Breast cancer occurs when one normal cell in the breast changes and turns into a cell that grows and divides uncontrollably. These abnormal (cancerous) cells form a mass within the breast and have the potential to spread (metastasize) elsewhere in the body. 

Breast Cancer Statistics 

Approximately 280,000 women are diagnosed each year in the U.S. with breast cancer making it the most common cause of cancer in women. Although breast cancer remains the second most common cause of cancer death in American women, death rates have dropped approximately 20% in the past 2 decades in large part due to increased screening (which allows patients to be diagnosed with smaller, more curable tumors) as well as due to new effective therapies that have been developed in the past few decades. 

What causes Breast Cancer? 

Although the specific cause of breast cancer cannot usually be determined in an individual patient, there are a variety of factors that have been associated with an increased risk of developing breast cancer. The number one risk factor is age: as a woman ages her risk of breast cancer rises. Other factors that have been associated with breast cancer risk include early onset of menstruation (<13 years) or late menopause, delay in child-bearing (>30 years old) or lack of child bearing, use of hormone replacement therapy (especially progesterone-containing regimens) after menopause, and history of prior radiation to the chest region.  Additional risk factors that have been associated with breast cancer include obesity and alcohol intake. Women who have had previous breast biopsies or a previous diagnosis of ductal carcinoma in situ, lobular carcinoma in situ or invasive breast cancer are at higher risk of developing breast cancer.  Family history is another important factor to consider in assessing one’s risk of breast cancer. A family history of breast cancer in first (mother, sister, daughter) or second degree (grandmother) relatives, especially if the diagnosis was under the age of 50 indicates a possible increased risk of cancer. In addition, a family history of ovarian cancer increases one’s risk of breast cancer.  That said, the majority of patients diagnosed with breast cancer have no family history of breast cancer. Approximately 5-10% of breast cancer is associated with a mutation in a gene called BRCA1 or BRCA2 which is passed down from the mother or father to their son or daughter.  The vast majority of breast cancer occurs in women, but annually around 1500 to 2000 men are diagnosed in the US with breast cancer.  

What are early symptoms of Breast Cancer? 

The earliest sign of cancer may be a lump in one breast. Occasionally a woman may detect redness, dimpling, thickening or warmth of the breast skin, flaking or retraction of the nipple region or a lump in the armpit region. Sometimes these symptoms are caused by conditions that are not cancer but a woman should let her doctor know immediately if she detects one of these abnormalities.  Many times cancer is detected by mammogram in a person who has no symptoms or signs of cancer.

How does my doctor know I have Breast Cancer? 

There are several types of tests that can be done to visualize the breast tissue in a woman who is suspected of having breast cancer. A mammogram is an x-ray that is used to screen (or look for) for breast cancer. It is also used to evaluate the breast in a woman has a lump in her breast. Other common tests used to visualize the breast tissue include ultrasound and MRI. If an abnormality is discovered on physical exam and/or an imaging study, a biopsy is performed. A biopsy involves the removal of a small amount of the abnormal breast tissue using a needle. This allows the doctor to evaluate the cells under the microscope to determine whether abnormal/cancerous cells exist.

What does Classification and Staging of my Breast Cancer mean?

For more than a century, breast cancer has been classified by how the cells appear when looked at under the microscope. Early, non-invasive cancers are termed “in situ” because they have not yet invaded beyond the duct (tubes that transport milk) or lobule (where milk is made) tissue. While ductal carcinoma in situ (DCIS) is thought to be a precancerous lesion that should usually be surgically removed, lobular carcinoma in situ (LCIS) is most often not considered a precancerous lesion. Instead, it is considered to be a risk factor for the development of breast cancer.

Invasive breast cancer, or cancer that has invaded past the ducts or lobules into the surrounding tissue, accounts for the majority of breast cancer. Invasive breast cancer has been subclassified into multiple subtypes based on how the cells arrange themselves and appear under the microscope such as ductal (most common), lobular (second most common), medullary, tubular, and metaplastic, to name a few.  While the “histological” subtype of cancer sometimes provides information regarding the behavior of the cancer (for example, tubular cancers are generally slow growing and do not metastasize), usually the histological subtype does not tell us what therapy will be most effective for a given cancer. 

More recently, breast cancer has been subclassified by the presence or absence of several proteins on the cancer cells. These include the hormone receptors (estrogen receptor-ER, progesterone receptor-PR) and HER2 (Human Epidermal growth factor Receptor-2). The presence or absence of these receptors on the cell are very important in determining the best systemic treatment. At the time of biopsy and/or surgery the tumor tissue will be tested for these three receptors. Another important feature that is evaluated on the tumor tissue is the grade of the tumor. Tumor grade relates to how the individual cancer cells look under the microscope; cells that appear similar to normal breast cells and are not dividing quickly are low grade and cells that are unrecognizable as breast tissue and are dividing fast are more aggressive and high grade. The grade of the tumor provides useful information in deciding what medical treatment should be used. 

TNM Classification: Staging is a way to classify how large a cancer has grown and how far it has spread at the time of diagnosis. Knowing the stage of the cancer helps determine the best treatment for the cancer. Cancer doctors use the “TNM” staging system to classify a patient’s stage of cancer. “T” stands for the tumor size, “N” stands for whether the lymph nodes in the region have cancer in them, and “M” stands for whether the cancer has spread (or metastasized) from the breast to other parts of the body such as the liver, lungs, bones. The T, N, and M are then combined and form the stage of the cancer (from stage 0 to stage IV). 

Clinical staging: When a patient is initially diagnosed with breast cancer (after the biopsy is performed but before surgery has been done), the doctor will assess the clinical stage, based on the physical exam and imaging findings. They will estimate the size of the mass in the breast and will assess for the presence of any abnormal lymph nodes by physical exam and imaging studies. Occasionally, scans of the body will be performed (such as a CT scan, bone scan, PET scan, chest x-ray, MRI or ultrasound of the abdomen). These imaging studies are usually not recommended unless the lymph nodes are felt to be abnormal on examination or the patient has signs or symptoms that the cancer has spread to other parts of the body.

Pathologic staging: At the time of surgery (for stage 0-III breast cancer), the surgeon will remove the breast tumor and (for stage I-III breast cancer) some of the regional lymph nodes. After surgery, a pathologist will examine all the tissue removed at the time of surgery and will generate a “pathological stage.” This stage is most accurate as the pathologist is able to give an accurate size of the actual tumor (which is sometimes different than the imaging or examination estimated prior to surgery) and will also give an accurate assessment of whether lymph nodes are involved by cancer.

Stage 0 breast cancer is ductal carcinoma in situ (DCIS), which is a pre-cancer that does not have the potential to spread elsewhere.  It is considered to be curable by surgery. Often radiation is also offered, to reduce the risk of cancer returning in the same breast. Patients with stage 0 cancer are at higher risk of developing a new cancer in either breast compared to someone who never has had DCIS. For this reason, sometimes patients are treated with medicine (such as tamoxifen or an aromatase inhibitor) to reduce the risk of another breast cancer in either breast.

Stage I and II breast cancers are early stage, localized tumors. Stage I breast cancer is small (less than 2 cm) and has not spread to the lymph nodes. Stage II cancers are up to 5 cm and may have some lymph nodes involved by cancer. These tumors are generally treated with surgery and sometimes radiation to the breast and nearby lymph nodes. Patients will also receive systemic therapy. Those patients with hormone receptor positive tumors will generally be given endocrine therapy for at least 5 years. Patients with HER2 positive tumors will almost always be given HER2-targeted therapy plus chemotherapy. And patients without ER, PR, or HER2 expression (so called “triple negative” tumors) will be treated often with chemotherapy and sometimes with immune therapy.

Stage III breast cancers are larger tumors (over 5 cm), often with spread to the lymph nodes.  These tumors are still potentially curable, but are considered to be “locally advanced” and are generally treated aggressively with surgery, radiation therapy, chemotherapy, sometimes immune therapy (pembrolizumab, if triple negative), hormonally targeted therapy (if hormone receptor positive), and if HER2-positive, HER2-targeted therapy (trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1) and/or neratinib). Additionally, if a patient is a carrier of a BRCA1 or BRCA2 mutation, they may also be eligible to receive a pill called olaparib.

Stage IV (metastatic) breast cancer is breast cancer that has spread outside of the breast and lymph nodes and can be seen on an imaging scan in other organs such as the bone, brain, skin, liver, or lungs. (Note: When cancer has spread to a different organ, it is called metastatic breast cancer of that organ. It is not a new cancer in that organ. For example, when breast cancer has spread to the liver, it is not called “liver cancer,” it is called “metastatic breast cancer to the liver.”) Metastatic breast cancer is sometimes diagnosed in a woman who never has been diagnosed with breast cancer before. This is termed “de novo” metastatic breast cancer and occurs only ~10% of the time in the US. The majority of patients diagnosed with metastatic breast cancer have a prior history (months or years before) of early stage breast cancer. In either case, it is important for a patient to have a biopsy of the metastatic tumor seen on imaging studies to confirm that it is indeed breast cancer and to retest the tumor subtype (ER, PR and HER2 protein expression). Metastatic breast cancer is a chronic illness. It is not considered to be curable however it is highly treatable. Due in large part to significant advances made in the systemic treatment of breast cancer, patients can often live many years with metastatic disease. There are two main goals of treatment for patients with metastatic disease: (1) to control the disease with medicine and (2) to preserve (or improve) quality of life.  There are numerous therapies available to women with metastatic breast cancer, and many innovative, targeted treatments are currently in late stage clinical trials that have the potential to improve long-term outcomes for women with metastatic disease.

What are treatments for Breast Cancer?

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, immune-based 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 Therapy:  Two-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. A number of new endocrine therapies are in development now, with studies ongoing in TRIO and at UCLA to evaluate whether these new drugs have a better antitumor activity and/or improved safety and tolerability.

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 (HER2-positive breast cancer). Women with HER2 normal tumors do not appear to benefit from this type of medicine. Since the FDA approval of trastuzumab in 1998, seven other HER2-targeted therapies have been developed and FDA approved, including lapatinib (Tykerb®), pertuzumab (Perjeta®), trastuzumab emtansine or T-DM1 (Kadcyla®), neratinib, tucatinib (Tukysa®), margetuximab (Margenza®), and trastuzumab deruxtecan. (Enhertu®, T-DXd).  UCLA and TRIO-US have led several of the studies that 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. They may often also be candidates for therapy with T-DM1 and/or neratinib. 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, a number of newly approved agents are available (T-DXd, tucatinib, margetuximab).  Because of the development and availability of these effective HER2-targeted therapies the overall survival for a patient diagnosed with HER2 positive breast cancer has significantly improved in recent years. A number of clinical trials are actively enrolling patients 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, usually 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. In triple negative breast cancer, chemotherapy may sometimes be combined with immune therapy [pembrolizumab (Keytruda)]. 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: Laboratory work performed at UCLA demonstrated that some breast cancers are very sensitive to a drug that inhibits proteins called cyclin dependent kinases 4/6 (CDK4/6). This discovery led to several clinical trials (run by UCLA and in the TRIO network) that showed the use of CDK4/6 inhibitors such as palbociclib (Ibrance), ribociclib (Kisquali) or abemaciclib (Verzenio) in combination with endocrine therapy improves outcomes for patients with hormone receptor positive metastatic breast cancer. The first FDA approval for a CDK4/6 inhibitor, Palbociclib, was in February 2015 for metastatic ER+ disease based on a study led by UCLA and TRIO. In addition, these promising therapies are also being evaluated in early stage (stage I-III) breast cancer in clinical trials. New clinical trials incorporating novel use of CDK4/6 inhibitors are opening at UCLA and in the TRIO-US network.

PI3K-pathway inhibitors: Some patients may benefit from a medicine that targets a signaling pathway in cancer cells called the PI3 Kinase (PI3K) pathway. One protein in that pathway, called mammalian target of rapamycin (mTOR), can make some breast cancers resistant to endocrine therapy. An oral 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. Another drug, alpelisib (Piqray) that targets PI3K has been shown to be effective when added to endocrine therapy for patients whose tumors have a gene mutation in the gene for PI3K. Clinical trials in TRIO are evaluating therapies like this for other types of breast cancer including HER2 positive and triple negative breast cancer.

PARP inhibitors such as olaparib (Lynparza) and talazoparib (Talzenna) are oral medicines that target a protein that is important in repairing tumor DNA breaks in patients who carry BRCA1 or BRCA2 genetic mutations. TRIO and UCLA were involved in the phase III clinical trial that led to the approval of talazoparib for metastatic BRCA-mutation associated breast cancer. Olaparib was also approved by the FDA in 2021 for early stage BRCA-mutation associated breast cancer.

Sacituzumab govitecan (Trodelvy) is an “antibody drug conjugate,” a therapy made up of an antibody that is loaded with chemotherapy. The antibody homes the chemotherapy payload to cancer cells. Sacituzumab is FDA approved for patients with metastatic triple negative breast cancer after two lines of therapy. UCLA was involved in leading the phase III trial that resulted in full FDA approval of this therapy.

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.

Who are the people that research Breast Cancer at our affiliate UCLA?

The Medical Director of the Breast Cancer Clinical Trials Program is Sara A Hurvitz, MD. Studies within this program are also led or supported by Dennis Slamon, MD, PhD, John Glaspy, MD, Nicholas McAndrew, MD, Kelly McCann, MD, PhD, Alexandra Drakaki, MD, PhD, Lee Rosen, MD, and Saeed Sadeghi, MD.  

There are numerous members of the UCLA Breast Surgical Oncology team who participate in our clinical research program and care for patients with breast cancer. The breast surgeons partner with medical oncology as well as radiation oncology on many different studies and programs.  Patients at UCLA also receive expert services from breast imaging specialists and breast cancer pathologists at UCLA.