July 2008: Triple-Negative Breast Cancer

Protection after triple-negative treatment?

Question from KoKo: My mom was recently diagnosed with triple-negative breast cancer. She is Stage I with no lymph node involvement. She underwent six chemo treatments and the 5-day MammoSite radiation. Everyone seems to feel that her prognosis is so grim due to the triple-negative. What can she do now to protect herself?

Answers —George Sledge, M.D.: A good place to start is what's a common misconception in that triple-negative breast cancer has a truly awful prognosis. But in fact, that's not really the truth. Factors such as size of tumor and lymph node status are still very important. For a Stage I breast cancer patient, even with a triple-negative breast cancer, most patients live to a ripe old age. In addition, if the patient received adjuvant chemotherapy, there are significant reductions in the risk of recurrence and death due to breast cancer. So I would not consider this a matter of gloom and doom. Beyond this, there is an emerging area of what we can do after chemotherapy for women with triple-negative breast cancer. There are some fascinating recent data from a trial that was conducted by Dr. Rowan Chlebowski of University of California, San Francisco, that looked to see whether or not modifying one's dietary fat intake would have any effect on outcome for early stage breast cancer patients. While dietary fat reduction had relatively little effect in women who had estrogen-receptor-positive breast cancers, in women with estrogen-receptor-negative breast cancers, there was a significant reduction in the risk of recurrence for women with a low dietary fat intake. There's also increasing evidence, most prominently from the Women's Health Study in Boston, that women who exercise regularly (3 hours a week or more) have a lower risk of recurrence of their breast cancer than women who do not exercise regularly. So these studies point to the possibility that lifestyle interventions may be important for the breast cancer survivor.

Beth DuPree, M.D., F.A.C.S.: As far as exercise and diet are concerned, studies are very positive in the overall effect that diet and exercise have in women during and after chemotherapy as well as long term in decreasing fatigue and side effects of chemotherapeutic agents and radiation therapy. So even in women who are not estrogen-receptor negative, progesterone-receptor negative, and HER2 negative, the effects of exercise can be incredibly powerful and is something I recommend for patients regardless of whether they've never exercised in their life, that they add cardiovascular exercise to their daily living.

George Sledge, M.D.: That is a great point!

Clinical trials for triple-negative?

Question from Padma Tadi Uppala: I am a breast cancer researcher. My patient has been diagnosed with Stage IV triple-negative breast cancer. She has open sores on the right side of her body including the stomach. She is currently undergoing chemotherapy -- Taxol and Xeloda. What kind of clinical trials (that seem to work) are available for triple-negative breast cancer patients such as my patient? What is her prognosis?

Answer —George Sledge, M.D.: We have relatively little in the way of studies regarding specific agents for triple-negative breast cancer, but there is some emerging data that I think is interesting. If we look in the E2100 trial of Taxol (chemical name: paclitaxel) alone vs. Taxol with Avastin (chemical name: bevacizumab) as front-line therapy for metastatic breast cancer, Taxol and Avastin was superior to Taxol in triple-negative patients to the same degree it was in estrogen-receptor-positive patients. On the opposite end, we have some very interesting and recent adjuvant data which is from a trial performed by the CALGB (Cancer and Leukemia Group B) in elderly breast cancer patients (age 65 or greater) newly diagnosed and receiving adjuvant chemotherapy. This trial randomized patients to one of two older chemotherapy regimens, AC (Adriamycin [chemical name: doxorubicin] and Cytoxan [chemical name: cyclophosphamide]) or CMF (Cytoxan, methotrexate, and fluorouracil) vs. the use of single agent Xeloda (chemical name: capecitabine). The results of that trial were particularly interesting in that in women who had steroid-receptor-negative tumors, Xeloda appeared to perform particularly poorly with a hazard ratio for recurrence of 4.4 vs. other groups treated with chemotherapy and estrogen-receptor-positive patients. This suggests the possibility that Xeloda is simply not a very good drug for triple-negative breast cancer patients, certainly not in the adjuvant setting. There is another trial that I presented at ASCO a little over a year ago, called the XCALIBr trial, which looked at the combination of Xeloda and Avastin as front line therapy for metastatic breast cancer. While patients who were estrogen-receptor positive did relatively well in this trial, the triple-negative patients did extremely poorly. Putting together the CALGB trial as well as the XCALIBr trial, one lesson I draw from this is that Xeloda would not be my initial therapy for patients with a triple-negative breast cancer.

What fuels triple-negative breast cancer?

Question from Marilyn in Miami: If ER/PR/HER2 fuels breast cancer, what is fueling triple-negative breast cancer and when will targeted therapies be available?

Answers —Beth DuPree, M.D., F.A.C.S.: There are some trials that are attempting to develop regimens for triple-negative cancers. They're trying to determine whether antiangiogenic agents can specifically target the triple-negative cancers better than the standard chemotherapy. That would be the drug Avastin (chemical name: bevacizumab). There are other emerging targeted therapies that are working on trying to incorporate aspects of increasing cellular proliferative pathways and cellular repair pathways. These are looking at growth factor receptors such as EGFR (epithelial growth factor receptor) but most of these studies are Phase I evaluations and not quite ready for prime time yet. In order to develop a targeted therapy, we have to know exactly what pathway of cell division and cancer proliferation we're trying to stop. So there is ongoing research but most of those studies are within Phase I and Phase II.

George Sledge, M.D.: An area that is of real interest now in the laboratory and the clinic are new drugs called PARP inhibitors. These are drugs that interfere with DNA repair in breast cancer and there is laboratory evidence to suggest that particularly for BRCA1 and BRCA2 tumors, these PARP inhibitors may turn out to be active agents for the treatment of these cancers since these cancers tend to have altered and impaired DNA repair. There has already been Phase I data in ovarian cancers presented at this year's ASCO meeting in a fairly heavily pretreated population of BRCA1 and 2 with ovarian cancer, suggesting significant activity with this agent. There are now trials going on in BRCA1 and BRCA2 mutation carriers in breast cancer. What is particularly interesting about this is that the great majority of BRCA1 mutation carriers have triple-negative breast cancers. Indeed, there is certainly a suggestion from some of the laboratory studies that other triple-negative breast cancers may at least share some of these problems with DNA repair that make the mutation carriers more sensitive. So this is an exciting and emerging area of research for which we should keep our eyes peeled over the next few years.

MRI and mammograms as annual checkup post-treatment?

Question from Radha: Do you recommend MRI along with mammograms as part of the annual checkup, for someone who has had triple-negative breast cancer high grade, stage I, who has been through the standard AC plus radiation treatment after lumpectomy? ACS recommends MRI be done in high-risk survivors. Insurance is not likely to agree even if the oncologist agrees to do it. Should one try to insist on MRI as part of the testing?

Answers —George Sledge, M.D.: I think the MRI recommendations made by the American Cancer Society (ACS) are reasonable. In essence, the ACS has recommended MRIs for women who are BRCA1 or BRCA2 mutation carriers, or women who have a lifetime risk of breast cancer of 20% or greater. I think certainly for standard screening, I only recommend MRI for such really high-risk women. For a woman who has already had breast cancer, such as the case you describe, there is no striking reason to believe that that would need to be imaged in a different way than the normal breast cancer patient. It is important to recognize that for any woman with an invasive breast cancer, the greatest risk is not the risk of a secondary breast cancer tumor but rather the risk of a distant metastasis of her first breast cancer. So while continuing imaging of the breast is important, that is likely to be determined by whether or not she has had appropriate therapy to prevent a systemic recurrence.

Beth DuPree, M.D., F.A.C.S.: I agree with the ACS recommendation in the BRCA-positive patients and women with a 20% risk. The other subgroup that I will use MRI for screening is the group of women whose breast cancers were undetectable by mammography, whose mammograms didn't reveal the primary tumor. This is typically a group of women whose mammograms reveal very dense fibroglandular tissue that reduces the sensitivity to detecting an ipsilateral [same breast] recurrence or a contralateral [other breast] primary cancer. This is a small subset of patients, but the inability for the mammogram to have detected the first cancer decreases my confidence in the mammogram to be used as that patient's only screening tool.

Recommendations for after triple-negative treatment?

Question from KathyK: What are the most important recommendations you can make that patients can follow after treatment for triple-negative breast cancer? Aren't there any things we can do to help ourselves?

Answer —Beth DuPree, M.D., F.A.C.S.: I think that you can refer to the first question regarding diet and exercise and the overall benefit of reducing the risk of a recurrent cancer. Another factor at the completion of treatment, which I always find very difficult for patients, is to go on and live their life. Once the chemotherapy or radiation or treatment is completed, it is often very difficult to stop focusing on the treatment of the cancer, and to begin living their life once again. With the completion of chemotherapy and the surgical therapy for the cancer, you need to be able to get to a place where you can realize you've done everything you can from a medical standpoint to beat the cancer. At that point focus on living each day to the fullest and making the lifestyle changes to promote a healthier lifestyle overall to reduce the risk of a recurrent cancer.

Best chemo combination for triple-negative?

Question from Jason222: What is the best chemo combination for the triple-negative?

Answer —George Sledge, M.D.: Let me answer in general terms. When we have looked at chemotherapy regimens over the past 2 decades in the adjuvant setting or early disease setting, what we have learned is the addition of taxanes such as Taxol (chemical name: paclitaxel) or Taxotere (chemical name: docetaxel) to previous regimens has added benefit. We also have evidence to suggest that using these regimens in what is called a dose-dense fashion, i.e., more frequent administration of the agents, seems to improve benefit. This appears to be true in triple-negative breast cancers as it is in other subtypes, but perhaps more so in triple-negative breast cancers. We are still wrestling with whether specific drugs should be included or excluded for triple-negative breast cancers. For instance, oncologists are currently arguing over the role of Adriamycin (chemical name: doxorubicin) in early stage breast cancer. Over the next few years we are likely to see a number of new agents enter the adjuvant setting. Currently, for instance, Avastin (chemical name: bevacizumab; an agent that targets blood vessels) is being studied in large adjuvant trials for early stage breast cancer including triple-negative breast cancer. There are also robust studies going on to see whether platinum-based chemotherapies, which damage DNA, may work better in triple-negative breast cancers than they do in other cancer types, but we do not yet have an answer to this question for early stage breast cancer patients.

Taxol only used in some cases of triple-negative?

Question from Kelly: Why is it that some triple-negatives receive Taxol during chemotherapy and some patients do not?

Answers —George Sledge, M.D.: In my clinic, if I’m going to give a patient chemotherapy for a triple-negative breast cancer, that chemotherapy regimen will virtually always include a taxane.

Beth DuPree, M.D., F.A.C.S.: All of my patients also get a taxane, unless they're allergic to it.

Infertility drugs and triple-negative breast cancer?

Question from Kim: Has there ever been an association between use of infertility drugs and triple-negative breast cancers?

Answer —George Sledge, M.D.: I'm unaware of any. However, recent epidemiological studies suggest that the risk factors for triple-negative breast cancer may be somewhat different than for estrogen-receptor-positive breast cancers. So for estrogen-receptor-positive breast cancers, for instance, risk factors include the age at first birth and how many pregnancies one has. Indeed, for these women, having many children and starting having children at a young age are protective for those tumors. In contrast, recent studies say that for triple-negative breast cancers, higher parity and young age at first birth may in fact be a risk factor (increased risk). This was not observed in older studies because these cancers represent a small minority of all cancers. In addition, there also appears from an epidemiological standpoint for there to be an interaction with race and age, so that younger women and African-American women are more likely to develop a triple-negative or basal breast cancer. In particular, young African-American women are more likely to have a triple-negative breast cancer.

Significance of progesterone-receptor positive?

Question from Judy P: I am triple-negative. I had a retest done where they found focal areas of progesterone-receptor positive. My oncologist put me on Arimidex -- said it wouldn't hurt. What is the significance of progesterone-receptor positive?

Answer —George Sledge, M.D.: If we look at hormone receptor status, women who are estrogen-receptor negative but progesterone-receptor positive represent a true minority and a small minority of breast cancer patients, probably representing less than 5% of all breast cancer patients. Many pathologists looking at this issue feel that estrogen-receptor negative/progesterone-receptor positive may represent an artifact of pathology, i.e., an error in testing. The error could be in two ways -- one could be that the tumor is estrogen-receptor positive and progesterone-receptor positive or the tumor could be truly estrogen-receptor negative and progesterone-receptor negative. So if there is any serious question then it is always reasonable to ask the pathologist to cut another slice from the block and retest. From a treatment standpoint, if a tumor is estrogen-receptor negative and progesterone-receptor positive, it is reasonable to consider hormonal therapy, though one suspects that the benefit for such patients would be less with hormonal therapy than in a patient who is strongly estrogen-receptor positive or progesterone-receptor positive.

When was triple-negative identified?

Question from Skippy123: When did the cancer community begin to identify triple-negatives? How long have we been tracking triple-negative survivors?

Answers —George Sledge, M.D.: When we say triple-negative, we mean estrogen-receptor negative, progesterone-receptor negative, and HER2 negative. Routine HER2 testing did not become possible until a decade ago. Interestingly, if one looks in the medical literature, one never sees the term triple-negative breast cancer prior to 3-4 years ago. Indeed, focused studies for triple-negative breast cancer have almost entirely been conducted within the last 3-4 years. That is not to say that we don't know a great deal about triple-negative breast cancers. Because clinical researchers collect slides and tissue blocks as part of clinical trials, we are able to go back to those blocks and slides, sometimes from decades ago, and look at clinical trials through the lens of triple-negative breast cancers.

Beth DuPree, M.D., F.A.C.S.: The term triple-negative seemed to become quite popular, particularly in distinguishing patients as a subgroup once the drug Herceptin became available to treat patients that were HER2/neu positive and previously thought to be a subgroup of having an incredibly aggressive form of cancer. Once there was a treatment for HER2/neu, the term triple-negative became more used in distinguishing this group from a subset of breast cancer patients.

Triple-negative fast- or slow-growing?

Question from Jack: Is triple-negative breast cancer a fast-growing or slow-growing type of cancer?

Answers —George Sledge, M.D.: In general, triple-negative breast cancers are characterized by being highly proliferative: that is they are typically faster-growing breast cancers than are, say, estrogen-receptor-positive breast cancers. This may explain both why they are potentially dangerous breast cancers, but also perhaps why they are more sensitive to chemotherapy drugs that affect dividing cancer cells, so that they are in general more sensitive to chemotherapy agents than are estrogen-receptor-positive breast cancers in many cases.

Beth DuPree, M.D., F.A.C.S.: When we characterize tumors, we look at the stage of the disease as well as the grade of the disease when we determine treatment. The stage of a breast cancer is determined by the size of the tumor, whether or not lymph nodes are involved with metastasis of the tumor, and whether the tumor has spread to someplace distant in the body. The grade of the tumor is a characterization of the tumor by the pathologist that allows us to determine how fast the cells are dividing. Women with a high grade, or a grade III, breast cancer may be recommended to have chemotherapy even when they are diagnosed with a very early Stage I breast cancer. Therefore we use multiple factors in determining how we treat each and every patient and not one factor alone can make these determinations. Depending on the biological behavior of the tumor, we may tailor the patient's treatment by trying to prevent a cancer from recurring not only in the breast, but also systemically in the body.

Higher triple-negative risk due to genetics or environment?

Question from Stej: Studies have presented some evidence about greater risk of triple-negative breast cancers among African-American women and Latinas compared to white women. Is the risk of triple-negative breast cancers due to differences in genes or is it environmental exposures?

Answer —George Sledge, M.D.: This is one of those $64,000 questions that we don't know the answer to. It is interesting that if one looks at women in Nigeria, a high percentage of women there have triple-negative breast cancers. So this may indeed be more than just environment; there may be an important genetic component although we have not identified what that is at present. Indeed, the only genetic factor we have identified so far for triple-negative breast cancers (and only in a small percentage) is the BRCA1 mutation.

Basal-like carcinoma and triple-negative cancer?

Question from Rocky: I have triple-negative breast cancer and the pathologist characterized it as basal-like carcinoma. Is it correct to think of basal-like carcinoma as a subset of triple-negative cancer? My understanding is that basal-like carcinoma has an even worse prognosis than triple-negative. Can you comment on this?

Answer —George Sledge, M.D.: Basal-like cancers and triple-negative cancers overlap with each other. Not all triple-negative breast cancers are basal-like, and not all basal cancers are triple-negative, though most triple-negative breast cancers are basal and most basal cancers are triple-negative. Since the definition of a basal cancer is a definition derived from the area of genomics, my suspicion here is that the pathologist was using basal and triple-negative in the overlapping sense rather than in a well-defined genetic sense. From a prognostic standpoint, if a tumor is basal or if it is triple-negative, that is a tumor that probably puts one at higher risk of recurrence in the absence of systemic therapy. But as we have mentioned earlier, these tumors are frequently very sensitive to systemic chemotherapy in terms of preventing recurrence and death. And as we mentioned, this is only one factor among many that determines prognosis; other factors being the stage and grade of the tumor.

Radio frequency ablation for triple-negative?

Question from AMel: Why isn't radio frequency ablation more often used in combination with chemotherapy as a weapon, especially against triple-negative? Please address the particulars of RFA as a breast cancer weapon. It is used in colon cancer. What is the difference?

Answers —Beth DuPree, M.D., F.A.C.S.: Radio frequency ablation is not a standard treatment for breast cancer. It is used in clinical trial settings, but as a standard therapy for breast cancer I would not put it in that list of treatments that would be considered standard of care in our current breast cancer armamentarium.

George Sledge, M.D.: I agree!

Flaxseed and vitamin D for triple-negative?

Question from Marc-2: Do you recommend that triple-negative breast cancer patients take flaxseed and vitamin D?

Answers —Beth DuPree, M.D., F.A.C.S.: A recent study that was published in the July 2008 edition of the New England Journal of Medicine discussed therapeutic levels of vitamin D in the prevention of cancers such as breast cancer, colon cancer, and prostate cancer. The current recommendation is for maintaining levels of greater than 45 nanograms per milliliter. Vitamin D levels can be evaluated by a blood test specifically for 25-hydroxy vitamin D. Patients who are deficient in vitamin D can increase their levels by taking an oral supplement of vitamin D3 or their body can produce vitamin D with 15-20 minutes per day of sun exposure. Flaxseed has been touted in many trials, none of which I believe are randomized, to have anti-cancer properties. But in and of itself, I do not believe it has ever been proven to prevent cancer. Flaxseed can help to eliminate excess fats in the colon from colonic absorption, therefore the decrease in the absorption of fat can lead to decreased body fat being converted to estradiol. Therefore you could postulate the positive effects, particularly in patients with estrogen-receptor-positive breast cancers, through this pathway.

George Sledge, M.D.: At this year's ASCO symposium, Dr. Pamela Goodwin of Toronto, Canada presented an interesting study regarding vitamin D levels. In this study, women with newly diagnosed breast cancer had vitamin D levels drawn, and then these patients were followed for many years. In this study, patients who had low levels of vitamin D at the time of diagnosis were at greater risk for later recurrence of their breast cancer than patients who had normal levels of vitamin D. The difference was quite impressive. While this certainly in no way proves that vitamin D prevents recurrence of breast cancer, as that question would require a prospective study to answer, taking vitamin D at the level of say 1000 units per day is cheap and safe and appropriate from a bone health standpoint. So it is difficult for me to imagine why we couldn't recommend this to women who have been diagnosed with early stage breast cancer.

Beth DuPree, M.D., F.A.C.S.: I encourage my patients, after testing to determine their baseline level, to have vitamin D replacement to a therapeutic level and I explain to them that although I do not believe that this is the silver bullet to prevent breast cancer recurrence, it certainly won't hurt them and as previously stated by Dr. Sledge, the information that we currently know supports the fact that vitamin D does play a role in this process. Therefore I think the benefits of 1000 I.U. per day certainly outweigh any risk that vitamin D could possibly present for patients.

Upcoming triple-negative clinical trials?

Question from Whoopsiedoodles: How do we stay informed of upcoming clinical trials for triple-negative breast cancer after we're finished with treatment?

Answer —George Sledge, M.D.: There are a number of wonderful sources for looking at clinical trials. The National Cancer Institute maintains through its Physician Data Query and ClinicalTrials.gov databases great up-to-date summaries of breast cancer trials that are NCI-sponsored and going on around the United States. It's also reasonable to ask your medical oncologist if he/she participates in clinical trials for breast cancer in general and triple-negative breast cancer in particular. Indeed, if your medical oncologist does not routinely participate in clinical trials, you probably need a new medical oncologist.

Role of p53 gene in triple-negative?

Question from Jason222: How about the p53 gene? Seems that the triple-negative is also commonly associated with the overexpression of p53. What significance does this gene play in the outcome of the treatment?

Answer —George Sledge, M.D.: p53 has been called the “guardian of the genome.” That is to say p53's role in normal cells is to tell a cell to in essence commit suicide if its DNA has been damaged. In many cancers, but particularly in triple-negative breast cancers, p53 may be mutated and may no longer be performing the purpose intended by nature. Unfortunately, while we can measure p53 in cancer cells and while it is clear that mutated p53 is a poor prognostic factor in many human cancers, there is little we can do therapeutically about this problem at present, although this is an active area of pre-clinical research.

Alcohol safe for triple-negative patients?

Question from Marc: I have read that alcoholic beverages are worse for estrogen-receptor-positive patients than estrogen-receptor-negative patients. Is this true? How much alcohol can triple-negative breast cancer patients safely consume?

Answers —Beth DuPree, M.D., F.A.C.S.: Alcohol has been listed as a carcinogen and can have significantly negative effects on women who consume too much alcohol. Alcohol has its greatest effects in inhibiting the liver's ability to clear certain substances from the body. The studies have shown that postmenopausal women, who by virtue of being postmenopausal have a higher incidence of estrogen-receptor-positive breast cancers, are at greatest risk for consuming excess amounts of alcohol. Women who consume 1/2 glass of wine per day in the postmenopausal period increase their risk of developing a breast cancer by 6%. Women who consume 2-3 glasses of alcohol per day increase their risk of developing breast cancer by close to 40%. There is definitely a direct relationship between the amount of alcohol consumed and the increased risk of breast cancer. In the estrogen-receptor-negative patients, there has not been such a direct correlation but looking at the overall detrimental effects of excess alcohol consumption, this is one lifestyle modification that can benefit women in multiple ways. I have been asked by women why their cardiologist recommends they drink a glass of red wine per day, when I recommend moderation in alcohol consumption. The effects on cholesterol in the body that may be beneficial from the red wine need to be weighed carefully by each individual woman, as cardiac disease is very prominent and also a major risk factor for premature death in women. Therefore, this is a subject that should be specifically discussed with an individual patient and their physician team in order to make an educated choice as to what amount of alcohol is deemed to be safe for that woman. Alcohol in excess should be considered an increased risk factor in the development of breast cancer in the average postmenopausal woman.

George Sledge, M.D.: The data suggesting that alcohol intake increases the risk of breast cancer I think is compelling, and I would agree with everything that Dr. Dupree has said. It is important to distinguish the increased risk of developing breast cancer with the risk of having a recurrence of breast cancer for someone already diagnosed. At present, we have no data suggesting that alcohol intake after a diagnosis of breast cancer increases the risk of recurrence of breast cancer. Some of the epidemiology studies that have demonstrated an increased risk based upon alcohol intake have also suggested that this risk may be decreased by intake of folic acid. As Dr. Leslie Bernstein, one of the epidemiologists at University of Southern California who first demonstrated this link once told me, perhaps what a woman should do is to wash down a multivitamin with her Chablis. Make that Merlot - we want a good red. :-)

Pregnancy okay for triple-negative survivors?

Question from Asics Girl: Since triple-negative breast cancer is not fueled by hormones, is it safe for a triple-negative survivor to become pregnant after treatment or could it start metastasis to occur?

Answers —Beth DuPree, M.D., F.A.C.S.: Pregnancy after breast cancer is always one of the most difficult topics to discuss with patients. First and foremost, the treatment of the cancer with surgery, chemotherapy, and radiation needs to be the first and foremost important aspect in this discussion, as caring for the woman who has the breast cancer and treating her appropriately to allow her to have the greatest chance for long term disease-free survival is of the utmost importance. Once a patient has completed her treatment, it is recommended in my practice, as well as those of the medical oncologists I work with, that the patient wait for at least a 2-3 year period after treatment of their cancer prior to initiating attempts to become pregnant. If I have patients in their mid-30s who are about to undergo chemotherapy, I will discuss with them prior to their treatment what options would be available to them to help to maintain fertility: to potentially perform egg retrieval and fertilization prior to their treatment if pregnancy is of utmost importance to them after completion of their chemotherapy. In women who are estrogen-receptor positive, the concern about pregnancy immediately after treatment is from the overabundance of hormones such as estrogen and progesterone that are produced during pregnancy that could potentially fuel any cancer cells that may have been left over from the initial cancer. In my patients who are estrogen-receptor positive in a premenopausal setting I recommend that they complete their 5 years of tamoxifen, but there are many medical oncologists who would, after 2 years, allow the patient to go off their tamoxifen to initiate pregnancy. There are many factors beside just estrogen-receptor positivity that would need to be taken into account when considering pregnancy after breast cancer. Each patient needs to be counseled individually and when all of the risks, benefits, and potential rewards of the pregnancy are discussed, that couple can then make an educated decision about how and when to proceed with pregnancy.

George Sledge, M.D.: I agree with everything Dr. Dupree mentioned. I approach things slightly differently in my clinic. The first question I think we need to ask is whether a pregnancy subsequent to breast cancer diagnosis increases the risk of recurrence of that cancer. While it is very difficult to say for certain, such evidence as we have suggests that there is not likely to be a major increase in risk of recurrence. The second question is a much more difficult one to my mind, and that is to say should a patient become pregnant knowing that it is possible that the child she brings into this world may grow up without a mother? This gets to the question of risk of recurrence, and in particular the risk of the recurrence that a woman would have with or without a pregnancy. As Dr. Dupree mentioned, one of the reasons for waiting for a pregnancy, especially in triple-negative breast cancer survivors, is that the greatest risk of recurrence in triple-negative breast cancer occurs relatively early on, in the first few years after diagnosis. Other factors that help determine the risk of recurrence are classic factors such as tumor size and number of lymph nodes involved. The patient and her spouse therefore need to consider what degree of risk they are willing to accept prior to a patient becoming pregnant. This is often one of the more difficult discussions that families and physicians can ever have, but certainly a very important one.

Mastectomy recommended for triple-negative?

Question from Judy: Do you recommend mastectomy for triple-negative?

Answers —Beth DuPree, M.D., F.A.C.S.: The decision to perform a mastectomy or lumpectomy is not based upon the tumor being triple-negative or being estrogen-receptor positive or progesterone-receptor positive or HER2/neu positive. Lumpectomy followed by radiation therapy and mastectomy are equal treatment options for the local treatment of breast cancer. The determination for whether or not radiation therapy would be required after mastectomy would be determined by whether or not more than three lymph nodes were involved with tumor, or whether the tumor had spread beyond the capsule of the lymph node. Removing a woman's breast does not guarantee that a tumor will not recur elsewhere in the body. I always begin my breast cancer consults with my patients by stating to them that no woman ever died of breast cancer in her breast; women die of breast cancer as a result of cancer cells spreading outside the breast and lodging in other organs. Because of this fact, mastectomy would be the option for the treatment of breast cancer for several reasons. If a breast cancer is what we call locally advanced or inflammatory, where the actual skin of the breast shows signs of edema or actually has cancer cells within the dermis of the breast, then chemotherapy would be given in what we call neoadjuvant or prior to surgery, and regardless of the clinical response of that breast, the mastectomy and radiation therapy would be indicated. If a tumor is identified in the breast that is so large that the cosmetic defect of the breast would be great, mastectomy would also be an option, but neoadjuvant chemotherapy to shrink the tumor would also be an option to preserve the breast. Just because a tumor is triple-negative does not mean a mastectomy is mandatory.

George Sledge, M.D.: Would you feel differently in a young woman with a breast cancer who was BRCA1 positive?

Beth DuPree, M.D., F.A.C.S.: In a patient that is BRCA1 positive, I would discuss what the risk of a contralateral breast cancer would be in her lifetime. Because this risk by the age of 87 can be as high as 70%, in those patients bilateral mastectomy with reconstruction would be a very good option. I do not believe that a mastectomy in a BRCA1 patient is mandatory, but it's important for them to understand what their risk is. Because many of the triple-negative tumors can develop quickly, many of these patients will opt for the surgical treatment of breast removal and reconstruction to be able to move forward with their life and feel they have done everything they can surgically to reduce the change of a cancer developing in the opposite breast. The cosmetic results after current reconstruction procedures are excellent, and therefore bilateral mastectomy is not the disfiguring operation that it was 20 years ago. I always explain to my patients who choose this operation that their risk will never go to zero, as there is approximately a 2% risk of a primary breast cancer occurring in the skin flap, since not every single cell can be removed at the time of surgery.

Triple-negative treatment an area of high interest?

Question from AngieSuarez: How much interest is there in the medical community in finding treatments for triple-negative breast cancer? Is this currently a "hot area" of research?

Answer —George Sledge, M.D.: This is an exceptionally hot area of research in the breast cancer field. From the standpoint of being an unmet medical need, this is an area that many pharmaceutical companies are interested in as the therapeutic niches of estrogen-receptor-positive and HER2-positive breast cancer are already occupied with active agents. Whereas outside chemotherapy, we currently lack any targeted therapies for triple-negative breast cancer. So there is immense interest among drug developers, pharmaceutical companies, and breast cancer laboratory researchers in finding targeted therapies for these patients. Simply to call a cancer a triple-negative breast cancer to a certain extent points to some of the problem that we are dealing with. Imagine walking down the street, seeing a red-headed woman and turning to the person you are walking with and saying, "There is a non-blonde non-brunette who doesn't have a beard!" That is the current status of triple-negative breast cancer. We need to turn it from a negative definition into a biologically positive definition by coming up with therapeutic targeting of growth factors for triple-negative breast cancer. When we do so, we will have certainly advanced therapy for women with this disease.