April 2011 Ask the Expert: Research and Treatment Options for Triple-Negative Breast Cancer
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.
Dr. Rugo: Triple-negative breast cancer is often high grade, or grade 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 aggressive types. Interestingly, this type of cancer is also very sensitive to chemotherapy, 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 lymph nodes means something important. For example, a small cancer that has spread to many nodes is acting more aggressively than a large tumor without positive nodes, regardless of being triple-negative.
For adjuvant treatment of these cancers, we recommend something like FEC or an Adriamycin regimen followed by a taxane. 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 therapy 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 PARP 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 surgery does not yet have results.
In addition to PARP inhibitors, many agents are being tested that target different pathways including angiogenesis, 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.
Dr. Rugo: First, congratulations on being 8 years out!
The majority of recurrences for this disease occur in the first 3-5 years after diagnosis. 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 clinical trials now.
For prevention, 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 BRCA1 mutations and looking at diet and lifestyle factors that could contribute to the development of this subtype of breast cancer.
Dr. Rugo: This is very much dependent on how much tumor was present at the time of diagnosis. 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 surgery (neoadjuvant), then response to therapy is a useful predictor of both risk of recurrence and survival. Because this cancer is very sensitive to chemotherapy, adjuvant treatment has a big impact on survival.
Dr. Rugo: There is no data that routine testing impacts outcome. In other words, it is not helpful to obtain routine scans looking for recurrence. Scans should be done as needed based on symptoms, findings on blood tests or physical examination. Clearly, symptoms should not be ignored. However, finding metastases “early,” by scan 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.
Dr. Rugo: This global statement is not true. If the disease recurs in distant sites (metastatic breast cancer), it is true that we do not know of a treatment option that will cure it. However, we have a number of chemotherapy and clinical trial 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 therapy, there are many agents in clinical trials that appear quite promising. Information about these trials can be found on the NCI clinical trials website.
Dr. Rugo: Yes, if the surgical margins are clear and radiation is given after chemotherapy, 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 surgeon and a genetic counselor.
Dr. Rugo: There is not a specific size. The size issue impacts the cosmetics of the resulting surgery, however this is all related to the size of the breast and where the tumor 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.
Dr. Rugo: The answer to this question is dependent on whether this applies to early- or late-stage disease.
Based on current knowledge, it appears that weekly paclitaxel is as effective as but significantly less toxic than larger doses of paclitaxel or docetaxel given less frequently. Any study that has demonstrated improved outcome with one treatment compared to another has shown that this is also true in the more rapidly growing tumor subtypes like TNBC.
Dr. Rugo: DCIS is noninvasive—in other words, it has not yet invaded blood or lymph vessels. There is research directed toward preventing new cancers after a diagnosis 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 cancer. Overall, the appropriate treatment for this disease is excision with clear margins, radiation following breast conserving surgery and surveillance for new cancers.
Dr. Rugo: Risk of recurrence is affected by a number of factors. The two most important are the biology and stage of the tumor, followed closely by the age and health of the patient and extent of adjuvant or neoadjuvant chemotherapy. However, triple-negative breast cancer is often very sensitive to chemotherapy, so even higher risk cancers still can be cured.
Dr. Rugo: Yes, it appears that there are subtypes within triple-negative disease that vary based on some biologic features, sensitivity to chemotherapy and behavior in the body. Very few triple-negative cancers are slow growing; the majority are more aggressive 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 BRCA1 mutations have specific sensitivity to PARP 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 therapy.
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 NCI’s clinical trial 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 response to cancer, as the immune response may promote resistance to chemotherapy.
Dr. Rugo: If you have not seen a genetic counselor for counseling and BRCA testing, I would strongly encourage you to consider this. Presumably you received chemotherapy after your surgery? As you are now likely to be done with your adjuvant therapy, trial participation depends on availability of a post adjuvant study. Usually these trials randomize to treatment or placebo.
One such trial is studying a drug called metformin to see if this will reduce recurrence (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.
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 regimen—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 oncologist 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.
Dr. Rugo: I would ask the following:
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 taxane, or TAC for 6 cycles. It is important that the full doses be given with growth factor support as necessary.
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 chemotherapy 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!
Dr. Rugo: PARP 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 cell death.
For patients with sporadic triple-negative cancers, some data has suggested benefit from combination chemotherapy and PARP inhibition. However, this is only in patients with advanced, previously treated metastatic 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 trial 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 chemotherapy after surgery. We don’t know whether this treatment is better than standard therapy, or if perhaps there are certain cancers that are better treated with this combination. If there is a reasonable clinical trial to participate in, and you have a large triple-negative tumor, I would consider participating.
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 premenopausal women.
Your family history is important, and certainly it would be worthwhile to discuss this with a genetic counselor and to consider testing if your history supports an increased risk.
Dr. Rugo: I think women with triple-negative disease who are younger, have a family history, are of Ashkenazi ethnicity or have bilateral cancer should be considered for BRCA testing.
Genetic testing 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.