Breast Cancer

Breast cancer is a feared diagnosis. Approximately one out of seven women will develop this disease during her life. While breast cancer is mainly a disease of older women, it is important to remember that one out of four cases occurs when the patient is premenopausal.

Risk Factors

Who gets breast cancer? Unfortunately, almost anyone can get breast cancer. There are specific factors that may increase your risk, but many women appear to have no risk factors and yet come down with this illness. Interestingly, 1 in 100 cases of breast cancer occurs in men.

Risks for breast cancer include:

1. A previous bout with breast cancer.

2. First degree relatives with breast cancer. This includes mother, sisters and aunts,

both maternal and paternal. This is especially true if the breast cancer was bilateral and occurred when the relative was premenopausal.

3. Hormonal influences.

4. Older age at first pregnancy or no pregnancies.

5. A change in genetic structure called BRCA-1 or BRCA-2. BRCA-1 is a tumor suppressor gene. Thus, when it is mutated (altered), tumor growth is not suppressed. BRCA-1 is located on chromosome 17. BRCA-1 carries an increased risk of ovarian cancer as well as breast cancer. BRCA-2 is also a tumor suppressor gene. It is located on chromosome 13. There is only a slightly increased risk of ovarian cancer in women who have this genetic change. Both BRCA-1 and BRCA-2 maybe inherited from either your mom’s or your dad’s side of the family.

BRCA-1 mutation leads to a lifetime risk of breast cancer of about 70% and nearly a 30% lifetime risk of ovarian cancer. This gene mutation gives men a 10% risk of breast cancer. BRCA-2 is associated with about a 70% lifetime risk of breast cancer. BRCA-2 also increases the risk for prostatic and pancreatic cancer.

BRCA-1 and BRCA-2 mutations usually occur in Caucasians. African-American families with a high incidence of breast cancer may also carry mutations on the

same chromosomes but at different loci (positions on the chromosome).

If you have several close relatives with breast cancer, you may wish to discuss with your physician whether or not screening for the BRCA-1 and/or the BRCA-2 gene mutation or other gene mutations would be worthwhile.

Prevention

All women would like to reduce their risk of breast cancer as much as possible. While not proven, it is likely that a healthy lifestyle will help the body defend itself against tumor formation.

The Tamoxifen (Nolvadex) vs. placebo study involved thousands of American women. In this trial, 50% of the women got Tamoxifen and 50% got placebo. All the women who participated were at high risk of developing breast cancer. There was a 50% reduction in the incidence of breast cancer in the Tamoxifen treated women. Your physician can tell you if your risk is high enough for you to consider the use of Tamoxifen. He may use the Gail Model or the Breast Cancer Assessment profile to do this. Your composite risk of breast cancer is based on several factors such as family history, age, previous breast biopsy showing diagnosis of atypical ductal hyperplasia, age at 1^st live birth, nulliparity (having no children) and age at menarche.

Women may be candidates for the use of Tamoxifen (Nolvadex) as prevention if

(a) They have a diagnosis of lobular carcinoma in situ

(b) They are 35-59 years old and have a projected five-year risk of invasive breast cancer equal to or greater than a woman aged 60 years.

Recently, Evista has shown a protective effect and is another option.

There are additional options for patients who are BRCA-1 or 2 positive. These include:

· Increased surveillance. Start screening with mammograms and an exam at an earlier age and perhaps at more frequent intervals. Consider a breast MRI .

· Prophylactic mastectomy. This results in about a 90% reduction of breast cancer risk. The risk reduction is not 100% because a mastectomy with nipple preservation allows some breast tissue to remain. There may also be some breast tissue still extending up under the arm (axillary tail).

· Chemoprevention with Nolvadex reduces breast cancer risk by about 50% in women at high risk for this illness and in women who are BRCA-2 carriers. Unfortunately it is not as effective for woman with the BRCA-1 mutation.

The United States Prevention Services Task Force recommends that doctors discuss chemoprevention with women at high risk who are also at low risk for adverse side effects. Tamoxifen (Nolvadex) significantly reduces the risk of estrogen receptor positive breast cancer.

Evista is also effective in at risk women. Both Tamoxifen and Evista increase the risk of blood clots and strokes. Tamoxifen also increases the risk of endometrial cancer. However, this remains an uncommon complication.

Recent data suggest that the combination of estrogen (Premarin) and progesterone (Provera) increases the breast cancer risk. Estrogen alone appears to have a minimal increase in risk. The decision to take or not to take postmenopausal hormone replacement is individual and should be discussed with your doctor.

Screening

Many women ask about how they should be screened for breast cancer. All

women need to practice breast self-examination on a monthly basis. Every woman’s breasts feel different, and it is important that you become familiar with the normal “lumps” and “bumps” that may be found in your breasts. You are especially likely to have “lumpy-bumpy” breasts if you are premenopausal or taking hormone replacement. Your breasts are usually easiest to examine right after you have finished your period. It is also important that you have a breast exam by a physician yearly.

Screening mammograms should begin at about age 40, although some doctors recommend waiting until the age 45 or 50.

Screening mammograms do have the advantage that they may be able to pick up very early lesions. It is important to realize that 20% of breast cancers may be missed by a mammogram. Also, many times a biopsy will be done for benign disease.

You may be asked to return for special “coned-down” views, which will give the radiologist a better view of the breast. At other times, a sonogram may be done to determine whether a lesion seen on a mammogram is a cyst or not.

Recently, MRI has been shown to be of some benefit in the detection of breast cancer. MRI is not a standard screening modality and is used only in special cases such as in a young woman with a gene mutation that increases her risk.

It is important to remember that only a biopsy can determine cancer; a mammogram cannot; neither can physical examination. If you have a suspicious lesion on mammogram, or a palpable mass, your physician will probably suggest a biopsy. A single dominant, palpable lesion (lump that can be felt) is usually biopsied even if the mammogram is negative. In a young woman a “lump” can be followed through a menstrual cycle as it may be secondary to hormonal changes and disappear after her next period.

There are several ways to do biopsies. One is called needle localization. In this procedure, under x-ray guidance, a needle is placed in the breast and the exact area of concern is sampled. A palpable lesion may be excised (removed totally).

A Cancer Diagnosis

A pathologist looks at tissue under a microscope and determines the presence or absence of a malignancy. There are several types of breast cancer. The most common is infiltrating ductal. A second less common type is lobular carcinoma. There are also several distinctly uncommon types such as tubular carcinoma.

Often the pathologist will return a diagnosis of frankly malignant tissue or frankly benign tissue; but at times he may return a diagnosis of atypical ductal hyperplasia. This is a signal that the breast is “disturbed” and has a predicative value for subsequent malignancies. Patients with this diagnosis should discuss possible use of Nolvadex with their physician. Lobular carcinoma is situ is not a “true cancer”, but should be excised and Nolvadex treatment should be considered. In situ ductal carcinoma is very early disease. This disease (by definition) has not traveled anywhere. However, it does need to be treated.

If you are found to have a breast cancer, your surgeon will most likely recommend additional treatment. The recommended treatment will depend on several tumor characteristics and on tumor stage. Additional treatment may include surgery, radiation, chemotherapy, hormonal therapy, or a monoclonal antibody.

You need to discuss with your oncologist what option or options are best for you. Do not hesitate to seek a second opinion, possibly from someone who is not directly involved in the immediate decision to be made.

Surgical options include mastectomy, sentinel node biopsy and possibly an axillary dissection or lumpectomy, sentinel node biopsy and possibly an axillary dissection and radiation. Axillary dissection means to take out the lymph nodes under the arm. To perform a sentinel node biopsy, either a colored dye or a radioactive material is injected next to the cancer, and the surgeon removes the node the injected material reaches first. Probably all the nodes are negative (do not have cancer in them) if the sentinel node biopsy is negative. If the sentinel node biopsy is positive, consideration should be given to formal axillary dissection (removal of all lymph nodes under the armpit).

Studies have shown that lumpectomy, plus axillary dissection, plus radiation therapy to the breast or mastectomy plus axillary dissection yield identical survival. There are, however, some instances in which a mastectomy is clearly preferable. These include:

1. Multi-focal disease ( including multi-focal carcinoma in situ)

2. A large tumor ( cosmetic result may not be good)

Sometimes a mastectomy, an axillary dissection, and chest wall radiation are all

used. Women who received all three treatments usually have a large (greater than 5cm) tumor or four or more positive nodes or extracapsular disease (tumor cells that have burst through the wall of the lymph node) or the tumor cells are close to or involve the margin of the removed tissue.

Local Disease Versus Systemic Disease

My surgeon said he “got it all”, but now he has sent me to an oncologist! I don’t understand this! When the surgeon says he “got it all” he is saying he got all of the tumor present in the breast and lymph nodes.

Breast cancer starts as a local problem (a tumor in the breast), but very early in its natural history, the tumor becomes systemic (spreads throughout the body). Breast cancer cells “learn” how to invade blood vessels; the malignant cells are then distributed to many places in the body where they may grow. This is breast cancer metastatic to (traveled to) another body organ, such as bone, lung, or liver. It is these secondary tumor deposits that result in the patient’s death.

The ability of cancer cells to metastasize is their most important clinical attribute.

Cancers start as a single cell, which gives rise to daughter cells. Some of these daughter cells “pick up and leave”, wandering through adjacent tissue.

There are three main prognostic factors, which your doctor will evaluate prior to recommending treatment for you.

Prognostic factor

· Size of the tumor. Any tumor greater than 1.0cm (.45 inches) is “big”.

· Nodal involvement. Even having one lymph node involved with tumor is “bad”. Lymph node involvement indicates that the tumor has “learned” to “dig” into lymph vessels. This “skill” also enables tumor cells to “dig” into blood vessels and thus to circulate widely. Lymph node status is the single most important prognostic finding.

· Markers. Three markers are currently used clinically to help your doctor make decisions. They are ER (estrogen receptor), PR (progesterone receptor) and Her-2-Neu. ER and PR positive values are “good”, as positive values indicate that the tumor may be less aggressive than ER negative, PR negative tumors. Also, these tumors are likely to respond to anti-hormone pills such as Tamoxifen (Nolvadex) or an aromatase inhibitor( Arimidex, Femara, Aromasin). Faslodex, a monthly shot may also be used.

HER-2-NEU is a marker for a “meanness factor”. 0 is “good”. A plus 3 is “bad”.

The value of chemotherapy to an individual patient varies. Patients who are ER and PR negative receive more benefit than those whose receptors are positive. In general, younger woman receive more benefit than older women.

Generally, chemotherapy is considered for all women whose tumor is greater than or equal to 1cm. Occasionally younger women with smaller tumors and poor prognostic factors may receive chemotherapy. The decision to recommend or not recommend chemotherapy is complex. This decision is best discussed with your oncologist.

Shared Decision Making

Talk to your oncologist about your prognosis. She or he may use adjuvant online to help you in decision making.

In this example, a 55 year old woman with a triple negative breast cancer (er and pr negative and Her 2 neu negative) 1 to 3 positive nodes and moderately differentiated has a 58%chance of recurrence in the absence of treatment. Hormones will not help as the tumor is er and pr negative. Chemotherapy will give her an extra 25 chances of survival. You doctor can use this program to input your age and tumor characteristics and tell you what your chances are with different treatments.

Types of Adjuvant Chemotherapy

There are several very acceptable drug regimens available to treat this disease. These include:

· CMF ( Cytoxan, Methotrexate, and 5FU)

· CAF ( Cytoxan, Adriamycin, and 5FU)

TCH carboplatin and taxotere and Herceptin

· CNF ( Cytoxan, Novantrone, and 5FU)

· AC-T (Adriamycin + Cytoxan followed by Taxol or Taxotere)

· FEC (5FU, epirubicin, Cytoxan)

· Herceptin has recently been approved for use in the adjuvant setting. This drug is only useful for patients who are her2neu positive. Use of this drug in combination with chemotherapy has increased survival by 50%.

When nodes are involved with tumor, many oncologists recommend using a Taxane following Adriamycin and Cytoxan.

(Taxol or Taxotere) after using an athracycline (Adriamycin) based regiment.

Oncologist recommend using Herceptin if the tumor is her2 neu positive.

A typical treatment course for a woman who is node negative would be “AC x 4”. A stands for a drug named Adriamycin and C stands for Cytoxan. The two drugs are given in the office every three weeks for 4 doses. Taxotere and Cytoxan would be another good drug combination

Recently a study was published using dose dense chemotherapy. Preliminary results are promising but no long-term data is available. This study gave the drugs every 2 weeks rather than every 3 weeks. A special shot (growth factor, colony stimulating factor, Neulasta) was used to keep the white blood cell count high enough for treatment.

Adjuvant treatment has some major side effects. These include a low white count. The white blood cells fight infection and when they are low an infection may occur which can be serious or life threatening. Your cancer doctor or nurse will let you know when your counts are low. They will inform you of any special precautions that you will need to take. You will be advised to report to the office or to the emergency room at any sign of fever. A Neupogen shot may be given to return the white cells toward normal more quickly. Anemia (low red blood) may also occur.

Alopecia (hair loss) is universal and may be complete. It usually occurs ten days after the first dose.

Nausea and vomiting are not major problems as long as anti-emetics (anti-nausea drugs) are taken as directed. If you have problems, be sure to let your doctor or nurse know. Often times there is an easy solution.

Adriamycin can cause a cardiomyopathy (weak heart muscle) if the total dose is high. The dose used in the adjuvant setting is well within the safe range. However, to be extra cautious, your doctor may do a baseline Mugga or ECHO (special heart x-ray) to be sure there are no problems with the heart muscle.

Some patients complain of “chemo brain”. This is a poorly understood complex of symptoms that includes memory loss and difficulty with abstract concepts. Most patients seem to recover from this and return to normal. Researchers are only now starting to study this problem.

Fatigue is very common in cancer survivors who receive chemotherapy; often the women who were the most active prior to treatment notice this problem the most. A gentle, regular exercise program can ameliorate fatigue to some extent. You may need extra time to do your job and/or help with household chores. Fatigue usually resolves about 3 months after the completion of chemotherapy.

If you are premenopausal at the time of chemotherapy, there is a good chance that you will enter menopause. You will know by the hot flashes and the lack of periods. The menopause may (or may not) be permanent. The older you are, the less likely the ovaries will recover.

People who receive chemotherapy have a small but real increased risk of a second malignancy.

Of course, pregnancy is strictly and completely contradicted during chemotherapy treatment.

ADJUVANT HORMONAL THERAPY

Unless there is a clear contraindication , all women with ER /PR positive tumors should receive estrogen deprivation therapy either alone or following chemotherapy. A recent trial randomized postmenopausal women to Tamoxifen or Arimidex. Arimidex showed a small but real advantage at four years. Arimidex prevents the formation of estrogen by the adrenal glands. In general, Arimidex was well tolerated, some women had hot flashes and bone aches. There is an increased risk of bone fracture with the use of Arimidex . Evista is not FDA approved for use in the adjuvant setting. Adjuvant hormonal therapy should be continued for at least five years. New data suggests that starting Arimidex after two to five years of Tamoxifen may provide additional benefit.

Adjuvant hormonal therapy should be given to all women who are estrogen/progesterone positive.

How is metastatic disease treated?

Metastatic disease means disease “traveled to” another part of the body. The disease is then breast cancer metastatic (“traveled”) to bone, liver, lung, and etc. The cells of these secondary tumors act like breast cancer cells (not like cancer cells that originate from the bone, liver, etc).

There are three major treatment methods for metastatic disease. These are hormonal therapy, chemotherapy, and biologic therapy (Herceptin). Radiation therapy may be used to “touch up” a problem spot, such as a painful bone lesion. Radiation therapy is the preferred treatment for brain metastasis and spinal cord metastasis.

There are numerous effective chemotherapy drugs for breast cancer. These include Adriamycin, Taxol, Taxotere, Doxil, Epirubicin, Cytoxan, Methotrexate, 5FU, Novantrone, Carboplatin, Cisplatinum, Thiotepa, Navelbine, Gemzar, Xeloda, Mitomycin C and Veblen. Ixempra is a new drug which may provide great value.

The two which are usually the most effective are Adriamycin and a Taxane (Taxol or Taxotere). Several drugs are often given together.

Drug treatment of metastatic breast cancer often produces a dramatic regression of tumor; however, with time the tumor almost always recurs.

Hormonal therapy is often useful in women whose tumors are ER positive and PR positive. A widely used agent is Nolvadex (Tamoxifen). This drug is estrogenic in some tissues and anti-estrogenic in others. Tamoxifen has a remarkable record of safety and efficacy. About fifty percent of patients whose tumors contain the estrogen receptor will have a decrease in the size of their tumor. Side effects include nausea, hot flashes, blood clots, and cancer of the endometrium (lining of the uterus). While the incidence of endometrial cancer is increased by Nolvadex, it remains an uncommon tumor, which usually can be successfully treated.

Aromatase inhibitors are taken once a day. These drugs decreases the production of estrogen. Side effects are few and include myalgias (aching muscles) and hot flashes.

Aromatase inhibiters are only effective in postmenopausal women. They are not an option for premenopausal women unless the patient is made post menopausal. A postmenopausal state can be induced surgically by removing the ovaries or medically by a shot which tells the ovaries to “go to sleep” (Lupron, Zoladex).

Faslodex is a monthly shot which may be helpful and has few side effects.

Some breast cancers contain a receptor on their surface called Her-2-neu. Her-2-neu “looks for” growth factors and uses them to grow-giving these tumor cells an advantage over normal surrounding tissues. Herceptin is a monoclonal antibody that “fits over” the Her-2-neu receptor so that it cannot get the desired growth factors.

Herceptin is a biologic therapy. It is a monoclonal antibody that selectively seeks an antigen – Her-2-Neu.This drug is only useful in Her -2 -neu positive tumors.

Herceptin has activity when used alone; its activity is greatly increased when used with a variety of chemotherapy drugs. Herceptin does not cause hair loss, nausea or vomiting, or suppression of blood counts.

Herceptin is synergistic with several drugs. Synergistic means 2 + 2 = 5 not 4. Excellent drugs to use in combination with Herceptin include a platinum and a Taxane or Navelbine. Patients who do well with Herceptin may receive this drug for a long period of time. Herceptin is often given weekly in the vein over about thirty minutes. Recently, some doctors have used a larger dose IV every three weeks. This schedule is also effective. Herceptin is often continued as a single agent in patients who have entered into remission with the use of Herceptin and chemotherapy. Tykerb is an oral drug which can also be used.

Women who have metastatic disease to the bone are likely to benefit from Zometa (a bisphosphate) given IV monthly. This drug strengthens the bones and makes it more difficult for a cancer cell to grow there.

There will be many advances in the treatment of breast cancer over the next several years. As yet, there is no cure for metastatic disease, but there are many agents that will extend the quality and duration of the patient’s life. Also, there are medications that can help the patient deal with the symptoms of her illness.

Remember, get the opinion of a Board Certified Medical Oncologist – this is one time that “a little piece of paper” does make a difference.

Special Report on Triple Negative Breast Cancer

Atlanta recently hosted the Second Annual Triple Negative Breast Cancer Symposium given in honor of Jean Sindab. Dr. Sindab was an African American and a Yale educated PHD. She died at the age of 61 as a result of breast cancer.

Many of you have heard of triple negative breast cancer and been frightened by ominous stories of its behavior. Our first task is to ask, “What is triple negative breast cancer?” The answer is really quite easy. Triple negative breast cancer means that the patient’s tumor does not have 3 specific characteristics that have an impact on its treatment. First, the tumor does not have an estrogen receptor; second, her tumor does not have a progesterone receptor. The lack of these receptors means that her tumor will not respond to oral medications such as Tamoxifen, Femara, Aromasin or Arimidex. The third negative in a triple negative is that the tumor is HER-2neu negative, so the tumor will not respond to either Herceptin or Tykerb. These characteristics place the patient at a significant disadvantage because the only method for treating her breast cancer, other than surgery and/or radiation, is chemotherapy but the powerful chemotherapy drugs that I mentioned earlier in this paragraph won't work for her.

The overall incidence of triple negative breast cancer is 30%. It has been puzzling that African American woman often do more poorly than white women despite equal access to care and insurance coverage. One of the reasons African American women do not as well as white women is that of all African American women who have breast cancer, 46% have triple negative tumors as opposed to only 22% of white patients. Thus more black women than white women have this high risk tumor type, which may in part explain their worse survival. The incidence is also much higher in women under age 55.

A proportion of triple negative breast cancer patients will be what we call BRCA-1 positive and this has important implications as this means that the occurrence of second malignancies is increased. Family members may carry the BRCA-1 gene and thus require increased surveillance.

Triple negative tumors tend to be aggressive and to metastasize (spread) to other sites in the body. These breast cancers tend to form secondary tumors at visceral sites (liver and lung) and for the brain. Triple negative status is the single greatest risk factor for the development of brain metastasis. The median time to development of brain metastasis is 22 months, and median survival is short – only four months. This aggressive behavior is obviously very serious for thee patient.

However, when treated adjuvantly, recurrences will be early – usually less than five years or not at all. So, if the patient does not have a recurrence within five years, it is likely that she is cured; this is in stark contrast to patients who have estrogen receptor positive tumors where late recurrences, even after 20 years, are not rare.

There are several important points about treating triple negative cancers. Many of these tumors are very sensitive to certain specific types of chemotherapy. In the adjuvant setting, dose dense treatment should be considered. That is, treatments should be given close together. If you receive Adriamycin/Cytoxan in the adjuvant setting, it should be given every two weeks rather than every three weeks.

When treated neoadjuvantly (prior to surgery) 27% of women will have a complete disappearance of the cancer. An additional 56% will have a partial response in this setting. Those patients who achieve a pathologic complete response are usually “home free”. Patients who do not have a response have a very high recurrence rate.

Some active agents are shown in table 1. Therapeutic Strategies in Triple-Negative Breast Cancer

Treatment Approach Status

Adriamycin Proven efficacy

Taxol, Taxotere Proven efficacy

Platinum agents Active; comparison to other drugs unclear

Bevacizumab (Avastin) Suggested activity in trial E2100 FDA approved.

Ixempra Promising activity; now available and FDA approved.

Sunitinib Activity suggested in subset analyses of a phase II trial

EGFR inhibition ( cetuxamab) Modest activity when combined with chemotherapy

PARP inhibition Exciting clinical data; not yet FDA approved.

EGFR = epidermal growth factor receptor; PARP = poly ADP-ribose polymerase.

Patients who are triple negative and BRCA-1 positive have an excellent response to Platinum. This does not hold true if they are BRCA-1 negative.

Triple negative tumors also do quite well with Avastin and the addition of Avastin to Taxol in the metastatic setting gives a six month longer disease free survival than does Taxol alone.

Ixempra (Ixabepilone) is a new drug which shows promise in these tumors. Ixempra has a 26% complete response rate in triple negative breast cancer; the highest ever published for a single agent. When used with Avastin, this drug has a 70% response rate in triple negative metastatic tumors.

After adjuvant chemotherapy estrogen receptor positive patients are treated for 5+ years with either Tamoxifen or an aromatase inhibitor. HER-2neu positive patients continue on Herceptin for one year. Triple negative patients have fewer options, but restricting dietary fat to less than 15% of total calories is important. The WINS study randomized women who had completed chemotherapy to a control group given “eat healthy” advice and an experimental group. The later group was given nutritional support and restricted fat calories to less than 15% of total calories. Weight loss was not a goal.

In the receptor negative group, 59 out of 273 "eat healthy" patients (22%) relapsed and in the low fat group, only 28 out of 205 (14%) patients relapsed. This difference is statistically significant with a P value of 0.018. The RMC Cancer Center has a trained Nutritional Counselor available – call 256-235-5084 and ask for Wendy or Charlotte to arrange an appointment.

Exciting progress is occurring both in the laboratory and in the clinic.

Clinical research involves both testing new drugs and using FDA approved drugs in different ways.

The RMC Cancer Center is proud to participate in two of these studies. In 1 of these protocols, women who are being treated in the adjuvant setting are randomized to Avastin plus chemotherapy or chemotherapy alone. We know that Avastin works in the metastatic setting. This trial asks if Avastin will also work in earlier stage disease.

RMC Cancer Center also has a protocol using Ixempra in the adjuvant setting. This drug is likely going to be a “winner” – but time will tell.

Call Wendy at 256-235-5084 for more information or call me at 238-1011 and ask for Debi.

Estrogen and progesterone receptor positive tumors are homogeneous (all alike) in one respect. Namely, they have a target; the estrogen or the progesterone receptor. Similarly, HER-2neu positive breast cancers have a target; namely,HER-2neu. Triple negatives do not have a unique target.

Target selection and the development of agents to attack the chosen target is an area of intense interest and exciting research; but may not be ready for “prime time” for several years.

PARP (poly ADP-ribose polymerase) inhibition may be the next advance in triple negative treatment.

PARP is an enzyme which plays a central role in DNA repair in cancer cells. PARP inhibitors are likely to be very effective in triple negative breast cancer cells. This is so because, in these cells, PARP is very important and is up- regulated; i.e. there is more of it than there is in breast cancer cells that are not triple negative. PARP is also critically important in triple negative BRCA-1 mutation carriers because they have a very special defect in DNA repair. There are two PARP inhibitors in clinical trials and results have recently been reported. One is named BSI-201 and the other is named Olaparib. They both work by promoting the death of cancer cells by thwarting the cells’ ability to repair DNA damage.

Dr. Joyce O’Shaughnessy reported that BSI-201 prolonged median survival and increased response rates for women who were treated for metastatic triple negative breast cancer. In her study half the women got standard chemotherapy and the other got the same standard chemotherapy plus BSI-201.

Clinical benefit tripled with the use of BSI-201; 62% of the women treated with BSI-201 plus chemo achieved stability of disease or better for a minimum of six months. This compares with only 16% of women who were given the chemotherapy alone.

Olaparib has also been studied in BRCA deficient metastatic breast cancer patients who have had extensive prior treatment. This drug is given orally. In a group of 27 patients who received the drug, 41% had a complete disappearance of all disease and an additional 40% had a partial response. This drug was very well tolerated.

Neither of these drugs is currently available outside of clinical trials.

Creating targets is a new approach. For example – what if the tumor could be induced to express the estrogen receptor? Were it so, Tamoxifen, Femara, Arimidex, Faslodex, etc. would become effective and nontoxic treatments. This goal has been accomplished in mice and human trials are planned.

If you have a triple negative breast cancer which is metastatic and refractory to standard therapy, you might want to discuss with your physician whether or not you would be eligible for a clinical trial.

In summary, triple negative breast cancer remains a challenge. However, important advances have been made within the last year and we anticipate that additional advances are soon forthcoming.

I hope that you have enjoyed reading this report. I will be happy to answer any questions. Please refer your questions to Debi at 256-238-1011, and I will do my best to respond to them.