About three years ago, Fox News correspondent Jennifer Griffin felt an orange-sized lump in her breast while weaning her third child. She figured she had a blocked milk duct or maybe an infection.
She never dreamed it could be breast cancer.
But she soon discovered that the conventional wisdom about the disease - who gets it, when, and why - does not apply to the aggressive subtype known as "triple negative."
"I thought when you were pregnant and nursing you were protected," recalled Griffin, 43, who blogged about her battle against triple negative cancer at jengriffinblog.blogspot.com. "But now, almost weekly, there's a young mother who reaches out to me and says she's been diagnosed, and it's triple negative."
Triple negative is shorthand for breast cancers that lack the three "receptors" that targeted treatments need to work.
Although triple negative was identified well over a decade ago, only in recent years have experts recognized it as an important subgroup with distinctive biology, risk factors, and treatment challenges.
Although it accounts for only about 16 percent of all breast cancers, triple negative is responsible for a disproportionate number of deaths, and it disproportionately develops in women who are premenopausal, African American, or Latina, or who have hereditary BRCA1 gene mutations.
Unlike other breast cancer subtypes, triple negative does not have a "targeted" drug therapy that interferes with a molecular pathway of cancer. Conventional chemotherapy and radiation, with their toxic side effects, are the mainstays of treatment.
On a positive note, scientists are rapidly unraveling the biology of triple negative cancer. Finding a targeted treatment is a priority of researchers, drug companies, the U.S. Food and Drug Administration, and advocacy groups.
"As of February, there were 82 active clinical trials of new drugs," said triple negative survivor Lori Redmer, executive director of the six-year-old Triple Negative Breast Cancer Foundation in Norwood, N.J. "There's a real sense of urgency to find" a targeted therapy.
Most women are aware, at least vaguely, that cumulative lifetime exposure to estrogen plays a role in breast cancer. Factors that increase the number of menstrual cycles, such as early puberty, late menopause, no pregnancies or no breast-feeding, increase the risk of the disease.
But this epidemiology applies only to the most common type of breast cancer, which accounts for 70 percent of diagnoses. It's called "estrogen-receptor positive," meaning that the malignant cells depend on the hormone estrogen to grow. Most of these tumors are also fueled by a complementary hormone, progesterone.
Beginning in the mid-1970s, drugs such as tamoxifen, which blocks estrogen receptors in cells, became important in treating this subtype, and preventing recurrence.
Another big advance came in 1998, when the FDA approved Herceptin for breast cancer that overproduces receptors for a powerful growth factor called HER2. By 2006, survival rates for "HER2-positive" breast cancer had dramatically improved, and pathologists were routinely testing tumors for all three receptors: estrogen, progesterone, and HER2.
Tumors that are negative for all three receptors pose a major treatment challenge.
Triple negative cancers are sometimes called "basal-like" because their gene activity profile resembles that of healthy basal cells of the milk ducts, although it is unclear whether this similarity has clinical significance. The profile was identified in 2000, but the terminology has not caught on with doctors because there is no routine lab test for basal-like cancers, and not all triple negative cancers fit the profile.
Many aspects of triple negative cancers remain mysterious. Researchers don't know, for example, why this subtype accounts for almost a third of African American breast cancers and three-quarters of BRCA1-related cancers.
Recent studies "also raise interesting questions about traditional risk factors," according to University of North Carolina breast cancer researcher Lisa Carey. For example, having several children starting at a young age may actually increase the chance of triple negative - just the opposite of the effect on estrogen-fueled cancers.
Like Griffin, Redmer had given birth to her third child not long before her diagnosis in 2010.
"I had just finished breast feeding," she recalled. "I was in a complete panic, thinking 'Am I going to be gone in six months?' "
She soon learned that modern chemotherapy regimens and radiation, which damage DNA in fast-growing cells, are highly effective against triple negative. Unfortunately, healthy cells in the hair, the gut, the blood, and the heart may suffer collateral damage.
Griffin says she "demanded" to undergo a punishing regimen of high-dose chemotherapy, followed by a double mastectomy and radiation. Having reported for Fox News from such dicey places as Afghanistan and the Middle East, "I never thought the greatest danger to my life would come from inside of me," she told one interviewer.
She also adopted a low-fat diet and exercised rigorously after reading research that shows such measures can lower the chance of triple negative recurrence.
"I did Pilates throughout my treatment," she said. "Friends sent vegan food, and I learned to eat whole grain everything."
Last month, she marked a crucial anniversary: three years cancer-free.
Unlike estrogen-fueled cancer, triple negative rarely recurs after three years, and if it does come back, said Constantine Kaniklidis, director of medical research at No Surrender Breast Cancer Foundation, its recurrence does not increase the risk of metastatic disease.
In June, the FDA issued new guidelines aimed at speeding the availability of promising drugs for triple negative cancer.
The agency said drugs that induce a "pathologic complete response" - eradicating all sign of the cancer in the breast or lymph nodes - can win accelerated approval.
Researchers are racing to find such drugs. They are testing targeted treatments, such as Avastin and Erbitux, that are already approved for other cancers, as well as seeking new targets.
At Thomas Jefferson University, cell biologist Renato V. Iozzo has led mouse studies that show decorin, a natural protein known to halt tumor growth, may reduce or prevent triple negative cancer cells from spreading beyond the breast.
His Jefferson colleague Agnieszka K. Witkiewicz has correlated high levels of a protein called MCT4 in cells surrounding triple negative tumors with decreased survival.
"MCT4 is also a druggable target, and drugs are in development," she said.
Antigen Express, a biotech company in Worcester, Mass., has had encouraging results from clinical trials of a therapeutic vaccine. It revs up T cells, the big guns of the immune system, to attack triple negative tumor cells that express a low or moderate level of the HER2 protein - levels too low for Herceptin to be effective.