ado-trastuzumab emtansine, formerly known as T-DM1) is an antibody-drug conjugate that combines Herceptin and a chemotherapy drug (DM1) that interferes with cancer cell growth. Kadcyla delivers Herceptin and DM1 directly to HER2-positive cells, and limits exposure of the rest of the body to the chemotherapy. Kadcyla has been demonstrated to delay cancer progression and prolong survival compared to Tykerb plus Xeloda (capecitabine) and Herceptin plus docetaxel in women with recurrent metastatic, HER2-over expressed breast cancer. Kadcyla has also been evaluated as the initial treatment for metastatic HER2 + breast cancer and found to produce similar outcomes as Herceptin plus taxane or T-DM1 plus pertuzumab.21-25
- Perjeta (perjeta) targets a different part of the HER2 protein than Herceptin. Since the two drugs target different regions of HER2, they are believed to work in a way that is complementary to each other. In a comparative clinical study called the CLEOPATRA trial, the combination of Herceptin and Perjeta plus chemotherapy improved survival compared to treatment with Herceptin alone.29,30
BRCA Mutations - About 3% of breast cancers are in people who inherited BRCA mutations. BRCA1 and BRCA2 are tumor-suppressor genes that encode proteins involved in DNA repair through the homologous recombination repair pathway. Mutations in the BRCA gene raise the risk of cancer because they make the body less likely to repair damage to its DNA, making the mutations that lead to cancer more likely. Poly ADP-ribose polymerase (PARP) inhibitors block enzymes involved in repairing damaged DNA. By disrupting a cancer cells’ ability to repair itself PARP inhibitors slow uncontrolled growth and replication of cancer cells.31,32 There are several PARP inhibitors in development.
- Lynparza (olaparib) is the first PARP inhibitor approved for use in breast cancer. Lynparza was demonstrated to be superior to chemotherapy for treatment of HER2-negative advanced breast cancer patients who have a BRCA mutation.31 Women with BRCA positive breast cancers have hereditary breast cancers and related individuals may be at increased risk of breast cancer and should be evaluated.
Hormone Receptor–Negative Breast Cancer
The treatment for hormone receptor–negative breast cancer is systemic therapy with chemotherapy and/or immunotherapy. Patients with breast cancer that does not have estrogen/progesterone receptors, those not responding to hormonal treatment, and individuals requiring symptomatic relief from progressive breast cancer may benefit from treatment with chemotherapy.
There are currently several standard chemotherapy drugs and treatment regimens available, and approximately 25% of patients who undergo chemotherapy will experience a complete remission of their cancer. Patients should discuss their goals of treatment with their physician and consider participation in a clinical study as their initial treatment.
- Taxanes Taxotere (docetaxel) and Taxol (paclitaxel) are both taxanes that, when used in combination or sequentially with other chemotherapy drugs, appear to have more anti-cancer activity than non-taxane chemotherapy for the treatment of metastatic breast cancer.
- Abraxane (nanoparticle albumin-bound paclitaxel): A technique for delivering anti-cancer drugs is called nanoparticle albumin-bound (nab) technology. Abraxane is a treatment that delivers the anti-cancer drug paclitaxel using nab technology. This technique utilizes albumin, the most abundant protein in the body, to deliver the paclitaxel directly to cancer cells. With Abraxane 50% more drug can be administered, more active drug is transported into the cancer cells, and patients experience fewer side effects.33
- Xeloda (capecitabine) is a well-tolerated, oral chemotherapy drug that can be taken at home for treatment of breast cancer. Research indicates that 20-30% of patients experience a measurable shrinkage of their cancer following treatment with Xeloda. Xeloda is well-tolerated, and the average duration of survival of patients treated with Xeloda is almost 13 months.
Triple Negative Breast Cancer (TNBC)
Approximately 12-15% of all breast cancers are triple negative, meaning that they are estrogen and progesterone-receptor negative, and human epidermal growth factor receptor 2-negative (HER2-). This means that TNBC is not stimulated to grow from exposure to the female hormones, estrogen or progesterone, nor through an overactive HER2 pathway.
Understanding DNA Damage Response or DDR and Cancer Treatment
What is DNA Damage Response or DDR?
TNBC tends to be an aggressive type of cancer, is often diagnosed at a more advanced stage, and proportionately affects younger women more often than other breast cancers. Novel treatment options for TNBC have lagged behind that of other types of breast cancers and the development of more effective treatment for triple negative breast cancer (TNBC) requires that new and innovative therapies be evaluated in TNBC patients.
- Trodelvy (sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate comprised of an antibody that attaches to specific receptors called Trop-2 receptors and delivers an attached drug that kills cancer cells, called SN-38. By targeting Trop-2 receptors, larger amounts of chemotherapy can be delivered to the cancer cells because healthy cells are largely spared from the cancer-killing effects of the treatment. Trodelvy was approved by the U.S. FDA for the treatment of patients with TNBC on April 5th, 2020.39
Trodelvy has also been shown to extend the survival of patients with advanced HER2 negative hormone-sensitive breast cancer that has stopped responding to at least two earlier courses of therapy. Trodelvy improved survival by 3.3 months and reduced the risk of death by 21% when compared to chemotherapy. The study was presented at the 2022 European Society for Medical Oncology's annual meeting in Paris. Average overall survival for those who received Trodelvy was 14.4 months compared with 11.2 months for chemotherapy treated patients.
Checkpoint Inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 receptor these drugs restore an immune cells’ ability to recognize and fight the breast cancer cells. A diagnostic test to measure the level of PD-L1 is available.
- Tecentriq (atezolizumb) checkpoint inhibitor when combined with Abraxane in women with advanced TNBC produced an anti-cancer response in 71% of patients. The combination of Tecentriq and Abraxane improved average survival duration from 15.5 months among patients with PD-L1–positive tumors to 25 months leading to accelerated FDA approval in 2020.34-36
- Keytruda (pembroluzumab) Initial results from the KEYNOTE-355 clinical trial in previously untreated advanced TNBC and some level of PD-L1 expression were released at the 2020 American Society of Clinical Oncology Annual Meeting. Over all 847 patients were treated with Keytruda plus chemotherapy or chemotherapy alone and directly compared. Patients were evaluated based on their CPS which measures the amount of PD-L1 expression on cancer cells. In patients with the highest CPS of 10 or greater the addition of Keytruda to chemotherapy significantly prolonged survival without cancer progression.38
Managing Bone Metastases
Recurrent breast cancer often includes cancer that has spread to the bones, called bone metastases. Cancer can spread to the bones when individual cancer cells break off from the original tumor and travel in the circulatory or lymph system until they get lodged in a small vessel in a new area. The cell then grows into another tumor. Management of bone metastases may include a RANK ligand inhibitor or a bisphosphonate drug, and the use of bone-modifying therapy to reduce skeletal morbidity in patients with bone metastases should be considered.39-42
- XGEVA (denosumab) is indicated for the prevention of skeletal-related events in patients with bone metastases from breast cancer. XGEVA targets a protein known as the RANK ligand. This protein regulates the activity of osteoclasts (cells that break down bone). In patients with bone metastases, increased RANK ligand production can cause destruction of bone. XGEVA has been directly compared with the bisphosphonate drug Zometa and shown to be more effective at delaying skeletal complications such as fracture, spinal cord compression, surgery to the bone, and radiation to the bone.39-40
- Bisphosphonates are a class of drugs that decrease the rate of bone destruction in patients with cancer. Clinical studies have shown that bisphosphonate therapy can prevent or delay bone destruction, including fractures and related pain, in women with breast cancer that has spread to the bone.41,42
- Strontium89 is a radionuclide therapy that is used to alleviate pain caused by bone metastases. Strontium89 delivers radiation directly to the boney cancerous sites and has been shown to provide pain relief from bone with a single injection.43
Doctors refer to isolated metastases as “oligometastatic” cancer and have often advocated treatment with surgery or stereotactic body radiation therapy (SBRT). Research now suggests that adding metastasis-directed therapy to standard-of-care systemic therapy does not improve progression-free survival or overall survival in patients with 1-4 isolated metastases.47
The randomized phase 2/3 NRG-BR002 trial designed to assess the addition of SBRT or surgical resection to systemic therapy for breast cancer patients with only a few metastases was halted early due to lack of benefit. The trial included 125 patients with controlled locoregional breast cancer and four or fewer metastases, randomly allocated to metastasis-directed therapy plus systemic therapy, or to systemic therapy alone. At 36 months from initiation of treatment the overall survival rate was 69% with metastasis-directed therapy compared with 72% with standard-of-care systemic therapy only.
There are situations where SBRT or surgery may offer benefit-the risks and benefits should be carefully discussed with a patients treating physician.
Surgery may be indicated for certain situations
- Fungating/painful breast lesions can be treated with mastectomy however mastectomy is only used in select circumstances.
- Brain or vertebral metastases with spinal cord compression.
- Isolated lung metastases.
- Pathologic (or impending) fractures.
- Pleural or pericardial effusions.
Radiation therapy has a major role in the palliation of localized symptomatic metastases. Indications for external-beam radiation therapy include the following:
- Painful bony metastases.
- Unresectable central nervous system metastases (i.e., brain, meninges, and spinal cord).
- Bronchial obstruction.
- Fungating/painful breast or chest wall lesions.
- After surgery for decompression of intracranial or spinal cord metastases.
- After fixation of pathologic fractures.
Strategies to Improve Treatment
The development of more effective cancer treatments requires that new and innovative therapies are evaluated with cancer patients. Clinical trials are studies that measure the effectiveness of new drugs or treatment strategies. All patients with metastatic breast cancer should discuss the role clinical trials can play in the management of their cancer.
Immunotherapy: Drugs that help the body’s immune system attack cancer cells are now used to treat many cancers including TNBC. These drugs “take the brakes off” the natural factors that limit how the immune system can control tumor cells or stimulate the immune system. Many types of immunotherapy drugs and other immune mediated strategies are currently being evaluated in breast cancer.
New Precision Cancer Medicines: Breast cancers may differ from one another based on what genes have mutations, and “genomic testing” can be performed on a biopsy sample of the cancer and sometimes with a "blood biopsy" to identify the specific genetic abnormality driving the growth of the breast cancer. Once the cancer driving mutation is identified a specific precision cancer medicine or immunotherapy can be developed to attack that specific mutation or other cancer-related change in the DNA programming of the cancer cells.
All patients should discuss the role of genomic biomarker testing with their doctor to determine if they have a treatable mutation or are eligible for participation in a clinical trial evaluating newer precision cancer medicines and immunotherapies. Precision cancer medicines can be used both instead of and in addition to chemotherapy to improve treatment outcomes.
PI3 kinase inhibitors - Alpelisib (pictilisib, GDC-0941) PI3 kinase is an enzyme important in cell growth. The PIK3CA gene helps control PI3 kinase enzyme activity. PI3KCA is mutated in approximately 40% of patients with HR-positive, HER2-negative advanced breast cancer, and is associated with treatment resistance and poor outcomes. Alpelisib is an oral PI3K inhibitor and clinical trials show the addition of Alpelisib to Faslodex delays the time to cancer recurrence in women with advanced breast cancer who are positive for both ER and PR and have previously failed treatment with an aromatase inhibitor.
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- Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results. Presented at: ASCO20 Virtual Scientific Program. J Clin Oncol. 2020;38(suppl):abstr 1006.
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