Multiple Childbirth linked to Triple-Negative Breast Cancer

The more times you give birth, the higher your risk of triple-negative breast cancer. In fact, women who never have given birth had a 40 percent s reduced risk of TNBC, although they do face an increased risk of hormone-positive disease. This comes in a study at the Fred Hutchinson Cancer Research Center recently published in the Journal of the National Cancer Institute. It is based on Women’s Health Initiative data on the reproductive histories of 150,000 postmenopausal women, 300 of whom ultimately developed triple-negative breast cancer.

The news release from the Hutchinson Center:

SEATTLE — Feb. 24, 2011 — Full-term pregnancy has long been associated with a reduced risk of breast cancer, but a new study finds that the more times a woman gives birth, the higher her risk of “triple-negative” breast cancer, a relatively uncommon but particularly aggressive subtype of the disease. Conversely, women who never give birth have a 40 percent lower risk of such breast cancer, which has a poorer prognosis than other types of breast cancer and doesn’t respond to hormone-blocking therapies such as tamoxifen.

These findings, from a study led by Amanda Phipps, Ph.D., a postdoctoral research associate in the Public Health Sciences Division of Fred Hutchinson Cancer Research Center, are published online ahead of the March 16 issue of the Journal of the National Cancer Institute.

“Unlike most breast cancers, triple-negative tumors don’t depend on hormonal exposures to grow and spread, so our assumption going into the study was that reproductive factors would not be associated with a woman’s risk of this cancer subtype,” Phipps said. “We were surprised by these findings because researchers have known for quite some time that women who have children, especially those who have them at an early age and have multiple full-term pregnancies, have a lower risk of breast cancer overall.”

While never giving birth appears to be protective against triple-negative breast cancer, the researchers found that women who remain childless have about a 40 percent higher risk of estrogen-receptor-positive breast cancer – the most common form of the disease, which can be treated with estrogen-blocking drugs – as compared to those who have one or more offspring. This higher risk of estrogen-receptor-positive breast cancer among women who have not had children is well established, and it is thought to be related to the fact that such women do not undergo pregnancy-related changes in the breast that confer a lifelong protective effect.

“The mechanisms by which full-term pregnancy contributes to an increased risk of triple-negative breast cancer and a decreased risk of other forms of the disease are not clear,” Phipps said. “We do know that the hormones of pregnancy induce certain changes in the cellular structure of the breast. Overall, those changes seem to make the breast less susceptible to cancer. It is possible, however, that the increased risk of triple-negative breast cancer we found in women who had given birth may be due to some abnormal response of their breast tissue to the hormones of pregnancy. Another possibility is that pregnancy somehow makes the breast more susceptible to certain carcinogens even while reducing breast cancer risk overall,” she said.

For the study, which was based on data from the Women’s Health Initiative, Phipps and colleagues analyzed the detailed reproductive histories of some 150,000 postmenopausal women, more than 300 of whom went on to develop triple-negative breast cancer. “This particular study is significant because it is one of the largest studies ever conducted on the impact of reproductive history on triple-negative breast cancer,” Phipps said.

Triple-negative breast cancer, which refers to any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu, accounts for only 10 percent to 20 percent of all breast cancers, and only in the past decade have researchers become aware that this cancer subtype exists. “This research reinforces the notion that breast cancer is not just one disease,” Phipps said.

“The mechanisms that lead to triple-negative breast cancer are likely different from those that lead to other forms of the disease. We still have a lot to learn about what causes this more aggressive form of breast cancer, but we hope that research like this will help us develop better tools to identify those women at greatest risk.”

It is known that this cancer subtype is more predominant in African American women and it tends to be diagnosed at an earlier age. Researchers also know there is a strong link between genetic mutations in the so-called “breast cancer gene,” BRCA1, and triple-negative breast cancer.

“More research is needed to better understand the causes of the most aggressive and lethal forms of breast cancer. While this study adds to our knowledge base, it should not change women’s approaches to breast cancer screening,” Phipps said.

The National Heart, Lung and Blood Institute of the National Institutes of Health funded the study, which also involved researchers from Albert Einstein College of Medicine, Georgetown University, Harbor-UCLA Medical Center, Stanford University, State University of New York at Stony Brook, the University of Buffalo, the University of Pittsburgh and Wake Forest University.

What, Me Worry? And Worry, and Worry

I know a woman who has lived more than 30 years after a diagnosis of estrogen-negative beast cancer. When I asked her recently if she still worried about it returning, she said, “Not really.” I love that the fear eventually goes away, but I hope it is far sooner than 30 years , as by then I will be 90 and, at the rate I am going, I will no doubt have already forgotten just about everything.

Now, though, the concern remains. It’s not a constant worry, not something I jump to immediately. I do not live a paranoid existence, waiting for the next health shoe to drop. But occasionally, when I have a minor issue, two and two adds up to cancer in my crazy mind.

I have a history of stomach ulcers, which I usually can control with diet. It has been almost eight years since they bothered me. Lately, though, I have ignored my usual healthy eating and have been having too much Diet Coke, fried foods, and coffee.

So my stomach has been hurting. I self-medicate—antacids, aloe vera juice, lots of water. And, of course, no Diet Coke, fried foods, and coffee. And I am fine.

But it was a long winter and I ended up with a nasty cold that did not go away, so I resorted to the comfort of Alka Seltzer Plus, which clears up my head marvelously. It also contains aspirin, which is a sin against ulcers.

So this past week, I was awakened at night with the stomach pain. Pain that kept me up. I’d had a martini and knew my stomach could not handle it.

But I worried that I had stomach cancer. Before I had breast cancer, I never jumped to that conclusion. I knew it was my ulcers acting up and I dealt with it. If I needed stronger medicine, I got it.

This time I decided to go to the doctor for peace of mind. He, however, also did not like the idea of stomach pain waking me up, so he ordered an endoscopy. “I do not think I am going to find anything, but I would feel better if we checked you out,” he said.

He also raised the specter of stomach cancer, something he has not mentioned in the nearly 20 years I have been going to him. But there was the big red flag was on my chart: breast cancer. Breast cancer once means the possibility some other cancer eventually. Of course, I always had the risk of cancer in my future, but it did not seem all that real. I was happily oblivious to that possibility.

And I am now told by doctor after doctor that my risk is elevated. I am at code orange, always open to a full-body search, that happy oblivion gone.

And so, despite my reluctance to have unnecessary tests, despite fairly conclusive evidence that this was all related to stomach ulcers, I had the endoscopy.

I am fine. My stomach was simply irritated. The doctor took a biopsy and, even though results are not back, he says he is confident it is not cancer. The stomach looks and acts like it has in the past. I also am confident it is nothing more than irritation.

He gave me stronger medicine and I now stay away from problem foods and aspirin,. And I no longer am worried about stomach cancer.

Mostly. And for now. I am almost five years past diagnosis and I may celebrate my anniversary by instituting a no-worry rule.

I do worry, though, that I can pull that off.

Dose-dense chemo best for hormone-negative

Dose-dense chemotherapy is most effective for hormone-negative breast cancer, according to a review of clinical trials published in the Journal of the National Cancer Institute. The trials used doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan) followed by paclitaxel. Dose-dense treatments for TNBC resulted in better overall and disease-free survival.

Anthracyclines Better for TNBC

Adriamycin and Cytoxan, two common chemo drugs called anthracyclines, used in conjunction with a taxane are an effective treatment for TNBC, but not for other types of breast cancer. In a commentary on treatment protocols in the journal Oncology, Ruth O'Regan, M.D., the the Emory University School of Medicine, notes that the combination works best in adjuvant treatment—that is, chemo after surgery.

Antioxidant may help fight TNBC

According to a news release from the Kimmel Cancer Center at Thomas Jefferson University, researchers there have shown the effectiveness of antioxidant in fighting tumor growth. The research is in the February 15 issue of Cancer Biology and Therapy. The study looked at the protein Caveolin-1 (Cav-1), which can inhibit cancer, cardiovascular disease, and muscular dystrophy and can be of special significance to triple-negative cancers In previous studies, Cav-1 was effective in killing breast cancer cells when used with Taxol.

The news release:

PHILADELPHIA—Researchers from Jefferson's Kimmel Cancer Center have genetic evidence suggesting the antioxidant drugs currently used to treat lung disease, malaria and even the common cold can also help prevent and treat cancers because they fight against mitochondrial oxidative stress—a culprit in driving tumor growth.

For the first time, the researchers show that loss of the tumor suppressor protein Caveolin-1 (Cav-1) induces mitochondrial oxidative stress in the stromal micro-environment, a process that fuels cancer cells in most common types of breast cancer.

"Now we have genetic proof that mitochondrial oxidative stress is important for driving tumor growth," said lead researcher Michael P. Lisanti, M.D., Ph.D., professor of cancer biology at Jefferson Medical College of Thomas Jefferson University and member of the Kimmel Cancer Center at Jefferson. "This means we need to make anti-cancer drugs that specially target this type of oxidative stress. And there are already antioxidant drugs out there on the market as dietary supplements, like N-acetyl cysteine."

These findings were published in the online February 15 issue of Cancer Biology & Therapy.

Lisanti's lab previously discovered Cav-1 as a biomarker that functions as a tumor suppressor and is the single strongest predictor of breast cancer patient outcome. For example, if a woman has triple negative breast cancer and is Cav-1 positive in the stroma, her survival is greater than 75 percent at 12 years, versus less than 10 percent at 5 years if she doesn't have the Cav-1 protein, according to Dr. Lisanti.

The researchers also established Cav-1's role in oxidative stress and tumor growth; however, where that stress originates and its mechanism(s) were unclear.

To determine this, Jefferson researchers applied a genetically tractable model for human cancer associated fibroblasts in this study using a targeted sh-RNA knock-down approach. Without the Cav-1 protein, researchers found that oxidative stress in cancer associated fibroblasts leads to mitochondrial dysfunction in stromal fibroblasts. In this context, oxidative stress and the resulting autophagy (producton of recycled nutrients) in the tumor-microenvironment function as metabolic energy or "food" to "fuel" tumor growth.

The researchers report that the loss of Cav-1 increases mitochondrial oxidative stress in the tumor stroma, increasing both tumor mass and tumor volume by four-fold, without any increase in tumor angiogenesis.

"Antioxidants have been associated with cancer reducing effects—beta carotene, for example—but the mechanisms, the genetic evidence, has been lacking," Dr. Lisanti said. "This study provides the necessary genetic evidence that reducing oxidative stress in the body will decrease tumor growth."

Currently, anti-cancer drugs targeting oxidative stress are not used because is it commonly thought they will reduce the effectiveness of certain chemotherapies, which increase oxidative stress.

"We are not taking advantage of the available drugs that reduce oxidative stress and autophagy, including metformin, chloroquine and N-acetyl cysteine," Dr. Lisanti said. "Now that we have genetic proof that oxidative stress and resulting autophagy are important for driving tumor growth, we should re-consider using antioxidants and autophagy inhibitors as anti-cancer agents."

The diabetic drug metformin and chloroquine, which is used for the prevention and treatment of malaria, prevent a loss of Cav-1 in cancer associated fibroblasts (which is due to oxidative stress), functionally cutting off the fuel supply to cancer cells.

This research also has important implications for understanding the pathogenesis of triple negative and tamoxifen-resistance in ER-positive breast caner patients, as well as other epithelial cancers, such as prostate cancers.

"Undoubtedly, this new genetically tractable system for cancer associated fibroblasts will help identify other key genetic 'factors' that can block tumor growth," Dr. Lisanti said.

An overview of Basal-Like and TNBC

Medcscape has just published a good review article on the interrelationship between basal-like and triple-negative breast cancers, with a good definition of each one, and the implications for treatment and prognosis. When I was diagnosed in 2006, TNBC was just hitting the radar screen, and few people talked about it or any other form of hormone-negative breast cancer. It is nice to see the progress, nice to see that TNBC has become and important research focus. If only the writers would focus less on the negatives up front and explain that, in fact, most women do survive this disease.

Did Cancer Make You Want to Sing About George Clooney?

I love this story!

During chemotherapy for triple-negative breast cancer in 2008 and 2009, singer-songwriter Laura Roppe wrote 13 songs that became her album "I'm Still Here." One song, "George Clooney," says "I bet he smells real good." I bet he does, Laura.

The lyrics to another song, "Float Away:"

She says, this life’s too heavy

I’ve reached the breaking point

If I check out now

I can leave it all behind

And float

Float away

But she hears the voice

Of her little girl

Only thing that matters

In this whole world

Gotta find a way

Not to fade away

The San Diego Reader ran an interview with Laura. You can buy her album for $12 and $3 shipping.

Good for you, Laura, for turning to your art during this journey.

A Hint on How and Why TNBC Spreads?

Princeton University researchers have discovered the mechanism by which triple-negative breast cancer might spread. This discovery, they say, could lead to the development of drugs for metastatic TNBC. Check out the story in the New Jersey Star Ledger.