Treatment of Breast Cancer

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The optimal treatment of breast cancer depends on several factors including the cancer stage, the subtype of cancer, patient’s age, patient’s general health status, and patient’s preferences. There are many types of treatment available including surgery, radiation, chemotherapy, anti-hormonal treatment (also known as endocrine therapy), targeted therapy and bone-strengthening therapy. Surgery and radiation therapy are types of “local-regional” treatment because the goal of these therapies (in stage 0-III) is to remove the tumor and prevent the tumor from returning in the breast/lymph node region. Systemic treatment is medicine (given by mouth or into the blood through a vein) that goes throughout the body to try to kill any cancer cells that have microscopically spread from the original site. The reason that systemic treatment is so important for early stage breast cancer (even when the cancer is small and has not spread to the lymph nodes) is that cancer can escape the breast (through blood vessels inside the breast) microscopically before the breast cancer is ever diagnosed. These microscopic breast cancer metastases cannot be seen on any scans or detected by any blood test and they can live elsewhere in the body for years before growing into a detectable tumor in a distant organ. Systemic therapy aims to kill those microscopic metastases elsewhere in the body and has been shown in multiple clinical trials to increase rates of long term survival and cure of early stage breast cancer. For this reason, patients with any stage of disease will usually be offered some form of medicine to prevent the cancer from returning. The remainder of this section will focus on the systemic treatment for breast cancer.

Timing of Therapy Adjuvant therapy is systemic treatment given to patients with stage I-III breast cancer after surgery to reduce the chances that cancer will return. Neoadjuvant therapy is systemic treatment given to patients prior to surgery. Similar to adjuvant therapy, it reduces the chance that the tumor will come back in the future. Studies have shown that neoadjuvant therapy can reduce the size of the tumor, and thus increase the likelihood that a patient can save their breast (avoid a mastectomy and instead have a lumpectomy). Giving therapy prior to surgery also allows the doctor and patient to see whether the tumor is responding (shrinking) from the medicine. If the tumor is not responding appropriately, this gives the doctor an opportunity to change the type of therapy used. Treatment for metastatic disease is not termed “adjuvant” or “neoadjuvant.” Rather, doctors refer to treatment by which “line” of therapy a patient is on. For example, the first treatment a woman receives for stage IV breast cancer is termed “first-line” therapy.  If the disease grows (or “progresses”) on this first-line therapy, then the patient will switch to a new treatment, called “second-line” therapy, and so-on. In general, women with metastatic breast cancer will always need to be on systemic therapy to control their disease.

Endocrine TherapyTwo-thirds to three-quarters of breast cancer have ER and/or PR expressed (termed “ER positive” or “hormone receptor positive” cancer). These cancers require estrogen (which is produced in the ovaries of premenopausal women and produced by an enzyme called aromatase in women who have gone through menopause) for their growth and survival.  Women with cancer that is positive for the hormone receptors are likely to benefit from medicines that either block ER (so that estrogen cannot interact with the receptor (for example, tamoxifen or fulvestrant) or block production of estrogen [for example, aromatase inhibitors such as anastrozole (Arimidex), exemestane (Aromasin) or letrozole (Femara) or medicines such as leuprolide (Lupron) or goserelin (Zoladex) that block the ovaries from producing estrogen in a woman who has not gone through menopause yet]. These medicines are termed “endocrine therapy,” “hormone therapy,” or “anti-hormone therapy.” Women with tumors that do not express the hormone receptors (ER negative and PR negative) will not benefit from these medicines. Women with all stages of disease will be offered endocrine therapy if their tumor expresses the hormone receptors as this therapy has been shown to significantly prolong survival.

HER2-targeted Therapy: Research at UCLA in the 1980s led by Dr. Dennis Slamon demonstrated that up to 25% of breast cancer is characterized by production of too much of a protein called HER2, caused by a mutation in the cancer cell whereby there are too many copies of the HER2 gene in the cell. This discovery led to the development of medicines that target the HER2 protein on cancer cells. Cutting edge clinical trials of the first of these medicines, trastuzumab (Herceptin), were led by Slamon’s team at UCLA and the TRIO network. These studies showed that trastuzumab significantly improved the survival of women whose tumors have too much HER2 protein expressed. Women with HER2 normal tumors do not appear to benefit from this type of medicine. Since the FDA approval of trastuzumab in 1998, several other HER2-targeted therapies have been developed and FDA approved, including lapatinib (Tykerb®), pertuzumab (Perjeta®), and trastuzumab emtansine or T-DM1 (Kadcyla®).  UCLA and TRIO-US have led several of the studies that have led to the FDA approval of these drugs. Women with early-stage breast cancer that is HER2-positive (stage I-III) will be offered treatment with trastuzumab, and sometimes pertuzumab as well in combination with chemotherapy. Patients with stage IV breast cancer have all these HER2-targeted therapies available as either single agent treatment or in combination with chemotherapy, in combination with one another or in combination with endocrine therapy. In addition, clinical trials are ongoing and in development to evaluate newer therapies that target HER2. Patients with any stage of HER2-positive breast cancer who are interested in possibly receiving a new, targeted therapy should talk with their doctor about the availability of a clinical trial.

Chemotherapy is medicine, generally given intravenously that kills rapidly dividing cancer cells. In general it is not given daily, but instead periodically (once a week or once every three weeks for example). Sometimes a combination of different chemotherapy drugs will be used. Combination regimens are usually given in the neoadjuvant or adjuvant setting for non-metastatic disease. In HER2-positive breast cancer, chemotherapy is combined with HER2-targeted therapy. Examples of chemotherapy drugs commonly used in breast cancer include the taxanes [docetaxel (Taxotere), paclitaxel (Taxol), nab-paclitaxel (Abraxane)], anthracyclines (doxorubicin (Adriamycin), pegylated doxorubicin (Doxil), epirubicin), capecitabine (Xeloda), vinorelbine (Navelbine), gemcitabine (Gemzar), eribulin (Halaven), ixabepilone (Ixempra), cyclophosphamide (Cytoxan), and platinums (carboplatin or cisplatin).

CDK4/6 inhibitors: Recently, laboratory work performed at UCLA demonstrated that some breast cancers are very sensitive to a drug that inhibits a protein called cyclin dependent kinase 4/6 (CDK4/6). This discovery led to several clinical trials (run by UCLA and in the TRIO network) that showed the use of a CDK4/6 inhibitor called palbociclib (Ibrance) in combination with endocrine therapy improves outcomes for patients with hormone receptor positive metastatic breast cancer. This drug was FDA approved in February 2015 for metastatic ER+ disease. Other inhibitors of CDK4/6 are currently being evaluated in clinical trials. In addition, these promising therapies are also being evaluated in early stage (stage I-III) breast cancer in clinical trials. Several clinical trials of CDK4/6 inhibitors are open at UCLA and in the TRIO-US network.

mTOR inhibitors: Some patients may benefit from a medicine that targets a protein called mammalian target of rapamycin (mTOR). This protein can make some breast cancers resistant to endocrine therapy. One drug, everolimus (Afinitor) has been FDA approved for hormone receptor positive metastatic breast cancer in post-menopausal patients in combination with exemestane. This combination was shown to improve the length of time that disease remained under control in patients whose disease had grown (progressed) on an aromatase inhibitor. Clinical trials are evaluating this and other medicines that target the mTOR pathway for other stages of breast cancer.

Bone modifying therapy are medicines used to strengthen the bone. They include drugs such as bisphosphonates [for example: alendronate (Fosamax), clodronate (Bonefos), pamidronate (Aredia), ibandronate (Boniva), and zoledronic acid (Reclast or Zometa)] or the receptor activator of nuclear factor kappa B (RANK) ligand inhibitor, denosumab (Prolia or Xgeva). These medicines may be used in early stage breast cancer to reduce bone loss from anti-estrogen endocrine therapy. There is mounting evidence that bisphosphonates may also reduce the risk of metastatic breast cancer in post-menopausal women diagnosed with early stage breast cancer. These drugs are also used in women with metastatic breast cancer that is involving the bone to reduce the risk of fracture.