Overview of TNBC Teleconference April 12, 2011

Below are my notes of the teleconference today, "Triple-Negative Breast Cancer: Medical Review," with Lisa Carey, M.D. sponsored by Living Beyond Breast Cancer and the Triple-Negative Breast Cancer Foundation. Ultimately, a transcript and podcast will be available that will offer more comprehensive information. For now, though, this is what I jotted down.

• How research has progressed:

In 2005—TNBC had not even been named yet.

By 2010—several hundred publications in that year alone.

• Prognosis of TNBC is not entirely different from other types, but it is more likely to relapse because it does not respond to typical treatment, such as tamoxifen or an aromatase inhibitor.

• Most cases of TNBC are cured by standard therapy, but there still is room for improvement.

• About a third of breast cancer deaths come from TNBC.

• 70 percent of TNBC tumors are basal like—

• Claudin low breast cancer, a new subtype, is also likely to be TNBC.

• It is increasingly clear that TNBC is not one disease, but many.

• The question of who gets breast cancer has gotten complicated lately. If you ask that question broadly, the answer is genetic mutations such as BRCA1 and BRCA2. But only about 5-10 percent of all breast cancers are related to the genetic mutations. The rest are sporatic breast cancers—we do not know what causes them. Reproductive risk factors are “soft factors”—don’t have a big influence. We have to change the question to “What causes specific types of breast cancer?”

• The Carolina Breast Cancer Study (there have been three versions; it’s a large study) looked specifically at groups who weren’t normally studied—African-Americans and young women. Carolina study was set up to oversample these groups. Researchers found that basal-like was overrepresented in young women and African-American. Nearly 1/3 of cases in young African-American women.

• It also looks like some of the risk factors may differ between types. Reproductive risk factors may be different for TNBC cancers—we don’t know how to act on that yet. Makes us less global in our recommendations.

• TNBC carries a comparatively worse risk factor. But risk seems to happen in the first three years and, after about 6,7,8 years, the risk of relapse lower for those with TNBC.

• If cancer comes back, HR+ more likely to come back in bones, TNBC more likely to involve lungs and the brain. Much research is being done now on brain relapses.

• Inherited breast cancer—BRCA1 and BRCA2—women with these have 50-80 percent risk of breast cancer over their lives. Recommend mastectomy and removal of ovaries for these women. If women with BRCA1 mutations gets cancer, 80 percent of time it is TNBC. This is called BRCA-associated breast cancer. Why is there such close associations? If a woman without mutation gets TNBC, what does this tell us? We don’t know yet.

• Chemotherapy is the mainstay across all subtypes. Has a bad rap that is deserved. Can have complications and side effects that we can increasingly manage. But it has less than a 1 percent risk of serious complications. Advances in chemotherapy have clearly made a difference in treatment with TNBC—dense-dose chemo, addition of taxanes. Have made some significant advances in treatment. Chemo quite effective and will be in use for many years, and we will continue to work to reduce side effects.

• It is not true that TNBC not sensitive to drugs. It is sensitive to chemo. Studies on neo-adjuvant chemo (before surgery) showed quite clearly that the response to drugs is greater in TNBC than in other cancers.

•Anti-angiogenic treatments are treatments that target the blood vessels. Cancers have a system for creating their own blood supplies. Avastin is an antibody-based therapy that targets the blood supply. One thing that is frustrating for us: When we use drugs like Avastin, they seem to be effective, but there is not a selection strategy as to who should get them and who should not. Studies of women treated with chemo and Avastin found equal benefit between TNBC and other types of cancers. One argument is that this is a targeted drug for TNBC. European trial looked at chemotherapy alone and chemo with Avastin in neoadjuvant setting. Not a strong impact, but TNBC had slightly more of an impact. Lends support to the position that this is a valuable place to research.

• EGFR as a target—EGFR inhibitors. Studies on chemo alone as well as chemo plus treatment for TNBC showed a relatively low response rate—not enough to give to all patients with TNBC.

• Greatest interest recently in a new class of drugs called PARP inhibitors. Connected to BRCA1—one of its roles is repairing cell’s damage to DNA. Without BRCA, cell does not have the system for repairing itself. Has to go to emergency back-up systems. If BRCA working, cancer cells are more likely to be killed. PARP inhibitors work with cells that are less likely to repair themselves.

• No PARP inhibitors approved yet. Interesting study in BRCA-associated cancers. Women given just a PARP inhibitor—without chemo---and the tumor shrunk. Drugs in early development, may be a positive way forward for those with inherited mutations.

• What about women without inherited mutations? (Sporatic cancers.) A study on women with metastatic TNBC who were given iniparib, a PARP inhibitor, which was added to the therapy; it controlled cancers longer; women lived longer. Not replicated in a larger study, however. Disappointing result.

• Lots and lots of these approaches are being pursued. We are likely to sort this out. Many good people spending a lot of time on this.

•Ten different angiogenetic drugs being studied. PARP inhibitors also being studied.

• It is possible we are not going to have a home-run drug for TNBC. It may well be that the way forward is personalized medicine. We are trying to determine what the Achilles heel of that cancer is, and target that. TNBC will be the first type of breast cancer to try that personalized approach.

• Clinical trials are essential—consider enrolling.

Q&A

Relapse to the brain. Reseachers pay attention to brain metastases because the brain acts differently—it responds to surgery. Most common type to move to brain is Her2-positive. Second is TNBC. With Her2, can move only to brain. TNBC tends to come back in the brain as well as other places at the same time; it may have to be treated differently than Her2-positive cancer. Brain metastases research is a very active field. In the past, there had been a tendency to lump brain metastases together—breast, melanoma, lung. Now, break into different types of cancer and different types of breast cancer. The blood-brain barrier needs to be considered. Research now specifically on PARP inhibitors for TNBC that has metastasized to the brain. There have been advances in standard therapy, such as surgery, for brain metastases.

BRCA testing. Is it worth it? Most, but not all of the time. Testing might be called for in a person with a personal history of more than one cancer, any history of ovarian cancer, or any first-degree relatives with breast cancer. Suggest talking to genetic counselor.

What can do to reduce risk, especially without risk factors. Most of the time, we do not know why one woman gets breast cancer and another one doesn’t. There’s the risk of getting the cancer—research is ongoing on how to peg individual risk. Separate from that is how to reduce the risk of an already-formed cancer from coming back. Know how to prevent from recurring—surgery, chemo, radiation. Beyond that, everything is an investigation. There is reason to think a healthy lifestlye helps across the board. Simply do not know how it affects the risk of relapse.

Are treatments different for women with BRCA mutations and those without? No, at this point both would be treated the same.

CMF: One of our earliest drug regimens that has been effective but is being replaced by more modern regimens. Still being used for women who cannot tolerate newer ones. One study showed that CMF actually better than AC chemo. Not a significant benefit, but would not avoid CMF.

Follow-up Testing: What is the best method in following after treatment? ASCO Guidelines—physical and careful history every three to six months for the first three years; every six to 12 months in years four and five. Breast imaging, usually mammography, but sometimes MRI every year. In most cases, no bone scans or CAT scans, or blood work.

Metaplastic breast cancer as is relates to TNBC. Metaplastic are relatively unusual. (As few as 1 percent of all cases.) It is a specific subtype. Most breast cancers are either ductal or lobular. Others are pathologically different. Metaplastic has a funny appearance. Unusual. Almost always TNBC. Don’t know if there is a specific treatment difference. Acts like other breast cancers. May have more of the claudin low subtype.

If you have cancer in one breast, should you have the other breast removed? Prophylactic mastectomy in general is limited to those with an inherited risk. If have risk factors and are having mastectomy, it makes some sense to remove both breasts at the same time. For women who have sporatic TNBC, the decision between lumpectomy and mastectomy is a personal one. The decision there is not different for women with TNBC as opposed to others.