Overview of Staging
Similarly to other cancers, breast cancer treatments vary depending the cancer’s stage of progression. After a biopsy is taken of the tumor, the cancer can be staged according to the American Joint Committee on Cancer TMN (tumor, nodes, metastasis) system:
T categories: These are divided into four categories (14) and describes the local extent of the tumor.
❖ TX: tumor not assessed.
❖ T0: no evidence of tumor.
❖ T1: tumor is 2 cm or less across.
❖ T2: tumor is between 2 and 5 cm across.
❖ T3: tumor is more than 5 cm across.
❖ T4: tumor has spread into chest wall.
N categories: These categories describe the condition of lymph nodes near the cancer.
❖ NX: lymph nodes are not assessed.
❖ N0: nearby lymph nodes not affected.
❖ N1: tumor has spread to 1 to 3 nearby lymph nodes.
❖ N2: tumor has spread to 4 to 9 lymph nodes.
❖ N3: tumor has spread to 10 or more lymph nodes or to lymph nodes under the clavicle.
❖ M0: cancer has not spread to lymph nodes.
❖ M1: cancer has spread beyond nearby lymph nodes.
Based on TMN scores and other diagnostic tests, the patient’s cancer will be staged from 14. From there, a personalized treatment can be planned to combat the cancer. In addition, the type of breast cancer plays a large role in the treatment options available topatients. There are various types of breast cancer including:
❖ Ductal carcinoma in situ: a noninvasive breast cancer that accounts for about 18% of cases. Common treatment options are breast conserving surgery, radiation , and total mastectomy (with or without tamoxifen).
❖ Invasive ductal carcinoma: this is the most common form of breast cancer and accounts for about 80% of all cases. It is called invasive because it originates in the milk ducts and invades the surrounding tissue. Most of the treatments listed in the following section will be recommended for treating IDC.
❖ Inflammatory: this type of breast cancer is very rare (15% of cases) and rather aggressive, progressing to stage 3 or 4 in weeks or months. It is named this way because the breasts become inflamed due to lymph vessel blockage caused by the cancer. The treatments described in the following section are also used to treat inflammatory breast cancer.
❖ Triple negative: type of breast cancer that tests negative for the receptors of estrogen(ER), progesterone (PR), and HER2. The absence of these receptors renders the cancer immune to hormone therapy and targeted therapies such as Herceptin. Triple negative cancers are usually treated with a combination of surgery, radiation therapy, and chemotherapy.
❖ Metastatic breast cancer: advanced breast cancers that have spread to distant organs or tissues. Most of the research going down the pipeline is targeting this form of cancer. Other less common types are medullary carcinoma, tubular carcinoma, mucinous carcinoma and Paget Disease.
Treatments: Best Practices
Breast Conserving Surgery (Partial Mastectomy)
This type of surgery is able to spare the breast by only removing the tumor and marginal tissue surrounding the tumor. The margin depends on how many factors, including the size and location of the tumor. There are two types of partial mastectomy. The first is called lumpectomy, where only the lump and marginal tissue is removed. Quadrantectomy involves removing about a quarter of the breast. In both cases, radiation is given after the surgery to make sure any of the surviving cancer cells are killed off and lymph nodes are checked to see if the cancer has spread. In addition, the removed tumor is examined to see if cancer cells are still present. If there are, this is called a positive margin, and the surgeon must go in and perform a reexcision surgery. An advantage to this type of surgery is that reconstructive surgery can be done shortly after the tumor is removed.
Mastectomy is a surgery that removes the entire breast. In a simple mastectomy, the entire breast, including the nipple, but excluding the lymph nodes are removed. In some cases, a double mastectomy must be performed as a preventative measure for women at extremely high risk.
Another mastectomy option is the skin sparing mastectomy. It removes the same amount of tissue as the simple mastectomy, but it allows for reconstruction immediately after. It uses skin and tissue from other parts of the body in order to reconstruct the breast. If the tumor is not too large, this surgery is a viable option. Unfortunately, the nipple and areloa cannot be spared in this surgery, however there is a nipple sparing surgery available. This type of surgery is a good option for women will smaller tumors and smaller breasts. This will lead to less deformity of the breast and nipple. Nipple sparing mastectomy leaves less obvious scarring is preferred among most patients. If lymph nodes are affected, surgeons must resort to modified radical mastectomy. In this surgery, the entire breast is removed along with lymph nodes under the arm. This surgery is an improvement of the radical mastectomy which is a very disfiguring surgery. The modified version has shown equal success rates.
The most common form of radiation therapy is external beam radiation. The amount of radiation needed is dependent on whether or not surgery was performed or if lymph nodes are affected. If surgery was done, then the entire breast would receive radiation, including an extra dose at the location where the tumor was removed. If lymph nodes in the area were affected, radiation will be directed to those areas as well. If therapy is to be given after surgery, the tissue needs to have had time to heal before any doses are given. Doses of radiation are usually given 5 days a week for approximately 5 to 6 weeks. Treatment sessions only last a few minutes and the procedure is painless.
The dosing schedule mentioned above can be rather taxing on most patients. Another option is called hypofractionated radiation therapy. It employs larger doses of radiation given over a shorter period of time, only 3 weeks.
Newer techniques, such as 3D conformal radiation therapy accurately maps the tumor. This targeted therapy decreases the likelihood that healthy tissue gets damaged by the radiation. The radiation is given twice a day for 5 days.
In brachytherapy a pellet of radioactive material is inserted adjacent to the cancerous tissue. The pellet is only left in the chest for a short period of time and is then removed so that healthy tissue is not damaged. Seed particles are left behind for a longer term release of radiation which weakens over time.
Chemotherapy can be used in two different scenarios. In adjuvant therapy, the chemo drugs are given after surgery is performed. The purpose is to eliminate any remaining cancer cells that were left behind from surgery. The other scenario is neoadjuvant therapy, where the chemo drugs are given before surgery with the purpose of shrinking the tumor large tumor so that surgery is more likely to succeed. The most commonly used drug combinations are given below:
❖ cyclophosphamide, doxorubicin (Adriamycin), and 5FU
❖ docetaxel (Taxotere), doxorubicin (Adriamycin), and cyclophosphamide
❖ doxorubicin (Adriamycin) and cyclophosphamide followed by paclitaxel (Taxol) or docetaxel (Taxotere).
❖ 5FU, epirubicin, and cyclophosphamide followed by docetaxel (Taxotere) or paclitaxel (Taxol)
❖ docetaxel (Taxotere) and cyclophosphamide
❖ docetaxel, carboplatin, and trastuzumab (Herceptin) for HER2/neu positive tumors
These drugs target specific changes in cells and act by different mechanisms than chemo drugs. They usually also have much less severe side effects. One of the main targets these drugs are directed toward is the protein HER2/neu. This protein is overexpressed in about 20% of breast cancer cases and results in aggressive progression of the cancer.
Herceptin is a monoclonal antibody that binds to HER2 to slow the growth of cells and to stimulate the immune system. It is administered through IV once a week. Herceptin can be given as an adjuvant or neoadjuvant therapy, but is most effective when combined with chemo.
Herceptin has been modified by attaching a chemo drug called DM1 to the antibody in a drug called Kadcyla. The advantage to this drug is that it can be given independently since it combines chemo and the targeted therapy. In addition, it is more specific since the antibody will deliver the chemo drug directly to the cancer cell. Doses are given once every 3 weeks via IV injection.
Other drugs of this type are Perjeta and Tykerb and they are used to treat women with advanced HER2positive breast cancers. Perjeta is usually given with Herceptin and Taxotere, while Tykerb is given to women who have cancers that are no longer responsive to Herceptin or chemo.
Afinitor is a different targeted therapy drug that targets the protein mTOR. mTOR is part of the PI3K-AKT-mTOR signalling pathway. This pathway is important in cell metabolism, proliferation and overall survival. It is known that abnormal activity of this pathway can initiate tumors. Inhibiting this pathway altogether can arrest cell growth and induce cell death. Afinitor is given daily as a pill and should only be taken by women who have gone through menopause.
This treatment can be used before surgery, after surgery, or if the cancer is recurring. Approximately 2 out of 3 cases of breast cancer are hormone receptor positive. These receptors are sensitive to the female hormones estrogen and progesterone. Drugs have been designed to either block the hormones from interacting with the receptors or to lower estrogen levels. Common drugs of both kinds are described below:
❖ Tamoxifen: this estrogen blocking drug inhibits the binding of estrogen to its receptor, thusterminating the signal that tells the cancer cell to proliferate. Drug in its class are called selective estrogen receptor modulators (SERM). This drug is particularly successful since it has been shown to prolong the life of many patients and cuts the likelihood of the cancer coming back by about half. It can even be used in cases where the breast cancer has metastasized. Tamoxifen is usually given orally as a pill.
❖ Fareston: a SERM like tamoxifen and works by the same mechanism.
❖ Faslodex: an antiestrogen that is the only FDA approved drug safe for postmenopausal women can take. It is used to treat advanced metastatic cancers.
❖ Aromatase inhibitors (AIs): these drugs halt estrogen production in postmenopausal women and can treat early or advanced cancers. The three drugs on the market are: Femara, Arimidex, and Aromasin. They act by inhibiting the enzyme aromatase, which produces small amounts of estrogen in fatty tissue. These drugs are only effective in postmenopausal women because they do not target the ovaries.
Depending on the case, tamoxifen and AIs will be combined or cycled for 5 to 10 years after surgery.
In April of 2013, the FDA granted palbociclib Breakthrough Therapy Designation for thetreatment of breast cancer. It is a drug being developed by the pharmaceutical giant Pfizer and acts as a selective cyclin dependent kinase (CDK) 4 and 6 inhibitor. This designation is one of the FDA’s mechanism of expediting the approval process of drugs that show particular promise. In phase II clinical trials, palbociclib was combined with the drug letrozole and showed a significant measurement of progression free survival that was about 4 times longer than with letrozole alone. Phase III trials of this drug are currently recruiting and involve patients with estrogen receptor positive (ER+) and HER2 negative, advanced metastatic cancers. The hope is that this drug will be a first line treatment for women with this kind of breast cancer.
CDK 4 and 6 are implicated as major components of the cell growth cycle. They are necessary for DNA replication and for cell division. By arresting these enzymes, palbociclib has been shown to effectively slow the spread of cancerous cells.
This drug is also a CDK 4/6 inhibitor but is being developed by Novartis. In their research, Novartis Oncology has found that CDK 4/6 are regulated by cyclin D, whose overexpression is caused by the genes BRAF and PIK3CA. There are drugs on the market that target these genes, but most cases of cancer seem to build a resistance to the drugs. One of the major findings regarding LEE011 is that it was able to prevent the resistance of the cancer cells to these BRAF and PIK3CA drugs.
Similarly to palbociclib, trials are being conducted with patients that have ER+, HER2 breast cancers. Novartis very recently announced that LEE011 will enter phase III trials in December 2013.
Poly ADP-ribose Polymerase (PARP) Inhibitors
The most studied enzymes of the PARP enzymes are PARP1 and PARP2. One of their main functions is to repair broken DNA, particularly in the base excision repair (BER) mechanism. The idea behind inhibiting these enzymes is that cancer cells already have defects in their ability to repair DNA. By inhibiting PARP1 and PARP2, other mechanisms of repair are relied on. However, if PARP inhibitors are used in cancer cells, synthetic cell death is induced.
One of these PARP inhibitors is called rucaparib. It was actually the first PARP inhibitor to enter clinical trials. In phase I clinical trials, rucaparib was combined with carboplatin and showed encouraging results and adequate safety. These results have led to a phase II trial involving patients with advanced metastatic breast or ovarian cancer. The study should conclude in September of 2014. Other drugs in this class are veliparib, niraparib, and BMN 673 all in phase I trials.
Centers of Excellence
❖ University of Texas MD Anderson Cancer Center, Houston, Texas
❖ Dana Farber Cancer Institute, Boston, Massachusetts
❖ Memorial Sloan Kettering Cancer Center, New York, New York
❖ John Hopkins Hospital, Baltimore, Maryland
❖ Fox Chase Cancer Center, Philadelphia, Pennsylvania
❖ Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, Pennsylvania