April 2011 Ask the Expert: Research and Treatment Options for Triple-Negative Breast Cancer

April 1, 2011

During the month of April 2011, Living Beyond Breast Cancer expert HopeS. Rugo, MD, answered your questions about which groups are at highest risk for developing triple-negative breast cancer, the types of treatments available in early-stage and metastatic disease and the latest research on promising new developments in the pipeline.

You may also be interested in Triple-Negative Breast Cancer: Medical Update and Triple-Negative Breast Cancer: Fear of Recurrence.

Question: I have been diagnosed with triple-negative, grade 3, invasive breast cancer, 5.5 cm x 4.0 cm, and have had mastectomy with axillary surgery. No metastases found in nodes, but large tumor with necrosis. I am having FEC chemotherapy right now, probably followed by radiotherapy. Is there any targeted treatment coming up soon for this condition? I am concerned whether this standard treatment will be enough. I am a retired health professional. Thank you.

Dr. Rugo: Triple-negative breast cancerinfo-icon is often high gradeinfo-icon, or gradeinfo-icon 3, which is what I think you mean. High grade refers to the way the cancer looks under the microscope and includes several features. There are only three grades, and grade 3 cancers are usually faster growing, more aggressiveinfo-icon types. Interestingly, this type of cancer is also very sensitive to chemotherapyinfo-icon, as chemotherapy targets rapidly dividing cells. So adjuvant or neoadjuvant chemotherapy is very important for triple-negative disease and can prevent many recurrences.

The behavior of your cancer is important. The fact that the cancer got to be very big without spreading to the lymphinfo-icon nodes means something important. For example, a small cancer that has spread to many nodes is acting more aggressively than a large tumorinfo-icon without positive nodes, regardless of being triple-negative.

For adjuvant treatment of these cancers, we recommend something like FEC or an Adriamycin regimeninfo-icon followed by a taxaneinfo-icon. Depending on the agent we give it weekly for 12 weeks, or every 2 to 3 weeks for 4 doses. I think the addition of the taxane is really important in triple-negative disease, and this has been shown in a number of trials. I would only give 4 cycles of the FEC or AC type treatment.

There is intense interest in finding active targeted agents for triple-negative disease. It turns out to be more difficult than we first thought. Because the disease is not one type, but many, one targeted agent is unlikely to work for all triple-negative tumors. Biologically we have identified different subgroups, but this work is still evolving.

The most exciting therapyinfo-icon in the last couple of years was adding agents that blocked the ability of the cancer to repair DNA to standard chemotherapy. These agents are called PARPinfo-icon inhibitors. One very promising study did not have the same benefits when repeated in a larger population of patients, and we are still trying to figure out which tumors benefit the most from this type of treatment. All of the trials reported so far have been done in advanced cancer, and one trial giving these agents before surgeryinfo-icon does not yet have results.

In addition to PARP inhibitors, many agents are being tested that target different pathways including angiogenesisinfo-icon, or new blood vessel growth.

That said, you should receive an anthracyline (like FEC or AC) for 4 cycles followed by a taxane, as outlined above. That treatment has very good success rates in a cancer like yours.

Question: I am 8 years out from my triple-negative breast cancer. The label did not even exist at that time, as little was known. I would like to learn more about ongoing studies, or clinical trials that are focused on preventing recurrence of triple-negative cancers. How can I find out if such trials exist?

Dr. Rugo: First, congratulations on being 8 years out!

The majority of recurrences for this disease occur in the first 3-5 years after diagnosisinfo-icon. There are many ongoing studies; these can be accessed at the NCI patient data query site online, as everyone is required to register and list all clinicalinfo-icon trials now.

For preventioninfo-icon, there are a number of ongoing investigations, both in the clinic and in the laboratory. Much of the work has been focused on testing for BRCA1info-icon mutations and looking at diet and lifestyle factors that could contribute to the development of this subtype of breast cancer.

Question: What is the 5-year survival rate for triple-negative metastatic cancer?

Dr. Rugo: This is very much dependent on how much tumorinfo-icon was present at the time of diagnosisinfo-icon. Due to the diversity of this type of cancer, as well as the impact of extent of disease at diagnosis and the type and intensity of treatment, it is impossible to give an overall value across the board.

If treatment was given before surgeryinfo-icon (neoadjuvant), then response to therapyinfo-icon is a useful predictor of both risk of recurrenceinfo-icon and survival. Because this cancer is very sensitive to chemotherapyinfo-icon, adjuvant treatment has a big impact on survival.

Question: Since triple-negative breast cancer returns often, and to other vital organs such as the liver and lungs, how often and what testing should be done?

Dr. Rugo: There is no data that routine testing impacts outcomeinfo-icon. In other words, it is not helpful to obtain routine scans looking for recurrenceinfo-icon. Scans should be done as needed based on symptoms, findings on blood tests or physical examinationinfo-icon. Clearly, symptoms should not be ignored. However, finding metastases “early,” by scaninfo-icon alone, does not change survival from or treatment for this disease. Recurrence in other sites in the body is treatable but not curable regardless of when the disease is discovered.

Question: When I was diagnosed with triple-negative breast cancer, I was told that if it came back, there would not be anything else that they could do for me. Are you finding this true for other TNBC patients?

Dr. Rugo: This global statement is not true. If the disease recurs in distant sites (metastaticinfo-icon breast cancer), it is true that we do not know of a treatment option that will cureinfo-icon it. However, we have a number of chemotherapyinfo-icon and clinical trialinfo-icon options that can extend survival and control the cancer. Unfortunately this is not the case in all patients, but it certainly is in the great majority. In addition to standard therapyinfo-icon, there are many agents in clinicalinfo-icon trials that appear quite promising. Information about these trials can be found on the NCI clinical trials website.

Question: Is breast conversation surgery a safe choice for triple-negative cancers?

Dr. Rugo: Yes, if the surgical margins are clear and radiationinfo-icon is given after chemotherapyinfo-icon, this is a safe surgical option for TNBC. One caveat is in patients with BRCA mutations—these women are at higher risk for new cancers, particularly in the unaffected breast, and should discuss surgical options with their surgeoninfo-icon and a geneticinfo-icon counselor.

Question: Is there a size tumor you'd want to stay below to recommend breast conservation surgery?

Dr. Rugo: There is not a specific size. The size issue impacts the cosmetics of the resulting surgeryinfo-icon, however this is all related to the size of the breast and where the tumorinfo-icon is located in the breast. If you are large breasted, you have more leeway. Breast conservation, in general, is influenced by the size of the tumor, its location in the breast and the size and shape of the breast.

Question: I'd like to know the doctor’s thoughts on chemo treatments, large doses vs. smaller daily doses. Is one more effective for TNBC?

Dr. Rugo: The answer to this question is dependent on whether this applies to early- or late-stageinfo-icon disease.

Based on current knowledge, it appears that weekly paclitaxelinfo-icon is as effective as but significantly less toxicinfo-icon than larger doses of paclitaxel or docetaxelinfo-icon given less frequently. Any study that has demonstrated improved outcomeinfo-icon with one treatment compared to another has shown that this is also true in the more rapidly growing tumorinfo-icon subtypes like TNBC.

Question: Is there any research relating specifically to triple-negative DCIS?

Dr. Rugo: DCISinfo-icon is noninvasiveinfo-icon—in other words, it has not yet invaded blood or lymphinfo-icon vessels. There is research directed toward preventing new cancers after a diagnosisinfo-icon of DCIS and reducing the extent of treatment for lower risk disease.

 Other work is focusing on developing a predictive model to estimate an individual’s risk for subsequent invasive cancerinfo-icon. Overall, the appropriate treatment for this disease is excisioninfo-icon with clear margins, radiationinfo-icon following breast conserving surgeryinfo-icon and surveillance for new cancers.

Question: How should a patient gauge her likelihood of recurrence/metastasis when she has an early-stage diagnosis?

Dr. Rugo: Risk of recurrenceinfo-icon is affected by a number of factors. The two most important are the biology and stageinfo-icon of the tumorinfo-icon, followed closely by the age and health of the patient and extent of adjuvant or neoadjuvant chemotherapyinfo-icon. However, triple-negative breast cancerinfo-icon is often very sensitive to chemotherapy, so even higher risk cancers still can be cured.

For an individual who has surgeryinfo-icon first followed by chemotherapy, risk is estimated based on the clinicalinfo-icon features of the cancer.

Question: My oncologist said that there are studies indicating that there are different types of triple-negative disease—some types are very aggressive, and some types are less aggressive. Can you comment?

Dr. Rugo: Yes, it appears that there are subtypes within triple-negative disease that vary based on some biologicinfo-icon features, sensitivity to chemotherapyinfo-icon and behavior in the body. Very few triple-negative cancers are slow growing; the majority are more aggressiveinfo-icon and rapidly growing. Most are very sensitive to chemotherapy, but some are quite resistant.

Laboratory research is now directed toward trying to better understand differences between triple-negative breast cancers, with the goal of trying to find the right treatment for these specific cancer subsets. We understand, for example, that triple-negative cancers associated with BRCA1info-icon mutations have specific sensitivity to PARPinfo-icon inhibitors and to agents that damage DNA. So even within triple-negative disease, it is clear that one size does not fit all in terms of the most effective therapyinfo-icon.

Question: Are there any new treatment options for triple-negative breast cancer patients beside the PARP Inhibitor?

Dr. Rugo: Yes, there are a number of new agents that are being tested in triple-negative disease, some with very promising early results. Trials are listed on the NCIinfo-icon’s clinical trialinfo-icon database, as investigators are now required to list all trials on that site. One exciting area for investigation in the near future is targeting the body’s immune responseinfo-icon to cancer, as the immune response may promote resistance to chemotherapyinfo-icon.

Question: I am 30 years old. Diagnosed last year with TNBC. Bilateral mastectomies, chemo. No lymph node involvement. Stage II. Should I ask my doctor about getting into trials? Do you recommend getting into trials? Could it cause problems?

Dr. Rugo: If you have not seen a geneticinfo-icon counselor for counselinginfo-icon and BRCA testing, I would strongly encourage you to consider this. Presumably you received chemotherapyinfo-icon after your surgeryinfo-icon? As you are now likely to be done with your adjuvant therapyinfo-icon, trial participation depends on availability of a post adjuvant study. Usually these trials randomize to treatment or placeboinfo-icon.

One such trial is studying a drug called metformin to see if this will reduce recurrenceinfo-icon (not just in triple-negative disease). Metformin is a drug used to treat diabetes that may have anti-cancer effects. This trial, run by our colleagues in Canada, is not yet open in the United States but should be soon.

Question: What are your recommendations when two highly qualified oncologists recommend different treatments, followed by two more oncologists each agreeing with one of the first two? Two recommended TAC (Taxotere, Adriamycin and Cytoxan) and two recommended TC( Taxotere and Cytoxan) x 4. Are both reasonable?

Dr. Rugo: This is of course a difficult situation! Much of these recommendations are influenced by physicianinfo-icon biasinfo-icon regarding use of anthracyclines and assessment of risk.

Physicians are more likely to suggest TAC for a young woman with higher risk disease and TC for intermediate risk disease. The problem is there is a significant difference in intensity, number of cycles (6 vs. 4) and potentially effectiveness.

I don’t use TAC myself, although of course it is a very effective regimeninfo-icon—I use sequential AC followed by T as that is what our group has studied. I am comfortable using TC for patients with intermediate risk, as I mentioned, but assessment of risk can be tricky.

So, what should you do at this point? Obviously I cannot make a recommendation about which regimen is reasonable, or even if both are reasonable, as I don’t know anything about you or your cancer. I don’t know if you went to an academic center, but my recommendation would be to go to an academic oncologistinfo-icon specializing only in breast cancer and have that opinion be the tie breaker. The other option is to bring the recommendations to the oncologist you like the best and discuss together what would be best.

Question: I have just been diagnosed with Stage II, triple-negative breast cancer. I am about to have an appointment with an oncologist in the coming week. What are the best types of questions I can ask to better get myself acclimated to my newly-diagnosed situation?

Dr. Rugo: I would ask the following:

1. Should I talk with geneticinfo-icon counselors about possible genetic testinginfo-icon? I want to understand my risk of having a mutationinfo-icon before I just have the test.

2. Should I have a CT scaninfo-icon and bone scaninfo-icon, or a PET/CT scan for staginginfo-icon?

3. Are we confident about the pathology reportinfo-icon? In other words, is there any reason to repeat the tests for the estrogeninfo-icon and progesterone receptorinfo-icon and HER2/neuinfo-icon?

4. (If you have not yet had surgeryinfo-icon) Do you recommend neoadjuvant chemotherapyinfo-icon? What chemotherapy would you give? How will you follow my cancer?

5. Can you tell me about the short- and long-term side effects from chemotherapy and what treatment you would recommend to manage these side effects?

The standard chemotherapy for this cancer would be AC followed by a taxaneinfo-icon, or TAC for 6 cycles. It is important that the full doses be given with growth factor support as necessary.

Question: I was diagnosed with TNBC (Stage IIIA) just as the worldwide shortage of Adriamycin hit the U.S. As a result, after a double mastectomy, I began my chemotherapy with Abraxane followed by AC (dose dense). Do you have any ideas on how this change in the recommended sequence might impact the effectiveness of the treatment, if at all?

Dr. Rugo: Actually, there is some data to suggest that this reverse sequence might be more effective against the cancer than the standard schedule. Data from an animal model as well as a neoadjuvant chemotherapyinfo-icon study suggested that the reverse sequence resulted in improved response. We don’t know this for sure, but clearly there is no downside at all to the order in which you are receiving your chemotherapy!

Question: What do you think are the benefits of neoadjuvant PARP therapy for a patient who is not BRCA1 or 2 positive?

Dr. Rugo: PARPinfo-icon inhibitors block an important DNA repair enzyme. Patients with cancers associated with BRCA mutations already have a problem with DNA repair, so further blocking this process can result in cancer cellinfo-icon death.

For patients with sporadic triple-negative cancers, some data has suggested benefit from combination chemotherapyinfo-icon and PARP inhibition. However, this is only in patients with advanced, previously treated metastaticinfo-icon cancer. Further analysis on a recent large study will hopefully help us to figure out which patients actually could benefit from PARP inhibitors.

There is one non-randomized clinical trialinfo-icon in the neoadjuvant setting ongoing in the U.S. So far, there is no reported data on effectiveness, and most patients go on to receive standard chemotherapyinfo-icon after surgeryinfo-icon. We don’t know whether this treatment is better than standard therapyinfo-icon, or if perhaps there are certain cancers that are better treated with this combination. If there is a reasonable clinical trialinfo-icon to participate in, and you have a large triple-negative tumorinfo-icon, I would consider participating.

Question: I am Hispanic and do not understand how I have triple-negative breast cancer. The readings and research I have done lead to African-American woman and Mediterranean woman. I do have family ancestry in Italy dating to 1400. Thank you for any information that you may provide.

Dr. Rugo: Triple-negative disease can occur at any age or in any ethnic group. Women belonging to certain ethnic groups and younger women may have an increased risk of having triple-negative disease if they develop breast cancer, but all women who develop breast cancer are at risk that the cancer might be triple-negative.

Overall, about 15 percent of breast cancers are triple-negative, with a lower percentage in much older women and a higher percentage in young women, particularly African-American premenopausalinfo-icon women.

Your family history is important, and certainly it would be worthwhile to discuss this with a geneticinfo-icon counselor and to consider testing if your history supports an increased risk.

Question: Do you think that women with triple-negative breast cancer should be tested for the BRCA gene mutations?

Dr. Rugo: I think women with triple-negative disease who are younger, have a family history, are of Ashkenazi ethnicity or have bilateralinfo-icon cancer should be considered for BRCA testing.

Genetic testinginfo-icon should be discussed with all women who develop triple-negative disease, although for older women with no family history the cost would outstrip the potential benefit. Genetic testing should be discussed then ordered based on a thorough discussion with the patient and a full understanding of the family tree.

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